pubs.acs.

org/joc

Synthesis of Enantiopure 3-Substituted Morpholines hydroxylation.5 However, the number of easily accessible en-
antiopure β-amino alcohols are still limited so new strategies are
Jan Bornholdt,† Jakob Felding,‡ and continuously being developed.
Jesper Langgaard Kristensen*,† Herein, we wish to describe a novel approach to enantiopure
3-substituted morpholines based on the strategy outlined in
†
Department of Medicinal Chemistry, University of Figure 1. Regioselective and stereospecific ring-opening of a
Copenhagen, Universitetsparken 2, Copenhagen DK-2100, suitably functionalized aziridine with organocuprates should
Denmark, and ‡LEO Pharma, Industriparken 55, provide N-sulfonyl-protected β-amino alcohols6 that would be
Ballerup DK-2750, Denmark directly applicable in the synthesis of morpholines as described
by Yar et al.3,4
jekr@farma.ku.dk
Received August 1, 2010

FIGURE 1. Retrosynthetic approach to substituted morpholines.

We envisioned that enantiopure methyl 1-tritylaziridine-2-
carboxylate 1 would be a convenient starting point for the
synthesis of the chiral morpholines since both enantiomers of
1 are commercially available or readily prepared on large
scale (>100 g) from D- or L-serine in three high yielding steps
without chromatographic purification.7
Enantiopure 3-substituted morpholines were assembled Different groups have been employed for the activation of
through ring-opening of a N-2-benzothiazolesulfonyl aziridines,8 but this is most effectively done with sulfon-
(Bts) activated aziridine with organocuprates followed by amides like the tosyl group due to its electron-withdrawing
a ring annulation reaction with a vinylsulfonium salt nature.9-11 Although progress has been made toward the
under microwave conditions. Deprotection of the N-Bts development of new protocols for the deprotection of the
group proceeds under very mild conditions with 2- tosyl group,12 this transformation often requires quite harsh
mercaptoacetic acid and LiOH at rt. conditions like strong acids or dissolving metal reductions.
The 2- and 4-nitrobenzenesulfonyl (nosyl) groups introduced
by Fukuyama have been very well accepted by the synthetic
The morpholine moiety has found widespread use in medic- community.13,14 The most important feature of the nosyl group
inal chemistry, and many drugs contain this subunit.1 Due to (compared to the tosyl group) is that the amines can be liberated
the eletronegativity of oxygen, morpholine is a weaker base under very mild conditions with thiolates. However, the electro-
than, e.g., piperidine, which often provides improved physio- philic nature of the nitro group limits the types of reagents which
chemical properties.1 Although it is a very popular building are compatible with the nosyl group, in particular, organo-
block in drug discovery, the number of commercially available metallic and strongly reducing agents. We recently reported
substituted morpholines is quite limited. Synthetic routes to a study where heterocyclic sulfonamides were screened for their
substituted morpholines usually involve β-amino alcohols that ability to activate 2-methylaziridine toward ring-opening
are cyclized into 3-oxomorpholines and reduced.2 Recently, Yar while still being easily cleavable with thiolates.15 From that
et al. reported an improved procedure in which vinyl- and investigation, the 2-pyrimidinesulfonyl (pymisyl) group and
2-bromoethylsulfonium salts are used for the direct conver- the 2-benzothiazolesulfonyl (Bts) groups emerged as potential
sion of N-sulfonyl-protected β-amino alcohols into N-sulfonyl-
protected morpholines.3,4 Enantiopure β-amino alcohols can be (5) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326.
accessed through the chiral pool of amino acids or a number of (6) Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1997, 62, 2671.
(7) Compound 1 can be prepared from serine by formation of the methyl
different asymmetric methodologies like the Sharpless amino- ester with acetyl chloride in methanol, N-tritylation with trityl chloride and
Et3N, and finally one-pot O-mesylation and intramolecular aziridine ring
(1) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; formation by methanesulfonyl chloride and Et3N; see the Supporting
Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641. Information for references.
(2) (g) Henegar, K. E.; Cebula, M. Org. Process Res. Dev. 2007, 11, 354. (8) Hu, X. E. Tetrahedron 2004, 60, 2701.
For other recent approaches towards morpholines, see: (a) Dave, R.; Sasaki, (9) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney, J. B. Tetra-
N. A. Org. Lett. 2004, 6, 15. (b) Lanman, B. A.; Meyers, A. G. Org. Lett. hedron 1993, 49, 6309.
2004, 6, 1045. (c) Wilkinson, M. C.; Bell, R.; Landon, R.; Nikiforov, P. O.; (10) Church, N. J.; Young, D. W. Tetrahedron Lett. 1995, 36, 151.
Walker, A. J. Synlett 2006, 2151. (d) Penso, M.; Lupi, V.; Albanese, D.; (11) Beresford, K. J. M.; Church, N. J.; Young, D. W. Org. Biomol. Chem.
Foschi, F.; Landini, D.; Tagliabue, A. Synlett 2008, 2451. (e) Ghorai, M. K.; 2006, 4, 2888.
Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013. (f) Ritzen, B.; Hoekman, (12) Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503.
S.; Verdasco, E. D.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2010, 75, (13) Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995, 36,
3461. 6373.
(3) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. (14) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
2008, 47, 3784. (15) Bornholdt, J.; Felding, J.; Clausen, R. P.; Kristensen, J. L. Chem.;
(4) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257. Eur. J. 2010, in press. DOI: 10.1002/chem.201001026.

7454 J. Org. Chem. 2010, 75, 7454–7457 Published on Web 09/29/2010 DOI: 10.1021/jo101339g
r 2010 American Chemical Society
Bornholdt et al.
JOC Note
TABLE 1. Four-Step Synthesis of 3-Substituted Morpholines Starting from 3

entry R= product yielda (%) product yielda (%) product yielda (%) product yieldb (%)
1 Me- 4a 91 5a 83 6a 83 7a 81c
2 Et- 4b 66 5b 92 6b 86 7b 74
3 vinyl- 4c 87 5c 83 6c 75 7c 75
4 cyclopropyl- 4d 86 5d 91 6d 76 7d 57
5 Ph- 4e 87 5e 89 6e 76 7e 75
6 4-MeO-Ph- 4f 70 5f 90 6f 72 7f 78
a
Isolated yields after chromatographic purification. bIsolated yields after aqueous work up and precipitation with oxalic acid. cIsolated as a mixture of
hydrogenoxalate and oxalate salts.

nosyl surrogates with the noteworthy addition of being protected β-amino alcohols 5a-f were isolated in 82-93%
compatible with organocuprate reagents. In this study, the yield.
pymisyl performed better than the Bts group, and therefore, Subsequently, ring formation to the corresponding mor-
it was initially tested in the sequence outlined in Figure 1. The pholines using vinyldiphenylsulfonium triflate as described
ring-opening with organocuprate reagents worked well, giv- by Yar et al.3 was attempted. When the reaction mixture was
ing the desired products in 83-89% yield. However, depro- allowed to stir overnight at rt, low conversion was observed.
tection of the TBS group was accompanied by the formation LC-MS confirmed that the reaction proceeded in two
of byproducts, and the yield of the pymisyl protected β- discrete steps; the first being addition of the deprotonated
amino alcohols was low. Numerous different conditions sulfonamide to the vinylsulfonium ion forming a new sulfo-
were tested, but the formation of byproduct could not be nium salt; see Scheme 2.
suppressed and instead we turned our attention to the Bts
SCHEME 2. Observed Intermediate in the Morpholin Synthesis
group.16
SCHEME 1. Synthesis of Bts-Protected Aziridine 3 from 1

This proceeded within 1 h at 0 °C, but the subsequent ring

closure via extrusion of diphenyl sulfide proved to be very slow
The key Bts-protected aziridine 3 was accessed from 1 as at ambient temperature, and several days were required to
outlined in Scheme 1. Reduction of 1 with LiAlH4 followed obtain full conversion. Microwave heating (90 °C in CH2Cl2 at
by O-silylation of the resulting alcohol with TBSCl gave 2 in 3-4 bar) considerably shortened the reaction times, and under
88% yield. Subsequently, the trityl group was removed with these conditions, only 15-20 min was required to reach full
TFA/Et3SiH followed by treatment of the aziridinium salt conversion. Subsequently, the Bts-protected morpholines 6a-f
with BtsCl which provided the desired building block 3 in were isolated in 72-86% yield; see Table 1. We propose that
50% yield from 2 after recrystallization. microwave heating will also prove beneficial to the annulation
The CuBr 3 Me 2S catalyzed ring-opening of 3 with reaction of other N-sulfonylated β-amino alcohols and signifi-
Grignard reagents was attempted. Alkyl, vinyl, cyclopropyl, cantly shorten reaction times.
and aryl Grignard reagents worked well in analogy with the To verify that the stereochemical integrity was preserved
results obtained with the pymisyl-protected aziridine. Thus, in the sequence from serine to the 3-substituted morpholines,
the desired products 4a-f were isolated in 66-91% yield, compound 6e was compared with a racemic sample using
see Table 1. To our delight, the removal of the TBS group chiral HPLC. To our delight, only a single enantiomer could
was not compromised by the same problems that plagued be detected; see the Supporting Information for details.
the pymisyl-protected products.16 Deprotection proceeded Finally, the Bts group was removed under very mild
smoothly with both TBAF in THF and 40% HF in CH3CN, conditions with 2-mercaptoacetic acid and lithium hydro-
the latter being preferred due to ease of work up, and the Bts xide in DMSO17 at rt. The free morpholines were extracted
into Et2O and precipitated with anhydrous oxalic acid to
(16) Full experimental details on the ring opening of the pymisyl-pro- yield the pure morpholines 7a-f as hydrogenoxalate salts in
tected aziridine is provided in the Supporting Information, including details
of the unfruitful attempts to deprotect the TBS-group from the pymisyl-
57-78% yield. The overall yield of the morpholines from the
protected amino alcohols. The resulting N-pymisyl protected amino alcohols key intermediate 3 is in the range of 34-51% over four steps.
are not stable and presumably decompose via Smiles-type rearrangements.
See: (a) Kleb, K. G. Angew. Chem., Int. Ed. 1968, 7, 291. (b) Truce, W. E.;
Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99. (c) Wang, H. Y.; Liao, (17) The use of DMF as solvent gave morpholines contaminated with
Y. X.; Guo, Y. L.; Tang, Q. H.; Lu, L. Synlett 2005, 8, 1239. small amounts of dimethylammonium oxalates.

J. Org. Chem. Vol. 75, No. 21, 2010 7455

JOC Note Bornholdt et al.

SCHEME 3. Synthesis and Stability of BtsCl and BtsOPFPa opened byproduct and some triethylsilyl-containing byproduct.
Recrystallization from methanol by dissolving it in 40 °C warm
methanol and cooling to -78 °C afforded 3 (3.30 g, 50%) as a
slightly rose-colored solid: mp 56.5-57.5 °C; [R]20D = -32.0 (c
1.10, EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.31-8.20 (m, 1H),
8.05-7.95 (m, 1H), 7.69-7.54 (m, 2H), 3.84-3.72 (m, 2H),
3.31-3.19 (m, 1H), 2.93 (d, J = 7.0, 1H), 2.50 (d, J = 4.8, 1H),
0.80 (s, 9H), -0.02 (s, 3H), -0.04 (s, 3H); 13C NMR (75 MHz,
a
Key: (a) NaOCl, HCl, CH 2 Cl2 , -10 °C;20 (b) HOPFP, Et3 N, CDCl3) δ 163.1, 152.5, 137.0, 128.2, 127.7, 125.8, 122.3, 61.8, 42.2,
CH 2 Cl2, -30 °C.21
32.2, 25.8, 18.4, -5.3, -5.4; HRMS calcd for C16H25N2O3S2Si
The very mild conditions used for the deprotection highlight [M þ H] 385.1075, found 385.1061.
the advantage of using the Bts-group. BtsCl, originally intro- General Procedure for Ring-Opening of 3 with Grignard
Reagents: Synthesis of (S)-N-(1-(tert-Butyldimethylsilyloxy)-
duced by Vedejs,18 is readily prepared from inexpensive19 pentan-2-yl)benzo[d]thiazole-2-sulfonamide (4b). Copper(I) bro-
2-mercaptobenzothiazole (8) using NaOCl as the oxidant;20 mide dimethyl sulfide (72 mg, 0.35 mmol) was added to a flame-
see Scheme 3. BtsCl can be stored for several months in the dried Schlenk flask under argon. Dry THF (14 mL) was added,
freezer with minimal deterioration. Alternatively, BtsCl can be and the slurry was stirred at rt for 15 min and then cooled to
converted to the corresponding pentafluorophenyl sulfonate -55 °C (externally). Ethylmagnesium bromide (3.10 mL,
ester (BtsOPFP) (10), which is stable at rt and reacts readily with 0.97 M, 3.00 mmol) in THF was added dropwise at -55 °C.
primary and secondary amines to form the corresponding Bts- The resulting mixture was stirred at -55 to -50 °C for 30 min
protected amines in very high yields.21 Most importantly, the and then cooled to -78 °C. Compound 3 (769 mg, 2.00 mmol) in
Bts group is readily removed under mild conditions using dry THF (3.5 mL) was added dropwise by syringe. The reaction
thiolates,22 analogously to the nosyl group. Thus, the Bts group mixture was stirred at -78 °C for 1 h and then quenched with
8 mL of an aqueous (NH4)2SO4/NH3 solution (1 mol of (NH4)2SO4
should be applicable in many other settings where the tosyl and and 30 mL of 25% NH4OH diluted to 500 mL with water) at
nosyl groups currently are being used. -78 °C and then allowed to warm to rt. The mixture was
In conclusion, we have developed a new Cu-catalyzed transferred to a 100 mL flask, and the THF was removed in vacuo.
ring-opening of an N-Bts activated aziridine with Grignard The aqueous residue was extracted with ether (1  25 mL and 2 
reagents. Subsequent ring annulation and deprotection 15 mL), and the combined organic phases were washed with 0.05 M
under mild conditions provided enantiopure 3-substituted Na2EDTA (10 mL) and brine (20 mL), dried with Na2SO4, filtered,
morpholines. This efficient protocol can be used to access and concentrated in vacuo. The residue was purified by FC on silica
both enantiomers of 3-substituted morpholines, not directly (EtOAc/PE, 0:100-1:3) to afford 4b (545 mg, 66%) as a colorless
accessible from the chiral pool of amino acids. solid: mp 49.5-50.5 °C; [R]20D = -10.2 (c 1.07, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 8.19-8.13 (m, 1H), 8.00 -7.94 (m, 1H),
Experimental Section 7.65-7.51 (m, 2H), 5.25 (d, J = 8.4, 1H), 3.71-3.48 (m, 3H),
1.61-1.50 (m, 2H), 1.47-1.23 (m, 2H), 0.87 (t, J = 7.3, 3H), 0.81
(S)-2-(2-((tert-Butyldimethylsilyloxy)methyl)aziridin-1-ylsul- (s, 9H), -0.05 (s, 3H), -0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
fonyl)benzo[d]thiazole (3). Trifluoroacetic acid (5.51 mL, 72 mmol) 167.0, 152.6, 136.6, 127.7, 127.5, 125.3, 122.3, 64.3, 56.1, 34.5, 25.9,
was added dropwise by syringe to a stirred solution of 2 (7.73 g, 19.0, 18.4, 13.9, -5.5; HRMS calcd for C18H31N2O3S2Si [M þ H]
18 mmol) and triethylsilane (11.5 mL, 72 mmol) in dry CH2Cl2 415.1545, found 415.1532.
(90 mL) at -5 °C under argon. The mixture was stirred 2.5 h at General Procedure for the Deprotection of the TBS Group
-5 to þ4 °C until TLC showed full consumption of the starting Exemplified by the Synthesis (S)-N-(1-Hydroxypentan-2-yl)benzo-
material. The reaction mixture was poured into cold 2 M K2CO3 (90 [d]thiazole-2-sulfonamide (5b). HF (87 μL, 40%, 1.23 mmol,
mL) under vigorous stirring. The layers were separated, and the 1.5 equiv) was added to a stirred solution of 4b (415 mg, 1.30
aqueous layer was extracted with ether (2  30 mL). The combined mmol) in acetonitrile (2.3 mL) cooled to 0 °C in an ice bath. The
organic layers were concentrated in vacuo to remove the CH2Cl2. mixture was stirred 30 min at 0 °C and then at ambient
The residue was dissolved in EtOAc (80 mL), 2 M K2CO3 (35 mL) tempratue for 2 h while the reaction progress was moni-
was added, and the mixture was cooled to 0 °C in an ice bath. Solid tored by TLC and UPLC-MS. The reaction mixture was then
benzothiazole-2-sulfonyl chloride (BtsCl) (4.00 g, 17.1 mmol) was neutralized with satd NaHCO3 and concentrated in vacuo to
added in small portions under vigorous stirring. After 2 h at 0 °C, remove acetonitrile. The residue was partitioned between brine
the mixture was allowed to warm to rt. Excess BtsCl was quenched (10 mL) and EtOAc (15 mL). The aqueous layer was extracted
with 25% NH4OH (2  200 μL) until TLC showed full conversion. with EtOAc (2  15 mL). The combined organic layers were
The reaction mixture was then diluted with EtOAc (20 mL), and the washed brine (10 mL), dried over Na2SO4, and concentrated in
layers were separated. The aqueous layer was extracted with ether vacuo. The solid residue was purified by FC on silica (EtOAc/
(40 mL). The combined organic layers were washed with 0.5 M PE, 7:13) to afford the title compound 5b as a colorless solid (361
NaH2PO4 (40 mL), water (40 mL), and satd Na2SO4 (40 mL), dried mg, 92%): mp 136-137 °C; [R]20D = þ4.5 (c 1.00, EtOAc); 1H
over Na2SO4, filtered, and concentrated in vacuo. The residue was NMR (300 MHz, CDCl3) δ 8.12-8.06 (m, 1H), 7.98-7.93 (m,
purified by flash chromatography (FC) on silica (EtOAc/PE, 5:95 to 1H), 7.62-7.51 (m, 2H), 5.74 (d, J = 8.1, 1H), 3.80-3.65 (m,
14:86) providing 4.96 g of material containing 3% of a chloride ring 2H), 3.57 (dd, J = 5.7, 11.8, 1H), 3.26 (s, 1H), 1.61-1.50 (m,
2H), 1.49-1.28 (m, 2H), 0.88 (t, J = 7.2, 3H); 13C NMR (75
(18) Vedejs, E.; Lin, S. Z.; Klapars, A.; Wang, J. B. J. Am. Chem. Soc. MHz, CDCl3) δ 167.9, 151.6, 136.4, 127.9, 127.7, 124.9, 122.4,
1996, 118, 9796.
(19) 2-Mercaptobenzothiazole is used on large scale in several industrial
64.6, 57.4, 34.5, 19.0, 13.8; HRMS calcd for C12H17N2O3S2
settings, among them as a vulcanizing agent in the rubber and latex industry. [M þ H] 301.0681, found 301.0693.
Thus, 2-mercaptobenzothiazole is readily available at very low cost. General Procedure for the Annulation Reaction: Synthesis of
(20) Wright, S. W.; Hallstrom, K. N. J. Org. Chem. 2006, 71, 1080. (S)-3-Propyl-4-(benzo[d]thiazol-2-ylsulfonyl)morpholine (6b). To
(21) Bornholdt, J.; Fjaere, K. W.; Felding, J.; Kristensen, J. L. Tetra-
hedron 2009, 65, 9280.
a 20 mL capped microwave vial under argon was added triethyl-
(22) Wuts, P. G. M.; Gu, R. L.; Northuis, J. M.; Thomas, C. L. Tetra- amine (600 μL, 4.26 mmol, 4 equiv) dropwise to a stirred mix-
hedron Lett. 1998, 39, 9155. ture of 5b (320 mg, 1.07 mmol) in dry CH2Cl2 (8 mL) at 0 °C.

7456 J. Org. Chem. Vol. 75, No. 21, 2010

Bornholdt et al.
JOC Note
The mixture was stirred for 5 min at 0 °C, and then diphenyl- added to a stirred suspension of lithium hydroxide monohydrate
vinylsulfonium trifluoromethanesulfonate3 (584 mg, 1.60 mmol) (168 mg, 4 mmol, 4 equiv) in DMSO (2 mL) under argon. The
in dry CH2Cl2 (7 mL) was added dropwise by syringe. The mixture was stirred 5 min at rt. Compound 6a-f (1.0 mmol) in
mixture was stirred for 1 h at 0 °C. By then, UPLC-MS showed DMSO (1 mL) was added and the mixture stirred at rt until
full conversion of 5b into an uncyclized sulfonium intermediate. TLC/UPLC-MS showed full conversion of 6a-f (5 min-30
The reaction mixture was then heated to 90 °C (3-4 bar) in a min). The reaction mixture was partitioned between 2 M K2CO3
microwave reactor for 15 min. The reaction mixture was then (12 mL) and ether (16 mL). The aqueous layer was extracted
partitioned between 1 M NaH2PO4 (16 mL) and CH2Cl2 3-5 times with ether (16 mL) until TLC (MeOH/CH2Cl2, 1:4,
(10 mL), and the aqueous layer was extracted with CH2Cl2 ninhydrin) showed only traces of product in the extract. The
(2  15 mL). Drying over Na2SO4 and concentration in vacuo combined organic layers were dried twice over solid crushed
gave an oily residue. Purification by FC on silica (EtOAc/ KOH. Anhydrous oxalic acid (99 mg, 1.1 mmol, 1.1 equiv) in dry
CH2Cl2/PE, 1:1:8) gave 6b (300 mg, 86%) as a colorless oil that ether (1-2 mL) was added, and the precipitate was filtered
solidified after standing at 4 °C: mp 69-70 °C; [R]20D = þ59.0 through a glass sintered funnel size 4, washed with dry ether, and
(c 1.06, EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.21-8.15 (m, dried under high vacuum.
1H), 8.01-7.95 (m, 1H), 7.65-7.52 (m, 2H), 3.96 (td, J = 2.9,
7.5, 1H), 3.87-3.65 (m, 3H), 3.57-3.37 (m, 3H), 1.84-1.64 (m, Acknowledgment. J.B. is grateful to LEO Pharma and the
2H), 1.47-1.31 (m, 2H), 0.93 (t, J = 7.3, 3H); 13C NMR (75 Drug Research Academy for a grant. We also thank the staff at
MHz, CDCl3) δ 167.0, 152.7, 136.5, 127.7, 127.6, 125.3, 122.3, LEO Pharma, in particular Charlotte Rune, Karin Kryger,
68.5, 66.1, 54.5, 41.8, 30.9, 19.5, 13.9; HRMS calcd for Hans Henrik Grant, and Else Kristoffersen.
C14H19N2O3S2 [M þ H] 327.0837, found 327.0823.
General Procedure for Deprotection of the Bts Group and Supporting Information Available: Full experimental details
Isolation of the Morpholines as Hydrogen Oxalates. 2-Mercap- including copies of NMR spectra. This material is available free
toacetic acid (137 μL, 2 mmol, 2 equiv, freshly distilled) was of charge via the Internet at http://pubs.acs.org.

J. Org. Chem. Vol. 75, No. 21, 2010 7457