Lewis acid mediated SN2-type nucleophilic ring opening followed by [4+2] cycloaddition of N-tosylazetidines with aldehydes and ketones: synthesis of chiral 1,3-oxazinanes and 1,3-amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2007.04.097

A highly efficient strategy for Cu(OTf)₂ mediated S_N2-type nucleophilic ring opening followed by [4+2] cycloaddition reactions of enantiopure 2-phenyl-N-tosylazetidines with various aldehydes and ketones afforded a variety of substit

Full text of DOI:10.1016/j.tetlet.2007.04.097

Tetrahedron Letters 48 (2007) 4373–4377
Lewis acid mediated S 2-type nucleophilic ring opening
N
followed by [4+2] cycloaddition of N-tosylazetidines
with aldehydes and ketones: synthesis of chiral
1
,3-oxazinanes and 1,3-amino alcohols
*
Manas K. Ghorai, Kalpataru Das and Amit Kumar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 29 January 2007; revised 10 April 2007; accepted 19 April 2007
Available online 22 April 2007
Abstract—A highly efficient strategy for Cu(OTf) mediated S 2-type nucleophilic ring opening followed by [4+2] cycloaddition
2
N
reactions of enantiopure 2-phenyl-N-tosylazetidines with various aldehydes and ketones afforded a variety of substituted 1,3-oxa-
zinanes and 1,3-amino alcohols in excellent yields, excellent de and good to excellent ee. The proposed S
the cycloaddition reaction is supported by experimental evidence.
N
2-type mechanism of
ꢀ
2007 Elsevier Ltd. All rights reserved.
Azetidines are an important class of small ring N-het-
erocycles found in many naturally occurring and syn-
thetically important organic compounds, which exhibit
dines, herein, we report a highly efficient strategy for
Lewis acid mediated nucleophilic ring opening of 2-phen-
yl-N-tosylazetidines in polar and coordinating solvents
1
interesting biological and pharmacological properties.
via an S 2 pathway, followed by a [4+2] cycloaddition
N
In recent years, azetidines have been utilized in fragmen-
with carbonyl compounds to give non-racemic 1,3-oxa-
zinanes and 1,3-amino alcohols. All these compounds
are of considerable synthetic and pharmacological util-
2
3a–c
tation, ring opening
or in association with ring
3
d–g
4
expansion
and cycloaddition reactions to generate
7
–9
a wide variety of nitrogen-containing compounds. In
spite of the great synthetic potential, the chemistry of
azetidines has not been much explored, probably
ity. There are only a few reports in the literature on
7
a,b
the synthesis of oxazinanes,
bonyl equivalents
which are important car-
7
d,e
and have been used for the synthe-
5
8
because of their exceptional stability and the lack of
ses of several biologically important molecules. In the
present paper, we report for the first time, a direct syn-
thesis of non-racemic 1,3-oxazinanes via ring opening of
enantiopure 2-phenyl-N-tosylazetidine followed by
[4+2] cycloaddition reactions with various carbonyl
compounds. The oxazinanes are easily converted to c-
amino alcohols, which are important precursors in
availability of suitable methodologies. To date, BF3Æ
OEt mediated nucleophilic ring opening or [4+2] cyclo-
2
addition of 2-aryl-N-sulfonylazetidines are known where
the reaction is believed to proceed through a stable 1,4-
4
a–c
dipolar intermediate.
Hence, the possibility of a
stereoselective version of such reactions is restricted.
9
Recently, we reported the ZnX (X = I, OTf) mediated
medicinal chemistry. Our observations provide con-
2
nucleophilic ring opening of 2-aryl-N-sulfonylazetidine
leading to c-iodoamines and tetrahydropyrimidines.
vincing evidence that the cycloaddition proceeds
6
through an S 2-type pathway, and not through the
N
intermediacy of a stable 1,4-dipolar intermediate as
invoked earlier.
In continuation of our synthetic and mechanistic inves-
tigations towards the chemistry of N-activated azeti-
In order to elucidate the mechanism of nucleophilic ring
opening of 2-phenyl-N-tosylazetidine 1, we studied its
fate in the presence of a Lewis acid (LA) in polar and
coordinating solvents and discovered an unprecedented
rearrangement to allylamine 2 as shown in Scheme 1.
Our study began with the nucleophilic ring opening of
Keywords: N-Tosylazetidine; Nucleophilic; Ring opening; Carbonyl;
Lewis acid; Cu(OTf)
2
; [4+2] Cycloaddition; 1,3-Oxazinane; 1,3-Amino
2; Mechanism.
Corresponding author. Tel.: +91 512 2597518; fax: +91 512
597436; e-mail: mkghorai@iitk.ac.in
alcohol; Non-racemic; S
N
1
0
*
2
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.097

4374
M. K. Ghorai et al. / Tetrahedron Letters 48 (2007) 4373–4377
Ph
Ts
formed in CH Cl using 5 equiv of the aldehyde and
2 2
Cu(OTf)2 (1.0 equiv.)
DMSO, 65 oC, 2 h
N
Ts
identical results were obtained. The progress of the reac-
tion was comparatively slow when the reaction was per-
formed using fewer equivalents of the Lewis acid,
1 equiv of the LA was necessary for completion of the
reaction. Racemic 1 reacted smoothly with various alde-
hydes in CH Cl at ambient temperature to produce
Ph
N
H
1
2
Scheme 1. Ring opening rearrangement of 2-phenyl-N-tosylazetidine.
2
2
trans-1,3-oxazinanes 4a–f, stereoselectively (de 92–
99%), in very high yields and the results are summarized
in Table 1. All the products were fully characterized by
spectroscopic techniques and elemental analyses. The
trans stereochemistry of the 1,3-oxazinanes was deter-
mined by NOE measurements. Further the structure of
1,3-oxazinane 4c was unambiguously confirmed by
Ph
Ts
O
R
O
Ph
Cu(OTf)2
N
+
R
H
N
CH Cl2
2
Ts
rt, 5 min
1
3
4
R = a: C H , b: C H , c: CH Ph, d: Ph e: -CH=CH-Ph, f: furyl
2
5
3
7
2
Scheme 2. Cu(OTf)
tosylazetidine 1 with aldehydes.
2
promoted [4+2] cycloaddition of 2-phenyl-N-
1
3
X-ray crystallography (Fig. 1).
2
-phenyl-N-tosylazetidine 1 using acetone as the polar
To investigate the mechanism of the cycloaddition we
carried out the reaction with enantiomerically pure
coordinating solvent in the presence of Cu(OTf)2 as
the LA at ambient temperature. The corresponding
1
1
4
(S)-1 (ee >99%). The enantioselectivity for the cyclo-
addition of (S)-1 with benzaldehyde in CH Cl as the
,3-amino alcohol 6 was obtained in 85% yield instead
2
2
of 2 via a [4+2] cycloaddition reaction with acetone fol-
lowed by hydrolysis within a very short period of time
solvent was found to be poor (ee 18%). However, the
ee increased gradually with increasing concentration of
benzaldehyde (Fig. 2) and the maximum ee (75%) was
obtained when benzaldehyde (neat) was used as the sol-
vent (Table 1, entry 4). A number of aldehydes were
studied with (S)-1 and good enantioselectivity was ob-
served in all the cases (Table 1). Little enhancement in
(
Scheme 3). This observation prompted us to explore
the ring opening of azetidines with carbonyl compounds
and to investigate the mechanism of the reaction. Inter-
estingly, when racemic 1 was treated with Cu(OTf) as
2
the Lewis acid and benzaldehyde as the solvent at ambi-
1
1
ent temperature, the corresponding trans-1,3-oxaz-
the enantioselectivity was noted when BF
ÆOEt or
3 2
1
2
inane 4d was produced stereoselectively (de >99%) in
Zn(OTf) was used as the Lewis acid. 1,3-Oxazinanes
2
9
2
0% yield via a [4+2] cycloaddition reaction (Scheme
). For easy purification, the same reaction was per-
derived from ketones were found to be comparatively
less stable and during work-up, these were hydrolyzed
a
2
Table 1. Cu(OTf) promoted [4+2] cycloaddition of 2-phenyl-N-tosylazetidine 1 with aldehydes
b
c
d
Entry
Carbonyl
Product
4 de (%)
ee (%)
Yield (%)
Pr
O
O
Ph
Ph
1
2
PrCHO
4a (94)
4b (92)
63
59
93
90
N
N
Ts
Et
EtCHO
Ts
PhH C
O
Ph
2
e
3
2
PhCH CHO
4c (94)
62
89
N
Ts
Ph
Ts
O
Ph
Ts
4
5
PhCHO
4d (>99)
4e (>99)
75
65
90
85
N
N
CHO
Ph
Ph
O
Ph
O
Ph
O
6
4f (>99)
63
92
O
CHO
N
Ts
Reaction conditions:
a
1
.0 equiv of Cu(OTf)
2
, 5 equiv of aldehyde, unless otherwise mentioned all the reactions were performed in CH Cl for 5 min at 25 ꢁC.
2 2
b
c
1
De was determined from the H NMR of the crude reaction mixture.
Determined by chiral HPLC, (S)-1 was used and the aldehyde served as the solvent.
Yield of the isolated trans diastereomer.
d
e
Trans stereochemistry was determined by single-crystal X-ray analysis.

M. K. Ghorai et al. / Tetrahedron Letters 48 (2007) 4373–4377
4375
(
1) were the same. The formation of 6 with inverted
stereochemistry (R) confirms the involvement of an
SN2-type pathway in the ring opening reaction of
(
S)-1 by carbonyl compounds.
Based on, (i) the exclusive formation of trans-substi-
tuted-1,3-oxazinanes 4d–f from the cycloaddition of
racemic 1 with aldehydes and, (ii) the formation of
non-racemic 1,3-oxazinanes and c-amino alcohols with
inverted stereochemistry from the cycloaddition of
enantiomerically pure (S)-1 with different aldehydes
and ketones, respectively, we believe that the cycloaddi-
tion reaction proceeds through the mechanism shown in
Scheme 4. The reactive species 7 undergoes S 2-type
N
nucleophilic ring opening followed by cyclization from
the si-face of the carbonyl functionality of 9 to produce
4
via a six-membered TS 10. The minor cis-diastereo-
Figure 1. Crystal structure of 4c (diamond view).
mers are formed because of possible cyclization from
the re-face of the aldehydes having smaller alkyl substit-
uents (Et, Pr). It is clear that the reaction does not pro-
ceed through a stable benzylic carbocation intermediate
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
8
from which a racemic product could be expected from
enantiomerically pure (S)-1 and in which 4 would have
been formed as a diastereomeric mixture from racemic
1
the cases being due to partial racemization (through a
reversible ring opening and closing step) of the starting
azetidine (S)-1 before the nucleophilic ring opening step
. We rationalized the reduced enantioselectivity in all
1
6
(
Scheme 4).
The scope of the methodology was further extended for
the cycloaddition of enantiomerically pure cis-(2S,4S)-2-
ethyl-4-phenyl-1-tosylazetidine 11 with benzaldehyde
in CH Cl to give highly substituted oxazinane
1
4
2
2
(
2R,4S,6R)-4-ethyl-2,6-diphenyl-3-tosyl-1,3-oxazinane 12
with 4,6-trans geometry as the major diastereomer
12:13 89:11) in 90% combined yield (Scheme 5). The rel-
(
0
20
40
60
80
100
ative stereochemistry of oxazinanes 12 and 13 was deter-
mined by NOE measurements (Fig. 3). In this case, the
relative stereochemistry of the starting azetidine 11 at
C4 had been inverted in cycloaddition product 12. The
synthetic significance of the method was further demon-
strated by the facile conversion of the inseparable diaste-
reomeric mixture of cycloadducts 12 and 13 into two
diastereo- and enantiomerically pure substituted-1,3-
amino alcohols 14 and 15, by treatment with PTSA in
MeOH (Scheme 5). 1,3-Amino alcohols 14 and 15 were
obtained in pure forms by simple column chromato-
graphic separation.
Vol % of PhCHO
Figure 2. Effect of concentration of PhCHO on the % ee of 4d.
1
5
to c-amino alcohol 6. (S)-1 provided non-racemic 6 in
5% yield with 62% ee when acetone was used as the sol-
1
7
8
vent. 1,3-Oxazinane 4d was easily hydrolyzed to the
same amino alcohol 6 employing PTSA in MeOH
(
Scheme 3). The absolute stereochemistry of the major
enantiomer of 6 was determined by comparison with
the optical rotation and chiral HPLC analysis of an
authentic sample of (R)-6 (ee >98%) prepared from
(
S)-mandelic acid (ee >99%). The absolute configuration
To conclude, we have demonstrated that the nucleo-
of 1,3-amino alcohol 6 prepared from (S)-mandelic acid
and that obtained from (S)-2-phenyl-N-tosylazetidine
philic ring opening of 2-aryl-N-sulfonylazetidines pro-
ceeds through an S 2 pathway. We report for the first
N
Ph
Ts
O
OH
Ph
O
R
Cu(OTf)2
PTSA
N
+
R1
R2
Ph
NHTs
N
rt, 5 min
up to 85%
MeOH
Ts
rt, 3 h, 80%
1
5
6
4d
R = Ph
1
2
R = CH , C H ; R = CH ,
3
2
5
3
1
2
-
R , R = -(CH )
2
5
2
Scheme 3. Cu(OTf) promoted [4+2] cycloaddition of 2-phenyl-N-tosylazetidine 1 with ketones.

4376
M. K. Ghorai et al. / Tetrahedron Letters 48 (2007) 4373–4377
Ts
Ts
N
LA*
Ph
Ts
LA
N
1
N
Ph
Ph
O
LA
O
4
H
H
O
H
7
RCHO
R
R 9
10
R
Ph
N
Ts
*
2 3 2 2
LA = Cu(OTf) , BF .OEt or Zn(OTf)
8
Scheme 4. Proposed mechanism for the formation of 4 from 1.
Ph
O
Ph Ph
O
Ph
Ph
Ts
Et
O
Cu(OTf)2
CH Cl
rt, 20 min
PTSA
OH NHTs
OH NHTs
N
+
N
+
N
+
Ts
Ts
Ph
H
2
2
MeOH Ph
12 h
Et
Ph
Et
Et
Et
11
12
13
14
15
90% (dr: 89:11)
80% (ee: >99%)
Scheme 5. Cycloaddition of 2,4-disubstituted-N-tosylazetidine 11 with benzaldehyde.
V.; De Kimpe, N. Org. Lett. 2006, 8, 1105–1108; (f)
Golding, P.; Millar, R. W.; Paul, N. C.; Richards, D. H.
Tetrahedron 1995, 51, 5073–5082; (g) Vanecko, J. A.;
West, F. G. Org. Lett. 2005, 7, 2949–2952.
. (a) Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A.
Chem. Commun. 2001, 958–959; (b) Ungureanu, I.; Klotz,
P.; Schoenfelder, A.; Mann, A. Tetrahedron Lett. 2001, 42,
Ph
O
Ph
Ts
H
H
Et
N
Ph
O
Ph
N
12 Ts
H
Et 12
4
Figure 3. Diagnostic NOE observations for the oxazinane 12 (major
diastereomer).
6
087–6091; (c) Prasad, B. A. B.; Bisai, A.; Singh, V. K.
Org. Lett. 2004, 6, 4829–4831; (d) Yadav, V. K.;
Sriramurthy, V. J. Am. Chem. Soc. 2005, 127, 16366–
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6367; (e) Baeg, J.-O.; Bensimon, C.; Alper, H. J. Org.
time a direct synthesis of non-racemic 1,3-oxazinanes by
a [4+2] type cycloaddition of azetidines and carbonyl
compounds. Our strategy is very important as numerous
Chem. 1995, 60, 253–256; (f) Baeg, J.-O.; Bensimon, C.;
Alper, H. J. Org. Chem. 1995, 60, 3092–3095.
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1
Chemistry of Heterocyclic Compounds—Small Ring Het-
erocycles, Part 2; Hassner, A., Ed.; Wiley: New York,
5
1
,3-amino alcohols can be synthesized in enantiomeri-
cally pure forms starting from the appropriate chiral
disubstituted azetidines. Further applications of this
methodology are in progress in our laboratory.
984; Vol. 7, pp 237–284; (b) Moore, J. A.; Ayers, R. S. In
1
983; pp 1–217; (c) De Kimpe, N. In Three- and Four-
Membered Rings, With All Fused Systems Containing
Three- and Four-Membered Rings; Padwa, A., Ed.; Com-
prehensive Heterocyclic Chemistry II; Elsevier: Oxford,
Acknowledgements
1
996; Vol. 1, Chapter 1.21, (d) Gribble, G. W.; Joule, J. A.
M.K.G. is grateful to IIT-Kanpur and DST, India. K.D.
and A.K. thank IIT-Kanpur and CSIR, India,
respectively, for research fellowships. We gratefully
acknowledge Mr. Kuntal Pal for helping with X-ray
crystallographic analysis.
In Progress in Heterocyclic Chemistry; Elsevier: Oxford,
2004; Vol. 16, p 475.
6. Ghorai, M. K.; Das, K.; Kumar, A.; Das, A. Tetrahedron
Lett. 2006, 47, 5393–5397.
. Synthetic importance of 1,3-oxazinanes: (a) Wang, X.;
7
Dong, Y.; Sun, J.; Xu, X.; Li, R.; Hu, Y. J. Org. Chem.
2
005, 70, 1897–1900; (b) Zanatta, N.; Squizani, A. M. C.;
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Deb, P. K. Tetrahedron 2004, 60, 9171–9177; Biological
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K. K.; Floss, H. G.; Leistner, E. Chem. Pharm. Bull. 2004,
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References and notes
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Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.;
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+
8
. (a) Singh, H.; Singh, K. Tetrahedron 1989, 45, 3967–3974;
b) Singh, K.; Deb, P. K. Heterocycles 1999, 51, 1509–
512.
. Synthetic and biological importance of c-amino alcohols:
a) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71,
159–2162; (b) Cimarelli, C.; Giuli, S.; Palmieri, G.
141.0, 143.7; FAB Mass = m/z 394 (M +1). Anal. Calcd
for C23 S: C, 70.20; H, 5.89; N, 3.56. Found: C,
(
1
H23NO
3
70.02; H, 5.86; N, 3.41. When chiral (S)-1 (ee >99%) was
9
used and benzaldehyde served as the solvent, non-racemic
2
5
D
(
2
4d was obtained, optical rotation: ½aꢁ ꢀ19.30 (c 0.114,
3
CHCl ), with 75% ee [Chiracel AD-H column; hexane/
Tetrahedron: Asymmetry 2006, 17, 1308–1317; (c) Wessig,
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13. Crystallographic data of compound 4c in this Letter have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
643311. Copies of the data can be obtained free of charge,
on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
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2
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0. Ghorai, M. K.; Kumar, A.; Das, K., unpublished results.
1. General procedure for the Cu(OTf) mediated [4+2]
cycloaddition of 2-phenyl-N-tosylzetidine with carbonyl
compounds (Table 1): solution of azetidine
0.174 mmol) and carbonyl compound (0.870 mmol) in
1
1
2
15. Procedure for the synthesis of N-(3-hydroxy-3-phenylpro-
pyl)-4-methyl-benzenesulfonamide 6: The general proce-
A
1
(
2
dure described above for the Cu(OTf) mediated [4+2]
0
.7 mL of CH Cl was added to a suspension of anhy-
cycloaddition of 2-phenyl-N-sulfonylazetidine with car-
2
2
drous Cu(OTf)2 (0.174 mmol) in 0.3 mL of CH Cl at
bonyl compounds was followed except that ketone was
2
2
2
5 ꢁC under an argon atmosphere. The mixture was stirred
2 2
used as the solvent instead of CH Cl . The crude
for 5 min and then the reaction was quenched with
saturated aqueous NaHCO solution. The aqueous layer
was extracted with CH
anhydrous Na SO . The crude product was purified by
flash column chromatography on silica gel (230–400 mesh)
using 5% ethyl acetate in petroleum ether to provide the
pure product. When chiral (S)-2-phenyl-N-tosylazetidine
was used, non-racemic 4 was obtained. Greater enantio-
selectivity was observed when aldehydes or ketones were
used as the solvent. In the case of ketones, the cycload-
dition product was found to be very unstable and during
work-up was hydrolyzed to the substituted 3-amino-1-
phenyl-1-propanol.
compound was purified by flash column chromatography
on silica gel (Rf 0.36, EtOAc/petroleum ether 1:1) to
provide 3-amino alcohol 6 in up to 85% yield as a white
solid, with a mp of 118 ꢁC. When (S)-1 was used and
acetone served as the solvent, non-racemic 1,3-amino
3
2 2
Cl (3 · 5.0 mL) and dried over
2
4
25
alcohol 6 was obtained. Optical rotation: ½aꢁ +24.0 (c
D
3
0.20, CHCl ) for a 62% ee sample. Optical purity was
determined by chiral HPLC analysis (Chiralcel AD-H
column; hexane/isopropanol, 90:10; flow rate = 1.0 mL/
min). 1,3-Oxazinanes 4 derived from aldehydes were
hydrolyzed to the same amino alcohol 6 employing PTSA
in MeOH. N-(3-Hydroxy-3-phenylpropyl)-4-methyl-benz-
9
c
ꢀ1
enesulfonamide 6: IR mmax (KBr, cm ): 3453, 3176,
1
1
2. Characterization data of 2,6-diphenyl-3-(4-methylphenyl-
sulfonyl)-1,3-oxazinane 4d (Table 1, entry 4): Following
the general procedure outlined above, 2-phenyl-N-tosyl-
azetidine 1 was reacted with benzaldehyde to afford a
single trans diastereomer of 4d as a white solid in 90%
2922, 2868, 1596, 1322, 1155, 1094, 810, 747, 696, 549; H
3
NMR (400 MHz, CDCl ): d 1.75–1.80 (m, 2H), 2.36 (s,
3H), 2.95–3.01 (m, 1H), 3.06–3.13 (m, 1H), 4.73 (t,
J = 6.4 Hz, 1H), 7.15–7.25 (m, 7H), 7.67 (d, J = 8.3 Hz,
1
3
3
2H); C NMR (100 MHz, CDCl ): d 21.5, 37.6, 40.8,
yield. R
f
0.35 (EtOAc/petroleum ether, 1:4); mp 135 ꢁC;
73.1, 125.5, 127.1, 127.8, 128.6, 129.7, 136.8, 143.3, 143.6;
FAB Mass m/z = 306 (M +1).
ꢀ
1
+
IR mmax (KBr, cm ): 3057, 3028, 2965, 2924, 2845, 2370,
1
7
1
598, 1491, 1451, 1330, 1213, 1157, 1056, 976, 925, 814,
16. With increasing concentration of the carbonyl compound,
(i) the concentration of the nucleophile increases and, (ii) 7
is better stabilized in more polar medium, thus the
enantioselectivity of 4 is enhanced. In CH Cl , racemiza-
1
39, 691, 649, 584; H NMR (400 MHz, CDCl
3
): d 1.14–
.28 (m, 2H), 2.41 (s, 3H), 3.35–3.43 (m, 1H), 3.88–3.93
(
m, 1H), 4.57 (dd, J = 11.5, 2.7 Hz, 1H), 6.84 (s, 1H),
2
2
6
7
.86–6.88 (m, 2H), 7.17–7.21 (m, 3H), 7.26–7.38 (m, 5H),
tion of the starting azetidine (S)-1 is appreciable and hence
the enantioselectivity is reduced.
17. Although 12 and 13 are inseparable by TLC or simple
column chromatography, they were separated by HPLC.
1
3
.45–7.47 (m, 2H), 7.90 (d, J = 8.04 Hz, 2H); C NMR
): d 21.5, 30.1, 40.2, 71.3, 84.4, 125.8,
27.0, 127.8, 127.9, 128.3, 128.4, 129.1, 129.8, 135.9, 138.1,
(
100 MHz, CDCl
3
1