A smooth rearrangement of N-p-toluenesulfonyl 2-tert- butyldiphenylsilylmethyl-substituted azetidines into N-p-toluenesulfonyl 3-tert-butyldiphenylsilyl-substituted pyrrolidines

Article abstract of DOI:10.1039/c2ob07140a

The rearrangement of N-p-toluenesulfonyl 2-tert-butyldiphenylsilylmethyl- substituted azetidines into 3-tert-butyldiphenylsilyl-substituted pyrrolidines under Lewis acid conditions in dichloromethane involves 1,2-migration of silicon through a siliranium ion. The formation of siliranium ion was discovered not to be in concert with σ_C-N cleavage from stereochemical analysis of the pyrrolidine products formed from 3- and 4-substituted-2-tert- butyldiphenylsilylmethyl azetidines and also from the optical rotation data and chiral HPLC analysis of the pyrrolidine product formed from N-p-toluenesulfonyl 2(R)-tert-butyldiphenylsilylmethyl azetidine. The formation of sterically less hindered siliranium ion is followed by its S_N2 opening by the internal nitrogen nucleophile. Oxidative cleavage of σ_C-Si bond leads to the formation of 3-hydroxypyrrolidines.

Full text of DOI:10.1039/c2ob07140a

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PAPER
A smooth rearrangement of N-p-toluenesulfonyl 2-tert-butyldiphenyl-
silylmethyl-substituted azetidines into N-p-toluenesulfonyl
3-tert-butyldiphenylsilyl-substituted pyrrolidines†
Bharat D. Narhe, Vardhineedi Sriramurthy‡ and Veejendra K. Yadav*
Received 20th December 2011, Accepted 3rd April 2012
DOI: 10.1039/c2ob07140a
The rearrangement of N-p-toluenesulfonyl 2-tert-butyldiphenylsilylmethyl-substituted azetidines into
3-tert-butyldiphenylsilyl-substituted pyrrolidines under Lewis acid conditions in dichloromethane
involves 1,2-migration of silicon through a siliranium ion. The formation of siliranium ion was
discovered not to be in concert with σC–N cleavage from stereochemical analysis of the pyrrolidine
products formed from 3- and 4-substituted-2-tert-butyldiphenylsilylmethyl azetidines and also
from the optical rotation data and chiral HPLC analysis of the pyrrolidine product formed from
N-p-toluenesulfonyl 2(R)-tert-butyldiphenylsilylmethyl azetidine. The formation of sterically less
hindered siliranium ion is followed by its SN2 opening by the internal nitrogen nucleophile. Oxidative
cleavage of σC–Si bond leads to the formation of 3-hydroxypyrrolidines.
Introduction
We have previously communicated on the rearrangement of
( )-N-p-toulenesulfonyl-2-tert-butyldiphenylsilylmethylazetidine,
1a, into ( )-3-tert-butyldiphenylsilylpyrrolidine, 3a, on exposure
to BF3·Et2O in CH2Cl2 (Scheme 1).1 The process was envi-
Scheme 1 Rearrangement of ( )-N-p-toluenesulfonyl 2(R)-tert-butyldi-
phenylsilylmethylazetidine into ( )-3-tert-butyldiphenylsilylpyrrolidine.
sioned to involve silicon migration through the siliranium
species 2.2 Intramolecular SN2 capture of the siliranium ion by
the nitrogen anion in 5-exo-trig fashion resulted in the formation
The ease of the above azetidine → pyrrolidine rearrangement
of the observed ( )-3-tert-butyldiphenylsilylpyrrolidine, 3a. The
coupled with the significant pharmacological activities associ-
heterolysis of the σC–N bond in the azetidine is rendered facile
ated with the pyrrolidines6 prompted us to explore this reaction
by the combined electron-withdrawing effect of the sulfone func-
in detail to (a) study tolerance to additional substituents on the
tion which is enhanced further on complexation with a Lewis
azetidine ring with a view to generate differently substituted
acid such as BF3·Et2O and the β-cation stabilizing effect of
pyrrolidines, and (b) delineate the influence of an additional
silicon.3,4 The large substituents on silicon prevented its loss in
ring-substituent on the relative stereochemistry in the product.
Sakurai fashion5 by effectively shielding it from any nucleophile
We describe the details of our results herein and demonstrate that
(a) the azetidine → pyrrolidine rearrangement is general in
nature for fruitful synthetic exploitation, (b) the σC–N cleavage
and the siliranium ion formation are non-concerted, and (c) the
that may be present in the reaction medium. Pyrrolidines are ubi-
quitous natural products with desirable pharmacological activi-
ties.6 In addition, small molecule heterocycles play a pivotal role
in the drug discovery process.7
silicon-substituents control the formation of the less hindered
siliranium ion in instances where the azetidine ring has an
additional substituent. Since the tert-butyldiphenylsilyl group is
a latent hydroxyl group,1,4h–i,8 the present protocol may be
Department of Chemistry, Indian Institute of Technology, Kanpur 208
016, India. E-mail: vijendra@iitk.ac.in; Fax: +91-512-259-7436; Tel:
+91-512-259-7439
viewed as one that generates substituted 3-hydroxypyrrolidines.
†Electronic supplementary information (ESI) available: Electronic sup-
plementary data H and 13C NMR spectra (PDF) of all new compounds
1
Results and discussion
and CIFs for 1a, 1f2, 3c1, 3c2, 3e1, 5a (R = benzyl) and 5b (R = p-
fluorophenyl). CCDC 859591–859597. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2ob07140a
‡Current address: Chemical Development, TCI America, 9211
N. Harborgate Street, Portland, OR 97203, USA
For our studies, we prepared the chiral azetidines 1b–1g by fol-
lowing the reactions given in Scheme 2. The addition of
an ester-derived enolate to the imine formed from condensation
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of α-tert-butyldiphenylsilylacetaldehyde and (S)-p-toluenesulfi-
namide in the presence of ClTi(i-PrO)3 generated the product 5
as a diastereomeric mixture. The diastereoisomeric excess was
dependent on the ester : ClTi(i-PrO)3 stoichiometry as also
observed previously by Tang and Ellman.9a We have optimized
this reaction for the (S)-p-toluenesulfinylimine of 2-tert-butyl-
diphenylsilylacetaldehyde and discovered that usage of 1 : 2 stoi-
chiometry was optimum to achieve a high diastereoisomeric
excess (>98 : 2). However, for the present work, we have
used the 1 : 1 stoichiometry to allow us isolate the minor diaster-
eoisomers in decent quantities to study their reactions as well
to delineate stereochemical issues. The diastereoisomeric ratios
obtained for different esters are collected in Table 1.
The diastereoisomeric mixtures of 5a and 5b were separated
into the individual components by either gravity column or
radial chromatography. The stereostructures of 5a (R = benzyl)
and 5b (R = p-fluorophenyl) were confirmed by X-ray structure
analysis (see Fig. 1). The sulfinyl group in 5 was oxidized to the
sulfone 6 by m-CPBA in CH2Cl2. The ester group in 6
was reduced to the alcohol 7 by LiAlH4. Finally, ring closure
via p-toluenesulfonate under basic conditions10 for 1° alcohols
with alkyl substituents and under Mitsunobu conditions11a for 1°
alcohols with aryl substituents and all the 2° alcohols generated
the azetidines 1b–1g. The p-toluenesulfonate pathway for ring
closure of 1° alcohols with aryl substituents and the 2° alcohols
suffered from noticeable isomerization and resulted in the for-
mation of diastereoisomeric mixtures.
Preparation of the azetidines 1h1 and 1h2 commenced from
the enantiomerically pure alcohol 7 (R = H) as shown in
Scheme 3. Oxidation of 7 by pyridinium chlorochromate gener-
ated 8 which reacted with Me3SiCH2MgBr to generate the
alcohol 9 as a 3 : 2 diastereomeric mixture. The transformation
9 → 10 via Peterson olefination was best achieved by the appli-
cation of concentrated sulfuric acid in THF at 25 °C; reactions
using trifluoroacetic acid in CH2Cl2 (−78 °C–25 °C, 8 h) and p-
toluenesulfonic acid in THF (25 °C, 3 h) returned the starting
material and reactions with BF3·OEt2 in CH2Cl2 at 0 °C resulted
in severe decomposition. Dihydroxylation of 10 to 11 and selec-
tive TBDPS-protection of the 1° alcohol generated a 1.3 : 1 dia-
stereomeric mixture of 12. Chromatographic separation resulted
Table 1 Diastereomeric ratios obtained from the addition of different
ester enolates using 1 : 1 ester : ClTi(i-PrO)3 stoichiometry
Entry Ester
Time (h) Yield % (dr = 5a/5b)
1
2
3
4
5
6
7
CH3CO2Me
C2H5CO2Me
CH2vCHCH2CH2CO2Me 4.0
PhCH2CH2CO2Me
CH2vCHCH2CO2Me
PhCH2CO2Me
3.0
3.5
87 (14 : 1)
90 (1.8 : 1)
84 (1.2 : 1)
86 (3.7 : 1)
85 (1.1 : 1)
91 (4.4 : 1)
93 (3 : 1)
Scheme 2 General protocol for the preparation of N-p-toluenesulfonyl
2-tert-butyldiphenylsilylmethylazetidines: reagents and conditions: (a)
(i) LDA, THF, −0 °C (ii) ClTi(i-OPr)3, −78 °C (iii) (S)-tert-
BuPh2SiCH2CHvNS(O)C6H4CH3-p, −78 °C, ∼90%; (b) m-CPBA,
DCM, 0–25 °C; (c) LiAlH4, THF, 0–25 °C, >90% over the steps (b) and
(c); (d) Ph3P, DIAD, C6H6, 0 °C–rt, >90%; (e) TsCl, KOH, THF, >90%.
3.0
3.0
4.0
4.0
4-F-C6H4CH2CO2Me
Fig. 1 X-ray crystal structures of (i) 5a (R = benzyl) and (ii) 5b (R = p-fluorophenyl).
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in the isolation of the two alcohols that were separately subjected
to ring closure under Mitsunobu conditions to obtain the corre-
sponding azetidines.
Other than correlating to the stereochemical features present in
the open chain precursors, the cis- and trans-dispositions of the
azetidine substituents were discerned from nOe studies as well in
several instances. Irradiation of CH3 (δ 0.65) in 1b1 enhanced
C2-H (δ 3.85–3.80) resulted in 18% enhancement of the signal
due to the ortho-hydrogen atoms of the C3-phenyl group
(δ 5.64). The two substituents on the azetidine ring are, there-
fore, trans to each other. In 1e1, irradiation of one of the two
TBDPSCH2 hydrogen atoms (δ 1.47) enhanced the signal due to
̲
the ortho-hydrogen atoms of the p-fluorophenyl group (δ 6.67)
by 9% and indicated a cis-relationship of the substituents. In 1e2,
irradiation of C2-H (δ 3.80–3.74) enhanced the signal due to the
ortho-hydrogen atoms of the p-fluorophenyl group (δ 5.55) and
established the trans-relationship of the substituents.
the signal for one of the two hydrogen atoms in TBDPSCH2
̲
(δ 1.58) by 4% to establish cis disposition of the substituents.
Such an enhancement was not observed in 1b2. However,
irradiation of CH3 (δ −0.11) resulted in 7% enhancement of the
signal for C2-H (δ 3.43) to indicate trans disposition of the sub-
Irradiation of one of the two TBDPSCH2 hydrogen atoms
̲
(δ 1.77) in 1g1 caused 7.6% enhancement of the signal arising
from the internal olefinic hydrogen (δ 5.70–5.62). In 1g2,
irradiation of C3-H (δ 2.58) enhanced the signal arising from
stituents. In 1c1, irradiation of one of the two PhCH2
atoms (δ 2.59) enhanced the signal for one of the two
TBDPSCH2 hydrogen atoms (δ 1.84) by 4%. In contrast, in 1c2,
irradiation of one of the two PhCH2 hydrogen atoms (δ 2.13)
̲
hydrogen
̲
one of the two TBDPSCH2 hydrogen atoms (δ 1.87) by 3.4%.
̲
̲
Additionally, irradiation of the internal olefinic hydrogen
(δ 4.54–4.46) caused 2.2% enhancement of C2-H (δ 3.62–3.57).
These nOe results are in agreement with the cis- and trans-
stereostructural assignments of 1g1 and 1g2, respectively. Finally,
in 1h1, irradiation of one of the two C3-hydrogen atoms (δ 1.50)
showed, respectively, 3% and 2% enhancements of the signals
resulted in 5% enhancement of the signal for C2-H
(δ 3.66–3.62). These nOe results favor, respectively, the cis- and
trans-relationships of the substituents in 1c1 and 1c2.
Irradiation of one of the two TBDPSCH2 hydrogen atoms
̲
(δ 1.53) in 1d1 resulted in 2% enhancement of the signal due to
the ortho-hydrogen atoms of the C3-phenyl group (δ 6.77–6.74)
to favor cis-relationship of the substituents. In 1d2, irradiation of
arising from one of the two TBDPSCH2
̲
(δ 1.73) and
TBDPSOCH2 (δ 3.78) hydrogen atoms. Such a dual enhance-
̲
ment feat was absent in 1h2. Clearly, 1h1 and 1h2 have their sub-
stituents cis and trans to each other, respectively. The absolute
stereostructures of 2(R)-N-p-toulenesulfonyl 2-tert-butyldiphe-
nylsilylmethylazetidine, 1a, and 1f2 were secured from X-ray
structures (Fig. 2).
The results of azetidine → pyrrolidine rearrangement are
collected in Table 2. The reactions of 3-methyl-, 3-benzyl-, 3-
phenyl-, 3-p-fluorophenyl-, 3-allyl- and 3-vinyl-2-tert-butyldi-
phenylsilylmethylazetidines generated 4-methy, 4-benzyl-, 4-
phenyl-, 4-p-fluorophenyl-, 4-allyl- and 4-vinyl-3-tert-butyldi-
phenylsilylpyrrolidines, respectively, in good yields (entries
1–10). The E/Z-olefinic mixtures arising from deprotonation of
the in situ formed silylmethyl-substituted carbocation were also
formed in most instances.
Scheme 3 Preparation of the azetidines 1h1 and 1h2: Reagents and
conditions: (a) PCC, DCM, 2 h, rt, 86%; (b) BrMgCH2SiMe3, Et2O,
0 °C, 2 h, 82%; (c) H2SO4, THF, rt, 3 h, 91%; (d) OsO4, NMO,
CH3CN, H2O, 90%; (e) TPDPSCl, imidazole, DCM, 90%; (f) DIAD,
Ph3P, benzene, 0 °C–rt, 1 h, 95%.
The E/Z-composition of the olefinic mixtures was determined
from 1H integrals. The E/Z-stereochemical identities were
Fig. 2 X-ray stereostructures of (i) 2(R)-1a and (ii) 1f2.
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Table 2 Rearrangement of azetidines into pyrrolidinesa
Entry
1
Azetidine
Pyrrolidine product
Yield (%)b
80
Other products
Yields (%)b
10
2
3
4
80
78
77
10
15
15
5
6
1d1 Ar = C6H5
1e1 Ar = p-F-C6H4
3d1 Ar = C6H5
3e1 Ar = p-F-C6H4
25
40
15d1 Ar = C6H5
15e1 Ar = p-F-C6H4
50
35
1d2 Ar = C6H5
1e2 Ar = p-F-C6H4
3d2 Ar = C6H5
3e2 Ar = p-F-C6H4
25
40
15d2 Ar = C6H5
15e2 Ar = p-F-C6H4
50
40
7
8
9
70
70
35
20
18
55
10
11
30
80
60
15
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Table 2 (Contd.)
Entry
12
Azetidine
Pyrrolidine product
Yield (%)b
81
Other products
Yields (%)b
15
a All the reactions were carried out in dry DCM for 15 min using 1.0 equivalent of BF3·Et2O at 0 °C. b Isolated % yields.
inferred from the coupling constants between the vicinal olefinic
hydrogen atoms. In those instances where one of the two vicinal
olefinic hydrogen atoms was absent, nOe measurements were
used. For instance, Jvicinal for 15d and 15e were, respectively,
15.9 Hz and 15.5 Hz which corresponded to E-configuration.
The Jvicinal for an authentic Z-15d (prepared in our laboratory
through Wittig olefination) was 11.0 Hz. Irradiation of the
olefinic hydrogen in E-13 (δ 5.26) resulted in 12% enhancement
arising from either deprotonation of the carbocation formed from
σC–N cleavage or cyclo-fragmentation of the type discussed
above was isolated from either of these 3-vinylazetidines.
Noticeably, both the cis- and trans-substituted azetidines gen-
erated 1H- and 13C-identical products. However, the product
formed from the cis-isomer was enantiomeric to the product
formed from the trans-isomer from the (a) optical rotation data
that were nearly equal but opposite in sign, and (b) different
retention times (Rt) under identical HPLC conditions. Please
refer to the SI for the optical rotation and HPLC data†. Further,
irrespective of the substituents being cis or trans in the reacting
azetidine, they were always trans to each other in the pyrrolidine
product. This stereochemical characterization was discerned
from nOe measurements and, in select instances, from single
crystal X-ray structure determination.
In 3b2, irradiation of C3-H (δ 2.07–1.98) enhanced the signal
for CH3 (δ 0.79) by 6%. In 3d1, irradiation of C3-H (δ 2.29)
resulted in 15% enhancement of the signal due to the ortho-
hydrogen atoms of the C4-phenyl group (δ 6.97–6.95). Likewise,
in 3e1, irradiation of C3-H (δ 2.22) enhanced the signal due to
the ortho-hydrogen atoms of the C4-p-flurophenyl group
(δ 6.91–6.87) by 16%. All these nOe results require the two sub-
stituents to be trans to each other. In 3g1a, irradiation of the
internal olefinic hydrogen (δ 5.58–5.50) enhanced the signal due
to C3-H (δ 1.88) by 2% and indicated the trans relationship of
the substituents. The X-ray stereostructures of 3c1, 3c2 and 3e1
are collected in Fig. 3.
The observed enantio-convergence leading to only the trans-
3,4-disubstituted pyrrolidines may be explained by assuming
σC–N cleavage preceding siliranium ion formation in the reaction
of the cis-azetidine (eqn (1), Scheme 4). The resultant carbo-
cation allowed formation of a siliranium species in which the
large silicon substituent was anti to the other ring-substituent to
avoid otherwise acute steric interactions. Internal SN2 cleavage
of this siliranium species by the nitrogen nucleophile generated
the observed 3,4-trans-product. In contrast, the trans-azetidine
may be expected to react by a synchronous pathway as it leads
directly to the formation of a strain-free siliranium ion (eqn (2),
Scheme 4). However, a two-step pathway similar to the one
suggested above for the cis-azetidine cannot be ruled out for the
trans-azetidine also.
The mode of azetidine cleavage was probed further by study-
ing the reaction of N-p-toluenesulfonyl-2(R)-tert-butyldiphenyl-
silylmethylazetidine. Allowing for the ring enlargement to
proceed through a concerted σC–N cleavage, siliranium ion for-
mation, nucleophilic attack of the nitrogen anion on the remote
C–Si bond and migration of the silicon to the adjacent
of the signal for TsNHCH2
TBDPSCH2 (δ 1.90) in E-16 resulted in 8.7% enhancement of
the signal for CH2vCHCH2 (δ 3.07).
̲
(δ 3.23). Likewise, irradiation of
̲
̲
The yields of the pyrrolidine products from 3-phenyl- and 3-
p-fluorophenylazetidines were poor in comparison to the other
substrates. The reaction took predominantly a fragmentation
course to generate trans-3-phenylallyl tert-butyldiphenylsilane,
15d, and trans-3-p-fluorophenylallyl tert-butyldiphenylsilane,
15e, from both the cis- and trans-isomers of 2-tert-butyldiphe-
nylsilylmethyl-3-phenylazetidine (1d1 and 1d2) and 2-tert-butyl-
diphenylsilylmethyl-3-p-fluorophenylazetidine (1e1 and 1e2),
respectively, as shown in entries 5 and 6. The absence of the cis-
1
olefins in these reactions was ascertained from H NMR spectra
of the crude reaction mixtures. These fragmentations are
obviously not concerted, or else the relative cis- and trans-dispo-
sitions of the aryl and tert-butyldiphenylsilylmethyl substituents
in the corresponding azetidines had been transferred to the resul-
tant olefins. Such a fragmentation has previously been reported
from
N-allyl/benzyl-2-aryl/heteroaryl-3-phenoxy/phenyl/vinyl
azetidines when Et2AlCl was employed as the Lewis acid.12
However, unlike the present examples, the relative stereo-
chemistry of the azetidine-substituents was generally transferred
unaltered to the olefin through a concerted pathway.
2-tert-Butyldiphenylsilylmethyl-3-vinylazetidines, 1g1 and
1g2, reacted smoothly to generate the expected pyrrolidines, 3g1a
and 3g2a, respectively (entries 9 and 10). However, due probably
to the acidic conditions of the reaction, significant portions of
these azetidines underwent double bond isomerization prior to
the rearrangement to generate a racemic mixture of the ethyli-
dene derivative 3g; a rearrangement prior to isomerization will
be expected to yield a single enantiomer in each instance. The
orientation of the methyl group cis to the TBDPS-containing
ring-carbon was ascertained from the following observations:
(a) saturation of one of the two hydrogen atoms on C5 (δ 5.25)
caused 6.4% nOe enhancement of the signal due to the hydrogen
on C3 (δ 1.82–1.74), and (b) saturation of the other hydrogen
atom on C5 (δ 4.99–4.96) caused 8.2% nOe enhancement of the
signal due to olefinic-H (δ 4.31–4.25). The reason for this
specific olefin geometry is not understood. No olefinic product
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Fig. 3 X-ray stereostructures of (i) 3c1, (ii) 3c2, and (iii) 3e1.
Scheme 4 Mechanistic rationale for the observed enantio-control during azetidine → pyrrolidine rearrangement (both the bonds to silicon in the
siliranium ion must be treated as only partial bonds. The use of the full α and β bonds are required here to consider the relative stereochemistry of this
ring in relation to the substituent R).
carbocation, the reaction must generate N-p-toluenesulfonyl-3
(S)-tert-butyldiphenylsilylpyrrolidine as the sole product (eqn
(3), Scheme 4). In the event that this azetidine was reacted, the
product was obtained as a racemic mixture. The enantiomeric
composition was determined by chiral HPLC analysis. Similar
separate reactions of 77 : 23 and 58 : 42 mixtures of 2(R)- and
2(S)-N-p-toluenesulfonyl-2-tert-butyldiphenylsilylmethylazetidines
also generated racemic mixtures. Both the bonds to silicon
in the above siliranium ions must be treated as only partial
bonds.
racemic mixture. A similar argument for the cis-2,3-disubstituted
azetidine will require formation of only the cis-3,4-disubstituted
azetidine which contradicts the observed formation of the trans-
3,4-disubstituted species exclusively. Interestingly, application of
this argument to the trans-2,3-disubstituted azetidine will gener-
ate trans-3,4-disubstituted azetidine as indeed observed.
However, there is no specific reason why such a protocol should
be followed only by the trans-2,3-disubstituted azetidines but
not by the other substrates. Viewed in terms of a non-classical
carbocation, a migrating group must at least be partly bonded to
the migration terminus. This lends weight to the involvement of
a siliranium ion.
Alternatively, one may be tempted to construct a truly energy-
saving pathway by considering the conformer in which the σC–Si
bond is held antiperiplanar to the σC–N bond to allow σC–Si
→
The above analysis supports stepwise σC–N cleavage to gener-
ate a discrete carbocation, siliranium ion formation under the
excellent steric control of the other ring substituent and intramo-
lecular nucleophilic attack of the nitrogen anion on the remote
carbon of the siliranium ion to allow the silicon to migrate.
The diastereomeric substrates 1h1 and 1h2 rearranged to pyrro-
lidine 3h1 and 3h2, respectively (entries 11 and 12). These
rearrangements have obviously occurred under the strict steric
σ*C–N interaction and, thus, simultaneous migrations of the σC–N
and σC–Si bonds in a process that is driven by release of ring
strain and promoted by Lewis acid complexation to the sulfona-
mide group (eqn (4), Scheme 4). However, this explanation
also requires the formation of only the N-p-toluenesulfonyl-3(S)-
tert-butyldiphenylsilylpyrrolidine from N-p-toluenesulfonyl-2-
(R)-tert-butyldiphenylsilylmethylazetidine unlike the observed
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control of the C4-substituent. The chiral silyloxymethyl-substi-
tuted homoallyl amines 1713 and 18 were also isolated in small
amounts. The absolute stereochemistries of 3h1 and 3h2 were
correlated to those of the previously known N-p-toluenesulfonyl
4-hydroxy-2-hydroxymethylpyrrolidines obtained from oxidative
cleavage of the σC–Si bond (see below).
Conclusions
In summary, the stereospecific rearrangement of 2-tert-butyldi-
phenylsilylmethyl-substituted azetidines into 2-tert-butyldiphe-
nylsilylpyrrolidines on treatment with BF3·Et2O in CH2Cl2 is a
general reaction. The cleavage of the σC–N bond and the silira-
nium ion formation are not concerted. The siliranium ion for-
mation required for ring-enlargement was stereo-controlled
precisely by a ring substituent. The pyrrolidines formed from 3-
substituted and 3,4-disubsituted 2-tert-butyldiphenylsilylmethyl-
azetidines possessed the tert-butyldipenylsilyl substituent invari-
ably trans to the adjacent ring-substituent, irrespective of the
initial stereo-disposition in the azetidine molecule. Likewise, the
pyrrolidines formed from both the cis- and trans-4-substituted-2-
tert-butyldiphenylsilylmethylazetidines also possessed the two
ring substituents trans to each other. The oxidative cleavage of
the σC–Si bond in select pyrrolidine products was achieved on
employment of tert-BuOOH–KH in DMF as solvent to generate
the corresponding alcohols.
σC–Si → σC–OH Oxidative cleavage
It is synthetically important to oxidatively cleave the σC–Si bond
to generate the corresponding alcohol to demonstrate a possible
meaningful application of the present azetidine → pyrrolidine
protocol in organic synthesis. Since we have previously used
tert-BuOOH–KH–DMF successfully to accomplish such an
endeavour,1,4h–i we used the same in the present instance as well.
( )-N-p-Toluenesulfonyl 3-tert-butyldiphenylsilylmethyl pyrroli-
dine 3a was transformed into the previously known7d,14 ( )-N-p-
toluenesulfonyl-3-hydroxypyrrolidine, 19a, in 75% yield on
reaction with tert-BuOOH–KH in DMF at 40 °C for 24 h
(Scheme 5, eqn (1)). The σC–Si bond in N-p-toluenesulfonyl 3
(R)-tert-butyldiphenylsilyl-4(R)-methylpyrrolidine, 3b2, did not
cleave well under the above reaction conditions. However, a
raise in the temperature to 100 °C was beneficial when N-p-
toluenesulfonyl 3(R)-hydroxy-4(R)-methylpyrrolidine, 20b2, was
isolated in 70% yield (Scheme 5, eqn (2)). N-p-Toluenesulfonyl
2(S)-tert-butyldiphenylsilyloxymethyl-4(R)-tert-butyldiphenylsi-
lylpyrrolidine, 3h1, and N-p-toluenesulfonyl 2(R)-tert-butyldi-
phenylsilyloxymethyl-4(S)-tert-butyldiphenylsilylpyrrolidine, 3h2,
also reacted well at 100 °C to generate the corresponding 2-
hydroxymethyl-4-hydroxypyrrolidines, 21h1 and 21h2, respect-
ively, each in 70% yield (Scheme 5, eqn (3) and (4)). The
TBDPS-ether was also cleaved under the above reaction con-
ditions. The species 21h1 and 21h2 were different from each
other from chiral HPLC analysis (see SI†). Also, their optical
rotations matched well with those reported in the literature
values.15
Experimental section
General experimental methods
Melting points (mp) are reported without correction. H and 13C
1
NMR chemical shifts are expressed in parts per million (δ) rela-
tive to, respectively, TMS (as an internal standard) signal at
δ 0.00 and the central CDCl3 resonance at δ 77.0. IR spectra
of liquids were recorded as thin films and of solids as
KBr pellets. The enantiomeric and diastereomeric purities
were determined by HPLC using Chiralpak AD-H chiral
column (0.46 × 25.0 cm2) or Chiracel OD chiral column (0.46 ×
25.0 cm2) using i-PrOH/n-hexane solvent. Column chromato-
graphy was performed over silica gel (100–200 mesh) using
mixtures of hexanes and EtOAc as the eluent. The products were
purified further, when necessary, by radial chromatography using
plates coated with silica gel PF254. Solvents were removed under
reduced pressure on a rotovap. The organic extracts were dried
using anhydrous Na2SO4.
(S)-p-Toluenesulfinylimine of α-tert-butyldiphenylsilyl-
acetaldehyde16
In a 100 mL 2-neck round bottom flask fitted with condenser
and magnetic stirring bar was placed of (S)-(+)-p-toluenesulfina-
mide (0.31g, 2 mmol, ee = 98%, purchased from Sigma-
Aldrich). 2-tert-Butyldiphenylsilyl acetaldehyde (0.59 g,
2.1 mmol) dissolved in dry THF (15 mL) was added and the
resultant content was stirred for 5 min. Titanium(IV)isopropoxide
(2.71 mL, 10 mmol) was added and the reaction mixture was
heated to 40 °C. After 6 h, when the reaction was complete by
TLC, the reaction mixture was cooled to 0 °C and quenched by
brine (10 mL). The turbid solution was diluted with EtOAc
(10 mL) and filtered through celite. The filter cake was washed
with EtOAc (1 × 10 mL). The phases were separated and the
aqueous phase was extracted with EtOAc (2 × 10 mL). The com-
bined organic phase was dried and concentrated to give the
crude product that was purified by column chromatography.
Scheme 5 Oxidative cleavage of the σC–Si bond in select N-p-toluene-
sulfonyl 3-tert-butyldiphenylsilylpyrrolidine products. Reagents and
conditions: (a) KH, tert-BuOOH, DMF, 40 °C, 24 h, 75%, (b) KH, tert-
BuOOH, DMF, 100 °C, 24 h, 70%.
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General procedure for the addition of an ester enolate to
(S)-(+)-p-toluenesulfinyl imine of α-tert-butyldiphenylsilyl-
acetaldehyde9
reaction mixture was cooled to room temperature and mixed
with cold water (5 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (2 × 5 mL). The com-
bined organic solution was washed with brine, dried, and con-
centrated to give the crude product that was purified by
chromatography.
(b) A N-p-toluenesulfonyl 3-amino-4-tert-butyldiphenylsilyl-
propanol (0.1 mmol) dissolved in dry benzene (8 mL) was taken
in a 25 mL round bottom flask and mixed with Ph3P (53 mg,
0.2 mmol). The content was cooled to 0 °C. Diisopropyl azodi-
carboxylate (40 μL, 0.2 mmol) was added using a micro-syringe
and the resultant reaction mixture was stirred for 1 h with
gradual rise in the temperature. The solvent was removed under
reduced pressure and the residue was chromatographed over
silica gel to obtain the pure product.
A solution of i-Pr2NH (283 μL, 2.0 mmol) in THF (10 mL) was
placed in a 50 mL 2-neck round bottom flask fitted with mag-
netic stirring. This was cooled to 0 °C and mixed with n-BuLi
(1.6 M, 1.25 mL, 2.0 mmol). The solution was stirred for
30 min, cooled to −78 °C and mixed with an ester (2.0 mmol)
as neat. After 30 min, ClTi(Oi-Pr)3 (1.0 M in THF, 2.1 mL) was
added and the resultant content was stirred for 30 min. A sol-
ution of (S)-p-toluenesulfinamide (0.42 g, 1.0 mmol) in THF
(5 mL) was added dropwise and the solution was stirred for
3–5 h at −78 °C. On completion of the reaction, saturated
aqueous NH4Cl (2 mL) was added and the content was warmed
to room temperature. The mixture was diluted with H2O (5 mL)
and EtOAc (10 mL), stirred vigorously for 15 min, and filtered
through celite. The filter cake was washed with EtOAc (10 mL).
The phases were separated and the aqueous phase was extracted
with EtOAc (2 × 10 mL). The combined organic phase was
dried and concentrated to give the crude product that was
purified by column chromatography to get a mixture of diaster-
eomers that were generally separated by radial chromatography.
General procedure for rearrangement of an azetidine into
pyrrolidine
An azetidine (0.08 mmol) dissolved in dry DCM (4 mL) was
taken in a 10 mL round bottom flask and cooled to 0 °C.
BF3·OEt2 (10 μL, 0.08 mmol) was added using a micro-syringe
and the resultant mixture was stirred. On completion of the reac-
tion as determined by TLC (usually 15 min), saturated aqueous
NaHCO3 was added and the suspension was stirred vigorously at
room temperature for 30 min. The layers were separated and the
aqueous layer was extracted with DCM (2 × 5 mL). The com-
bined organic solution was washed with brine, dried, and con-
centrated to give the crude product mixture that was purified by
radial chromatography.
General procedure for consecutive m-CPBA oxidation and LAH
reduction
The solution of a 4-tert-butyldiphenylsilyl-3-p-toluenesulfenyl-
aminobutyrate (0.2 mmol) in dry CH2Cl2 (10 mL) was taken in
a 25 mL round bottom flask and cooled to 0 °C. m-CPBA (76%,
68 mg, 0.3 mmol) was added and the resultant mixture was
stirred for 30 min. On completion of the reaction, solid Na2SO3
(0.20 g) was added and the contents were stirred for 30 min.
Now, saturated aqueous NaHCO3 was added and the suspension
was stirred for 10 min. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The com-
bined organic solution was washed with brine, dried and concen-
trated to give the crude product that was purified by column
chromatography.
This product was taken in THF (6 mL) in a 25 mL 2-neck
round bottom flask fitted with a magnetic stirring bar, cooled to
0 °C and mixed with LAH (16 mg, 0.4 mmol). The reaction
mixture was stirred for 30 min. EtOAc (1 mL) was added, the
contents stirred for 5 min and then mixed with a few drops of
H2O. The resultant suspension was stirred vigorously for 15 min
and filtered through a cotton plug. The solid was washed with
EtOAc (10 mL). The combined organic layer was dried and con-
centrated to give the crude product that was purified by column
chromatography.
Oxidative cleavage of σC–Si bond in N-p-toluenesulfonyl-3-tert-
butyldiphenylsilylpyrrolidines: a general procedure
To an ice cold suspension of KH (186 mg, 1.4 mmol, 30% dis-
persion in mineral oil, washed with 3 × 2 mL of hexanes) in
DMF (2 mL) was added t-BuOOH (70%, 100 μL, 0.70 mmol)
dropwise. After 10 min, solution of a N-p-toluenesulfonyl-3-tert-
butyldiphenylsilylpyrrolidine (0.11 mmol) in DMF (3 mL) was
added. The mixture was stirred at 40–100 °C for 24–84 hours
and quenched by adding solid Na2SO3 (100 mg). The reaction
mixture was stirred for 30 min and partitioned between water
and Et2O. The aqueous layer was extracted with Et2O (5 ×
8 mL). The combined organic extract was washed with cold
water and brine, dried and evaporated to get the crude product
that was purified by column chromatography to isolate the
unreacted starting material and the expected alcohol.
N-p-Toluenesulfonyl 2(R)-amino-1-tert-butyldiphenylsilyl-4-
General procedures for cyclization of N-p-toluenesulfonyl
pentene, 10
3-hydroxypropylamines to azetidines
The following three reactions, one after the other, were used to
prepare this compound.
(a) Powdered KOH (17 mg, 0.3 mmol) was placed in a 25 mL 2-
necked round bottom flask fitted with a reflux condenser and a
magnetic stirring bar. The solution of a N-p-toluenesulfonyl 3-
amino-4-tert-butyldiphenylsilylpropanol (0.1 mmol) in THF
(5 mL) and TsCl (23 mg, 0.12 mmol) were added at room temp-
erature and the reaction mixture was refluxed for 2 h. The
(a) PCC (708 mg, 3.28 mmol) was taken in DCM (10 mL)
under nitrogen atmosphere and stirred at 25 °C. N-p-Toluenesul-
fonyl-3(R)-amino-4-tert-butyldiphenylsilylbutanol (790 mg,
1.64 mmol) was added as a solution in DCM (2.0 mL). The
reaction mixture was stirred for 2 h. Et2O (1.0 mL) was added to
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the reaction mixture and the solution was decanted from the
solid. The solid was washed with Et2O. The organic layer was
evaporated to get crude product that was purified by column
chromatography to obtain N-p-toluenesulfonyl-3(R)-amino-4-
tert-butyldiphenylsilylbutanal, 675 mg, 86% yield.
purified by column chromatography, and separated by radial
chromatography to obtain both the diastereomers of N-p-toluene-
sulfonyl-4(R)-amino-5-tert-butyldiphenylsilyl-1-tert-butyldiphenyl-
silyloxy-2-pentanol, 520 mg, in 91% combined yield.
(b) In a flame-dried two-neck round bottom flask, Mg
(150 mg, 6.1 mole atom) was taken under N2 atmosphere.
A small crystal of elemental iodine and Et2O (5 mL) were
added. This was cooled to °C and mixed with a solution of bro-
momethyltrimethylsilane (0.69 mL, 4.85 mmol) in ether
(10 mL) drop-wise. The mixture was stirred at 25 °C for 30 min
and cooled to 0 °C. The above aldehyde (580 mg, 1.21 mmol)
was added as a solution in ether (10 mL). The reaction mixture
was stirred at ambient temperature for 2 h. The reaction was
quenched by saturated aqueous NH4Cl solution (10 mL). The
layers were separated and the aqueous layer was extracted with
EtOAc (10 mL × 2). The organic extract was washed with brine
(10 mL × 1) and dried. The solvent was evaporated to obtain the
crude product which was purified by column chromatography to
obtain a mixture of the anti–syn (=2 : 3) diastereomers of the
expected product, 2-hydroxysilane, in 82% yield.
(c) To a stirred solution of the above diastereoisomeric
mixture of hydroxy silanes (0.455 g, 0.8 mmol) in THF (10 mL)
at rt was added conc H2SO4 (10 drops) and stirred for 3 h. The
reaction mixture was diluted with ethyl acetate (15 mL) and
washed with water (2 × 7 mL) and brine (1 × 7 mL). The
organic layer was dried and evaporated to get the crude product
that was purified by column chromatography to obtain N-p-
toluenesulfonyl-2(R)-amino-1-tert-butyldiphenylsilyl-4-pentene
a white solid (91%).
Acknowledgements
B.D.N. and V.S. thank CSIR for Research Fellowships. V.K.Y.
thanks Department of Science & Technology (DST) and Council
of Scientific & Industrial Research (CSIR), Government of
India, for financial support. This work is dedicated to the fond
memory of Professor Mugio Nishizawa who left for heavenly
abode on May 01, 2010.
Notes and references
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N-p-Toluenesulfonyl 4(R)-amino-5-tert-butyldiphenylsilyl-1-tert-
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compounds.
(a) N-p-Toluenesulfonyl-2(R)-amino-1-tert-butyldiphenylsilyl-
4-pentene (0.402 g, 0.84 mmol) was taken in CH3CN and H2O
(3 : 1, 16 mL) in a 50 mL round bottom flask, cooled to °C and
mixed with NMO (0.138 g, 1.4 mmol) and OsO4 (0.078M in
t-BuOH, 127 μL). The reaction mixture was stirred for 24 h with
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layers were separated and the aqueous layer was extracted with
EtOAc (3 × 1.0 mL). The combined organic solution was
washed by brine, dried, and concentrated to give the crude
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mixture of diastereomers (syn–anti = 1.3 : 1) of diols, 0.3g, 91%
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