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Efficient Synthesis of Pyrimido[1,2-c] (SAR) of PD 404182 has not been carried out, presumably due to
[1,3]benzothiazin-6-imines and Related Tricyclic the lack of an efficient synthetic method suitable for lead optimiza-
tion, as well as the cost of commercially available PD 404182.3
Heterocycles by SNAr-Type C-S, C-N, or C-O To develop a reliable, short-step synthetic method of
Bond Formation with Heterocumulenes tricyclic heterocycles related to PD 404182, we planned a
novel strategy based on carbon (sp2)-heteroatom bond
Tsukasa Mizuhara, Shinya Oishi, Nobutaka Fujii,* and formation using 2-(2-haloaryl)tetrahydropyrimidine deriva-
Hiroaki Ohno* tives. The carbon-heteroatom bond formation reaction is
becoming a powerful methodology for construction of var-
Graduate School of Pharmaceutical Sciences, Kyoto
University, Sakyo-ku, Kyoto 606-8501, Japan ious heterocycles, providing several biologically active com-
pounds.4 The nucleophilic aromatic substitution (SNAr)
nfujii@pharm.kyoto-u.ac.jp; hohno@pharm.kyoto-u.ac.jp reaction is a well-established transition metal-free5,6 car-
bon-heteroatom bond formation reaction.7,8 In general,
Received October 30, 2009 the SNAr reaction requires harsh conditions (>100 °C)
and/or sufficiently activated aromatic rings by powerful
electron-withdrawing group(s) (e.g., nitro). We describe a
direct synthesis of tricyclic heterocycles related to PD 404182
by a regioselective SNAr-type reaction of tetrahydropyrimi-
dine-substituted haloarenes with heterocumulene in the
absence of additional electron-withdrawing groups.9 The
efficient short-step synthesis of PD 404182 is also presented.

(3) $76.20/2 mg, Sigma-Aldrich.

A simple and practical synthetic method of pyrimido[1,2-c]- (4) For reviews on transition metal-catalyzed carbon-heteroatom bond
formation, see: (a) Hartwig, J. F. Synlett 1997, 329–340. (b) Baranano, G.
[1,3]benzothiazin-6-imines and related tricyclic hetero- M.; Hartwig, J. F. Curr. Org. Chem. 1997, 1, 287–305. (c) Hartwig, J. F.
cycles has been developed. Treatment of 2-(2-haloaryl)- Angew. Chem., Int. Ed. 1998, 37, 2046–2067. (d) Hartwig, J. F. Acc. Chem.
Res. 1998, 31, 852–860. (e) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
tetrahydropyrimidines with NaH and a heterocumulene Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818. (f) Hartwig, J. F. Pure
such as carbon disulfide, isothiocyanates, and isocyanates Appl. Chem. 1999, 71, 1417–1423. (g) Yang, B. Y.; Buchwald, S. L. J.
in DMF provides the desired cyclization products through a Organomet. Chem. 1999, 576, 125–146. (h) Hassan, J.; Sevingnon, M.; Gozzi,
C.; Shulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1469. (i) Muci, A. R.;
regioselective SNAr-type reaction. This method provides Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209. (j) Littke, A. F.; Fu, C.
direct access to PD 404182 and related compounds. C. Angew. Chem., Int. Ed. 2002, 41, 4177–4211. (k) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
(5) Separation of the transition metal catalyst sometimes can be proble-
matic during the synthesis of pharmaceuticals and fine chemicals because of
their residual toxicity. For recent examples on transition metal-free car-
bon-heteroatom bond formation via benzyne intermediate, see: (a) Shi, L.;
The pyrimidobenzothiazine derivative PD 404182 (1) was Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515–
recently discovered to be an antibiotic agent (Figure 1).1,2 3517. (b) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673–4675. (c) Narayan,
S.; Seelhammer, T.; Gawley, R. E. Tetrahedron Lett. 2004, 45, 757–759. (d)
Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99–102. (e) Liu, Z.; Larock, R. J.
Org. Chem. 2006, 71, 3198–3209. (f) Bolliger, J. L.; Frech, C. M. Tetrahedron
2009, 65, 1180–1187.
(6) (a) Carroll, M. A.; Wood, R. A. Tetrahedron 2007, 63, 11349–11354.
(b) Rey, V.; Soria-Castro, S. M.; Arguello, J. E.; Penenory, A. B. Tetrahedron
Lett. 2009, 50, 4720–4723.
(7) For reviews on nucleophilic aromatic substitution reaction, see: (a)
Bunnet, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273–412. (b) Buncel, E.;
FIGURE 1. Structure of PD 404182. Dust, J. M.; Terrier, F. Chem. Rev. 1995, 95, 2261-2280 and references cited
therein.
This compound inhibits 3-deoxy-D-manno-octulosonic acid (8) For recent examples on nucleophilic aromatic substitution reaction,
8-phosphate (KDO 8-P) synthase, which catalyzes the condensa- see: (a) Annulli, A.; Mencarelli, P.; Stegel, F. J. Org. Chem. 1984, 49, 4065–
4067. (b) Gorvin, J. H. J. Chem. Soc., Perkin Trans. 1 1988, 1331–1335. (c)
tion of phosphoenolpyruvate and arabinose 5-phosphate in the first Raeppel, S.; Raeppel, F.; Suffert, J. Synlett 1998, 794–796. (d) Ratz, A. M.;
committed step in the synthesis of KDO (an integral part of the Weigel, L. O. Tetrahedron Lett. 1999, 40, 2239–2242. (e) Rogers, J. F.; Green,
D. M. Tetrahedron Lett. 2002, 43, 3585–3587. (f) Grecian, S. A.; Hadida, S.;
lipopolysaccharide layer in Gram-negative bacteria). PD 404182 is Warren, S. D. Tetrahedron Lett. 2005, 46, 4683–4685. (g) Barbero, N.;
considered to be an important lead in the development of struc- SanMartin, R.; Domı́nguez, E. Tetrahedron 2009, 65, 5729–5732.
turally novel antibiotics effective against multidrug-resistant (9) For related reactions of electron-deficient haloarenes with carbon
disulfide, see: (a) D’Amico, J. J.; Tung, C. C.; Dahl, W. E.; Dahm, D. J. J.
bacteria.2b Extensive study of the structure-activity relationship Org. Chem. 1976, 41, 3564–3568. (b) Leymarie-Beljean, M.; Pays, M.; Richer,
J.-C. J. Heterocycl. Chem. 1980, 17, 1175–1179. (c) Anderson-McKay, J. E.;
Liepa, A. J. Aust. J. Chem. 1987, 40, 1179–1190. (d) Easmon, J.; Heinisch, G.;
(1) Birck, M. R.; Holler, T. P.; Woodard, R. W. J. Am. Chem. Soc. 2000, Hofmann, J.; Langer, T.; Grunicke, H. H.; Fink, J.; P€ urstinger, G. Eur. J.
122, 9334–9335. Med. Chem. 1997, 32, 397–408. (e) Kitson, T. M. Bioorg. Chem. 2000, 27, 73–
(2) (a) Golebiowski, A.; Klopfenstein, S. R.; Portlock, D. E. Curr. Opin. 88. (f ) Kobayashi, K.; Komatsu, T.; Konishi, H. Heterocycles 2009, 78,
Chem. Biol. 2001, 5, 273–284. (b) Sansom, C. Drug Discov. Today 2001, 6, 2559-2564. For a copper-catalyzed reaction with carbon disulfide, see: (g)
499–500. Murru, S.; Ghosh, H.; Sahoo, S. K.; Patel, B. K. Org. Lett. 2009, 11, 4254–4257.

DOI: 10.1021/jo902327n Published on Web 12/08/2009 J. Org. Chem. 2010, 75, 265–268 265
r 2009 American Chemical Society
JOC Note Mizuhara et al.

TABLE 1. Optimization of Reaction Conditions with CS2a TABLE 2. Reaction of Substituted 2-(2-Halophenyl)-1,4,5,6-tetrahy-
dropyrimidinesa

entry X base (equiv) solvent time (h) yield (%)b

1 Br NaH (5) MeCN 4 trace
2 Br NaH (5) THF 4 trace
3 Br NaH (5) DMF 6 75
4 Br NaH (2) DMF 12 88
5 Br none DMF 12 12
6 Br Et3N (2) DMF 12 trace
7 Br KH (2) DMF 6 trace
8 Br NaOt-Bu (2) DMF 6 27
9 F NaH (2) DMF 12 86
a
All reactions were carried out at 80 °C with 2 or 5 equiv of CS2
(corresponding to the base loading). bIsolated yields.

Initial experiments were carried out with bromoarene 2aa,

which can be readily obtained by oxidative amidination10 of 2-
bromobenzaldehyde with propanediamine, and carbon disul-
fide as a heterocumulene (Table 1). Exposure of 2aa with
sodium hydride (5.0 equiv) and carbon disulfide (5.0 equiv) in
acetonitrile or THF afforded only a trace amount of desired
compound 3a (entries 1 and 2). The desired reaction was effi-
ciently promoted in DMF to give 3a in 75% yield (entry 3). A
decreasing amount of sodium hydride and carbon disulfide
(2.0 equiv) slightly improved the yield of 3a (88%) under the
reaction for 12 h (entry 4).11 The reaction in the absence of
sodium hydride provided a yield of 3a of only 12%. We next
screened several bases such as triethylamine, potassium
hydride12 and sodium tert-butoxide (entries 6-8): sodium
hydride was the most effective (entry 4). The fluoride 2ab gave a
Unless otherwise stated, reactions were carried out with CS2 (2.0
a comparable result with the bromide 2aa to afford 3a in 86% equiv) and NaH (2.0 equiv) in DMF at 80 °C for 12 h. bIsolated yields. cA
yield under optimized conditions (entry 9). complex mixture formed. dYields in parentheses indicate those of the
reactions at rt.
With knowledge of the optimized conditions, we examined
the reaction of several substituted substrates (Table 2).
Substrates 2b-d having a methoxy, methyl, or fluoro group naphthalene derivative 8 afforded the tetracyclic compound 9
at the 4-position provided the corresponding cyclized pro- in quantitative yield (entry 9).
ducts 3b-d in good-to-excellent yields (76-95%, entries To further expand our methodology for construction of
1-3). Whereas the reaction of 2e bearing the 4-nitro group other heterocyclic frameworks, we investigated the reaction
at 80 °C resulted in formation of a complex mixture, the using isothiocyanates or isocyanates13,14 as heterocumulene
reaction at room temperature gave the cyclization product 3e (Table 3). When benzylisothiocyanate was employed, the
in 73% yield (entry 4). A methoxy group on the 5-position reaction of 2aa or 2ab efficiently proceeded to give the
considerably diminished the reactivity, affording 3f in only corresponding N-arylated product 10 in 82% and 97%
17% yield (entry 5). This was presumably due to increased yields, respectively (entries 1 and 2). The reaction with tert-
electron density at the carbon substituted by a bromine butylisothiocyanate exclusively furnished an S-arylated pro-
atom. In the case of 2g bearing a 5-nitro group, the corre- duct 11 as a single isomer (entry 3). These results indicate
sponding product 3g was obtained by the reaction at room
temperature (entry 6), similarly to 2e (entry 4). Pyridine (13) For related reactions of electron-deficient (haloaryl)isothiocyanates,
derivatives 4 and 6 showed different reactivity depend- see: (a) Muthusamy, S.; Paramasivam, R.; Ramakrishnan, V. T. J. Hetero-
ing on the position of the nitrogen atom: the 2-bromo- cycl. Chem. 1991, 28, 759–763. (b) Zambounis, J. S.; Christen, E.; Pfeiffer, J.;
Ribs, G. J. Am. Chem. Soc. 1994, 116, 925–931. (c) Huang, S.; Connolly, P. J.
pyridine derivative 6 gave a better result (71%, entry 8) Tetrahedron Lett. 2004, 45, 9373–9375.
than the 3-bromopyridine derivative 4 (18%, entry 7). The (14) For related transition metal-catalyzed reactions, see: (a) Ferraccioli,
R.; Carenzi, D. Synthesis 2003, 1383–1386. (b) Benedı́, C.; Bravo, F.; Uriz, P.;
Fern andez, E.; Claver, C.; Castill
on, S. Tetrahedron Lett. 2003, 44, 6073–
(10) Ishihara, M.; Togo, H. Tetrahedron 2007, 63, 1474–1480. 6077. (c) Yang, D.; Liu, H.; Yang, H.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y.
(11) Larger amounts of unidentified byproduct were formed when using 5 Adv. Synth. Catal. 2009, 351, 1999–2004. (d) Murru, S.; Mondal, P.; Yella,
equiv of NaH than in the reaction with 2 equiv of NaH (entry 4). R.; Patel, B. K. Eur. J. Org. Chem. 2009, 5406–5413. (e) Qiu, J.-W.; Zhang,
(12) A reason for the significant countercation effect (NaH vs. KH) on the X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Adv. Synth. Catal. 2009, 351, 2319–
reactivity is unclear. 2323. (f ) Shen, G.; Lv, X.; Bao, W. Eur. J. Org. Chem. 2009, 5897–5901.

266 J. Org. Chem. Vol. 75, No. 1, 2010

Mizuhara et al.
JOC Note
TABLE 3. Reaction with Isothiocyanates or Isocyanatesa SCHEME 1. Proposed Reaction Mechanisms

SCHEME 2. Synthesis of PD 404182

the heterocumulene may be involved in the reaction to form

the intermediate C in which the amidine moiety can be a
more powerful electron-withdrawing group suitable for the
SNAr-type reaction. The regioselectivity in the nucleophilic
attack on the aromatic ring (Y vs. Z) is controlled by a subtle
balance of inherent nucleophilicity and steric hindrance of
these functionalities.
We finally focused on the synthesis of PD 404182 (1)
(Scheme 2). Hydrolysis of the carbamodithioate derivative
3a followed by treatment with cyanogen bromide15 readily
afforded the desired compound 1. The same compound was
a
Unless otherwise stated, reactions were carried out with R-NCX (2.0 also obtained in a single step by heating compound 11 in
equiv) and NaH (2.0 equiv) in DMF at rt for 2-3 h. bIsolated yields. trifluoroacetic acid in the presence of molecular sieves.
c
These reactions were carried out at 80 °C. dA trace amount of
regioisomeric N-arylation product was also formed. eIsolated as a single In conclusion, we developed a simple and practical syn-
isomer. thetic method for tricyclic heteroarenes related to PD
404182. This reaction provides divergent access to several
that the regioselectivity of the reaction can be perfectly related heterocycles under mild conditions without a power-
switched by changing a substituent on the nitrogen atom. ful activating group. Further investigations including SAR
As expected, the reaction of 2ab with benzylisocyanate study of these derivatives are currently underway.
provided an N-arylated product 12 in quantitative yield
(entry 4) as in the case with isothiocyanate (entries 1 and 2). Experimental Section
Interestingly, tert-butylisocyanate showed moderate selec-
General Procedure for Synthesis of 3,4-Dihydro-2H-pyrimido-
tivity to mainly afford an N-arylation product 13 (54%), [1,2-c][1,3]benzothiazine-6-thione (3a) (Table 1, Entry 4). To a
formed by the arylation at the more bulky position, as well mixture of 2aa (59.8 mg, 0.25 mmol) and NaH (20.0 mg, 0.50
as an O-arylation product 14 (18%, entry 5). Phenylisocya- mmol; 60% oil suspension) in DMF (0.83 mL) was added
nate also provided an N-arylated product 15 (entry 6). The carbon disulfide (30.5 μL, 0.50 mmol) under an Ar atmosphere.
2-phenylimidazoline derivative 16 (a 5-membered-ring ami- After being stirred at 80 °C for 12 h, the mixture was concen-
dine congener) also provided the corresponding S-arylated trated in vacuo. The residue was purified by flash chromatog-
product 17 in a slightly decreased yield (49%, entry 7). raphy over silica gel with n-hexane-EtOAc (9:1) to give
This reaction would proceed via nucleophilic addition of compound 3a as a pale-yellow solid (51.4 mg, 88%): mp
the amidine moiety to heterocumulene followed by an in- 139-141 °C (from CHCl3-n-hexane); IR (neat) (cm-1) 1624
tramolecular SNAr reaction of the resulting adducts such as (CdN); 1H NMR (400 MHz, CDCl3) δ 2.01-2.07 (m, 2H,
B (Scheme 1). Nonactivated aromatic rings efficiently re-
acted under relatively mild conditions, so two molecules of (15) Peter, S.; Gerhard, S. Ger. Offen. DE2811131, 1979.

J. Org. Chem. Vol. 75, No. 1, 2010 267

JOC Note Mizuhara et al.

CH2), 3.76 (t, J = 5.6 Hz, 2H, CH2), 4.45 (t, J = 6.2 Hz, 2H, from the Ministry of Education, Culture, Sports, Science and
CH2), 7.03 (dd, J = 7.8, 1.5 Hz, 1H, Ar), 7.28-7.33 (m, 1H, Ar), Technology of Japan, the Program for Promotion of Funda-
7.41 (ddd, J = 8.0, 7.6, 1.5 Hz, 1H, Ar), 8.20 (dd, J = 8.0, 1.2 Hz, mental Studies in Health Sciences of the National Institute of
1H, Ar); 13C NMR (125 MHz, CDCl3) δ 21.6, 45.5, 48.6, 121.6, Biomedical Innovation (NIBIO), and Targeted Proteins
126.5, 127.5, 128.9, 131.1, 131.8, 144.2, 189.8. Anal. Calcd for Research Program.
C11H10N2S2: C, 56.38; H, 4.30; N, 11.95. Found: C, 56.23; H,
4.44; N, 11.85.
Supporting Information Available: Experimental proce-
dures, full characterization, and 1H and 13C NMR charts of
Acknowledgment. This work was supported by a Grant- substrates and cyclization products. This material is available
in-Aid for Encouragement of Young Scientists (A) (H.O.) free of charge via the Internet at http://pubs.acs.org.

268 J. Org. Chem. Vol. 75, No. 1, 2010