Synthesis of enantiopure 3-substituted morpholines

Article abstract of DOI:10.1021/jo101339g

Enantiopure 3-substituted morpholines were assembled through ring-opening of a N-2-benzothiazolesulfonyl (Bts) activated aziridine with organocuprates followed by a ring annulation reaction with a vinylsulfonium salt under microwave conditions. Deprotecti

Full text of DOI:10.1021/jo101339g

pubs.acs.org/joc
hydroxylation.5 However, the number of easily accessible en-
antiopure β-amino alcohols are still limited so new strategies are
continuously being developed.
Herein, we wish to describe a novel approach to enantiopure
3-substituted morpholines based on the strategy outlined in
Figure 1. Regioselective and stereospecific ring-opening of a
suitably functionalized aziridine with organocuprates should
provide N-sulfonyl-protected β-amino alcohols6 that would be
directly applicable in the synthesis of morpholines as described
by Yar et al.3,4
Synthesis of Enantiopure 3-Substituted Morpholines
Jan Bornholdt,† Jakob Felding,‡ and
Jesper Langgaard Kristensen*,†
†Department of Medicinal Chemistry, University of
Copenhagen, Universitetsparken 2, Copenhagen DK-2100,
Denmark, and ‡LEO Pharma, Industriparken 55,
Ballerup DK-2750, Denmark
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
through ring-opening of a N-2-benzothiazolesulfonyl
(Bts) activated aziridine with organocuprates followed by
a ring annulation reaction with a vinylsulfonium salt
under microwave conditions. Deprotection of the N-Bts
group proceeds under very mild conditions with 2-
mercaptoacetic acid and LiOH at rt.
Different groups have been employed for the activation of
aziridines,8 but this is most effectively done with sulfon-
amides like the tosyl group due to its electron-withdrawing
nature.9-11 Although progress has been made toward the
development of new protocols for the deprotection of the
tosyl group,12 this transformation often requires quite harsh
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
community.13,14 The most important feature of the nosyl group
(compared to the tosyl group) is that the amines can be liberated
under very mild conditions with thiolates. However, the electro-
philic nature of the nitro group limits the types of reagents which
are compatible with the nosyl group, in particular, organo-
metallic and strongly reducing agents. We recently reported
a study where heterocyclic sulfonamides were screened for their
ability to activate 2-methylaziridine toward ring-opening
while still being easily cleavable with thiolates.15 From that
investigation, the 2-pyrimidinesulfonyl (pymisyl) group and
the 2-benzothiazolesulfonyl (Bts) groups emerged as potential
The morpholine moiety has found widespread use in medic-
inal chemistry, and many drugs contain this subunit.1 Due to
the eletronegativity of oxygen, morpholine is a weaker base
than, e.g., piperidine, which often provides improved physio-
chemical properties.1 Although it is a very popular building
block in drug discovery, the number of commercially available
substituted morpholines is quite limited. Synthetic routes to
substituted morpholines usually involve β-amino alcohols that
are cyclized into 3-oxomorpholines and reduced.2 Recently, Yar
et al. reported an improved procedure in which vinyl- and
2-bromoethylsulfonium salts are used for the direct conver-
sion of N-sulfonyl-protected β-amino alcohols into N-sulfonyl-
protected morpholines.3,4 Enantiopure β-amino alcohols can be
accessed through the chiral pool of amino acids or a number of
different asymmetric methodologies like the Sharpless amino-
(5) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326.
(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
ester with acetyl chloride in methanol, N-tritylation with trityl chloride and
Et3N, and finally one-pot O-mesylation and intramolecular aziridine ring
formation by methanesulfonyl chloride and Et3N; see the Supporting
Information for references.
(1) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.;
Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
(2) (g) Henegar, K. E.; Cebula, M. Org. Process Res. Dev. 2007, 11, 354.
For other recent approaches towards morpholines, see: (a) Dave, R.; Sasaki,
N. A. Org. Lett. 2004, 6, 15. (b) Lanman, B. A.; Meyers, A. G. Org. Lett.
2004, 6, 1045. (c) Wilkinson, M. C.; Bell, R.; Landon, R.; Nikiforov, P. O.;
Walker, A. J. Synlett 2006, 2151. (d) Penso, M.; Lupi, V.; Albanese, D.;
Foschi, F.; Landini, D.; Tagliabue, A. Synlett 2008, 2451. (e) Ghorai, M. K.;
Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013. (f) Ritzen, B.; Hoekman,
S.; Verdasco, E. D.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2010, 75,
3461.
(8) Hu, X. E. Tetrahedron 2004, 60, 2701.
(9) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney, J. B. Tetra-
hedron 1993, 49, 6309.
(10) Church, N. J.; Young, D. W. Tetrahedron Lett. 1995, 36, 151.
(11) Beresford, K. J. M.; Church, N. J.; Young, D. W. Org. Biomol. Chem.
2006, 4, 2888.
(12) Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503.
(13) Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
(3) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int. Ed.
2008, 47, 3784.
(4) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257.
(14) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(15) Bornholdt, J.; Felding, J.; Clausen, R. P.; Kristensen, J. L. Chem.
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
2010 American Chemical Society
r

Bornholdt et al.
JOCNote
TABLE 1. Four-Step Synthesis of 3-Substituted Morpholines Starting from 3
entry
R =
Me-
Et-
product
yielda (%)
product
yielda (%)
product
yielda (%)
product
yieldb (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
91
66
87
86
87
70
5a
5b
5c
5d
5e
5f
83
92
83
91
89
90
6a
6b
6c
6d
6e
6f
83
86
75
76
76
72
7a
7b
7c
7d
7e
7f
81c
74
75
57
75
78
vinyl-
cyclopropyl-
Ph-
4-MeO-Ph-
aIsolated 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
compatible with organocuprate reagents. In this study, the
pymisyl performed better than the Bts group, and therefore,
it was initially tested in the sequence outlined in Figure 1. The
ring-opening with organocuprate reagents worked well, giv-
ing the desired products in 83-89% yield. However, depro-
tection of the TBS group was accompanied by the formation
of byproducts, and the yield of the pymisyl protected β-
amino alcohols was low. Numerous different conditions
were tested, but the formation of byproduct could not be
suppressed and instead we turned our attention to the Bts
group.16
protected β-amino alcohols 5a-f were isolated in 82-93%
yield.
Subsequently, ring formation to the corresponding mor-
pholines using vinyldiphenylsulfonium triflate as described
by Yar et al.3 was attempted. When the reaction mixture was
allowed to stir overnight at rt, low conversion was observed.
LC-MS confirmed that the reaction proceeded in two
discrete steps; the first being addition of the deprotonated
sulfonamide to the vinylsulfonium ion forming a new sulfo-
nium salt; see Scheme 2.
SCHEME 2. Observed Intermediate in the Morpholin Synthesis
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
at ambient temperature, and several days were required to
obtain full conversion. Microwave heating (90 °C in CH2Cl2 at
3-4 bar) considerably shortened the reaction times, and under
these conditions, only 15-20 min was required to reach full
conversion. Subsequently, the Bts-protected morpholines 6a-f
were isolated in 72-86% yield; see Table 1. We propose that
microwave heating will also prove beneficial to the annulation
reaction of other N-sulfonylated β-amino alcohols and signifi-
cantly shorten reaction times.
To verify that the stereochemical integrity was preserved
in the sequence from serine to the 3-substituted morpholines,
compound 6e was compared with a racemic sample using
chiral HPLC. To our delight, only a single enantiomer could
be detected; see the Supporting Information for details.
Finally, the Bts group was removed under very mild
conditions with 2-mercaptoacetic acid and lithium hydro-
xide in DMSO17 at rt. The free morpholines were extracted
into Et2O and precipitated with anhydrous oxalic acid to
yield the pure morpholines 7a-f as hydrogenoxalate salts in
57-78% yield. The overall yield of the morpholines from the
key intermediate 3 is in the range of 34-51% over four steps.
The key Bts-protected aziridine 3 was accessed from 1 as
outlined in Scheme 1. Reduction of 1 with LiAlH4 followed
by O-silylation of the resulting alcohol with TBSCl gave 2 in
88% yield. Subsequently, the trityl group was removed with
TFA/Et3SiH followed by treatment of the aziridinium salt
with BtsCl which provided the desired building block 3 in
50% yield from 2 after recrystallization.
The CuBr Me2S catalyzed ring-opening of 3 with
3
Grignard reagents was attempted. Alkyl, vinyl, cyclopropyl,
and aryl Grignard reagents worked well in analogy with the
results obtained with the pymisyl-protected aziridine. Thus,
the desired products 4a-f were isolated in 66-91% yield,
see Table 1. To our delight, the removal of the TBS group
was not compromised by the same problems that plagued
the pymisyl-protected products.16 Deprotection proceeded
smoothly with both TBAF in THF and 40% HF in CH3CN,
the latter being preferred due to ease of work up, and the Bts
(16) Full experimental details on the ring opening of the pymisyl-pro-
tected aziridine is provided in the Supporting Information, including details
of the unfruitful attempts to deprotect the TBS-group from the pymisyl-
protected amino alcohols. The resulting N-pymisyl protected amino alcohols
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,
Y. X.; Guo, Y. L.; Tang, Q. H.; Lu, L. Synlett 2005, 8, 1239.
(17) The use of DMF as solvent gave morpholines contaminated with
small amounts of dimethylammonium oxalates.
J. Org. Chem. Vol. 75, No. 21, 2010 7455

Bornholdt et al.
JOCNote
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]20 = -32.0 (c
D
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,
CDCl3) δ 163.1, 152.5, 137.0, 128.2, 127.7, 125.8, 122.3, 61.8, 42.2,
32.2, 25.8, 18.4, -5.3, -5.4; HRMS calcd for C16H25N2O3S2Si
[M þ H] 385.1075, found 385.1061.
aKey: (a) NaOCl, HCl, CH2Cl2, -10 °C;20 (b) HOPFP, Et3N,
CH2Cl2, -30 °C.21
The very mild conditions used for the deprotection highlight
the advantage of using the Bts-group. BtsCl, originally intro-
duced by Vedejs,18 is readily prepared from inexpensive19
2-mercaptobenzothiazole (8) using NaOCl as the oxidant;20
see Scheme 3. BtsCl can be stored for several months in the
freezer with minimal deterioration. Alternatively, BtsCl can be
converted to the corresponding pentafluorophenyl sulfonate
ester (BtsOPFP) (10), which is stable at rt and reacts readily with
primary and secondary amines to form the corresponding Bts-
protected amines in very high yields.21 Most importantly, the
Bts group is readily removed under mild conditions using
thiolates,22 analogously to the nosyl group. Thus, the Bts group
should be applicable in many other settings where the tosyl and
nosyl groups currently are being used.
In conclusion, we have developed a new Cu-catalyzed
ring-opening of an N-Bts activated aziridine with Grignard
reagents. Subsequent ring annulation and deprotection
under mild conditions provided enantiopure 3-substituted
morpholines. This efficient protocol can be used to access
both enantiomers of 3-substituted morpholines, not directly
accessible from the chiral pool of amino acids.
General Procedure for Ring-Opening of 3 with Grignard
Reagents: Synthesis of (S)-N-(1-(tert-Butyldimethylsilyloxy)-
pentan-2-yl)benzo[d]thiazole-2-sulfonamide (4b). Copper(I) bro-
mide dimethyl sulfide (72 mg, 0.35 mmol) was added to a flame-
dried Schlenk flask under argon. Dry THF (14 mL) was added,
and the slurry was stirred at rt for 15 min and then cooled to
-55 °C (externally). Ethylmagnesium bromide (3.10 mL,
0.97 M, 3.00 mmol) in THF was added dropwise at -55 °C.
The resulting mixture was stirred at -55 to -50 °C for 30 min
and then cooled to -78 °C. Compound 3 (769 mg, 2.00 mmol) in
dry THF (3.5 mL) was added dropwise by syringe. The reaction
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
and 30 mL of 25% NH4OH diluted to 500 mL with water) at
-78 °C and then allowed to warm to rt. The mixture was
transferred to a 100 mL flask, and the THF was removed in vacuo.
The aqueous residue was extracted with ether (1 ꢀ 25 mL and 2 ꢀ
15 mL), and the combined organic phases were washed with 0.05 M
Na2EDTA (10 mL) and brine (20 mL), dried with Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by FC on silica
(EtOAc/PE, 0:100-1:3) to afford 4b (545 mg, 66%) as a colorless
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),
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, 9H),-0.05 (s, 3H), -0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
167.0, 152.6, 136.6, 127.7, 127.5, 125.3, 122.3, 64.3, 56.1, 34.5, 25.9,
19.0, 18.4, 13.9, -5.5; HRMS calcd for C18H31N2O3S2Si [M þ H]
415.1545, found 415.1532.
Experimental Section
(S)-2-(2-((tert-Butyldimethylsilyloxy)methyl)aziridin-1-ylsul-
fonyl)benzo[d]thiazole (3). Trifluoroacetic acid (5.51 mL, 72 mmol)
was added dropwise by syringe to a stirred solution of 2 (7.73 g,
18 mmol) and triethylsilane (11.5 mL, 72 mmol) in dry CH2Cl2
(90 mL) at -5 °C under argon. The mixture was stirred 2.5 h at
-5 to þ4 °C until TLC showed full consumption of the starting
material. The reaction mixture was poured into cold 2 M K2CO3 (90
mL) under vigorous stirring. The layers were separated, and the
aqueous layer was extracted with ether (2 ꢀ 30 mL). The combined
organic layers were concentrated in vacuo to remove the CH2Cl2.
The residue was dissolved in EtOAc (80 mL), 2 M K2CO3 (35 mL)
was added, and the mixture was cooled to 0 °C in an ice bath. Solid
benzothiazole-2-sulfonyl chloride (BtsCl) (4.00 g, 17.1 mmol) was
added in small portions under vigorous stirring. After 2 h at 0 °C,
the mixture was allowed to warm to rt. Excess BtsCl was quenched
with 25% NH4OH (2 ꢀ 200 μL) until TLC showed full conversion.
The reaction mixture was then diluted with EtOAc (20 mL), and the
layers were separated. The aqueous layer was extracted with ether
(40 mL). The combined organic layers were washed with 0.5 M
NaH2PO4 (40 mL), water (40 mL), and satd Na2SO4 (40 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (FC) on silica (EtOAc/PE, 5:95 to
14:86) providing 4.96 g of material containing 3% of a chloride ring
General Procedure for the Deprotection of the TBS Group
Exemplified by the Synthesis (S)-N-(1-Hydroxypentan-2-yl)benzo-
[d]thiazole-2-sulfonamide (5b). HF (87 μL, 40%, 1.23 mmol,
1.5 equiv) was added to a stirred solution of 4b (415 mg, 1.30
mmol) in acetonitrile (2.3 mL) cooled to 0 °C in an ice bath. The
mixture was stirred 30 min at 0 °C and then at ambient
tempratue for 2 h while the reaction progress was moni-
tored by TLC and UPLC-MS. The reaction mixture was then
neutralized with satd NaHCO3 and concentrated in vacuo to
remove acetonitrile. The residue was partitioned between brine
(10 mL) and EtOAc (15 mL). The aqueous layer was extracted
with EtOAc (2 ꢀ 15 mL). The combined organic layers were
washed brine (10 mL), dried over Na2SO4, and concentrated in
vacuo. The solid residue was purified by FC on silica (EtOAc/
PE, 7:13) to afford the title compound 5b as a colorless solid (361
mg, 92%): mp 136-137 °C; [R]20D = þ4.5 (c 1.00, EtOAc); 1H
NMR (300 MHz, CDCl3) δ 8.12-8.06 (m, 1H), 7.98-7.93 (m,
1H), 7.62-7.51 (m, 2H), 5.74 (d, J = 8.1, 1H), 3.80-3.65 (m,
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
MHz, CDCl3) δ 167.9, 151.6, 136.4, 127.9, 127.7, 124.9, 122.4,
64.6, 57.4, 34.5, 19.0, 13.8; HRMS calcd for C12H17N2O3S2
[M þ H] 301.0681, found 301.0693.
(18) Vedejs, E.; Lin, S. Z.; Klapars, A.; Wang, J. B. J. Am. Chem. Soc.
1996, 118, 9796.
(19) 2-Mercaptobenzothiazole is used on large scale in several industrial
settings, among them as a vulcanizing agent in the rubber and latex industry.
Thus, 2-mercaptobenzothiazole is readily available at very low cost.
(20) Wright, S. W.; Hallstrom, K. N. J. Org. Chem. 2006, 71, 1080.
(21) Bornholdt, J.; Fjaere, K. W.; Felding, J.; Kristensen, J. L. Tetra-
hedron 2009, 65, 9280.
General Procedure for the Annulation Reaction: Synthesis of
(S)-3-Propyl-4-(benzo[d]thiazol-2-ylsulfonyl)morpholine (6b). To
a 20 mL capped microwave vial under argon was added triethyl-
amine (600 μL, 4.26 mmol, 4 equiv) dropwise to a stirred mix-
ture of 5b (320 mg, 1.07 mmol) in dry CH2Cl2 (8 mL) at 0 °C.
(22) Wuts, P. G. M.; Gu, R. L.; Northuis, J. M.; Thomas, C. L. Tetra-
hedron Lett. 1998, 39, 9155.
7456 J. Org. Chem. Vol. 75, No. 21, 2010

Bornholdt et al.
JOCNote
The mixture was stirred for 5 min at 0 °C, and then diphenyl-
vinylsulfonium trifluoromethanesulfonate3 (584 mg, 1.60 mmol)
in dry CH2Cl2 (7 mL) was added dropwise by syringe. The
mixture was stirred for 1 h at 0 °C. By then, UPLC-MS showed
full conversion of 5b into an uncyclized sulfonium intermediate.
The reaction mixture was then heated to 90 °C (3-4 bar) in a
microwave reactor for 15 min. The reaction mixture was then
partitioned between 1 M NaH2PO4 (16 mL) and CH2Cl2
(10 mL), and the aqueous layer was extracted with CH2Cl2
(2ꢀ15 mL). Drying over Na2SO4 and concentration in vacuo
gave an oily residue. Purification by FC on silica (EtOAc/
CH2Cl2/PE, 1:1:8) gave 6b (300 mg, 86%) as a colorless oil that
solidified after standing at 4 °C: mp 69-70 °C; [R]20D = þ59.0
(c 1.06, EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.21-8.15 (m,
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,
2H), 1.47-1.31 (m, 2H), 0.93 (t, J = 7.3, 3H); 13C NMR (75
MHz, CDCl3) δ 167.0, 152.7, 136.5, 127.7, 127.6, 125.3, 122.3,
68.5, 66.1, 54.5, 41.8, 30.9, 19.5, 13.9; HRMS calcd for
C14H19N2O3S2 [M þ H] 327.0837, found 327.0823.
added to a stirred suspension of lithium hydroxide monohydrate
(168 mg, 4 mmol, 4 equiv) in DMSO (2 mL) under argon. The
mixture was stirred 5 min at rt. Compound 6a-f (1.0 mmol) in
DMSO (1 mL) was added and the mixture stirred at rt until
TLC/UPLC-MS showed full conversion of 6a-f (5 min-30
min). The reaction mixture was partitioned between 2 M K2CO3
(12 mL) and ether (16 mL). The aqueous layer was extracted
3-5 times with ether (16 mL) until TLC (MeOH/CH2Cl2, 1:4,
ninhydrin) showed only traces of product in the extract. The
combined organic layers were dried twice over solid crushed
KOH. Anhydrous oxalic acid (99 mg, 1.1 mmol, 1.1 equiv) in dry
ether (1-2 mL) was added, and the precipitate was filtered
through a glass sintered funnel size 4, washed with dry ether, and
dried under high vacuum.
Acknowledgment. J.B. is grateful to LEO Pharma and the
Drug Research Academy for a grant. We also thank the staff at
LEO Pharma, in particular Charlotte Rune, Karin Kryger,
Hans Henrik Grant, and Else Kristoffersen.
General Procedure for Deprotection of the Bts Group and
Isolation of the Morpholines as Hydrogen Oxalates. 2-Mercap-
toacetic acid (137 μL, 2 mmol, 2 equiv, freshly distilled) was
Supporting Information Available: Full experimental details
including copies of NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 21, 2010 7457