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Intramolecular Nicholas Reactions in the Synthesis of

Dibenzocycloheptanes. Synthesis of Allocolchicine NSC 51046 and
Analogues and the Formal Synthesis of (-)-Allocolchicine
Sinisa Djurdjevic,†,‡ Fei Yang,† and James R. Green*,†
†
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada, and
‡
St. Clair College of Applied Arts and Technology, Windsor, ON N9A 6S4, Canada

jgreen@uwindsor.ca
Received October 3, 2010

The preparation of dibenzocycloheptyne-Co2(CO)6 complexes by intramolecular Nicholas reactions

of biaryl-2-propargyl alcohol-Co2(CO)6 derivatives is described. Reductive decomplexation of the
dibenzocycloheptyne-Co2(CO)6 complexes affords the corresponding dibenzocycloheptenes, indivi-
dual members of which have been employed in a formal total synthesis of (-)-allocolchicine, the
preparation of 6,7-dihydro-3,4,9,10,11-pentamethoxy-5H-dibenzo[a,c]cyclohepten-5-one, and the
enantioselective total syntheses of NSC 51046 and its 3,8,9,10-tetramethoxy regioisomer.

Introduction of additional naturally occurring allocolchicines, including

(-)-androbiphenyline (4), (-)-colchibiphenyline (5), (-)-
The allocolchicines are a group of compounds containing
jerusalemine (6), (-)-salimine (7), and (-)-suhailamine, have
a tricyclic 6,7,6-system with a highly oxygen-substituted A
also been isolated;2 the latter two of these have undergone
ring. Individual members of this group, including (-)-allo-
structural revision or are structurally in question (Figure 1).3
colchcine (1), N-acetylcolchicinol methyl ether (NSC 51046, 2),
Synthetic access to the allocolchicines historically has been
N-acetylcolchicinol (3), and its dihydrogenphosphate (ZD
based on oxidation of colchicine itself,4 although racemic
6126, 4) have gained considerable attention by virtue of
syntheses or those involving resolution are known.3,5 More
having been found to be active against a number of cancer
recently, the activity of these compounds has stimulated an
cell lines.1 These act by inhibiting tubulin assembly and
interest in the enantioselective synthesis of allocolchicines.
polymerization, therefore arresting cell mitosis. A number
Initiated by Wulff’s Diels-Alder based synthesis of (-)-
allocolchicine itself,6 members of this class of compounds
(1) (a) P
erez-Ramı́rez, B.; Gorbunoff, M. J.; Timasheff, S. N. Biochem-
istry 1998, 37, 1646–1661. (b) Guan, J.; Zhu, X.; Brossi, A.; Tachibana, Y.;
Bastow, K. F.; Verdier-Pinard, P.; Hamel, E.; McPhail, A. T.; Lee, K.
Collect. Czech. Chem. Commun. 1999, 64, 217–228. (c) B€ uttner, F.; (3) Banwell, M. G.; Fam, M.-A.; Gable, R. W.; Hamel, E. J. Chem. Soc.,
Bergemann, S.; Gu
enard, D.; Gust, R.; Seitz, G.; Thoret, S. Bioorg. Med. Chem. Commun. 1994, 2647–2649.
Chem. 2005, 13, 3497–3511. (d) Nakagawa-Goto, K.; Jung, M. K.; Hamel, (4) (a) Iorio, M. A. Heterocycles 1984, 22, 2207–2211. (b) Brecht, R.;
E.; W. C.-C.; Bastow, K. F.; Brossi, A.; Ohta, S.; Lee, K.-H. Heterocycles Haenel, F.; Seitz, G. Liebigs Ann./Receuil 1997, 2275–2279. (c) Diler, U.;
2005, 65, 541–550. Franz, B.; Roettele, H.; Schroeder, G.; Herges, R. J. Prakt. Chem./Chem.-
(2) (a) Tojo, E.; Abu Zarga, M. H.; Freyer, A. J.; Shamma, M. J. Nat. Zeit. 1998, 340, 468–471. (d) Bergemann, S.; Brecht, R.; B€ uttner, F.;
Prod. 1989, 52, 1163–1166. (b) Al-Tel, T. H.; Abu Zarga, M. H.; Sabri, S. S.; Gu
enard, D.; Gust, R.; Seitz, G.; Stubbs, M. T.; Thoret, S. Bioorg. Med.
Freyer, A. J.; Shamma, M. J. Nat. Prod. 1990, 53, 623–629. (c) Abu Zarga, Chem. 2003, 11, 1269–1281.
M. H.; Sabri, S.; Al-Tel, T. H.; Atta-ur-Rahman; Shah, Z.; Feroz, M. J. Nat. (5) (a) Cook, J. W.; Jack, J.; Loudon, J. D.; Buchanan, G. L.; Macmillan,
Prod. 1991, 54, 936–940. (d) See also: Yusupov, M. K.; Sadykov, A. S. J. Gen. J. J. Chem. Soc. 1951, 1397–1403. (b) Sawyer, J. S.; Macdonald, T. L.
Chem. USSR (Engl. Transl.) 1964, 34, 1686-1688; Zh. Obshch. Khim. 1964, Tetrahedron Lett. 1988, 29, 4839–4842. (c) Boy
e, O.; Brossi, A.; Yeh, H. J. C.;
34, 1677-1680. (e) Baudoin, O.; Gu
eritte, R. In Studies in Natural Products Hamel, E.; Wegrzynski, B.; Toome, V. Can. J. Chem. 1992, 70, 1237–1249.
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2003; Vol. 29, (6) Vorogushin, A. V.; Predeus, A. V.; Wulff, W. D.; Hansen, H.-J.
pp 355-417. J. Org. Chem. 2003, 68, 5826–5831.

DOI: 10.1021/jo101953n Published on Web 11/08/2010 J. Org. Chem. 2010, 75, 8241–8251 8241
r 2010 American Chemical Society
JOC Article Djurdjevic et al.

groups are sufficiently nucleophilic for facile reaction.15 In

particular, given the propensity of propargyldicobalt cations
for reaction with electron-rich arenes and the demonstrated
ability of (Z)-arylalkene substituted propargyl acetate complexes
to react to form benzocycloheptyne-Co2(CO)6 complexes,12d
we considered the potential applicability of intramolecular
Nicholas reaction chemistry to dibenzocycloheptanes and
consequently allocolchicines to be highly promising. We
have reported on the viability of this approach in preliminary
form and now describe this chemistry in complete fashion.16

Results and Discussion

The general outline of the access to the 6,7,6-system was
envisioned to occur by construction of the Co2(CO)6 com-
plexes of biaryl-2-propargyl alcohol derivatives (8), which
would deliver dibenzocycloheptyne-Co2(CO)6 complexes (9)
in the presence of a Lewis acid. The former were prepared
in most instances by Suzuki-Miyaura coupling reactions
of arylboronic acids (10) with bromobenzaldehydes (11)
according the conditions employed by F€ urstner,17 giving
biaryl-2-carboxaldehydes (12a-f) in good yield (Scheme 1,
Table 1). These aldehydes were subjected to the Corey-
Fuchs protocol, with trapping of the resulting acetylide by
FIGURE 1. Common allocolchicines. paraformaldehyde (Scheme 2). The resultant propargyl al-
cohols (13a-f) were formed in fair to good yields (56-80%)
have seen synthesis by way of enyne metathesis/Diels-Alder
except in the case of thienyl substituted 13d (40% yield); in
reactions ((-)-N-acetylcolchicine analogues), 7 oxidative
this case a significant amount of carbene insertion product 14
coupling and copper-mediated cross-coupling ((-)-N-
(53%) was formed competitively. Acetylation of 13a-f
acetylallocolchicinol),8 C-H activation reactions ((-)-allo-
under standard conditions and complexation with Co2(CO)8
colchicine formal synthesis),9 and aldol condensation chem-
then afforded 8a-f in good to excellent yields.
istry ((-)-N-acetylallocolchicinol).8b,10 In addition, a recent
Two additional substrates were prepared by procedures
siloxane coupling/ring expansion reaction chemistry approach
other than the standard one. Unsubstituted 8g was obtained
to (()-NSC 51046 has been reported.11
by way of Sonogashira reaction between 2-iodobiphenyl and
The application of alkyne-Co2(CO)6 complexes in the
synthesis of seven-membered ring compounds has been TABLE 1. Preparation of 8a-ga
demonstrated by our group12 and by other groups,13 most 10 11 12 13 8
often based on Nicholas reaction chemistry. The reactions 10a 11a 12a (85) 13a (80) 8a (86)
are suited to seven-membered ring synthesis because com- 10a 11b 12b (92) 13b (78) 8b (84)
plexation of alkynes to Co2(CO)6 induces a change in bond 10b 11a 12c (79) 13c (57) 8c (91)
angle to ca. 140°,14 in that SN10 reactivity on the cationic 10c 11a 12d (81) 13d (40) 8d (77)
10d 11a 12e (76) 13e (61) 8e (84)
propargyldicobalt complex to give a five-membered ring 10a 11c 12f (81) 13f (56) 8f (98)
system does not occur, and since the electrophilicity of these a
Yields are in parentheses.
cations is such that arenes substituted with electron-donating

SCHEME 1. Suzuki-Miyaura Coupling Reactions

8242 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
JOC Article
SCHEME 2. Preparation of Biaryl-2-propargyl Acetate-Co2(CO)6 Complexes (8)

propargyl alcohol to give 13g (87% yield) (Scheme 3), which SCHEME 3. Formation of 8g
was in turn subjected to acetylation and complexation with
Co2(CO)8 under conditions analogous to 13a-f, affording
8g in 86% yield.
Carbomethoxy-substituted 8h, the propargyl ether-Co2-
(CO)6 complex envisioned as the precursor to allocolchicine
itself, required a modified approach for its preparation. In
this case, methyl 4-bromo-3-iodobenzoate, prepared by con-
ventional esterification of the corresponding acid,18 was
subjected to Sonogashira reaction with propargyl methyl
ether to afford 15 in 92% yield (Scheme 4). The Suzuki-
Miyaura reaction of this halide with 2,3,4-trimethoxyboro-
nic acid was somewhat problematic, as conventional condi-
tions resulted in predominant boronic acid hydrolysis and
recovery of substantial 15, with only a small amount of 16
SCHEME 4. Preparation of 8h
(7) (a) Boyer, F.-D; Hanna, I. Org. Lett. 2009, 9, 715–718. (b) Boyer,
F.-D; Hanna, I. Eur. J. Org. Chem. 2008, 4938–4948. (c) Boer, F.-D.; Dubois,
J.; Thoret, S.; Dau, M.-E. T. H.; Hanna, I. Bioorg. Chem. 2010, 38, 149–158.
(8) (a) Wu, T. R.; Chong, J. M Org. Lett. 2006, 8, 15–18. (b) Besong, G.;
Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol. Chem.
2006, 4, 2193–2207. (c) Broady, S. D.; Golden, M. D.; Leonard, J.; Muir,
J. C.; Maudet, M. Tetrahedron Lett. 2007, 48, 4627–4630.
(9) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849–2852.
(10) Besong, G.; Billen, D.; Dager, I.; Kocienski, P.; Sliwinski, E.; Tai,
L. R.; Boyle, F. T. Tetrahedron 2008, 64, 4700–4710.
(11) Seganish, W. M.; DeShong, P. Org. Lett. 2006, 8, 3951–3954.
(12) (a) Green, J. R. Eur. J. Org. Chem. 2008, 6053–6062. (b) Amiralaei,
S.; Green, J. R. Chem. Commun. 2008, 4971–4973. (c) Ding, Y.; Green, J. R.
Synlett 2005, 271–274. (d) Green, J. R. Synlett 2001, 353–356. (e) Lu, Y.;
Green, J. R. Synlett 2001, 243–247. (f) Patel, M. M.; Green, J. R. Chem.
Commun. 1999, 509–510. (g) Green, J. R. Chem. Commun. 1998, 1751–1752.
(13) (a) Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. Soc.
1986, 108, 3128–3130. (b) Iwasawa, N.; Satoh, H. J. Am. Chem. Soc. 1999,
121, 7951–7952. (c) Tanino, K.; Shimizu, T.; Miyama, M.; Kuwajima, I.
J. Am. Chem. Soc. 2000, 122, 6116–6117. (d) Iwasawa, N.; Sakurada, F.;
Iwamoto, M. Org. Lett. 2000, 2, 871–873. (e) Tanino, K.; Kondo, F.;
Shimizu, T.; Miyashita, M. Org. Lett. 2002, 4, 2217–2219. (f) Carbery,
D. R.; Reignier, S.; Myatt, J. W.; Miller, N. D.; Harrity, J. P. A. Angew.
Chem. Int. Ed . 2002, 41, 2584–2587. (g) Tanino, K.; Onuki, K.; Asano, K.;
Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem.
Soc. 2003, 125, 1498–1500. (h) Young, D. G. J.; Burlison, J. A.; Peters, U.
J. Org. Chem. 2003, 68, 3494–3497. (i) Golovko, L. J.; Hope-Weeks, M. J.;
Mays, M. J.; McPartlin, M.; Sloan, A. M.; Woods, A. D. New. J. Chem. 2004,
28, 527–534. (j) Iwasawa, N.; Inaba, K.; Nakayama, S.; Aoki, M. Angew.
Chem., Int. Ed. 2005, 44, 7447–7450. (k) Olier, C.; Gastaldi, S.; Christie,
S. D. R.; Bertrand, M. P. Synlett 2007, 423–426. (l) Kennichi; Takaya, J.;
Iwasawa, N. Chem. Lett. 2007, 36, 474–475. (m) For the corresponding
ethers, see: Baba, T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59, 6851–6872. isolated (27% yield). Use of Pd2(dba)3 with PCy3, however,
and references therein. (m) For the corresponding amides, see: Closser,
K. D.; Quintal, M. M.; Shea, K. M. J. Org. Chem. 2007, 74, 2680–2688. gave 16 in acceptable yield (53%, 77% based on recovered
(14) Went, M. J. Adv. Organomet. Chem. 1997, 41, 69–125. starting material [brsm]), with recovery of 15 (31%). While most
(15) Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc. 1998, 120, 900–907.
(16) For a preliminary report, see: Djurdjevic, S.; Green, J. R. Org. Lett.
of the material was carried forward using this protocol, it was
2007, 9, 5505–5508. found ultimately that use of the PEPPSI-iPr catalyst enabled
(17) Mamane, V.; Hannen, P.; F€ urstner, A. Chem.;Eur. J. 2004, 10, formation of 16 in 79% yield.19 Formation of 8h was
4556–4575.
(18) Kraszkiewicz, L.; Sosnowski, M.; Skulski, L. Synthesis 2006, 1195– accomplished from 16 in a straightforward manner (83%
1199. yield) with Co2(CO)8.
J. Org. Chem. Vol. 75, No. 23, 2010 8243
JOC Article Djurdjevic et al.

TABLE 2. Intramolecular Nicholas Reactions of 8 trimethoxy-substituted 8b, TLC analysis suggested the onset
of some decomposition without complete conversion at 16 h,
so that the reaction was terminated at this point and small
amount of 8b (10%) could be recovered in addition to the
isolated 9b (59% yield) (entry 3). 3-Thienyl-substituted 8d
underwent competitive cyclization at C-20 and C-40 , afford-
ing 9d and 9d0 as a regioisomeric mixture (82%, 45:55
9d:9d0 ) (entry 5). It is also worthy of note that 8c f 9c
(entry 4) and 8g f 9g (entry 8) proceeded uneventfully, as the
less electron-rich arene nucleophiles would be of borderline
reactivity and insufficient reactivity, respectively, for parti-
cipation in intermolecular Nicholas reactions.15 Evidence of
restricted rotation about the aryl-aryl bond was present for
several of the cyclization products, as all dibenzocyclohep-
tyne-Co2(CO)6 complexes bearing an additional substituent
ortho to the biaryl gave diastereotopic CH2’s for the pro-
pargylic hydrogen atoms in the 1H NMR spectra (9a,b,f,g).
In addition, those bearing substitutents ortho to the cyclo-
heptyne either gave a diastereotopic CH2 (9c) or one right at
coalescence (9h).
Removal of the Co2(CO)6 fragment for use in synthesis
requires concomitant conversion of the alkyne function into
one compatible with the seven-membered ring.20,21 The most
commonly employed reagent for this purpose, Bu3SnH, has
caused some isomerization in related benzocycloheptyne
cases;12c consequently we chose to apply a modification of
Isobe’s hydrosilylation protocol20 that would afford the
entry 8 time (h) 9 yield (%) alkene. Addition of triethylsilane to the dibenzocycloheptyne
1 8a 2.5 9a 56a complexes 9 in the presence of bis(trimethylsilylacetylene)
2 8a 6 9a 71 (BTMSE) gave a regioisomeric mixture of silylated cyclo-
3 8b 16 9b 59 (66)b
4 8c 6 9c 85
heptenes, which were not isolated but subjected to in situ
5 8d 5 9d 82c desilylation with trifluoroacetic acid (TFA) to give the dibenzo-
6 8e 4.5 9e 91 cycloheptenes 17. These dibenzocycloheptenes (17a,e,f,h)
7 8f 4.5 9f 83 were isolated in good to excellent yields and with no evidence
8 8g 16 9g 58 of double bond isomerization during the reductive decom-
9 8h 5 9h 84
a
plexation process (Table 3).
No i-Pr2NEt added. bYields in parentheses based on recovered
Formal Synthesis of (-)-Allocolchicine. Since several of the
starting material. cIsolated as a 45:55 9d:9d0 mixture.
existing syntheses of allocolchicines employ the dibenzocy-
cloheptanones (18) as critical intermediates, conversion of
With the Nicholas reaction precursors in hand, attention dibenzocycloheptenes 17 to 18 was considered to be the most
was turned to investigation of the cyclizations. Under con- prudent approach toward their synthesis. Hydroboration-
ditions developed previously for benzocycloheptyne ring- oxidation of 17h with BH3-THF/H2O2, with further oxida-
closure reactions, 8a (0.005 M in CH2Cl2) underwent reac- tion of the intermediate alcohol using PDC, afforded ketone
tion in the presence of BF3-OEt2 (3 equiv), giving dibenzo- 18h in good yield (81%). Dibenzocycloheptanone 18h has
cycloheptyne 9a over 2.5 h (56% yield) (Table 2, entry 1). As been converted to (-)-allocolchine by Wulff,6 and as such
a small amount of decomposition was evident chromatogra- this represents a formal synthesis of this natural product.
phically during this process, and with the belief that this Similarly, treatment of 17f by BH3-THF/H2O2 followed
could be due to the acid liberated during the substitution by oxidation with PDC afforded 18f (67% yield). Dibenzo-
process, the reaction was conducted with the addition of 1.5 cycloheptanone 18f is a degradation product of (-)-andro-
equiv of i-Pr2NEt. Although the reaction occurred some- biphenyline that has been prepared previously by Seitz,22
what more slowly (6 h) (entry 2), 9a could be isolated in and found to be equally potent as (-)-androbiphenyline in
improved yield (71%). These conditions (3 equiv of inhibition of tubulin assembly.
BF3-OEt2, 1.5 equiv of i-Pr2NEt, 0.005-0.01 M) were Synthesis of (-)-N-Acetylcolchicine O-Methyl Ether (NSC
applied to 8b-8h (Table 2) and afforded fair to excellent 51046) and Analogue. Conversion of 17a to ketone 18a was
yields of 9b-h. While there was some variation in required accomplished by hydroboration-oxidation with further
reaction time (4.5-16 h) and substrate, there was no parti-
cular correlation between reaction time and substitution (20) For other reductive decomplexation reactions, see: (a) Hosokawa, S.;
pattern of the arene behaving as nucleophile. In the case of Isobe, M. Tetrahedron Lett. 1998, 39, 2609–2612. (b) Takai, S.; Ploypradith, P.;
Hamajima, A.; Kira, K.; Isobe, M. Synlett 2002, 588–592. (c) Isobe, M.; Yenjai,
C.; Tanaka, S. Synlett 1994, 916–918.
(21) Kira, K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai, S.; Isobe, M.
(19) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, Tetrahedron 2002, 58, 6485–6492.
G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.;Eur. J. 2006, 12, (22) Brecht, R.; Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med. Chem.
4743–4748. 2000, 8, 557–562.

8244 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
JOC Article
TABLE 3. Conversion of 9 to Dibenzocycloheptanones 18 SCHEME 5. Completion of Enantioselective Synthesis of NSC
51046 and Its 3,8,9,10-Tetramethoxy Isomer

In summary, intramolecular Nicholas reactions have pro-

ven to be effective in the synthesis of dibenzocycloheptyne-
Co2(CO)6 complexes. Ready decomplexation to the diben-
9 17 yield (%) 18 yield (%) zocycloheptenes allows application of this methodology to
9a 17a 97 18a 80a the synthesis of allocolchicines or their derivatives, including
9e 17e 94 18e 68 tubulin-inhibiting ketone 6,7-dihydro-3,4,9,10,11-penta-
9f 17f 90 18f 67
9h 17h 79 18h 81 methoxy-5H-dibenzo[a,c]cyclohepten-5-one (18f), a formal
a total synthesis of (-)-allocolchicine (1), the enantioselective
Oxidation under Swern conditions (oxalyl chloride-DMSO, Et3N).
total synthesis of N-acetylallocolchinol O-methyl ether
(NSC 51046, 2), and of the 3,8,9,10- tetramethoxy isomer
oxidation under Swern conditions (DMSO-oxalyl chloride, of NSC 51046 (21).
Et3N), giving the ketone in 80% yield. Adopting the approach of
Wulff’s group toward (-)-allocolchicine, the reduction of Experimental Section
ketone 18a using the LiBH4/tartrate derived boronate ester
General Methods. All reaction solvents were used after pas-
(TARB-NO2) protocol of Singaram23 gave alcohol 19a in
sage through a solvent purification system. Commercial BF3-
excellent yield and enantioselectivity (96% yield, 95% ee) OEt2 was distilled and stored under nitrogen. All reactions were
(Scheme 5). Substitution of azide for the alcohol function by conducted under a nitrogen atmosphere unless otherwise noted.
way of zinc azide/diisoproyl azodicarboxylate (DIAD)24 Flash chromatography was performed as described by Still
afforded 20a (64%), while azide reduction (H2, Lindlar using silica gel 60 (230-400 mesh).26 2-Bromo-5-methoxybenzal-
catalyst) of 20a and acetylation gave NSC 51046 (2) in dehyde27 and 6-bromo-2,3-dimethoxybenzaldehyde28 were pre-
88% (93% ee), which was spectroscopically identical to pared by literature methods and were >95% purity as deter-
literature report.11 Recrystallization of 2 gave this com- mined by 1H and 13C NMR spectroscopy. All new compounds
pound in >99% ee. To our knowledge this is the first were >95% purity as determined by 1H and 13C NMR spec-
asymmetric synthesis of 2. troscopy. NMR spectra were run at 500 or 300 MHz for 1H and
125 or 75 MHz for 13C in CDCl3; chemical shifts are given in
Similarly, dibenzocycloheptene 17e was converted to an
ppm and coupling constants (J) are given in Hz. High resolution
isomeric 3,8,9,10-tetramethoxyallocolchicine (21). Hydro- mass spectra were run by time-of-flight mass spectroscopy, in EI
boration-oxidation of 17e and further oxidation with PDC mode, at 70 eV.
afforded dibenzocycloheptanone 18e in 68% yield. LiBH4/ 20 ,30 ,4,40 -Tetramethoxy[1,10 -biphenyl]-2-carboxaldehyde (12a).
TARB-NO2 based reduction afforded the highly enantio- Prepared according to the method of F€ urstner,17 11a (0.3517 g,
merically enriched alcohol 19e (98% yield, 98% ee) provided 1.16 mmol) afforded 7a (0.4202, 85%): mp 102-3 °C (hexanes);
an extended period of substrate/TARB-NO2 mixing and lit.17 102-3 °C. This compound was >95% purity as determined
by 1H and 13C NMR spectroscopy.
slow LiBH4 addition protocol was followed.25 Zinc azide
2 0 ,30 ,4 0 -Trimethoxy[1,10 -biphenyl]-2-carboxaldehyde (12b).
based substitution of the alcohol afforded 20e without Prepared according to the method of F€ urstner,17 11b (0.2278 g,
incident (77% yield), while reduction and acetylation gave 1.23 mmol) affording 12b (0.3706 g, 92%): mp 105-5.5 °C
21 in 79% yield (95% ee); once again, a single recrystalliza- (hexanes); lit.17 98-99 °C. This compound was >95% purity
tion enriched this compound to >99% ee. To our knowl- as determined by 1H and 13C NMR spectroscopy.
edge, this is the first example of an allocolchicine with an 4-Methoxy-30 ,50 -dimethyl[1,10 -biphenyl]-2-carboxaldehyde (12c).
8,9,10-oxygenated A ring. Prepared as adapted from the method of F€ urstner,17 employing 11a
(0.9593 g, 4.46 mmol) and (3,5-dimethylphenyl)boronic acid (6b)

(23) (a) Suri, J. T.; Vu, T.; Hernandez, A.; Congdon, J.; Singaram, B. (26) Still, W. C.; M. Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
Tetrahedron Lett. 2002, 43, 3649–3652. (b) Cordes, D. B.; Nguyen, T. M.; 2925.
Kwong, T. J.; Suri, J. T.; Luibrand, R. T.; Singaram, B. Eur. J. Org. Chem. (27) Bianchi, D. A.; Cipulli, M. A.; Kaufman, T. S. Eur. J. Org. Chem.
2005, 5289–5295. 2003, 4731–4736.
(24) Viaud, M. C.; Rollin, P. Synthesis 1990, 130–132. (28) Kessar, S. V.; Gupta, V. P.; Balakrishnan, P.; Sawal, K. K.;
(25) Rapid addition of LiBH4 afforded 19b in ca. 50% ee. Mohammad, T.; Dutt, M. J. Org. Chem. 2003, 53, 1708–1713.

J. Org. Chem. Vol. 75, No. 23, 2010 8245

JOC Article Djurdjevic et al.

(1.3423 g, 8.96 mmol) to give 12c (0.8472 g, 79% yield), following 61.0, 60.9, 55.9, 55.3, 51.4; MS m/e 328 (Mþ); HRMS m/e for
flash chromatographic purification (15:1 petroleum ether/Et2O), as C19H20O5 calcd 328.1311 (Mþ), found 328.1311 .
a colorless viscous oil which solidified upon standing: mp 71-2 °C; 3-(20 ,30 ,40 -Trimethoxybiphenyl-2-yl)-2-propyn-1-ol (13b). Reaction
IR (KBr) νmax 3006, 2917, 1688, 1604 cm-1; 1 H NMR δ 9.97 (s, 1H), of aldehyde 12b (0.1514 g, 0.554 mmol) according to General
7.52 (d, J=2.8, 1H), 7.37 (d, J=8.5, 1H), 7.19 (dd, J=8.5, 2.8, 1H), Procedure A afforded 13b (0.1293 g, 78% yield) following prepara-
7.06 (br s, 1H), 6.97 (br s, 2H), 3.90 (s, 3H), 2.39 (s, 6H); 13C NMR tive TLC (1:2 hexanes/Et2O), as a viscous oil: IR (KBr) νmax 3379 br,
192.4, 159.0, 139.4, 137.9, 137.4, 134.5, 131.9, 129.3, 128.1, 121.2, 2933, 2227 cm-1; 1 H NMR δ 7.52 (dd, J=7.7, 1.0, 1H), 7.25-7.37 (m,
109.7, 55.5, 21.2; MS m/e 240 (Mþ); HRMS m/e for C16H16O2 calcd 3H), 6.98 (d, J=8.5, 1H), 6.71 (d, J=8.6, 1H), 4.29 (s, 2H), 3.91 (s,
240.1150 (Mþ), found 240.1140. 3H), 3.91 (s, 3H), 3.63 (s, 3H), 2.07 (br, 1H); 13C NMR 153.3, 151.5,
5-Methoxy-2-(3-thienyl)benzaldehyde (12d). Prepared as adapted 142.0, 140.8, 132.3, 130.2, 128.0, 127.5, 126.9, 125.3, 122.4, 106.8,
from the method of F€ urstner, 17 employing 11a (0.2301 g, 89.9, 85.2, 61.0, 60.9, 56.0, 51.4; MS m/e 298 (Mþ); HRMS m/e for
1.07 mmol) and 3-thienylboronic acid (10c) (0.2003 g, 1.56 mmol) C18H18O4 calcd 298.1205 (Mþ), found 298.1201.
to give 12d (0.1900 g, 81% yield) following flash chromatographic (3-Methoxy-30 ,50 -dimethylbiphenyl-2-yl)-2-propyn-1-ol (13c).
purification (15:1 petroleum ether/Et2O): mp 68-69 °C (CH2Cl2); Reaction of aldehyde 12c (0.8472 g, 3.53 mmol) according to
IR (KBr) νmax 3100, 2845, 1684 cm-1; 1 H NMR δ 10.08 (s, 1H), General Procedure A afforded 13c (0.5389 g, 57% yield) follow-
7.50 (d, J=2.7, 1H), 7.44 (dd, J=4.8, 3.0, 1H), 7.41 (d, J=8.5, 1H), ing flash chromatography (2:1 petroleum ether/Et2O) as a
7.24 (dd, J=3.0, 0.9, 1H), 7.19 (dd, J =8.5, 2.7, 1H), 7.17 (dd, J= viscous oil: IR (KBr) νmax 3400 br, 2917, 1603 cm-1; 1 H NMR
4.8, 0.9, 1H), 3.90 (s, 3H); 13C NMR 192.2, 159.0, 137.9, 134.7, δ 7.31 (d, J=8.5, 1H), 7.20 (s, 2H), 7.08 (d, J=2.8, 1H), 7.00 (s, 1H),
133.5, 131.8, 129.4, 126.1, 124.5, 121.5, 109.7, 55.5; MS m/e 218 6.96 (dd, J=8.5, 2.7, 1H), 4.37 (s, 2H), 3.84 (s, 3H), 2.38 (s, 6H), 1.55
(Mþ); HRMS m/e for C12H10O2S calcd 218.0402 (Mþ), found (br, 1H) ; 13C NMR 158.3, 140.0, 137.3, 136.9, 130.6, 128.7, 127.1,
218.0399. 121.6, 117.4, 115.4, 89.8, 85.6, 55.4, 51.6, 21.3; MS m/e 266
30 ,4,40 ,50 -Tetramethoxy[1,10 -biphenyl]-2-carboxaldehyde (12e). (M þ); HRMS m/e for C18H 18 O2 calcd 266.1307 (M þ), found
Prepared according to the method of F€ urstner17 employing 11a 266.1294.
(0.7000 g, 3.26 mmol) and 3,4,5-trimethoxyphenylboronic acid 3-(5-Methoxy-2-(3-thienyl)phenyl)-2-propyn-1-ol (13d) and
(10d) (1.0877 g, 4.89 mmol) to give 12e (0.7472 g, 76% yield) 7-Methoxynaphtho[2,1-b]thiophene (14). Reaction of aldehyde 12d
following flash chromatographic purification (3:1 petroleum (0.0876 g, 0.401 mmol) according to General Procedure A gave, in
ether/Et2O), as a colorless solid: mp 134-136 °C; IR (KBr) order of elution, 14 (0.0452 g, 53% yield) and 13d (0.0389 g, 40%
2931, 1687, 1604 cm-1; 1H NMR δ 9.96 (s, 1H), 7.47 (d, J = yield), following preparative TLC (1:1 petroleum ether/Et2O). 14 as a
2.8, 1H), 7.37 (d, J=8.5, 1H), 7.17 (dd, J=8.5, 2.8, 1H), 6.52 (s, colorless solid: mp 118-120 °C; IR (KBr) νmax 2956, 1621 cm-1; 1H
2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 6H); 13C NMR 192.2, NMR δ 8.26 (d, J = 8.8, 1H), 7.92 (d, J = 5.4, 1H), 7.87 (d, J =
159.1, 152.9, 139.0, 137.7, 134.5, 133.1, 131.7, 121.2, 109.8, 107.5, 8.7, 1H), 7.67 (d, J=8.7, 1H), 7.58 (d, J=5.4, 1H), 72.6-7.31 (m,
60.9, 56.2, 55.5; MS m/e (Mþ) 302; HRMS m/e for C17H18O5 2H), 3.97 (s, 3H); 13C NMR 157.2, 136.1, 135.4, 132.2, 125.9, 125.1,
calcd 302.1154, found 302.1139. 124.5, 124.3, 121.7, 121.2, 118.0, 107.6, 55.4; MS m/e 214 (Mþ);
20 ,3,30 ,4,40 -Pentamethoxy[1,10 -biphenyl]-2-carboxaldehyde (12f). HRMS for C13H10O2S (Mþ) calcd 214.0452, found 214.0454. 13d as
Prepared according to the method of F€ urstner17 employing 11c a viscous oil: IR (KBr) νmax 3384 br, 2928, 2228 cm-1; 1 H NMR δ
(0.7937 g, 3.24 mmol) and 2,3,4-trimethoxyphenylboronic acid 7.54 (dd, J=3.0, 1.4, 1H), 7.42 (dd, J=5.0, 1.4, 1H), 7.34 (d, J=
(10a) (1.0993 g, 5.18 mmol) to give 12f (0.8712 g, 81% yield) 8.6, 1H), 7.34 (dd, J=5.0, 3.0, 1H), 7.06 (d, J=2.7, 1H), 6.93 (dd, J=
following flash chromatographic purification (4:1 petroleum ether/ 8.6, 2.7,1H) 4.46 (d, J=4.2, 2H), 3.84 (s, 3H), 1.61 (br, 1H); 13C
EtOAc): mp 117-119 °C; IR (KBr) νmax 2938, 1699, 1593 cm-1; NMR 158.2, 140.5, 131.2, 130.2, 128.5, 124.7, 122.6, 121.2, 117.7,
H NMR δ 10.15 (s, 1H), 7.12 (d, J=8.4, 1H), 7.01 (d, J=8.4, 1H), 115.6, 90.2, 85.7, 55.4, 51.8; MS m/e 244 (Mþ); HRMS m/e for
1

6.87 (d, J=8.5, 1H), 6.71 (d, J=8.5, 1H), 3.96 (s, 3H), 3.93 (s, 3H), C14H12O2S calcd 244.0558 (Mþ), found 244.0550.
3.890 (s, 3H), 3.887 (s, 3H), 3.58 (s, 3H); 13C NMR 191.1, 153.2, 3-(30 ,4,40 ,50 -Tetramethoxybiphenyl-2-yl)-2-propyn-1-ol (13e).
152.0, 150.5, 149.9, 141.7, 131.7, 129.0, 126.6, 125.7, 124.5, 115.9, Reaction of aldehyde 12e (0.4674 g, 1.55 mmol) according to
106.9, 61.7, 60.7, 60.3, 55.74, 55.68; MS m/e 332 (Mþ); HRMS for General Procedure A gave 13e (0.3115 g, 61% yield), following
C18H20O6 (Mþ) calcd 332.1260, found 332.1275. flash chromatography (1:1 petroleum ether/Et2O), as a viscous
3-(20 ,30 ,4,40 -Tetramethoxybiphenyl-2-yl)-2-propyn-1-ol (13a). oil: IR (KBr) 3500 br, 2935, 2224, 1602 cm-1; 1H NMR δ 7.29 (d,
General Procedure A. To a solution of 12a (0.3378 g, 1.12 mmol) J=8.6, 1H), 7.06 (d, J=2.7, 1H), 6.92 (dd, J=8.6, 2.7, 1H), 6.79
in CH2Cl2 (10 mL) were added CBr4 (0.556 g, 1.68 mmol) and (s, 2H), 4.38 (s, 2H), 3.88 (s, 3H), 3.87 (s, 6H), 3.81 (s, 3H), 2.33
PPh3 (1.172 g, 4.47 mmol). After 4 h of stirring, petroleum ether (br s, 1H); 13C NMR 158.1, 152.5, 137.0, 136.1, 135.4, 130.3,
(10 mL) and iodomethane (0.4 mL) were added, and the mixture 121.3, 117.6, 115.2, 106.4, 90.3, 84.8, 60.7, 56.0, 55.2, 51.2; MS
was allowed to stir for 8 h. The volatiles were removed under m/e (Mþ) 328; HRMS m/e for C19H20O5 calcd 328.1311, found
reduced pressure, and the residue filtered through silica gel, 328.1308.
using 1:1 petroleum ether/Et2O as solvent). The filtrate was 3-(20 3,30 ,4,40 -Pentamethoxybiphenyl-2-yl)-2-propyn-1-ol (13f).
concentrated under reduced pressure to give the crude dibro- Reaction of aldehyde 12f (0.8629 g, 2.60 mmol) according to
mide, which was used without further purification. The dibro- General Procedure A gave 13f (0.5257 g, 56% yield), flash
mide was dissolved in THF (20 mL) and cooled to -78 °C. chromatography (1:1 hexanes/Et2O), as a viscous oil: IR (KBr)
Butyllithium (1.08 mL of a 2.58 M solution in hexanes, 2.79 3509 br, 2936, 2227, 1591 cm-1; 1H NMR δ 6.96 (d, J=8.5, 1H),
mmol) was added, and stirring was continued for 5 h. A 6.91 (d, J=8.6, 1H), 6.88 (d, J=8.5, 1H), 6.64 (d, J=8.6, 1H),
suspension of paraformaldehyde (0.4 g, excess) in THF (5 mL) 4.28 (br d, J=4.8, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83
was added, and the reaction was stirred for 8 h as the mixture (s, 3H), 3.61 (s, 3H), 2.88 (br, 1H); 13C NMR 152.8, 151.24,
gradually warmed to room temperature. A conventional extractive 151.17, 149.9, 141.6, 133.9, 126.7, 125.4, 125.3, 117.4, 112.0,
workup followed by flash chromatography (1:2 petroleum ether/ 106.4, 94.3, 80.3, 60.7, 60.61, 60.57, 55.6, 51.0; MS m/e 358 (Mþ);
Et2O) gave 13a (0.2919 g, 80%), as a viscous oil: IR (KBr) νmax HRMS m/e for C20H22O6 calcd 358.1416, found 358.1404.
3455 br, 2937, 2229 cm-1; 1 H NMR δ 7.22 (d, J=8.6, 1H), 7.05 (d, 3-Biphenyl-2-yl-2-propyn-1-ol (13g). To a solution of 20 -iodo-
J=2.7, 1H), 6.96 (d, J=8.5, 1H), 6.91 (dd, J=8.6, 2.7, 1H), 6.68 biphenyl (0.10 mL, 0.57 mmol), Pd(PPh3)4 (10 mg), and CuI (20
(dd, J=8.5, 1H), 4.29 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), mg) in degassed diisopropylamine (5 mL) was added propargyl
3.61 (s, 3H), 2.30 (br, 1H) ; 13C NMR 158.2, 153.1, 151.6, 142.0, alcohol (0.15 mL, 2.6 mmol). After 20 h of stirring, the volatiles
133.3, 131.3, 127.1, 125.6, 123.2, 116.8, 114.8, 106.7, 89.6, 85.2, were removed under reduced pressure, the residue was filtered

8246 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
JOC Article
through silica with Et2O, and the volatiles were again removed (excess) was added, and the mixture was stirred 4 h. After con-
in vacuo. Preparative TLC in 2:1 hexanes/Et2O gave 0.1025 g of centration under reduced pressure, flash chromatography (100%
13g (87% yield): bp 135-140 °C (0.15 Torr) (bulb-to-bulb); IR petroleum ether f 5:1 petroleum ether/Et2O) gave acetate complex
(KBr) νmax 3054, 3061, 2925, 2235 cm-1; 1 H NMR δ 7.58 (d, J= 8a (0.4952 g, 86% yield) as a red-brown solid: mp 122-124 °C ; IR
7.3, 2H), 7.57 (d, J = 7.9, 1H), 7.44 (apparent t, Jave=7.5, 2H), (KBr) νmax 2919, 2090, 2050, 2018, 1743 cm-1; 1 H NMR δ 7.30 (d,
7.35-7.41 (m, 3H), 7,31 (m, 1H), 4.35 (s, 2H), 1.63 (br s, 1H); 13C J=2.5, 1H), 7.00 (d, J = 8.5, 1H), 6.88 (dd, J = 8.5, 2.5, 1H), 6.80
NMR (40 °C) 144.0, 140.5, 133.1, 129.5, 129.2, 128.6, 127.9, (d, J=8.5, 1H), 6.73 (d, J = 8.5, 1H), 4.58 (d, J = 15.0, 1H), 3.97 (d,
127.4, 127.0, 121.0, 90.2, 85.4, 51.5; MS m/e 208 (Mþ); HRMS J = 15.0, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H), 3.59 (s, 3H),
m/e for C15H12O calcd 208.0888 (Mþ), found 208.0890. 2.02 (s, 3H); 13C NMR 199.4, 199.3, 170.3, 159.2, 153.9, 151.2,
Methyl 4-Bromo-3-iodobenzoate. To a solution of 4-bromo-3- 142.4, 137.6, 131.8, 129.4, 128.2, 125.4, 118.0, 114.5, 107.3, 92.5,
iodobenzoic acid (1.3227 g, 3.68 mmol) in methanol (40 mL) was 88.7, 64.4, 60.7, 60.4, 56.2, 55.0, 20.2 ; MS m/e 600 (Mþ - 2CO), 572
added H2SO4 (10 drops). The mixture was heated to reflux for 12 h. (Mþ - 3CO), 488 (Mþ - 6CO). Anal. Calcd for C27H22Co2O12 C,
Following a conventional extractive workup (Et2O) and extrac- 49.41; H, 3.38. Found: C, 49.68; H, 3.38.
tion of the Et2O layers with NaOH(aq), the Et2O layers were dried Hexacarbonyl[μ-η4-(3-acetoxy-(20 ,30 ,40 -trimethoxybiphenyl-
over MgSO4, filtered, and concentrated under reduced pressure. 2-yl)-1-propyne]dicobalt (8b). Subjecting 13b (0.1214 g, 0.407
Flash chromatography (8:1 petroleum ether/Et2O) afforded mmol) to General Procedure B afforded 18b (0.2140 g, 84%
methyl 4-bromo-3-iodobenzoate (1.2550 g, 91% yield) as a yield) following flash chromatographic purification (10:1 f
colorless solid: mp 70-71 °C; IR (KBr) νmax 3087, 1726 cm-1; 4:1 petroleum ether/Et2O), as a red-brown solid: mp 108-
H NMR δ 8.46 (s, 1H), 7.81 (d, J=8.2, 1H), 7.66 (d, J=8.2, 1H), 110 °C; IR (KBr) νmax 2938, 2090, 2052, 2022, 1745 cm-1; 1 H
1

3.90 (s, 3H); 13C NMR 164.8, 141.1, 135.2, 132.5, 130.12, 130.08, NMR δ 7.76 (d, J=7.8, 1H), 7.40 (apparent t, J=7.4, 1H), 7.31
101.0, 52.5; MS m/e (Mþ) 340/342; HRMS m/e for C8H6BrIO2 (apparent t, J=7.3, 1H), 7.11 (d, J = 7.5, 1H), 6.82 (d, J = 8.4, 1H),
calcd 339.8596, found 339.8603. 6.75 (d, J=8.4, 1H), 4.59 (d, J=14.5, 1H), 3.98 (d, J=14.5, 1H),
Methyl 4-Bromo-3-(3-methoxyprop-1-ynyl)benzoate (15). To a 3.98 (s, 3H), 3.94 (s, 3H), 3.60 (s, 3H), 2.03 (s, 3H); 13C NMR
solution of methyl 4-bromo-3-iodobenzoate (1.255 g, 3.21 mmol) 199.3, 170.4, 154.1, 151.5, 142.6, 137.1, 136.6, 134.3, 130.9,
and propargyl methyl ether (0.47 mL, 5.9 mmol) in diisopropyla- 128.6, 128.1, 127.4, 125.0, 107.5, 92.6, 88.6, 64.6, 60.8, 60.5,
mine (5 mL) were added CuI (0.0404 g, 0.212 mmol) and Pd- 56.4. 20.2 ; MS m/e 570 (Mþ - 2CO), 542 (Mþ - 3CO), 458
(PPh3)4 (0.070 g, 0.061 mmol). After 12 h of stirring, the mixture (Mþ - 6CO); HRMS for C26H20Co2O11 calcd 597.9720 (Mþ -
was subjected to a conventional extractive workup. Flash chro- CO), found 597.9741.
matography (5:1 petroleum ether/Et2O) afforded 15 (0.9599 g, Hexacarbonyl[μ-η4-(3-acetoxy-(3-methoxy-30 ,50 -dimethylbi-
92% yield) as yellow crystals: mp 42-43 °C; IR (KBr) νmax 3033, phenyl-2-yl)-1-propyne]dicobalt (8c). Subjecting 13c (0.0608 g,
2953, 1739, 1593 cm-1; 1H NMR δ 8.10 (d, J=2.0, 1H), 7.78 (dd, 0.228 mmol) to General Procedure B afforded acetate complex
J=8.4, 2.0, 1H), 7.64 (d, J=8.4, 1H), 4.37 (s, 2H), 3.89 (s, 3H), 3.48 8c (0.1232 g, 91% yield) of acetate complex (91% yield)
(s, 3H); 13C NMR 165.6, 134.4, 132.5, 130.6, 130.1, 129.2, 125.2, following flash chromatography (10:1 petroleum ether/Et2O),
90.7, 84.0, 60.2, 57.7, 52.3; MS m/e 282/284 (Mþ); HRMS for as a red-brown solid: mp 250 °C (dec); IR (KBr) νmax 2961,
C12H11BrO3 calcd 283.9891, found 283.9900. 2090, 2058, 1998, 1748 cm-1; 1 H NMR δ 7.28 (d, J = 2.7, 1H),
Methyl 20 ,30 ,40 -Trimethoxy-2-(3-methoxyprop-1-ynyl)biphenyl- 7.08 (s, 1H), 7.04 (d, J = 8.4, 1H), 6.89 (dd, J = 8.4, 2.7, 1H),
4-carboxylate (16). A mixture of methyl 4-bromo-3-(3-methox-
6.86 (s, 2H), 4.02 (s, 2H), 3.87 (s, 3H), 2.37 (s, 6H), 2.04 (s, 3H);
yprop-1-ynyl)benzoate (15) (0.0712 g, 0.251 mmol), 2,3,4-tri- 13
C NMR 199.4, 170.4, 159.2, 141.6, 138.2, 136.4, 134.2, 131.1,
methoxyphenylboronic acid (10a) (0.1333 g, 0.629 mmol), K3PO4
129.2, 127.4, 118.0, 114.6, 93.3, 88.9, 64.2, 55.2, 21.1, 20.3; MS
(0.1590 g, 0.750 mmol), Pd2(dba)3 (0.0046 g, 0.0050 mmol), and
m/e 566 (Mþ - CO), 510 (Mþ - 3CO), 426 (Mþ - 6CO);
PCy 3 (0.0035 g, 0.012 mmol) in toluene (10 mL) was heated to
HRMS m/e for C26H20Co2O9 calcd 565.9822 (Mþ - CO),
100 °C for 37 h. Following an extractive workup, radial chroma-
found 565.9811.
tography (5:1 petroleum ether/Et2O) afforded, in order of elu-
Hexacarbonyl[μ-η4-(3-acetoxy-1-(5-methoxy-2-(3-thienyl)phenyl)-
tion, recovered 15 (0.0218 g, 31% recovery), and 16 (0.0493 g,
1-propyne]dicobalt (8d). Subjecting 13d (0.0418 g, 0.171 mmol)
53% yield) as a viscous oil: IR (KBr) νmax 2936, 1730, 1605 cm-1;
to General Procedure B gave acetate complex 8d (0.0756, 77%
1
H NMR δ 8.22 (d, J = 1.8, 1H), 8.00 (dd, J = 8.1, 1.8, 1H), 7.41
yield) following flash chromatography (10:1 petroleum ether/
(d, J = 8.1, 1H), 7.01 (d, J = 8.5, 1H), 6.72 (d, J = 8.5, 1H), 4.20
Et2O), as a red-brown solid: mp 104-105 °C; IR (KBr) νmax
(s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.66 (s, 3H), 3.23 (s,
3H); 13C NMR 166.4, 153.8. 151.4, 145.3, 142.1, 133.7, 130.6, 2941, 2090, 2055, 2021, 1745 cm-1; 1 H NMR δ 7.46 (dd, J =
128.9, 126.6, 125.2, 122.9, 106.7, 88.2, 85.2, 61.2, 61.0, 60.2, 57.2, 4.7, 3.1, 1H), 7.28 (d, J = 2.6, 1H), 7.15 (m, 1H), 7.06 (d, J =
56.1, 52.2; MS m/e 370 (Mþ); HRMS for C21H22O6 (Mþ) calcd 8.4, 1H), 7.02 (d, J = 4.7, 1H), 6.88 (dd, J = 8.4, 2.6, 1H), 4.30
370.1416, found 370.1416. (s, 2H), 3.87 (s, 3H), 2.05 (s, 3H); 13C NMR 199.3, 170.5, 159.6,
A solution of potassium tert-butoxide (0.0351 g, 0.314 mmol) 141.9, 137.2, 131.8, 130.1, 128.3, 126.1, 123.8, 118.3, 114.7,
and (1,3-diisopropylimiazol-2-ylidene)(3-chloropyridyl)palladium- 93.1, 88.4, 63.9, 55.2, 20.3; MS m/e 544 (Mþ - CO), 488 (Mþ -
(II) dichloride (0.0014 g, 1 mol %) in isopropanol (1 mL) was 3CO), 404 (Mþ - 6CO); HRMS m/e for C22H14Co2O9S calcd
stirred for 10 min. To this solution was added 2,3,4-trimethoxy- 543.9073 (Mþ -CO), found 543.9078.
phenylboronic acid (10a) (0.0975 g, 0.460 mmol) and 15 (0.0590 g, Hexacarbonyl[μ-η4-(3-acetoxy-(,30 ,4,40 ,50 -tetramethoxybiphenyl-
0.209 mmol). After stirring for 12 h, diethyl ether was added, and 2-yl)-1-propyne)]dicobalt (8e). Subjecting 13e (0.2809 g, 0.855
reaction was subjected to a conventional extractive workup (Et2O). mmol) to General Procedure B afforded 8e (0.4722 g, 84%
Preparative TLC (5:1 petroleum ether/Et2O) afforded 16 (0.0612 g, yield) following flash chromatographic purification (3:1 pe-
79% yield). troleum ether/Et2O), as a red-brown solid: mp 126-128 °C; IR
Hexacarbonyl[μ-η4-(3-acetoxy-(20 ,30 ,4,40 -tetramethoxybiphe- (KBr) νmax 2938, 2090, 2010, 1974, 1748 cm-1; 1H NMR δ 7.27
nyl-2-yl)-1-propyne)]dicobalt (8a). General Procedure B. To (d, J = 2.6, 1H), 7.05 (d, J = 8.4, 1H), 6.89 (dd, J = 8.4, 2.6,
alcohol 13a (0.2875 g, 0.876 mmol) at 0 °C were added acetic 1H), 6.42 (s, 2H), 4.22 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.82 (s,
anhydride (1 mL) and pyridine (1 mL). The solution was stirred 4 h, 6H), 2.02 (s, 3H); 13C NMR 199.3, 170.3, 159.4, 153.2, 137.7,
as the solution came to room temperature. The volatiles were 137.3, 136.4, 133.6, 131.2, 117.7, 114.7, 106.9, 93.1, 88.3, 63.9,
removed under reduced pressure, and the residue was dissolved in 61.1, 56.1, 55.1, 20.2; MS m/e 628 (Mþ - CO), 600 (Mþ -
CH2Cl2 (25 mL). An unweighed amount of octacarbonyldicobalt 2CO), 572 (Mþ - 3CO), 544 (Mþ - 4CO), 516 (Mþ - 5CO),

J. Org. Chem. Vol. 75, No. 23, 2010 8247

JOC Article Djurdjevic et al.

488 (Mþ - 6CO); HRMS for C27H22Co2O12 calcd (Mþ - CO) 0.135 mmol) to General Procedure C (16 h), followed by flash
627.9826, found 627.9802. chromatography (5:1 petroleum ether/Et2O) afforded 9b
Hexacarbonyl[μ-η4-(3-acetoxy-(20 ,3,30 ,4,40 -pentamethoxy- (0.0452 g, 59% yield, 66% yield based on recovered starting
biphenyl-2-yl)-1-propyne)]dicobalt (8f). Subjecting 13f (0.5231 material) followed by recovered 8b (0.0085 g, 10% recovery).
g, 1.46 mmol) to General Procedure B afforded 8f (0.9818 g, 9b: red-brown solid, mp 116-118 °C; IR (KBr) νmax 3057, 2934,
98% yield) following flash chromatographic purification (4:1 2090, 2051 cm-1; 1 H NMR δ 7.69 (dd, J=7.4, 1.3, 1H), 7.63 (dd,
petroleum ether/Et2O), as a red-brown solid: mp 120-121 °C; J = 7.6, 1.3, 1H), 7.38 (apparent dt, J = 1.3, 7.4, 1H), 7.35
IR (KBr) νmax 3002, 2939, 2088, 2009, 1743 cm-1; 1H NMR δ (apparent dt, J=1.3, 7.6, 1H), 6.67 (s, 1H), 4.03 (d, J=14.0, 1H),
6.95 (d, J=8.4, 1H), 6.80 (d, J=8.4, 1H), 6.73 (d, J=8.4, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.66 (d, J = 14.0, 1H), 3.39 (s, 3H); 13C
6.71 (d, J = 8.4, 1H), 4.53 (d, J = 14.5, 1H), 4.07 (s, 3H), 3.95 NMR 198.9 (br), 153.1, 152.7, 142.5, 137.7, 137.5, 132.6, 132.4,
(s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.83 (d, J = 14.5, 1H), 3.61 132.0, 127.8, 126.4, 126.2, 107.9, 105.7, 92.9, 61.0, 60.4, 56.1,
(s, 3H), 2.00 (s, 3H); 13C NMR 199.8, 170.4, 153.9, 151.6, 40.0; MS m/e 538 (Mþ - 1CO), 510 (Mþ - 2CO), 482 (Mþ -
151.4, 149.5, 142.4, 131.3, 128.84, 128.79, 125.6, 125.4, 112.2, 3CO), 454 (Mþ - 4CO), 426 (Mþ - 5CO), 398 (Mþ - 6CO);
107.2, 94.3, 81.0, 65.4, 60.6, 60.3, 59.9, 56.2, 55.7, 20.2; MS HRMS m/e for C24H16Co2O9 calcd 537.9509 (Mþ - CO), found
m/e 630 (Mþ-2CO), 602 (Mþ - 3CO), 518 (Mþ - 6CO), 400 (Mþ - 537.9492 .
Co2(CO)6); HRMS for C28H24Co2O13 (Mþ - 2CO) calcd Hexacarbonyl[μ-η4-(9-methoxy-2,4-dimethyl-5H-dibenzo[a,
629.9997, found 629.9995. c]cycloheptyne]dicobalt (9c). Subjecting acetate complex 8c
Hexacarbonyl[μ-η 4 -(3-acetoxy-1-biphenyl-2-yl)-1-propy- (0.1232 g, 0.207 mmol) to General Procedure C (6 h) gave 9c
ne]dicobalt (8g). Subjecting 13g (0.0799 g, 0.384 mmol) to (0.0938 g, 85% yield), following flash chromatography (50:1
General Procedure B gave acetate complex 8g (0.1763 g, petroleum ether/Et2O), as a brown solid: mp 142-144 °C; IR
86% yield) following flash chromatography (50:1 petro- (KBr) νmax 2924, 2090, 2055, 2025 cm-1; 1 H NMR (-30 °C) δ
leum ether/Et 2 O), as a red-brown oil which gradually 7.54 (d, J=8.5, 1H), 7.21 (d, J = 3.0, 1H), 6.97 - 7.01 (m, 3H),
solidified: mp 99-101 °C; IR (KBr) ν max 3073, 2977, 2087, 4.49 (d, J = 14.0, 1H), 3.93 (s, 3H), 3.34 (d, J = 14.0, 1H), 2.50
2055, 2006, 1749 cm -1 ; 1 H NMR δ 7.77 (d, J = 7.8, 1H), (s, 3H), 2.29 (s, 3H) ; 13C NMR 199.1, 159.4, 140.6, 139.0,
7.45-7.52 (m, 3H), 7.42 (apparent t, J ave = 7.6, 1H), 7.34 136.20, 136.15, 134.1, 132.2, 132.0, 131.7, 130.0, 116.7, 113.5,
(apparent t, J ave =7.3, 1H), 7.26-7.30 (m, 2H), 7.14 (d, J= 105.2, 92.7, 55.4, 32.9, 21.0, 20.9; MS m/e 534 (Mþ), 450 (Mþ -
7.8, 1H), 4.02 (s, 2H), 2.02 (s, 3H); 13 C NMR 199.3, 170.4, 3CO), 394 (Mþ - 5CO); HRMS m/e for C24H16Co2O7 calcd
142.2, 141.2, 135.3, 134.3, 130.2, 129.3, 128.6, 128.3, 128.0, 533.9560 (Mþ), found 533.9569.
127.6, 93.1, 88.4, 64.1, 20.3; MS m/e 480 (M þ - 2CO), 452 Hexacarbonyl[μ-η4-(8-methoxy-4H-benzo[3,4]cycloheptyne-
(Mþ - 3CO), 396 (Mþ - 5CO), 368 (Mþ - 6CO). Anal. Calcd for [1,2-b]thiophene]dicobalt (9d) and Hexacarbonyl[μ-η4-(8-meth-
C 23 H 14 Co 2 O 8 C, 51.52; H, 2.63. Found C, 51.75; H, 2.51. oxy-4H-benzo[3,4]cycloheptyne[1,2-c]thiophene]dicobalt (9d0 ).
Hexacarbonyl[μ-η4-(3-methoxy-(4-carbomethoxy-20 ,30 ,40 -tri- Subjecting 8d (0.0654 g, 0.114 mmol) to General Procedure C
methoxybiphenyl-2-yl)-1-propyne)]dicobalt (8h). To a solution (5 h) afforded 9d/9d0 (0.0494 g, 82% yield) following flash
of 16 (0.1223 g, 0.330 mmol) in CH2Cl2 at 0 °C was added chromatography, as an inseparable 45:55 mixture, as a red-
octacarbonyldicobalt (excess). The cooling bath was removed, brown viscous oil: IR (KBr) νmax 2937, 2091, 2067, 2045, 1603 cm-1.
and the mixture was allowed to stir for 2 h. After concentration 1
H NMR: for 9d δ 7.53 (d, J=8.5, 1H), 7.24 (d, J=2.8, 1H), 7.18
under reduced pressure, flash chromatography (3:1 petroleum (d, J=5.3, 1H), 7.13 (d, J=5.3, 1H), 6.95 (dd, J = 8.3, 2.8, 1H),
ether/Et2O) afforded 8h (0.1797 g, 83% yield) as a red-brown 4.25 (s, 2H), 3.900 (s, 3H); for 9d0 δ 7.55 (d, J = 8.5, 1H), 7.28 (d,
solid: mp 143-144 °C; IR (KBr) νmax 2956, 2091, 2039, 2009, J = 3.1, 1H), 7.19 (d, J = 2.8, 1H), 7.14 (obscured d, 1H), 6.93
1726 cm-1; 1H NMR δ 8.45 (d, J=1.7, 1H), 7.93 (dd, J=7.9, (dd, J = 8.3, 2.8 1H), 4.17 (s, 2H), 3.897 (s, 3H); 13C NMR
1.7, 1H), 7.18 (d, J=7.9, 1H), 6.80 (1/2 AB quartet, J=8.5, 1H), 199.0, 159.6, 159.1, 141.3, 139.5, 138.0, 137.2, 136.9, 135.7,
6.74 (1/2 AB quartet, J=8.5, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.94 131.1, 130.2, 129.9, 127.1, 127.0, 125.4, 121.9, 121.5, 117.3,
(s, 3H), 3.87 (d, J = 13.4, 1H), 3.59 (s, 3H), 3.30 (s, 3H), 3.25 (d, 117.1, 114.0, 113.8, 100.9, 100.4, 92.5, 55.4, 34.8, 33.3; MS m/e
J=13.4, 1H); 13C NMR 199.4, 166.6, 154.0, 151.3, 142.4, 141.3, 512 (Mþ), 455 (Mþ - 2CO), 399 (Mþ - 4CO); HRMS m/e for
137.8, 135.7, 131.2, 130.1, 128.1, 127.8, 124.9, 107.1, 95.7, 86.0, C20H10Co2O7S calcd 511.8811 (Mþ), found 511.8808.
71.7, 60.8, 60.6, 58.6, 56.3, 52.3; MS m/e 572 (Mþ - 3CO), 516 Hexacarbonyl[μ-η4-(2,3,4,9-tetramethoxy-5H-dibenzo[a,c]cyclo-
(Mþ - 5CO); HRMS for C27H22Co2O12 calcd (Mþ - 3CO) heptyne]dicobalt (9e). Subjecting (8e) (0.6621 g, 1.01 mmol) to
571.9928, found 571.9924. General Procedure C (4.5 h) afforded 9e (0.5457 g, 91% yield)
Hexacarbonyl[μ-η4-(1,2,3,9-tetramethoxy-5H-dibenzo[a,c]cyclo- following flash chromatography (7:1 petroleum ether/Et2O), as
heptyne]dicobalt (9a). General Procedure C. To a solution of 8a a red-brown solid: mp 138-140 °C; IR (KBr) νmax 2938, 2091,
(0.1193 g, 0.182 mmol) in CH2Cl2 (35 mL) at 0 °C was added 2051, 2023, 1601 cm-1; 1H NMR δ 7.47 (d, J = 8.7, 1H), 7.22 (d,
diisopropylethylamine (48 μL, 1.5 equiv) and BF3-OEt2 (69 μL, J = 2.7, 1H), 6.98 (dd, J = 8.7, 2.7, 1H), 6.67 (s, 1H), 4.03 (v br,
3.0 equiv). The cooling bath was removed, and the reaction was 2H), 3.95 (s, 3H), 3.91 (s, 6H), 3.84 (s, 3H); 13C NMR 199.1,
allowed to stir for 6 h, at which time consumption of starting 159.5, 152.0, 150.1, 141.7, 138.9, 136.1, 131.35, 131.29, 127.1,
material was complete. Following an extractive workup, flash 116.8, 113.6, 112.7, 105.6, 92.6, 61.4, 60.9, 56.2, 55.4, 29.4; MS
chromatography (5:1 petroleum ether/Et2O) afforded 9a m/e 596 (Mþ), 568 (Mþ - CO), 540 (Mþ - 2CO), 512 (Mþ -
(0.0766 g, 71% yield), as a red-brown oil which gradually 3CO), 484 (Mþ - 4CO), 456 (Mþ - 5CO); HRMS for
solidified: mp 117-119 °C; IR (KBr) νmax 2939, 2090, 2020 C25H18Co2O10 (Mþ) calcd 595.9564, found 595.9548.
cm-1; 1 H NMR δ 7.57 (d, J=8.5, 1H), 7.21 (d, J=3.0, 1H), 6.92 Hexacarbonyl[μ-η4-(1,2,3,8,9-pentamethoxy-5H-dibenzo[a,c]cyclo-
(dd, J=8.5, 2.5, 1H), 6.65 (s, 1H), 4.01 (d, J=14.0, 1H), 3.91 (s, heptyne]dicobalt (9f). Subjecting (8f) (0.9250 g, 1.35 mmol) to
3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.63 (d, J=14.0, 1H) 3.38 (s, 3H); General Procedure C (4.5 h) afforded 9f (0.7021 g, 83% yield)
13
C NMR 199.3, 198.7, 158.9, 152.9, 152.2, 142.3, 138.9, 137.2, following flash chromatography (5:1 hexanes/Et2O), as a dark
133.7, 126.1, 124.8, 116.5, 112.0, 107.7, 105.4, 93.0, 60.9, 60.2, brown solid: mp 115-117 °C; IR (KBr) νmax 2939, 2090, 2054,
56.0, 55.1, 39.8; MS m/e 596 (Mþ), 540 (Mþ - 2CO), 512 (Mþ - 1593 cm-1; 1H NMR δ 7.30 (d, J = 8.7, 1H), 6.97 (d, J = 8.7,
3CO), 484 (Mþ - 4CO); HRMS m/e for C25H18Co2O10 calcd 1H), 6.63 (s, 1H), 3.99 (d, J = 14.0, 1H), 3.99 (s, 3H), 3.95 (s,
539.9666 (Mþ - 2CO), found 539.9642. 3H), 3.92 (s, 3H), 3.81 (s, 3H), 3.67 (d, J = 14.0, 1H), 3.40 (s,
Hexacarbonyl[μ-η4-(1,2,3-Trimethoxy-5H-dibenzo[a,c]cyclo- 3H); 13C NMR 199.5, 153.1, 152.3, 152.0, 148.4, 142.3, 137.3,
heptyne]dicobalt (9b). Subjecting acetate complex 8b (0.0848 g, 132.2, 128.3, 126.3, 125.9, 110.6, 107.5, 107.3, 85.8, 61.0, 60.7,

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Djurdjevic et al.
JOC Article
60.4, 56.1, 55.8, 40.3; MS m/e 626 (Mþ), 598 (Mþ - CO), 570 1573 cm-1; 1H NMR δ 7.55 (d, J = 8.7, 1H), 6.94 (d, J = 8.7,
(Mþ - 2CO), 542 (Mþ - 3CO), 514 (Mþ - 4CO), 486 (Mþ - 1H), 6.78 (d, J = 10.1, 1H), 6.58 (s, 1H), 6.29 (m, 1H), 3.95 (s,
5CO), 458 (Mþ - 6CO); HRMS for C26H20Co2O11 (Mþ) calcd 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H), 3.48 (s, 3H), 3.06 (dd,
625.9670, found 625.9673. J = 12.9, 7.9, 1H), 2.80 (ddd, J = 12.9, 5.9, 1.8, 1H); 13C NMR
Hexacarbonyl[μ-η4-(5H-dibenzo[a,c]cycloheptyne]dicobalt (9g). 152.3, 150.4, 145.2, 140.7, 140.1, 132.2, 131.1, 128.3, 127.5,
Subjecting 8g (0.0604 g, 0.127 mmol) to General Procedure C 124.0, 123.8, 109.9, 105.6, 61.0, 60.6, 60.4, 55.9, 55.8, 33.5; MS
(16 h) afforded 9g (0.0311, 58% yield) following flash chromatog- m/e 342 (Mþ); HRMS for C20H22O5 calcd 342.1467, found
raphy (100% petroleum ether), as a dark brown solid: mp 342.1475.
130-132 °C; IR (KBr) νmax 3059, 2959, 1688, 2091, 2052, 9-Carbomethoxy-1,2,3-trimethoxy-5H-dibenzo[a,c]cycloheptene
2022 cm-1; 1 H NMR δ 7.71 (m, 1H), 7.59 (s, 1H), 7.40-7.47 (17h). To a solution of 9h (0.1831 g, 0.293 mmol) in degassed 1,
(m, 3H), 7.28-7.36 (m, 3H), 4.05 (s, 2H); 13C NMR 199.0, 140.4, 2-dichloroethane (7 mL) was added bis(trimethylsilyl)acetylene
140.2, 138.5, 137.3, 133.2, 132.1, 130.4, 128.6, 128.3, 127.92, (0.14 mL, 0.59 mmol) and triethylsilane (0.23 mL, 0.14 mmol). The
127.86, 127.5, 104.2, 92.0, 39.9; MS m/e 420 (Mþ - 2CO), 336 mixture was heated to 65 °C for 6 h and cooled to room
(Mþ - 5CO), 308 (Mþ - 6CO); HRMS m/e for C21H10Co2O6 temperature, at which point trifluoroacetic acid (3.0 mL) was
calcd 447.9192 (Mþ - CO), found 447.9214. added. After stirring for an additional 12 h, the mixture was
Hexacarbonyl[μ-η4-(9-carbomethoxy-1,2,3-trimethoxy-5H- subjected to a conventional extractive workup. Preparative TLC
dibenzo[a,c]cycloheptyne]dicobalt (9h). Subjecting (8h) (0.2304 (5:1 hexanes/Et2O) afforded 17h (0.0789 g, 79% yield) as a
g, 0.351 mmol) to General Procedure C (5 h) afforded 9h colorless solid: mp 85-86 °C; IR (KBr) νmax 2950, 1722, 1594
(0.1831 g, 84% yield) following flash chromatography (5:1 cm-1; 1H NMR δ 8.03 (s, 1H), 7.91 (1/2 AB quartet, J = 8.3, 1H),
petroleum ether/Et2O), as a dark brown viscous oil: IR (KBr) 7.89 (1/2 AB quartet, J = 8.3, 1H), 6.62 (d, J = 10.0, 1H), 6.59 (s,
νmax 2952, 2092, 2055, 2023, 1730 cm-1; 1H NMR δ 8.30 (d, J= 1H), 6.29 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.46 (s,
1.9, 1H), 7.98 (dd, J = 8.2, 1.9, 1H), 7.69 (d, J = 8.2, 1H), 6.67 3H), 3.08 (m, 1H), 2.75 (m, 1H); 13C NMR 167.0, 153.3, 152.3,
(s, 1H), 4.05 (d, J = 14.1, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.84 (s, 140.8, 140.5, 139.4, 136.5, 133.2, 132.0, 130.1, 128.8, 127.6, 125.4,
3H), 3.65 (d, J = 14.1, 1H), 3.39 (s, 3H); 13C NMR 198.7, 123.3, 105.8, 61.1, 60.7, 55.9, 52.1, 33.3; MS m/e 340 (Mþ); HRMS
166.7, 153.24, 153.15, 142.4, 138.3, 137.9, 137.0, 132.9, 129.4, for C20H20O5 (Mþ) calcd 340.1311, found 340.1306.
126.8, 125.5, 107.9, 105.4, 91.4, 61.1, 60.6, 56.1, 52.3, 39.9; MS 6,7-Dihydro-3,9,10,11-tetramethoxy-5H-dibenzo[a,c]cyclohepten-
m/e 596 (Mþ-1CO), 568 (Mþ-2CO), 540 (Mþ - 3CO), 512 5-one (18a). To a solution of alkene 17a (0.0521 g, 0.167 mmol) in
(Mþ-4CO), 484 (Mþ-5CO);); HRMS for C26H18Co2O11 THF (7 mL) at 0 °C was added BH3-THF (0.75 mL of a 1 M
(Mþ - 3CO) calcd 539.9666, found 539.9683. solution). The cooling bath was removed, and the reaction was
1,2,3,9-Tetramethoxy-5H-dibenzo[a,c]cycloheptene (17a). To stirred at room temperature for 12 h. NaOH (1 mL of a 10%
a solution of 9a (0.0782 g, 0.131 mmol) in degassed 1,2-dichlo- aqueous solution) and H2O2 (1 mL of a 33% aqueous solution)
roethane (2 mL) was added bis(trimethylsilyl)acetylene (62 μL, were added, and the mixture was stirred for 4 h, followed by
0.274 mmol) and triethylsilane (0.10 mL, 0.63 mmol). The warming to 40 °C for 0.5 h. A conventional workup gave a crude
mixture was heated to 65 °C for 6 h and cooled to room alcohol which was added slowly as a solution in CH2Cl2 to a -78 °C
temperature, at which point trifluoroacetic acid (0.5 mL) was solution prepared from the addition of DMSO (0.14 mL, 2.0
added. After stirring for an additional 12 h, the mixture was mmol) to oxalyl chloride (86 μL, 1.0 mmol) in CH2Cl2 (10 mL)
subjected to a conventional extractive workup. Preparative TLC at -78 °C. Diisopropylethylamine (0.70 mL, 4.0 mmol) was
(4:1 hexanes/Et2O) afforded 17a (0.0396 g, 97% yield) as a added, and the solution was allowed to come to room temperature
colorless solid: mp 102-3 °C (MeOH), lit.29 102-3 °C (MeOH). over 6 h. A conventional workup gave a residue with a 96:4
2,3,4,9-Tetramethoxy-5H-dibenzo[a,c]cycloheptene (17e). To mixture of ketone regioisomers (by integration of relevant 1H
a solution of 9e (0.3492 g, 0.586 mmol) in degassed 1,2-dichlo- NMR resonances); preparative TLC (1:1 hexanes/Et2O) afford
roethane (20 mL) were added bis(trimethylsilyl)acetylene (0.27 18a (0.0440, 80% yield) as a colorless solid: mp 141-2 °C
mL, 1.2 mmol) and triethylsilane (0.47 mL, 2.9 mmol). The (hexanes), lit. 142-3 °C (MeOH),5a 140.5-141 °C,30 135-6 °C.11
mixture was heated to 65 °C for 6 h and cooled to room 6,7-Dihydro-3,8,9,10-tetramethoxy-5H-dibenzo[a,c]cyclohepten-
temperature, at which point trifluoroacetic acid (1.0 mL) was 5-one. (18e). To a solution of alkene 17e (0.1793 g, 0.574 mmol) in
added. After stirring for an additional 12 h, the mixture was THF (20 mL) at 0 °C was added BH3-THF (2.7 mL of a 1 M
subjected to a conventional extractive workup. Preparative TLC solution). The cooling bath was removed, and the reaction was
(10:1 petroleum ether/Et2O) afforded 17e (0.1718 g, 94% yield) stirred at room temperature for 12 h. NaOH (3 mL of a 10%
as a colorless viscous oil: IR (KBr) νmax 2936, 1604 cm-1; 1H aqueous solution) and H2O2 (3 mL of a 33% aqueous solution)
NMR δ 7.61 (d, J = 8.7, 1H), 6.95 (dd, J = 8.7, 2.6, 1H), 6.85 (d, were added, and the mixture was stirred for 4 h, followed by
J = 2.6, 1H), 6.82 (s, 1H), 6.57 (d, J = 10.0, 1H), 6.26 (m, 1H), warming to 40 °C for 0.5 h. A conventional workup gave a crude
3.94 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 2.47 (v br, alcohol which was dissolved in CH2Cl2 (20 mL). To this solution
2H); 13C NMR 158.2, 151.1, 148.9, 141.9, 137.4, 134.3, 132.8, was added PDC (0.55 g), and the mixture was stirred for 12 h. A
132.3, 130.7, 129.6, 128.3, 113.4, 112.9, 109.1, 61.5, 60.9, 56.2, conventional workup followed by preparative TLC (3:1 petroleum
55.3, 24.0; MS m/e 312 (Mþ); HRMS for C19H20O4 (Mþ) calcd ether/Et2O) afforded 18e (0.1291 g, 68% yield) as a colorless solid:
312.1362, found 312.1356. mp 123-125 °C; IR (KBr) νmax 2937, 1681, 1601 cm-1; 1H NMR
1,2,3,8,9-Pentamethoxy-5H-dibenzo[a,c]cycloheptene (17f). δ 7.36 (m, 1H), 7.14 (s, 1H), 7.13 (obscured m, 1H), 6.69 (s, 1H),
To a solution of 9f (0.0945 g, 0.151 mmol) in degassed 1,2- 3.92 (s, 3H), 3.89 (s, 3H), 3.88 (s, 6H), 2.97-3.00 (m, 2H),
dichloroethane (2 mL) were added bis(trimethylsilyl)acetylene 2.92-2.94 (m, 2H); 13C NMR 206.3, 158.9, 152.2, 150.1, 141.6,
(62 μL, 0.32 mmol) and triethylsilane (0.12 mL, 0.76 mmol). The 139.7, 134.4, 131.4, 130.5, 125.4, 118.8, 112.1, 109.0, 61.3, 60.8,
mixture was heated to 65 °C for 6 h and cooled to room 56.0, 55.4, 47.3, 20.4; MS m/e 328 (Mþ); HRMS for C19H20O5
temperature, at which point trifluoroacetic acid (0.5 mL) was (Mþ) calcd 328.1311, found 328.1322.
added. After stirring for an additional 12 h, the mixture was 6,7-Dihydro-3,4,9,10,11-pentamethoxy-5H-dibenzo[a,c]cyclohepten-
subjected to a conventional extractive workup. Preparative TLC 5-one (18f). To a solution of alkene 17f (0.2175 g, 0.636 mmol) in
(7:1 petroleum ether/Et2O) afforded 17f (0.0465 g, 90% yield) as THF (25 mL) at 0 °C was added BH3-THF (3.0 mL of a 1 M
a colorless solid: mp 163-165 °C; IR (KBr) νmax 3036, 2926,
(30) Rapoport, H.; Williams, A. R.; Cisney, M. E. J. Am. Chem. Soc.
(29) Boye, O.; Itoh, Y.; Brossi, A. Helv. Chim. Acta 1989, 72, 1690–1696. 1950, 72, 3324–3325.

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solution). The cooling bath was removed, and the reaction was 159.4, 151.7, 150.8, 143.2, 141.3, 135.4, 130.3, 129.0, 125.0, 112.5,
stirred at room temperature for 12 h. NaOH (3 mL of a 10% 108.7 (br), 107.9, 70.7 (br), 61.6, 61.0, 55.1, 55.4, 41.5, 21.5; MS m/e
aqueous solution) and H2O2 (3 mL of a 33% aqueous solution) 330 (Mþ); HRMS for C19H22O5 (Mþ) calcd 330.1467, found
were added, and the mixture was stirred for 4 h, followed by 330.1481.
warming to 40 °C for 0.5 h. A conventional workup gave a crude (5S)-5-Azido-6,7-dihydro-3,9,10,11-tetramethoxy-5H-dibenzo[a,
alcohol which was dissolved in CH2Cl2 (20 mL). To this solution c]cycloheptene (20a). To a suspension of alcohol 19a (0.0583 g,
was added PDC (0.55 g), and the mixture was stirred for 12 h. A 0.176 mmol), Zn(N3)2-(pyridine)2 (0.0810 g, 0.264 mmol), and
conventional workup followed by preparative TLC (3:1 petroleum triphenylphosphine (0.185 g, 0.704 mmol) in toluene (2 mL) was
ether/Et2O) afforded 18f (0.1505 g, 67% yield) as a colorless solid: added diisopropyl azodicarboxylate (0.14 mL, 0.70 mmol) in a
mp 164-165 °C, lit. 156-157 °C;22 IR (KBr) νmax 2939, 1701, dropwise fashion. After stirring for 4 h, the mixture was filtered
1598 cm-1; 1H NMR δ 7.26 (d, J = 8.6, 1H), 7.00 (d, J = 8.6, 1H), through a plug of silica gel, and concentrated under reduced
6.56 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.86 (s, 6H), 3.57 (s, 3H), pressure. Preparative TLC (4:1 hexanes/Et2O) afforded 20a con-
2.97-3.05 (m, 2H), 2.85 (m, 1H), 2.59 (m, 1H); 13C NMR 204.8, taminated by 10% of alkene 17a (0.0440 g, 64% of 20a, 7% of
152.6, 151.8, 151.7, 144.3, 141.4, 135.24, 135.21, 126.24, 126.16, 17a). Repeated preparative TLC (10:1 hexanes/EtOAc) afforded
123.8, 113.0, 107.5, 62.2, 61.0, 60.8, 55.9, 55.8, 49.6, 30.1; MS m/e pure 20a as a viscous oil, [R]22D 110° (c 0.0100) (93% ee material as
354 (Mþ); HRMS for C20H22O6 (Mþ) calcd 358.1416, found evaluated on 2); IR (KBr) νmax 2936, 2013 cm-1; 1 H NMR (major
358.1402. atropisomer, 91%) δ 7.42 (d, J = 8.5, 1H), 7.13 (d, J = 2.5, 1H),
6,7-Dihydro-3-carbomethoxy-9,10,11-trimethoxy-5H-dibenzo[a, 6.92 (dd, J = 8.5, 2.5, 1H), 6.60 (s, 1H), 4.44 (dd, J = 11.5, 7.0,
c]cyclohepten-5-one (18h). To a solution of alkene 17h (0.0307 g, 1H), 3.92 (s, 6H), 3.90 (s, 3H), 3.65 (s, 3H), 2.45-2.60 (m, 2H),
0.0902 mmol) in THF (5 mL) at 0 °C was added BH3-THF (0.45 2.33 (m, 1H), 2.00 (m, 1H); resonances from the minor atropi-
mL of a 1 M solution). The cooling bath was removed, and the somer (9%) could be observed at 7.42 (d, J = 8.8, 1H), 6.97 (dd,
reaction was stirred at room temperature for 12 h. NaOH (1 mL of J = 8.8, 2.6, 1H), 6.81 (d, J = 2.6, 1H), 6.58 (s, 1H), 4.71 (d, J =
a 10% aqueous solution) and H2O2 (1 mL of a 33% aqueous 6.8, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.62 (s, 3H); 13C NMR 159.0,
solution) were added, and the mixture was stirred for 4 h, followed 152.6, 150.9, 141.2, 138.6, 134.7, 131.7, 126.0, 124.3, 112.5, 109.2,
by warming to 40 °C for 0.5 h. A conventional workup gave a 107.6, 61.1, 61.0, 60.8, 56.0, 55.3, 38.9, 30.4; MS m/e 355 (Mþ); HRMS
crude alcohol which was dissolved in CH2Cl2 (10 mL). To this m/e for C19H21N3O4 calcd 355.1532 (Mþ), found 355.1541.
solution was added PDC (0.5 g), and the mixture was stirred for (S)-N-Acetyl-O-methyl-colchicinol (NSC 51046) (2). To a
12 h. A conventional workup followed by preparative TLC (1:1 solution containing azide 20a with 10% alkene 17a (0.0186 g,
petroleum ether/Et2O) afforded 18h (0.0.0260 g, 81% yield) as a 48.1 μmol 20a) in 100% EtOH saturated with H2 was added
colorless solid: mp 144-145 °C; lit.6 144.2-144.8 °C. Lindlar catalyst (0.0068 g). The mixture was stirred under H2 for
(5R)-6,7-Dihydro-3,9,10,11-tetramethoxy-5H-dibenzo[a,c]cyclo- 20 h, filtered through Celite, and concentrated under reduced
hepten-5-ol (19a). A suspension of 3-nitrophenylboronic acid pressure. The residue was dissolved in CH2Cl2 and cooled to
(0.334 g, 2.0 mmol), L-tartaric acid (0.0300 g, 2.0 mmol), and 0 °C, and acetic anhydride (0.2 mL) and pyridine (0.2 mL) were
CaH2 (0.168 g, 4.0 mmol) in THF (5 mL) was heated to reflux for added. The mixture was allowed to stir 12 h with gradual
1 h. After cooling and the solids were allowed to settle, the warming to room temperature. Concentration under reduced
supernatant solution (2.5 mL, ca. 1 mmol) was added to ketone pressure, followed by preparative TLC (19:1 CH2Cl2/MeOH)
18a (0.0634 g, 0.193 mmol). Lithium borohydride (0.5 mL of a 2 M afforded 2 (0.0157 g, 88% yield), which was spectroscopically
solution, 1.0 mmol) was added over a period of 5 min, and the identical with authentic material,5,11 93% ee (Chiralcel OD-H,
solution was stirred for 0.5 h. NaOH (1 mL of a 10% aqueous 10% i-PrOH/hexanes). A single recrystallization afforded 2 of
solution) and water (2 mL) were added, and the reaction subjected >99% ee: mp 203-4 °C (CH2Cl2/hexanes); lit.4b 204-5 °C
to a conventional extractive workup. Preparative TLC (2:1 petro- (CH2Cl2/hexanes); [R]24D -64° (c 0.0056, CHCl3); lit.4b [R]20D -
leum ether/Et2O) afforded 19a (0.0610 g, 96%), 95% ee (Chiralcel 65° (c 0.46, CHCl3); lit.4a [R]20D -64.9° (c 1.03%, CHCl3); 1 H
OD-H, i-PrOH/hexanes): mp 137-9 °C (CH2Cl2/petroleum NMR (DMSO-d6) δ 8.34 (d, J = 8.6, 1H), 7.25 (d, J = 8.4, 1H),
ether) [R]22D 120° (c 0.0144); 1 H NMR (DMSO-d6) δ 7.24 (d, 6.91 (d, J = 2.6, 1H), 6.87 (dd, J = 8.4, 2.6, 1H), 6.76 (s, 1H),
J = 8.4, 1H), 7.17 (d, J = 2.8, 1H), 6.85 (dd, J = 84, 2.8, 1H), 6.75 4.52 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.47 (s, 3H),
(s, 1H), 5.23 (d, J = 4.7, 1H), 4.27 (m, 1H), 3.82 (s, 3H), 3.80 (s, 2.48 (m, 1H, obscured), 2.15 (m, 1H), 2.07 (m, 1H), 1.88 (s, 3H),
3H), 3.75 (s, 3H), 3.48 (s, 3H), 2.32-2.45 (m, 2H), 2.06 (m, 1H), 1.85 (m, 1H); 13C NMR (DMSO-d6) 168.2, 158.3, 152.1, 150.3,
1.73 (m, 1H); 13C NMR (DMSO-d6) 158.3, 151.9, 150.2, 144.5, 141.8, 140.5, 134.7, 130.5, 126.1, 124.3, 110.7, 109.4, 108.1,
140.4, 135.2, 130.3, 124.9, 124.0, 111.2, 108.7, 107.9, 68.1, 60.5, 60.50, 60.45, 55.8, 54.9, 48.1, 30.1, 22.6.
60.4, 55.8, 54.9, 41.3, 29.9; HRMS m/e for C19H22O5 calcd (5S)-5-Azido-6,7-dihydro-3,8,9,10-tetramethoxy-5H-dibenzo-
330.1467 (Mþ), found 330.1479. [a,c]cycloheptene (20e). To a suspension of 19e (0.0346 g, 0.105
(5R)-6,7-Dihydro-3,8,9,10-tetramethoxy-5H-dibenzo[a,c]cyclo- mmol), Zn(N3)2-(pyridine)2 (0.0484 g, 0.157 mmol), and triphe-
hepten-5-ol (19e). A suspension of 3-nitrophenylboronic acid (0.334 nylphosphine (0.1099 g, 0.419 mmol) in toluene (3 mL) was
g, 2.0 mmol), L-tartaric acid (0.0300 g, 2.0 mmol), and CaH2 (0.168 added diisopropyl azodicarboxylate (81 μL, 0.42 mmol) in a
g, 4.0 mmol) in THF (5 mL) was heated to reflux for 1 h. After dropwise fashion. After stirring for 4 h, the mixture was filtered
cooling and the solids were allowed to settle, the supernatant through a plug of silica gel and concentrated under reduced
solution (2.5 mL, ca. 1 mmol) was added to ketone 18e (0.0217 g, pressure. Preparative TLC (4:1 hexanes/EtOAc) afforded 20e
0.0661 mmol). Lithium borohydride (0.2 mL of a 2 M solution, 0.4 (0.0286 g, 77% yield) as a viscous oil: [R]24D -126° (c 0.663,
mmol) was added over a period of 1.5 h, and the solution stirred for CHCl3) (95% ee material as evaluated on 21); IR (KBr) νmax
0.5 h. NaOH (1 mL of a 10% aqueous solution) and water (2 mL) 2937, 2095 cm-1; 1H NMR δ 7.31 (d, J = 8.4, 1H), 7.12 (br s,
were added, and the reaction subjected to a conventional extrac- 1H), 6.94 (dd, J = 8.4, 2.7, 1H), 6.70 (s, 1H), 4.46 (m, 1H), 3.94
tive workup. Preparative TLC (1:1 petroleum ether/Et2O) af- (s, 3H), 3.91 (s, 3H), 3.905 (s, 3H), 3.900 (s, 3H), 3.01 (br m, 1H),
forded 19e (0.0213 g, 98%), 98% ee (Chiralcel AS-H, 10% i- 2.55 (m, 1H), 2.06 (m, 2H); 13C NMR (DMSO-d6) 158.8, 151.6,
PrOH/hexanes) as a viscous oil, [R]22D 102° (c 0.533); IR (KBr) 150.3, 141.0, 138.0, 134.7, 130.7, 129.9, 123.4, 112.8, 110.6 (br),
νmax 3500 br, 2936, 1646 cm-1; 1H NMR (DMSO-d6) 7.30 (d, J = 108.2, 61.4, 61.2, 60.4, 55.8, 55.2, 38.1, 21.3; MS m/e 355 (Mþ);
8.5, 1H), 7.18 (d, J = 2.5, 1H), 6.91 (dd, J = 8.5, 2.5, 1H), 5.25 (d, HRMS for C19H21N3O4 (Mþ) calcd 355.1532, found 355.1537.
J = 4.5, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), (5S)-5-Acetamido-6,7-dihydro-3,8,9,10-tetramethoxy-5H-dibenzo-
2.86 (m, 1H), 2.38 (m, 3H), 1.75-1.86 (m, 2H); 13C NMR (CDCl3) [a,c]cycloheptene (21). To a solution containing azide 20e with

8250 J. Org. Chem. Vol. 75, No. 23, 2010

Djurdjevic et al.
JOC Article
(0.0286 g, 80.5 μmol) in 100% EtOH (10 mL) saturated with H2 2.16 (m, 1H), 1.95 (m, 1H), 1.89 (s, 3H), 1.78 (m, 1H); 13C NMR
was added Lindlar catalyst (0.0109 g). The mixture was stirred (DMSO-d6) 168.6, 158.9, 151.6, 150.4, 141.4, 140.9, 135.3, 130.9,
under H2 for 20 h, filtered through Celite, and concentrated under 129.3, 123.7, 111.3, 110.1, 108.3, 61.5, 60.4, 55.9, 55.1, 48.4, 22.7,
reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) 21.9; (a resonance at 40.0 in CDCl3 is obscured in DMSO-d6); MS
and cooled to 0 °C, and acetic anhydride (0.2 mL) and pyridine (0.2 m/e 371 (Mþ); HRMS for C21H25NO5 (Mþ) calcd 371.1733,
mL) were added. The mixture was allowed to stir for 12 h with found 371.1740.
gradual warming to room temperature. Concentration under
reduced pressure, followed by preparative TLC (19:1 CH2Cl2/ Acknowledgment. The authors are grateful to NSERC
MeOH) afforded 21 (0.0237 g, 79% yield) in 95% ee (Chiralcel (Canada), the Canada Foundation for Innovation (CFI),
OD-H, 10% i-PrOH/hexanes). A single recrystallization afforded and the Ontario Innovation Trust (OIT) for support of this
21 of >99% ee, as colorless crystals: mp 186-188 °C (Et2O/ research.
hexanes); [R]22D -52.4° (c 0.783, CHCl3); IR (KBr) νmax 3288 br,
2936, 1664 cm-1; 1H NMR (DMSO-d6) 8.41 (d, J = 8.4, 1H), 7.32 Supporting Information Available: 1H and 13C spectra for all
(d, J = 8.1, 1H), 6.88-6.94 (m, 2H), 6.79 (s, 1H), 4.51 (m, 1H), new compounds. This material is available free of charge via the
3.85 (s, 3H), 3.79 (s, 6H), 3.78 (s, 3H), 2.91 (dd, J = 13.2, 6.0, 1H), Internet at http://pubs.acs.org.

J. Org. Chem. Vol. 75, No. 23, 2010 8251