Intramolecular reductive amination strategy to the synthesis of (R)-N-Boc-2-hydroxymethylmorpholine, N-(3,4-dichlorobenzyl)(R)-2-hydroxymethylmorpholine, and (R)-2-benzylmorpholine

Article abstract of DOI:10.1016/j.tet.2010.01.047

A concise high yielding enantioselective synthesis of (R)-N-Boc-2-hydroxymethylmorpholine, N-(3,4-dichlorobenzyl)(R)-2-hydroxymethylmorpholine, and (R)-benzylmorpholine has been achieved by employing proline-catalyzed asymmetric α-aminooxylation of aldehyde and palladium-catalyzed intramolecular reductive amination of azido aldehyde as the key steps.

Full text of DOI:10.1016/j.tet.2010.01.047

Tetrahedron 66 (2010) 2010–2014
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular reductive amination strategy to the synthesis
of (R)-N-Boc-2-hydroxymethylmorpholine, N-(3,4-dichlorobenzyl)(R)-2-
hydroxymethylmorpholine, and (R)-2-benzylmorpholine
*
Rajiv T. Sawant, Suresh B. Waghmode
Department of Chemistry, University of Pune, Ganeshkhind Road, Pune 411 007, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2009
Received in revised form 18 December 2009
Accepted 12 January 2010
Available online 18 January 2010
A concise high yielding enantioselective synthesis of (R)-N-Boc-2-hydroxymethylmorpholine, N-(3,4-
dichlorobenzyl)(R)-2-hydroxymethylmorpholine, and (R)-benzylmorpholine has been achieved by
employing proline-catalyzed asymmetric
molecular reductive amination of azido aldehyde as the key steps.
Ó 2010 Elsevier Ltd. All rights reserved.
a-aminooxylation of aldehyde and palladium-catalyzed intra-
Keywords:
Proline
Asymmetric
Morpholines
a-aminooxylation
Pharmacologically active
Reductive amination
1. Introduction
Despite significant pharmacological activity and widespread
utility of 4–6, very few enantioselective synthesis of (R)-4, (R)-5,
(S)-5, and (R)-6 are known in the literature.5,6,9–11 Tamagnan and
co-workers and Henegar have reported synthesis of (S)-5 from (S)-
3-amino-1,2-propanediol6 and (S)-epichlorohydrin,10 respectively.
Wilkinson and co-workers reported synthesis of 6 by using
The 2-substituted chiral morpholine skeleton present in number
of pharmacologically highly active molecules1 such as, (S,S)-
reboxetine 1,2 NAS-181 2,3 urea 3,4 (R)-2-benzylmorpholine 45 etc.
(Fig. 1). These compounds exhibit wide range of application in the
treatment of depression,2 obesity,5 asthma, and rhinitis4 etc.
Enantiomerically pure (R)-N-Boc-2-hydroxymethylmorpholine 5
and its enantiomer are attractive chiral building blocks for the
synthesis of variety of pharmacologically active compounds.7 (R)-
N-Boc-2-hydroxymethylmorpholine 5 can be used as a useful chiral
intermediate for the synthesis of 5-HT1B receptor antagonist NAS-
181 2, since (R)-N-trityl derivative of morpholine 5 is a known
precursor of NAS-181 2.3a (R)-5 has also been used in the prepa-
ration of 2-aryloxymethylmorpholine benzamide 5-HT4 stim-
ulators3b and histamine H3 antagonists,3c whereas the (S)-5 is
a versatile intermediate in the synthesis of (S,S)-reboxetine6 and
many other morpholines.8 The urea based morpholine 3 and (R)-2-
benzylmorpholine 4 are potent antagonist of CCR3 and appetite
suppressant agent, respectively, which has potential therapeutic
applications.4,5
EtO
O
O
O
Ph
HN
NH
O
N
3
N
1
H
O
O
O
O
NH2
Cl
Cl
N
O
N
.CH3SO3H.H2O
H
O
N
2
R
O
O
Ph
HO
Cl
N
H
4
N
6, R = OH
7, R = NH2
Boc
5
Cl
* Corresponding author. Tel.: þ91 20 25601394; fax: þ91 20 25691728.
E-mail address: suresh@chem.unipune.ernet.in (S.B. Waghmode).
Figure 1. Pharmacologically active 2-substituted morpholines and their intermediate.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.047

R.T. Sawant, S.B. Waghmode / Tetrahedron 66 (2010) 2010–2014
2011
palladium-catalyzed asymmetric allylic substitution as a part of
a synthesis of aminomethylmorpholine 7.11a Only two enantiose-
lective synthesis of 4 have been reported, which involve resolution
of racemic 4 using (ꢀ)-dibenzoyl tartaric acid5a and chemo-enzy-
oxide (2 mol %) and p-toluenesulfonyl chloride. The crude mono-
tosylate was treated with sodium azide in dry DMF to afford azido
alcohol 1017 in 88% yield (over two steps) and >95% ee (determined
by 1H NMR analysis of its Mosher’s ester). The hydroxyl group of
azido alcohol 10 was alkylated with allyl bromide in DMF using
sodium hydride to afford azido allyl ether 11 in quantitative yield
(97%), which on exposure to potassium osmate mediated dihy-
droxylation and subsequent oxidative cleavage of the ensuing diol
using NaIO4 resulted in a crucial azido aldehyde 12.
Our next aim was to construct morpholine skeleton through
intramolecular reductive amination. The palladium-catalyzed
intramolecular reductive amination of crude azido aldehyde 12
underwent smoothly in the presence of hydrogen atmosphere
using Pd/C (10%) at 100 psi in MeOH to afford morpholine 13,
subsequent N-Boc-protection with (Boc)2O using NaHCO3 in
dioxane/water (3:1) gave N-Boc-morpholine (R)-5 in 57% yield
(over four steps) and >95% ee. Where as, synthesis of N-benzyl-
morpholine (R)-6 was achieved by the treatment morpholine 12,
with 3,4-dichlorobenzyl bromide using K2CO3 in CH3CN to afford
(R)-6 in 54% yield (over four steps) (Scheme 1). The synthesis of
aminomethylmorpholine core 7 of CCR3 antagonist 3 from (R)-6
has already been reported in the literature.11a
matic reduction of (Z)-a-bromocinnamaldehyde using bakers
yeast.5b Most of these methods for the synthesis of 4–6 involve
either a lengthy chiral pool approach or use of expensive transition
metal catalyst or chiral starting materials or low yielding and te-
dious classical or enzymatic resolution approach. Toward this end,
a simple, inexpensive and eco-friendly practical route to the syn-
thesis of enantiomerically pure 4–6 from achiral substrate is highly
desirable.
As part of our research program aimed toward the development
of new strategy for the enantioselective synthesis of biologically
active compounds and their chiral key intermediates12 based on
proline-catalyzed asymmetric a
-aminooxylation of aldehydes,13 we
were encouraged to design a short and effective route to 2-
substituted chiral morpholines. Herein we report a novel high
yielding enantioselective synthesis of (R)-4–6 by employing pro-
line-catalyzed asymmetric a-aminooxylation of aldehyde and pal-
ladium-catalyzed intramolecular reductive cyclization of azido
aldehyde as the key steps to introduce chirality and to generate
morpholine ring (Scheme 1 and 2).
2.2. Synthesis of (R)-2-benzylmorpholine 4
2. Result and discussion
Similarly, enantioselective synthesis of (R)-2-benzylmorpholine
4 was completed with the same reaction sequence as described for
the synthesis of morpholine (R)-5 and (R)-6 from readily available
2.1. Synthesis of 2-hydroxymethylmorpholine (R)-5 and (R)-6
3-phenylpropanaldehyde 14. The
L-proline catalyzed asymmetric
The synthetic sequence for the enantioselective synthesis of (R)-
5 and (R)-6 is started with aldehyde 8,14 which was prepared by IBX
oxidation of 3-benzyloxypropanol (Scheme 1). We planned to
prepare chiral building block 915 by using eco-friendly organo-
a-aminooxylation of aldehyde 13 afforded diol 15 in 69% yield.
Selective tosylation16 of diol 15 followed by displacement of cor-
responding tosylate with sodium azide in dry DMF gave azido al-
cohol 1619 in 88% yield (over two steps) and >95% ee (determined
by 1H NMR analysis of its Mosher’s ester). Allylation of alcohol 16
was accomplished using sodium hydride in dry DMF at 0 ꢁC to af-
ford azido allyl ether 17 in 98% yield. The dihydroxylation followed
by subsequent oxidative cleavage of olefin 17 gave crucial azido
aldehyde 18, which on palladium-catalyzed intramolecular
reductive amination using 10% Pd/C/H2 (1 atm) in MeOH afforded
(R)-2-benzylmorpholine 4 in 57% yield (over three steps) and >95%
ee (Scheme 2). All the compounds 4–18 were fully characterized by
spectroscopic technique. The spectral and analytical data of mor-
pholine (R)-4 and (R)-5 were found to be in good agreement with
literature data.5b,6
catalytic method to demonstrate the utility of asymmetric a-ami-
nooxylation reaction.13a Thus, aldehyde
8 was treated with
nitrosobenzene in the presence of
D
-proline in CH3CN at ꢀ20 ꢁC
followed by in situ reduction with NaBH4 in methanol to afford
aminoxy alcohol. The crude aminooxy intermediate was treated
with 30 mol % CuSO4$5H2O in methanol to cleave the O–N bond to
afford diol 915 in 66% yield. Selective tosylation16 of primary hy-
droxyl group was achieved using catalytic amount of dibutyltin
OH
OH
BnO
BnO
H
i
iii
O
ii
BnO
BnO
BnO
O
O
N3
8
OH
10
9
OH
N3
OH
OH
i
ii
iii
O
v
iv
H
O
HO
HO
15
14
16
O
N3
N3
N
H
13
11
12
O
O
O
iv
v
vii
vi
O
N
H
N3
N3
O
O
N
HO
17
18
4
ref. 11a
7
N
Scheme 2. Reagents and conditions: (i) (a) PhNO, L-proline (25 mol %), CH3CN, –20 ꢁC,
24 h then MeOH, NaBH4, 30 min, (b) H2 (1 atm), Pd/C (10%), MeOH, 10 h, 69% (over two
steps); (ii) (a) dibutyltin oxide (2 mol %), p-TsCl, Et3N, CH2Cl2, 0 ꢁC to rt, 1 h; (b) NaN3,
DMF, 70 ꢁC, 10 h, 88% (over two steps); (iii) allyl bromide, NaH, DMF, 0 ꢁC, 1.5 h, 98%;
(iv) (a) K2OsO4.H2O(2 mol %), NMO, acetone:H2O (8:2), rt, 10 h, (b) NaIO4, acetone:H2O
(9:1), rt, 4 h; (v) H2 (1 atm), Pd/C (10%), MeOH,12 h, 57% (over three steps).
Cl
Cl
6
O
O
5
Scheme 1. Reagents and conditions: (i) (a) PhNO, D-proline (25 mol %), CH3CN, –20 ꢁC,
24 h then MeOH, NaBH4, 30 min, (b) CuSO4 (30 mol %), MeOH, 0 ꢁC, 12 h, 66% (over two
steps); (ii) (a) dibutyltin oxide (2 mol %), p-TsCl, Et3N, CH2Cl2, 0 ꢁC to rt, 1 h, (b) NaN3,
DMF, 70 ꢁC, 10 h, 89% (over two steps); (iii) allyl bromide, NaH, DMF, 0 ꢁC 1.5 h, 97%;
(iv) (a) K2OsO4.H2O (2 mol %), NMO, acetone:H2O (8:2), rt, 12 h, (b) NaIO4, acetone:H2O
(9:1), rt, 4 h, (v) H2 (100 psi), Pd/C (10%), MeOH, rt, 24 h, (vi) (Boc)2O, dioxane:H2O
(3:1), NaHCO3, 0 ꢁC to rt, 4.5 h, (57% over four steps), (vii) 3,4-dichlorobenzyl bromide,
K2CO3, CH3CN, rt, 5 h (54% over four steps).
3. Conclusion
In conclusion, a new and efficient enantioselective synthesis of
(R)-N-Boc-2-hydroxymethylmorpholine, N-(3,4-dichlorobenzyl)-
(R)-2-hydroxymethyl morpholine, and (R)-2-benzylmorpholine

2012
R.T. Sawant, S.B. Waghmode / Tetrahedron 66 (2010) 2010–2014
has been achieved in 32%, 30%, and 33% overall yield, respectively.
The proline-catalyzed asymmetric -aminooxylation of aldehyde to
(m, 1H), 4.51 (s, 2H), 7.18–7.39 (m, 5H); dC (75 MHz, CDCl3) 63.7,
70.7, 71.3, 73.7, 127.5, 128.2, 137.4.
a
introduce chirality and palladium-catalyzed intramolecular re-
ductive cyclization of azido aldehyde to generate morpholine ring
are the key steps involved in the present synthesis. Our strategy
demonstrates the successful application of organocatalysis and
reductive cyclization for the synthesis of chiral 2-substitituted
morpholines and represent a good alternative to the known
methods.
4.1.3. (R)-1-Azido-3-(benzyloxy)propan-2-ol 10. To a stirred solu-
tion of diol 9 (0.7 g, 3.84 mmol) in dry CH2Cl2 (20 mL), dibutyltin
oxide (18 mg, 0.08 mmol) was added Et3N (0.54 mL, 3.91 mmol) at
0 ꢁC. To this solution was added p-toluenesulfonyl chloride (0.75 g,
3.91 mmol) and the reaction mixture was stirred for 1 h at room
temperature. The reaction mixture was diluted with water and
extracted with CH2Cl2 (2ꢂ30 mL). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. To a crude solution of tosylate
(1.24 g, 3.69 mmol) in dry DMF (15 mL) was added sodium azide
(0.53 g, 8.11 mmol) and stirred at 70 ꢁC for 10 h, cooled to room
temperature, diluted with water and extracted with ethyl acetate
(3ꢂ30 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude product was purified by silica gel
4. Experimental section
4.1. General experimental details
All 1H and 13C NMR spectra were recorded in CDCl3 unless
otherwise noted, on Varian Mercury spectrometer at 300 and
75 MHz, respectively with TMS as an internal standard. IR spectra
were recorded on Shimadzu FTIR 8400. Elemental analyses were
carried out with Thermo-Electron Corporation CHNS analyzer,
FLASH-EA 1112 at Shimadzu Analytical Centre, University of
Pune. Thin layer chromatography was performed on Merck 60 F254
silica gel plates and column chromatography on silica gel of
100–200 mesh. Melting points were recorded with Thomas Hoover
capillary melting point apparatus and are uncorrected. Optical
rotations were measured on Jasco P-1020 digital polarimeter. En-
antiomeric excesses were measured using either Mosher’s ester or
by comparison with specific rotation.
chromatography using ethyl acetate/hexane (10:90) to give pure
25
azide 10 (0.7 g, 88%) as a colorless oil. [
a]
þ11.7 (c 1.1, CHCl3), {lit.19
D
25
[a
]
þ11.5 (c 1.1, CHCl3)}. [Found C, 57.87; H, 6.54, N, 20.35%.
D
C10H13N3O2 required C, 57.96; H, 6.32; N, 20.28%]; Rf (20% ethyl
acetate/hexane) 0.25; nmax (CHCl3) 3433, 2104, 1267, 1097 cmꢀ1
;
dH
(300 MHz, CDCl3) 2.28 (br s, 1H), 3.30–3.39 (m, 2H), 3.45–3.54
(m, 2H), 3.91–3.98 (m, 1H), 4.54 (s, 2H), 7.29–7.36 (m, 5H);
dC (75 MHz, CDCl3) 53.4, 69.5, 71.2, 73.4, 127.6, 127.7, 128.3, 137.3.
4.1.4. General procedure for Mosher’s ester preparation. To a stirred
solution of alcohol (ꢃ)-1020 or (þ)-10 (20 mg, 0.096 mmol), (R)-
a-
4.1.1. 3-Benzyloxypropionaldehyde 814. A mixture of 3-benzyloxy-
propanol (3.0 g, 18.1 mmol) and IBX (6.5 g, 23.5 mmol) in DMSO
(35 mL) was stirred for 3.5 h at room temperature, then water
was added to the reaction mixture and 2-iodobenzoic acid was
filtered off. The filtrate was extracted with ethyl acetate
(3ꢂ25 mL), combined organic layer washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure and
the crude product was purified by silica gel column chromato-
graphy using ethyl acetate/hexane (10:90) afforded pure aldehyde
8 (2.57 g, 87%); as a colorless oil. [Found C, 73.34; H, 7.26%.
C10H12O2 required C, 73.15; H, 7.37%]; Rf (15% ethyl acetate/
hexane) 0.50; nmax (CH2Cl2) 2958, 2807, 2740, 1716, 1452, 1363,
methoxy-a-trifluoromethylphenyl acetic acid (24 mg, 0.106 mmol),
and 4-dimethylaminopyridine (2 mg) in dry CH2Cl2 (3 mL) was
added dropwise a solution of DCC (22 mg, 0.106 mmol) in CH2Cl2
(2 mL) at 0 ꢁC under a nitrogen atmosphere and stirred at the same
temperature for 30 min. Then reaction mixture was brought to
room temperature and stirred for 12 h. The reaction mixture was
diluted with CH2Cl2 (40 mL), washed with saturated aqueous
NaHCO3 solution followed by brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by silica gel chromatography using ethyl acetate/hexane
(4:96) to give Mosher’s ester in 87% yield.
1203, 1101, cmꢀ1
6.0 Hz), 3.79 (t, 2H, J¼6.0 Hz), 4.51 (s, 2H), 7.28–7.32 (m, 5H), 9.75
(t, 1H, J¼2.1 Hz); dC (75 MHz, CDCl3) 43.7, 63.7, 73.1, 127.5, 128.2,
137.5, 200.9.
;
dH (300 MHz, CDCl3): 2.67 (dt, 2H, J¼1.8,
4.1.5. Mosher’s ester of alcohol (ꢃ)-1020. Colorless oil; Rf (10% ethyl
acetate/hexane) 0.30; 1H NMR (400 MHz, CDCl3):
d 3.48–3.55
(m, 2H), 3.56 (s, 3H), 3.57 (s, 3H), 3.58–3.65 (m, 4H), 3.68–3.69
(m, 2H), 4.45 (AB quartet, 2H, J¼12.0 Hz), 4.54 (AB quartet, 2H,
J¼12.0 Hz), 5.31–5.39 (m, 2H), 7.22–7.58 (m, 20H).
4.1.2. (R)-3-(Benzyloxy)propane-1,2-diol 9. To a stirred solution of
aldehyde 8 (2 g,12.2 mmol) and nitrosobenzene (1 g, 9.34 mmol) in
4.1.6. Mosher’s ester of alcohol (þ)-10. Colorless oil; Rf (10% ethyl
CH3CN (25 mL) was added
D-proline (0.27 mg, 2.33 mmol) at
acetate/hexane) 0.30; 1H NMR (400 MHz, CDCl3):
d 3.50 (dd, 1H,
ꢀ20 ꢁC. The reaction mixture was stirred for 24 h at the same
temperature, then diluted with MeOH (15 mL) and to this solution
was added NaBH4 (1.06 g, 28 mmol). After 30 min, the reaction
mixture was carefully quenched with saturated aqueous NaHCO3,
extracted with ethyl acetate (3ꢂ30 mL), dried over Na2SO4 and
concentrated under reduced pressure. The CuSO4$5H2O (0.7 g,
2.8 mmol) was added at 0 ꢁC to the solution of crude product in
MeOH (20 mL) and stirred for 10 h. The reaction mixture was
quenched with saturated aqueous NH4Cl and extracted with ethyl
acetate (3ꢂ30 mL), washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
J¼6.4,13.2 Hz),3.54–3.58 (m,1H), 3.56(s, 3H), 3.68–3.69(m, 2H), 4.54
(AB quartet, 2H, J¼12.0 Hz), 5.35–5.38 (m, 1H), 7.29–7.57 (m, 10H).
4.1.7. 1-(((R)-2-(Allyloxy)-3-azidopropoxy)methyl)benzene 11. To a
stirred suspension of NaH (0.15 g, 6.28 mmol) in dry DMF (15 mL)
alcohol 10 (0.65 g, 3.14 mmol) in dry DMF (3 mL) was added at 0 ꢁC,
stirred for 5 min, followed by addition of allyl bromide (0.35 mL,
4.07 mmol). The resulting reaction mixture was stirred at same
temperature for 1.5 h, quenched with saturated aqueous NH4Cl and
extracted with ethyl acetate (3ꢂ25 mL). The combined organic ex-
tracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was purified by
purified by silica gel chromatography using ethyl acetate/hexane
25
(35:65) to give pure diol 9 (0.73 g, 66%) as a viscous liquid. [
a
]
silica gel chromatography using ethyl acetate/hexane (3:97) to give
D
22
25
þ5.63 (c 20, CHCl3), {lit.15
[a
]
þ5.5 (c 20, CHCl3)}. [Found C, 65.83;
pure olefin 11 (0.75 g, 97%) as colorless oil. [
a
]
ꢀ20.4 (c 1.2, CHCl3).
D
D
H, 7.79%. C10H14O3 required C, 65.91; H, 7.74%]; Rf (50% ethyl
[Found C, 63.05; H, 6.84, N, 17.06%. C13H17N3O2 required C, 63.14; H,
acetate/hexane) 0.20; nmax (CHCl3) 3414, 2928, 2872, 1082 cmꢀ1
(300 MHz, CDCl3) 3.15 (br s, 2H), 3.51–3.64 (m, 4H), 3.83–90
;
dH
6.93; N, 16.99%]; Rf (15% ethyl acetate/hexane) 0.50; nmax (CHCl3)
3030, 2924, 2858, 2100, 1278, 1101 cmꢀ1
; dH (300 MHz, CDCl3)

R.T. Sawant, S.B. Waghmode / Tetrahedron 66 (2010) 2010–2014
2013
3.48–3.50 (d, 2H, J¼5.7 Hz), 3.52–3.55, (m, 2H), 3.64–3.69 (m, 1H),
4.10–4.13 (m, 2H), 4.53 (s, 2H), 5.17 (bd, 1H, J¼10.2 Hz), 5.27 (dd, 1H,
J¼1.5 and 17.1 Hz), 5.86–5.95 (m, 1H), 7.23–7.36 (m, 5H); dC (75 MHz,
CDCl3) 52.0, 69.4, 71.3, 73.4, 77.0,117.2,127.5,127.6,128.3,134.3,137.7.
procedure for the preparation of 9 from 8; colorless solid, mp: 46–
25
22
47 ꢁC, {lit.18 46–47 ꢁC }. [
a
]
þ34.8 (c 1, EtOH); {lit.18
[
a
]
þ35.4
D
D
(c 1, EtOH). [Found: C, 71.21; H, 7.89; N, 21.12%. C9H12O2 required
C, 71.03; H, 7.95; N, 21.03%]; Rf (40% ethyl acetate/hexane) 0.20;
nmax (CH2Cl2) 3417, 2928, 2864, 1496, 1452, 1273, 1078 cmꢀ1
; dH
4.1.8. (R)-N-Boc-2-hydroxymethyl morpholine 5. To a stirred solu-
tion of olefin 11 (0.5 g, 2.02 mmol) in acetone/water (10 mL, 9:1) was
added NMO (0.47 g, 4.04 mmol) and potassium osmate
(K2OSO4$5H2O) (15 mg, 0.04 mmol) at 0 ꢁC. The reaction mixture
was stirred at room temperature for 12 h, and then solid sodium
sulfite (0.3 g) was added and stirred for 30 min. The solvent was
removed under reduced pressure; residue was extracted with ethyl
acetate (3ꢂ25 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure, to the crude solution of the diol in MeOH/H2O
(10 mL, 8:2), was added sodium metaperiodate (0.65 g, 3.03 mmol)
at 0 ꢁC and stirred at same temperature for 4 h. The reaction mixture
was quenched with ethylene glycol (0.1 mL). The solvent was re-
moved under reduced pressure; residue was extracted with ethyl
acetate (3ꢂ25 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, concentrated under re-
duced pressure to give aldehyde 12, which was used for next step
without any purification. The crude aldehyde 12 (0.50 g, 2.02 mmol)
and 10% Pd/C (40 mg) in MeOH (20 mL) was subjected to hydroge-
nation at room temperature at 100 psi. After 24 h the solution was
filtered through a pad of Celite, washed with MeOH. The solvent was
evaporated under reduced pressure to afford crude morpholine 13,
which was used for next step without any purification.
(300 MHz, CDCl3) 2.54 (br s, 2H), 2.71–2.76 (m, 2H), 3.48 (dd, 1H,
J¼7.2, 11.1 Hz), 3.64 (dd, 1H, J¼3.0, 11.4 Hz), 3.89–3.92 (m, 1H),
7.17–7.31 (m, 5H); dC (75 MHz, CDCl3) 39.6, 65.6, 72.9, 126.2, 128.3,
137.8.
4.1.11. (R)-1-Azido-3-phenylpropan-2-ol 16. Compound 16 (0.92 g,
88%) was obtained from diol 15 (0.9 g, 5.92 mmol) using the same
25
procedure for the preparation of 10 from 9; colorless oil. [a]
D
24
þ2.71 (c 2.1, CHCl3); {lit.19
[
a
]
D
þ2.76 (c 2.1, CHCl3)}. [Found: C,
61.16; H, 6.33; N, 23.67%. required C9H11N3O C, 61.00; H, 6.26; N,
23.71%]; Rf (20% ethyl acetate/hexane) 0.45; nmax (CH2Cl2) 3416,
2924, 2102, 1494, 1452, 1282, 1084 cmꢀ1
; dH NMR (300 MHz,
CDCl3): 2.0 (br s, 1H), 2.78–2.81 (m, 2H), 3.28 (dd, 1H, J¼6.6,
12.6 Hz), 3.37 (dd, 1H, J¼3.6, 12.3 Hz), 3.95–4.03 (m, 1H), 7.20–7.36
(m, 5H). dC (75 MHz, CDCl3) 40.7, 55.7, 71.5, 126.5, 128.4, 129.1,
136.9.
4.1.12. Mosher’s ester of alcohol (ꢃ)-1620. Mosher ester of alcohol
(ꢃ)-16 was prepared by using the same procedure as described for
the preparation of Mosher ester of (ꢃ)-10; colorless oil. Rf (10% ethyl
acetate/hexane) 0.45; dH NMR (400 MHz, CDCl3) 2.87 (dd, 1H, J¼7.0,
14.0 Hz), 2.96–3.04 (m, 3H), 3.39–3.41 (m, 2H), 3.42 (s, 3H), 3.49–3.50
(m,1H), 3.51 (s, 3H), 3.53–3.57 (m,1H), 5.36–5.45 (m, 2H), 7.09–7.47
(m, 20H).
To a stirred solution of crude morpholine 13 (0.23 g, 2.02 mmol)
in dioxane/H2O (6 mL, 3:1) were added NaHCO3 (0.20 g, 2.42 mmol)
and (Boc)2O (0.46 mL, 2.02 mmol) at room temperature. After 4.5 h
reaction mixture was diluted with water and extracted with ethyl
acetate (3ꢂ20 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography using ethyl acetate/hexane (30:70) to give pure
4.1.13. Mosher’s ester of alcohol (þ)-16. Colorless oil. Rf (10% ethyl
acetate/hexane) 0.45; dH NMR (500 MHz, CDCl3) 2.87 (dd, 1H, J¼7.1,
13.8 Hz), 2.98 (dd, 1H, J¼7.13, 13.3 Hz), 3.39 (dd, 1H, J¼4.0, 13.3 Hz),
3.51 (s, 3H), 3.55 (dd, 1H, J¼7.3, 13.0 Hz), 5.35–5.41 (m, 1H), 7.09–
7.41 (m, 10H).
N-Boc-morpholine 5 (0.25 g, 57% over four steps) as a colorless solid,
4.1.14. 1-(R)-2-(Allyloxy-3-azidopropyl)benzene 17. Compound 17
(0.72 g, 98%) was obtained from alcohol 16 (0.6 g, 3.38 mmol) using
25
mp 59–61 ꢁC [
a
]
ꢀ20.5 (c 1.0, CHCl3), {lit.6 (for (S)-enantiomer) mp.
D
20
60–62 ꢁC. [
a]
þ20.7 (c 1.01, CHCl3)}. [Found: C, 63.05; H, 6.98, Br,
the same procedure for the preparation of 11 from 10; colorless oil.
D
25
17.08%. C10H19NO4 required C, 63.14; H, 6.93; N,16.99%]; Rf (30% ethyl
acetate/hexane) 0.20; nmax (CHCl3) 3437, 2974, 2866, 1689, 1267,
[a
]
þ41.2 (c 1, CHCl3). [Found C, 66.42; H, 6.83; N, 19.46%.
D
C12H15N3O required C, 66.34; H, 6.96; N, 19.34%]; Rf (10% ethyl ac-
etate/hexane) 0.45; nmax (CH2Cl2) 3026, 2924, 2856, 2100, 1645,
1168, 1126 cmꢀ1
; dH (300 MHz, CDCl3) 1.46 (s, 9H), 1.79 (br s, 1H),
2.70–2.96 (m, 2H), 3.48–3.69 (m, 4H), 3.83–3.91 (m, 3H); dC (75 MHz,
1458, 1375, 1284, 1097 cmꢀ1
; dH (300 MHz, CDCl3) 2.77 (dd, 1H,
CDCl3) 28.4, 43.4, 44.9, 63.4, 66.3, 75.7, 80.1, 154.6.
J¼6.9, 13.8 Hz), 2.90 (dd, 1H, J¼6.3, 13.8 Hz), 3.15–3.27 (m, 2H),
3.65–3.71 (m, 1H), 4.01–4.03 (m, 2H), 5.16 (dd, 1H, J¼1.2, 10.2 Hz),
5.25 (dd, 1H, J¼1.5, 17.4 Hz), 5.79–5.92 (m, 1H), 7.16–7.30 (m, 5H); dC
NMR (75 MHz, CDCl3) 38.4, 53.2, 70.9, 79.2, 117.1, 126.3, 128.3, 129.2,
134.30, 137.3.
4.1.9. N-(3,4-Dichlorobenzyl)(R)-2-hydroxymethylmorpholine 6. To
a stirred solution of crude morpholine 13 (0.23 g, 2.02 mmol) in
CH3CN (5 mL) were added K2CO3 (0.31 g, 0.221 mmol) and 3,4-
dichlorobenzyl bromide (0.48 g, 2.02 mmol) at room temperature
and stirred for 5 h. The reaction mixture was diluted with water
(2 mL) and extracted with ethyl acetate (3ꢂ20 mL) The combined
organic extracts was washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to afford crude
N-benzylmorpholine, which was purified by silica gel chromatog-
4.1.15. (R)-2-Benzyl morpholine 4. Compound 4 (0.23 g, 57%) was
obtained from olefin 17 (0.5 g, 2.34 mmol) using the same pro-
25
cedure for the preparation of 13 from 11; colorless oil. [
a
]
D
þ1.28
20
(c 5, CHCl3), {lit.5b
[
a
]
D
þ1.32 (c 5, CHCl3)}. [Found C, 74.65; H, 8.60;
N, 7.79%. C11H15NO required C, 74.54; H, 8.53; N, 7.90%]; Rf (10%
MeOH/CHCl3) 0.30; nmax (CH2Cl2) 3432, 2924, 2852, 1494, 1452,
raphy using ethyl acetate/hexane (70:30) to give pure N-benzyl-
morpholine 6 (0.30 g, 54% over four steps) as a thick liquid. [
25
a
]
1273, 1095 cmꢀ1
; dH (300 MHz, CDCl3) 1.91 (br s, 1H), 2.53–2.66
D
ꢀ5.24 (c 0.4, CHCl3). [Found: C, 52.34; H, 5.36; N,
5.19%.C12H15Cl2NO2 required C, 52.19; H, 5.47; N, 5.07%]; Rf (70%
ethyl acetate/hexane) 0.30; nmax (CHCl3): 3443, 2928, 1456, 1288,
(m, 2H), 2.75–2.91 (m, 4H), 3.53–3.66 (m, 2H), 3.84–3.88 (m, 1H),
7.16–7.28 (m, 5H). dC NMR (75 MHz, CDCl3) 40.4, 45.8, 50.9, 68.1,
77.6, 126.1, 128.2, 129.1, 137.7.
1184, 1041, 820, 667 cmꢀ1
; dH NMR (300 MHz, CDCl3) 2.12–2.33 (m,
2H), 2.74–2.83 (m, 3H), 3.52–3.66 (m, 3H), 3.75–3.93 (m, 3H), 7.22–
7.46 (m, 3H); dC NMR (75 MHz, CDCl3) 52.7, 54.3, 61.8, 63.8, 66.2,
75.7, 126.4, 130.2, 130.8, 131.2, 132.2, 137.6.
Acknowledgements
R.T.S. thankful to CSIR, New Delhi, for the award of senior re-
search fellowship. We are grateful to BCUD and Shimadzu Analyt-
ical Centre, University of Pune for financial assistance and spectral
analysis, respectively.
4.1.10. (R)-3-Phenyl propan-1,2-diol 15. Compound 15 (0.98 g, 69%)
was obtained from aldehyde 14 (2.16 g, 12.1 mmol) using the same

2014
R.T. Sawant, S.B. Waghmode / Tetrahedron 66 (2010) 2010–2014
Aug. 8, 1994; CAN 114, 81222. (c) Carruthers, N.I.; Gomez, L.A.; Jablonowski, J.A.;
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