On the synthesis of α-amino sulfoxides

Article abstract of DOI:10.1039/c4ob00567h

A synthetic study on the preparation of N-Boc α-amino sulfoxides has revealed an unexpected instability which is believed to be due to α-elimination of the sulfoxide to give an iminium ion. Full synthetic details are reported on two main synthetic routes: lithiation and sulfinate trapping of N-Boc heterocycles and oxidation of N-Boc α-amino sulfides. Six novel α-amino sulfoxides were successfully prepared and isolated. It is speculated that four other α-amino sulfoxides were synthesised but could not be isolated due to their propensity to α-eliminate the sulfoxide. Ultimately, a stable, cyclic N-Boc α-amino sulfoxide was prepared and this successful synthesis relied on the α-amino sulfoxide being part of a bicyclic [3.1.0] fused ring system that could not undergo α-elimination of the sulfoxide. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00567h

Organic &
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On the synthesis of α-amino sulfoxides†‡
Peter J. Rayner,a Giacomo Gelardi,a Peter O’Brien,*a Richard A. J. Horanb and
Cite this: Org. Biomol. Chem., 2014,
12, 3499
David C. Blakemorec
A synthetic study on the preparation of N-Boc α-amino sulfoxides has revealed an unexpected instability
which is believed to be due to α-elimination of the sulfoxide to give an iminium ion. Full synthetic details
are reported on two main synthetic routes: lithiation and sulfinate trapping of N-Boc heterocycles and
oxidation of N-Boc α-amino sulfides. Six novel α-amino sulfoxides were successfully prepared and iso-
lated. It is speculated that four other α-amino sulfoxides were synthesised but could not be isolated due
to their propensity to α-eliminate the sulfoxide. Ultimately, a stable, cyclic N-Boc α-amino sulfoxide was
prepared and this successful synthesis relied on the α-amino sulfoxide being part of a bicyclic [3.1.0]
fused ring system that could not undergo α-elimination of the sulfoxide.
Received 14th March 2014,
Accepted 14th April 2014
DOI: 10.1039/c4ob00567h
www.rsc.org/obc
Introduction
Our group has an ongoing interest in the development of
methodology for the asymmetric synthesis of saturated nitro-
gen heterocycles (e.g. pyrrolidines1 and piperidines2), efforts
which have been spurred on by the prevalence of such hetero-
cyclic motifs in active pharmaceutical ingredients.3 The most
streamlined approach to α-substituted heterocycles is direct
α-functionalisation4 and, in this context, Beak’s lithiation-trap-
ping of N-Boc activated heterocycles5,6 using s-BuLi and di-
amines (such as TMEDA or (−)-sparteine) is one of the most
reliable and predictable methods.7 However, a key limitation
of the asymmetric variant is that reactions rarely generate pro-
ducts with ≥95 : 5 er. To address this limitation, we have been
exploring the synthesis and applications of N-Boc α-amino-
substituted sulfoxides 1. In particular, it was our intention
that N-Boc α-amino sulfoxides 1 of 99 : 1 dr and 99 : 1 er would
be direct precursors to chiral Grignard reagents 2 of 99 : 1 er
via sulfoxide to magnesium exchange (Scheme 1). This strategy
was successfully demonstrated with the synthesis of a bicyclic
α-substituted N-Boc heterocycle.8 However, in developing the
methodology, we were unable to synthesise a number of N-Boc
α-amino sulfoxides 1 which we believed was due to their un-
Scheme 1
expected instability. Our efforts on the synthesis of N-protected
α-amino sulfoxides 1 are the subject of this paper.
Before commencing the synthesis of α-amino sulfoxides 1,
a literature survey was carried out on all three classes of sulfur-
containing α-amino compounds with a focus on pyrrolidines
and piperidines (Fig. 1). There were numerous examples of
α-amino sulfides of which N-acyl pyrrolidine 3,9 N-Boc piper-
idine 45 and N-Boc pyrrolidine 510 are representative. Sulfide 3
was prepared via an intramolecular Pummerer reaction,
sulfide 4 was synthesised by Beak-style α-lithiation-trapping of
the parent N-Boc piperidine and sulfide 5 was accessed via
iminium ion chemistry.
In contrast, there were limited examples of pyrrolidinyl and
piperidinyl α-amino sulfones and sulfoxides and Fig. 1 rep-
resents a comprehensive list of the classes of known com-
pounds. There were a few α-amino sulfones such as 611 and 712
(prepared by reaction of the iminium ion with benzenesulfinic
acid) and 813 (synthesised by m-CPBA oxidation of the sulfide
and proceeding via the α-amino sulfoxide). It is useful to note
in passing that α-amino sulfones 6 and 7 have been used as
precursors to iminium ions (via α-elimination) although Lewis
acid activation is typically required.11,12 To the best of our
knowledge, there is only one known acyclic α-amino sulfoxide,
9,14 prepared by oxidation of the corresponding sulfide. Inter-
estingly, α-elimination of the sulfoxide in 9 was relatively facile
to give the putative iminium ion (which could be trapped with
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK.
E-mail: peter.obrien@york.ac.uk
bGlaxoSmithKline Research & Development Ltd, Medicines Research Centre, Gunnels
Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
cNeusentis Chemistry, Pfizer Worldwide Research and Development, The Portway
Building, Granta Park, Cambridge CB21 6GS, UK
†This article is published in Celebration of the 50th Anniversary of the Opening
of the Chemistry Department at the University of York.
‡Electronic supplementary information (ESI) available: Copies of 1H NMR and
13C NMR spectra. See DOI: 10.1039/c4ob00567h
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Scheme 2
methyl p-toluenesulfinate 17 gave a 71% yield of α-amino sulf-
oxide 18 (Scheme 2). Such a good yield of 18 was possible only
if 1% Et3N was added to the eluent during the column chrom-
atography. Without Et3N, significant decomposition occurred,
potentially via α-elimination of the sulfoxide to give the
iminium ion.
The analogous acyclic N-protected α-amino sulfoxides 23
and 24 were synthesised via a different approach as outlined
in Scheme 3. Alkylation of amide 1922 using chloromethyl
p-tolylsulfide23 under phase-transfer conditions24 gave α-amino
sulfide 21 (68% yield). Thioamide 22 was prepared from 20 in a
similar fashion. m-CPBA oxidation proceeded uneventfully to
give good yields of 23 and 24. N-protected α-amino sulfoxides
23 and 24 appeared to be more stable then α-amino sulfoxide
18: no decomposition was noted upon column chromatography
even in the absence of Et3N. This may be due to extra delocalisa-
tion of the nitrogen lone pair disfavouring α-elimination of the
sulfoxide to the iminium ion.
With the successful synthesis of α-amino sulfoxides 18, 23
and 24, our attention switched to compounds containing
further substitution α to the sulfoxide. The attempted syn-
thesis of α-amino sulfoxide 25 is shown in Scheme 4. Deproto-
nation of α-amino sulfoxide 18 with LDA was followed by
reaction with dimethylsulfate. After purification by chromato-
graphy (with 1% Et3N in the eluent), the only isolable product
was N-Boc methylamine 26 (59% yield). Since 26 was not
evident in the 1H NMR spectrum of the crude product, we
speculate that adduct 25 could have formed but then con-
verted into 26 via an iminium ion and hydrolysis during the
chromatography. N-Boc methylamine 26 could not have been
formed from unreacted 18 since 18 is stable to chromato-
graphy in the presence of Et3N.
Fig. 1 Examples of known α-amino sulfides, sulfones and sulfoxides.
methanol). Examples of cyclic α-amino sulfoxides include aze-
tidinones 1015 and 11,16 both synthesised by sulfide oxidation
and aziridines such as 1217 which was prepared by cyclisation
of the amine onto an α-chloro sulfoxide. The only pyrrolidine-
containing α-amino sulfoxide that we are aware of is 1318
which was obtained by oxidation of the sulfide. Examples of
penicillin-like19 and cephalosporin-like20 sulfoxides such as 14
and 15 respectively have also been described; both were syn-
thesised by sulfur oxidation.
In this paper, we present an overview of all our synthetic
efforts towards preparing α-amino sulfoxides 1. In general, the
approaches adopted to prepare α-amino sulfides, sulfones and
sulfoxides 3–15 were investigated. Surprisingly, our synthetic
efforts revealed an apparent instability of α-amino sulfoxides 1
and we conclude with some general guidelines about the types
of compounds that have been successfully synthesised.
Our approach to α-amino sulfoxides 28a/b involved starting
with the substituent in place and then lithiating and trapping
Scheme 3
Results and discussion
To start with, direct α-lithiation-sulfinate trapping from a
N-Boc activated amine was explored. Thus, lithiation of N-Boc
dimethylamine 16 was accomplished using s-BuLi/TMEDA in
Et2O at −78 °C. Pleasingly, subsequent reaction with known21
Scheme 4
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Scheme 7
Scheme 5
Our suggested explanation to account for the formation of
vinyl sulfoxide 32 (and analogously, 36) is presented in
Scheme 7. We believe that formation of the desired α-amino
sulfoxide 31 may well be occurring by lithiation-trapping.
However, as noted in other substituted α-amino sulfoxides
(e.g. 25 and 28a/b), α-elimination of the sulfoxide could occur
to give iminium ion 37 which can rearrange to enecarbamate
38. Vinylic lithiation of enecarbamates like 38 is well-known
and facile.27 In this case, untrapped lithiated N-Boc pyrrolidine
or excess s-BuLi could lithiate 38 to give vinylic organolithium
39 which is ultimately trapped by methyl p-toluenesulfinate 17
to give vinyl sulfoxide 32. We also considered the direct conver-
sion of 31 into 38 via sulfoxide cycloreversion but this seemed
less likely at such low reaction temperatures (–78 °C).28
The proposed mechanism for the formation of vinyl sulfox-
ide 32 would require 2 equivalents of base to give a quantitat-
ive yield. Therefore, we attempted to optimise the preparation
of vinyl sulfoxide 32, imagining that it could be a useful syn-
thetic intermediate. Treatment of N-Boc pyrrolidine 30 with
2.5 equivalents of s-BuLi in THF and trapping with 3.0 equiva-
lents of methyl p-toluenesulfinate 17 gave a 44% yield of vinyl
sulfoxide 32 (Scheme 8).
The synthesis of α-amino sulfoxide 41 from an alternative
N-Boc pyrrolidine, phenyl-substituted pyrrolidine 40,2a,29 was
also explored. Lithiation of 40 was accomplished using n-BuLi
in THF at 0 °C for 5 min according to the known procedure.2a
Subsequent reaction with methyl p-toluenesulfinate 17 did not
give any of the hoped-for product 41. Instead, enecarbamate
42 was isolated in 72% yield after chromatography (Scheme 9).
In this case, vinylic lithiation-trapping could not occur as ene-
carbamate 42 is already substituted. Nevertheless, this rep-
resents a convenient way of synthesising enecarbamates such
as 42 from the corresponding saturated heterocycle (40). As
noted previously by Tomooka, enecarbamate 42 readily
rearranged to N-Boc keto-amine 43 on standing (Scheme 9).30
At this stage, we were disappointed not to be able to
prepare a wide range of α-amino sulfoxides and the evidence
suggested that some compounds were unstable due to α-elimi-
nation of the sulfoxide group. With this issue in mind, we set
about trying to prepare cyclic N-protected α-amino sulfoxides
where the propensity for α-elimination might be reduced. Our
with methyl p-toluenesulfinate 17. Lithiation-trapping of N-Boc
benzylamine 27 is well-established from the work of Beak and
co-workers.25 Thus, lithiation of 27 using s-BuLi/TMEDA and
trapping with methyl p-toluenesulfinate 17 gave, after chrom-
atography (with Et3N), separable diastereomers 28a (30% yield)
and 28b (20% yield) of undetermined stereochemistry
(Scheme 5). α-Amino sulfoxides 28a/b, which were fully charac-
terised, were on the borderline of stability on silica (even in
the presence of Et3N). Frustratingly, we were unsuccessful in
reproducing the isolation of 28a/b: all subsequent attempts
led, after chromatography, to the generation of quantitative
yields of N-Boc amine 29 (presumably formed via α-elimi-
nation of the sulfoxide and hydrolysis of the so-generated
1
iminium ion) even though 28a/b were evident in the H NMR
spectra of the crude product.
Next, we moved on to investigating the preparation of cyclic
α-amino sulfoxides 31 and 35 derived from N-Boc pyrrolidine
30 and N-Boc piperidine 33 respectively. α-Amino sulfoxides 31
and 35 were key targets as they could ultimately provide ready
access to chiral α-amino Grignard reagents 2 suitable for incor-
poration into potential pharmaceutical building blocks. To start
with, N-Boc pyrrolidine 30 was subjected to diamine-free lithia-
tion (s-BuLi, THF, −78 °C, 1 h).26 Disappointingly, reaction of
the organolithium with methyl p-toluenesulfinate 17 did not
lead to the formation of any of the desired α-amino sulfoxide
31. After chromatography, the only product we could isolate
pure and in substantial amounts was vinyl sulfoxide 32, which
was fully characterised (Scheme 6). Use of different lithiation
conditions (e.g. s-BuLi/(−)-sparteine, Et2O, −78 °C) or reverse
addition of the organolithium to the electrophile gave similar
results. A similar, but lower-yielding outcome was observed with
N-Boc piperidine 33 (lithiation using s-BuLi/TMEDA, Et2O,
−78 °C5 and trapping with methyl benzenesulfinate 34): vinyl
sulfoxide 36 was isolated in 13% yield (Scheme 6).
Scheme 6
Scheme 8
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(entry 2). Lower temperature m-CPBA oxidation (–40 °C)33 on
all four α-amino sulfides 44–47 including more electron-rich
sulfides (p-MeOC6H4- and t-Bu-substituents) was uniformly
unsuccessful: hydroxy pyrrolidine 48 was generated in 74–86%
yields (entries 3–6). Finally, using α-amino sulfide 45, two
other oxidation conditions were explored: use of hydrogen per-
oxide in hexafluoroisopropanol34 and trimethylsilyl chloride/
potassium superoxide35 each gave hydroxypyrrolidine 48 as the
sole product (entries 7 and 8). The failure to prepare pyrrolidi-
nyl α-amino sulfoxides from α-amino sulfides 44–47 was par-
ticularly disappointing as this is the route that has been used
most often to prepare the stable α-amino sulfoxides 9–15
(Fig. 1). It seems that minor structural differences and/or
different N-protecting groups (e.g. amides) are apparently
responsible for whether α-amino sulfoxides are stable and isol-
able or not.
Since six of the seven known classes of α-amino sulfoxides
9–15 (Fig. 1) have the nitrogen as part of an amide, we next tar-
geted amide-protected pyrrolidinyl α-amino sulfoxides 50 and
51; a sulfonamide (52) was also included as part of this study.
Our plan was to use tin–lithium exchange to access the organo-
lithium intermediate. Thus, lithiation-trapping of N-Boc pyrro-
lidine 30 using s-BuLi/TMEDA gave known6 stannane 49. Boc
deprotection of 49 was best realised using Me3SiI as described
by Gawley36 and subsequent acylation/sulfonylation then deli-
vered 50–52 in 50–71% yields (Scheme 11).
Starting with N-benzamide stannane 50, treatment with
n-BuLi in THF at −78 °C over 5 min led to tin–lithium
exchange but subsequent attempted trapping with methyl
p-toluenesulfinate 17 gave no α-amino sulfoxide. Instead, the
only product isolated was keto-amide 53 in 62% yield
(Scheme 12). Keto-amide 53 was also formed when we tried to
trap the lithiated N-benzoyl pyrrolidine with methanol which
indicated that use of the sulfinate 17 was not the problem. Pre-
sumably, the lithiated N-benzoyl pyrrolidine forms and then
attacks the amide carbonyl group on starting stannane 50.
Subsequent tin–lithium exchange and protonation would then
give keto-amide 53. Due to this nucleophilic attack on the
amide, a more sterically hindered amide was investigated,
namely trityl amide 51. Tin–lithium exchange and trapping
with methyl p-toluenesulfinate 17 gave amide 55 (43% yield)
resulting from protonation of the lithiated N-tritylamide and
Scheme 9
first approach was to modify the sulfoxide group itself, with
the idea that more electron-rich sulfoxides might disfavour
α-elimination and so could be stable enough to be isolated. To
this end, the synthesis and oxidation of N-Boc α-amino sul-
fides was investigated. Lithiation of N-Boc pyrrolidine 30 and
disulfide trapping5 proceeded smoothly to give stable α-amino
sulfides 44–47 in 14–59% yields (Scheme 10).
The results of the attempted oxidation of α-amino sulfides
44–47 are shown in Table 1. Unfortunately, no α-amino sulfox-
ides were isolated. Starting from α-amino sulfide 44, oxidation
with m-CPBA at room temperature gave a 31% yield of known31
hydroxy pyrrolidine 48 (entry 1). Presumably, oxidation to the
sulfoxide occurred but was followed by α-elimination to the
iminium ion which was intercepted by water during work-up.
To be certain that over-oxidation to the sulfone was not the
source of the problem, a protocol developed by Ramesh et al.32
(m-CPBA, KF, MeCN–water, rt) was employed. However,
hydroxy pyrrolidine 48 was the only product in 57% yield
Scheme 10
Table 1 Oxidation of N-Boc α-amino sulfides
% Yield
Temp/°C of 48
Entry Sulfide Oxidant
Conditions
1
2
3
4
5
6
7
8
44
44
44
45
46
47
45
45
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
H2O2
Na2CO3, CH2Cl2 rt
KF, MeCN–H2O rt
31
57
86
81
74
77
43
52
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HFIP
–40
–40
–40
–40
rt
Me3SiCl–KO2 MeCN
–15
Scheme 11
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Scheme 14
Building on this preliminary success, an alternative strategy
for disfavouring α-elimination was ultimately devised. By
building the α-amino sulfoxide functionality into a [3.1.0]
fused bicycle as exemplified by syn-/anti-60, α-elimination
should be prohibited and did indeed lead to stable α-amino
sulfoxides. The α-substituted [3.1.0] bicyclic framework can be
crafted from 4-chloro N-Boc piperidine 59 as reported by
Beak25a,39 (and proceeding via α-lithiation, cyclisation, a
second α-lithiation of the now more acidic cyclopropyl
proton and trapping, Scheme 14). Thus, lithiation of 4-chloro
N-Boc piperidine 59 using 2.2 equivalents of s-BuLi/TMEDA in
Et2O at −78 °C presumably led to the lithiated bicyclic N-Boc
pyrrolidine. Subsequent trapping with methyl p-toluenesulfi-
nate 17 gave separable and stable α-amino sulfoxides syn-60
(34% yield) and anti-60 (35%) (Scheme 14), whose stereo-
chemical assignment has been described elsewhere.8 Our suc-
cessful application of syn-60 of 99 : 1 er as a precursor to an
enantiomerically pure Grignard reagent has previously been
reported.8
Scheme 12
vinyl sulfoxide 56 (21% yield) (Scheme 12). The hoped-for
α-amino sulfoxide 54 may well have formed but its subsequent
reaction led to vinyl sulfoxide 56, as observed with N-Boc pyrro-
lidine 30 (Scheme 6). With N-sulfonyl stannane 52, equipped
with an ortho-lithiation-resistant37 2,4,6-tri-i-Pr-benzenesulfo-
nyl group, tin–lithium exchange and attempted trapping with
methanol or methyl p-toluenesulfinate 17 led only to a
complex mixture of unidentified products (Scheme 12). In fact,
tin–lithium exchange on N-sulfonyl stannanes like 52 has not,
to the best of our knowledge, been reported previously.
At this point, we concluded that for cyclic N-acyl or N-Boc
α-amino sulfoxides, it was probably necessary to build in
specific structural aspects that would disfavour α-elimination.
Using azetidinones 10, 11, 14 and 15 (Fig. 1) as a guide, the
synthesis of α-amino sulfoxide 58 was investigated. The thio-
amide functionality was chosen as Hodgson has reported a
convenient procedure for the lithiation-trapping of N-thio-
amide azetidine 57.38 Lithiation of thioamide 57 was achieved
with s-BuLi/TMEDA in THF at −78 °C and subsequent trapping
with methyl p-toluenesulfinate 17 gave a 91 : 9 mixture of dia-
stereomeric α-amino sulfoxides 58. After chromatography, only
the major diastereomer (unknown stereochemistry) was iso-
lated in 9% yield (Scheme 13). Despite this reproducibly low
yield, this was our first example of a stable, isolable cyclic
α-amino sulfoxide. It appears that α-elimination is disfavoured
as the iminium ion would be part of a 4-membered ring.
Conclusions
In summary, our efforts on the synthesis of a range of structu-
rally diverse α-amino sulfoxides have been presented. To our
surprise, some targets were inaccessible and we attribute this
not to an inability to synthesise them but to their propensity
to α-eliminate the sulfoxide moiety to give an iminium ion.
Despite this issue, which appears to be more of a problem
with α-amino sulfoxides than with α-amino sulfides or sul-
fones, several novel α-amino sulfoxides (18, 23, 24, 28a/b, 58
and syn-/anti-60) have been successfully isolated as part of our
study. We believe that several of the α-amino sulfoxides were
synthesised but not isolated (25, 31, 35, 41 and 54). A full spec-
trum of stability for the new α-amino sulfoxides and the pre-
viously reported α-amino sulfoxides 9–15 is presented in
Fig. 2. In our opinion, the key aspect affecting the stability is
α-elimination of the sulfoxide. If α-elimination can be dis-
favoured by incorporating the nitrogen into an amide and/or a
3- or 4-membered ring then stable α-amino sulfoxides (9–15,
23, 24, 58 and syn-/anti-60) result. Further work is required to
establish unequivocally that sulfoxide α-elimination is the
reason for our inability to synthesise particular α-amino
sulfoxides.
Scheme 13
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Procedures and characterisation data
N-Methyl N-p-tolylsulfinylmethyl carbamic acid tert-butyl
ester 18. s-BuLi (1.00 mL of a 1.3 M solution in hexanes,
1.30 mmol, 1.3 eq.), was added dropwise to a stirred solution
of N-Boc dimethylamine 16 (145 mg, 1.00 mmol, 1.0 eq.) and
TMEDA (151 mg, 0.19 mL, 1.30 mmol, 1.3 eq.) in Et2O (2 mL)
at −78 °C under Ar. The resulting solution was stirred at
−78 °C for 2 h. Then, methyl p-toluenesulfinate 17 (340 mg,
2.00 mmol, 2.0 eq.) was added and the solution was allowed to
warm to rt over 2 h and stirred at rt for 16 h. Saturated
NH4Cl(aq) (10 mL) was added and the two layers were separ-
ated. The aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic layers were dried (Na2SO4) and evapor-
ated under reduced pressure to give the crude product. Purifi-
cation by flash column chromatography on silica with 98 : 2
CH2Cl2–acetone with 1% Et3N as eluent gave sulfoxide 18
(202 mg, 71%) as a colourless oil, RF (98 : 2 CH2Cl2–acetone
with 1% Et3N) 0.3; IR (Film) 2977, 2930, 1712 (CvO), 1493,
1454, 1370, 1288, 1163, 1045, 871 cm−1 1H NMR (400 MHz,
;
CDCl3) (50 : 50 mixture of rotamers) δ 7.55 (d, J = 8.0 Hz, 1H,
m-C6H4Me), 7.51 (d, J = 8.0 Hz, 1H, m-C6H4Me), 7.35 (d, J =
8.0 Hz, 1H, o-C6H4Me), 7.33 (d, J = 8.0 Hz, 1H, o-C6H4Me), 4.58
(d, J = 13.0 Hz, 0.5H, NCHAHB), 4.37 (d, J = 13.0 Hz, 0.5H,
NCHAHB), 4.30 (d, J = 13.0 Hz, 0.5H, NCHAHB), 4.11 (d, J =
13.0 Hz, 0.5H, NCHAHB), 3.06 (s, 1.5H, NMe), 2.94 (s, 1.5H,
NMe), 2.42 (s, 1.5H, C6H4Me), 2.41 (s, 1.5H, C6H4Me), 1.43 (s,
4.5H, CMe3), 1.39 (s, 4.5H, CMe3); 13C NMR (100.6 MHz,
CDCl3) (rotamers) δ 155.2 (CvO), 154.2 (CvO), 142.0 (ipso-
C6H4S(O)), 141.7 (ipso-C6H4S(O)), 138.7 (ipso-C6H4Me), 138.4
(ipso-C6H4Me), 130.1 (Ar), 129.9 (Ar), 124.3 (Ar), 124.2 (Ar), 81.2
(CMe3), 81.0 (CMe3), 74.6 (NCH2), 74.5 (NCH2), 37.0 (NMe),
36.3 (NMe), 28.2 (CMe3), 28.0 (CMe3), 21.4 (br, C6H4Me); MS
(ESI) m/z 306 [(M + Na)+, 100]; HRMS m/z calcd for C14H21NO3S
(M + Na)+ 306.1134, found 306.1135 (−0.3 ppm error).
Fig. 2 Spectrum of stability of α-amino sulfoxides.
Chloromethyl p-tolylsulfide.23 N-Chlorosuccinimide (3.67 g,
27.5 mmol, 1.1 eq., recrystallised from glacial AcOH) was
added to a stirred solution of methyl p-tolylsulfide (3.45 g,
25.0 mmol, 1.0 eq.) in CHCl3 (25 mL) at 0 °C. The resulting
solution was allowed to warm to rt over 5 min and then stirred
at rt for 18 h. Then, 4% NaI(aq) (50 mL) was added and the two
layers were separated. The organic layer was washed with 10%
Na2S2O3(aq) (50 mL), dried (Na2SO4) and evaporated under
reduced pressure to give a 90 : 10 mixture (by 1H NMR spec-
troscopy) of chloromethyl p-tolylsulfide and methyl p-tolylsul-
fide (4.12 g, 90% yield of chloromethyl p-tolylsulfide) as a pale
yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2 H,
o-C6H4Me), 7.18 (d, J = 8.0 Hz, 2 H, m-C6H4Me), 4.92 (s, 2H,
CH2), 2.36 (s, 3H, Me). Attempted purification by flash column
chromatography on silica gel or by fractional distillation led to
product decomposition. Therefore, the crude product was
used in the next step without further purification.
Experimental
General
All non-aqueous reactions were carried out under O2-free
Ar using flame-dried glassware. All reagents were used as
purchased without further purification unless otherwise
stated. Alkyllithiums were titrated against N-benzylbenzamide
before use. All diamines and electrophiles were distilled over
CaH2 before use. Et2O and THF were freshly distilled
from sodium and benzophenone ketyl. Petrol refers to the frac-
tion of petroleum ether boiling in the range 40–60 °C. Water
is distilled water. Brine refers to a saturated aqueous solution
of NaCl.
The following compounds were synthesised according to
the reported procedures: N-Boc dimethylamine 16,31 methyl
p-toluenesulfinate 17,8 N-(4-methoxyphenyl)benzamide 19,22
N-Boc, N-benzyl p-anisidine 27,25b N-Boc pyrrolidine 30,31
N-Boc piperidine 33,27 N-Boc 2-phenyl pyrrolidine 40,29 N-thio-
pivaloyl azetidine 5738 and N-Boc 4-chloro piperidine 59.8
N-(4-Methoxyphenyl)-N-p-tolylsulfanylmethyl
benzamide
21. A 90 : 10 mixture (by 1H NMR spectroscopy) of chloro-
methyl p-tolylsulfide and methyl p-tolylsulfide (1.80 g,
9.38 mmol of chloromethyl p-tolylsulfide, 2.5 eq.) was added
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to a stirred solution of tetraethylammonium iodide (430 mg, poured into saturated NH4Cl(aq) (10 mL). The two layers were
1.88 mmol, 0.5 eq.) and benzamide 19 (850 mg, 3.75 mmol, separated and the aqueous layer was extracted with Et2O (3 ×
1.0 eq.) in CH2Cl2 (7.5 mL) at rt. The resulting solution was 15 mL). The combined organic layers were dried (Na2SO4) and
cooled to 0 °C and 50% NaOH(aq) (17.5 mL) was added. The evaporated under reduced pressure to give the crude product.
resulting solution was stirred and heated at 50 °C for 18 h. Purification by flash column chromatography on silica with
Then, the solution was allowed to cool to rt and poured into 9 : 1 petrol–EtOAc as eluent gave sulfanyl thiobenzamide 22
saturated NH4Cl(aq) (50 mL). The two layers were separated and (204 mg, 54%) as a colourless oil, RF (9 : 1 petrol–EtOAc) 0.3;
the aqueous layer was extracted with Et2O (3 × 30 mL). The 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H, Ar),
combined organic layers were dried (Na2SO4) and evaporated 7.24–7.14 (m, 5H, Ar), 6.93 (br s, 2H, Ar), 6.70 (d, J = 8.5 Hz,
under reduced pressure to give the crude product. Purification 2H, Ar), 6.60 (d, J = 8.5 Hz, 2H, Ar), 4.64 (s, 2H, NCH2), 3.74 (s,
by flash column chromatography on silica with 65 : 35 petrol– 3H, OMe), 2.35 (s, 3H, Me); MS (ESI) m/z 402 [(M + Na)+, 100],
EtOAc as eluent gave benzamide 21 (922 mg, 67%) as a colour- 380 [(M + H)+, 50]; HRMS m/z calcd for C22H21NOS2 (M + Na)+
less oil, RF (65 : 35 petrol–EtOAc) 0.4; IR (film) 2955, 1649 402.0962, found 402.0968 (+2.5 ppm error).
(CvO), 1510, 1493, 1446, 1372, 1250, 1144, 1039, 729 cm−1
;
N-(4-Methoxyphenyl)-N-p-tolylsulfinylmethyl
benzamide
1H NMR (400 MHz, CDCl3) δ 7.27–7.21 (m, 5H, Ar), 7.16 (t, J = 23. m-CPBA (68 mg of ∼77% purity, 0.31 mmol, 1.1 eq.) was
7.5 Hz, 2H, Ar), 7.04 (d, J = 8.0 Hz, 2H, Ar), 6.93 (d, J = 8.0 Hz, added to a stirred solution of sulfanyl benzamide 21 (100 mg,
2H, Ar), 6.69 (d, J = 8.0 Hz, 2H, Ar), 5.30 (s, 2H, NCH2), 3.73 (s, 0.28 mmol, 1.0 eq.) in CH2Cl2 (1.8 mL) at −40 °C under Ar.
3H, OMe), 3.00 (s, 3H, Me); 13C NMR (100.6 MHz, CDCl3) The resulting solution was stirred at −40 °C for 1 h. Then,
δ 170.4 (CvO), 158.3 (ipso-C6H4OMe), 137.1 (ipso-Ar), 135.3 saturated Na2SO3(aq) (7 mL) and CH2Cl2 (10 mL) were added
(ipso-Ar), 135.1 (ipso-Ar), 132.2 (Ar), 130.9 (ipso-Ar), 130.4 (Ar), and the two layers were separated. The aqueous layer was
129.7 (Ar), 129.4 (Ar), 128.6 (Ar), 127.6 (Ar), 114.2 (Ar), 55.9 extracted with CH2Cl2 (2 × 10 mL). The combined organic
(NCH2), 55.3 (OMe), 21.0 (Me); MS (ESI) m/z 386 [(M + Na)+, layers were dried (Na2SO4) and evaporated under reduced
100], 364 [(M + H)+, 20], 240 (50); HRMS m/z calcd for pressure to give the crude product. Purification by flash
C22H21NO2S (M + Na)+ 386.1185, found 386.1175 (+2.6 ppm column chromatography on silica with 7 : 3 EtOAc–petrol as
error).
N-(4-Methoxyphenyl)thiobenzamide
eluent gave sulfoxide 23 (88 mg, 84%) as an orange oil, RF (7 : 3
20. Phosphorous(V) EtOAc–petrol) 0.3; IR (film) 3056, 2932, 2837, 1650 (CvO),
sulfide (918 mg, 4.13 mmol, 1.25 eq.) was added to a stirred 1513, 1446, 1359, 1294, 1178, 1084, 1045 cm−1 1H NMR
;
solution of benzamide 19 (750 mg, 3.30 mmol, 1.0 eq.) in pyri- (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.32
dine (15 mL) at rt under Ar. The resulting solution was stirred (d, J = 7.5, 2H Hz, o-Ph), 7.30 (d, J = 8.0 Hz, 2H, o-C6H4Me),
and heated at 75 °C for 6 h. The solution was allowed to cool 7.26 (br t, J = 7.5 Hz, 1H, p-Ph), 7.16 (t, J = 7.5 Hz, 2H, m-Ph),
to rt and then poured into 1 M HCl(aq) (50 mL). 1 M HCl(aq) 7.10 (d, J = 8.5 Hz, 2H, Ar), 6.69 (d, J = 8.5 Hz, 2H, Ar), 5.20 (d,
was added until pH 3 was obtained. The resulting solution was J = 12.5 Hz, 1H, NCHAHB), 4.49 (d, J = 12.5 Hz, 1H, NCHAHB),
stirred for 2 h and then extracted with CH2Cl2 (3 × 50 mL). 3.70 (s, 3H, OMe), 2.38 (s, 3H, Me); 13C NMR (100.6 MHz,
Combined organic extracts were washed with 1 M HCl(aq) CDCl3) δ 170.7 (CvO), 158.3 (ipso-C6H4OMe), 141.7 (ipso-Ar),
(50 mL), water (50 mL) and brine (50 mL), dried (Na2SO4) and 138.8 (ipso-Ar), 135.9 (ipso-Ar), 134.3 (ipso-Ar), 130.2 (Ar), 129.9
evaporated under reduced pressure to give the crude product. (Ar), 128.9 (Ar), 128.8 (Ar), 127.8 (Ar), 124.3 (Ar), 114.3 (Ar),
Purification by flash column chromatography on silica with 76.9 (NCH2), 55.3 (OMe), 21.4 (Me); MS (ESI) m/z 402
4 : 1 petrol–EtOAc as eluent gave thiobenzamide 20 (320 mg, [(M + Na)+, 100], 240 [(M − S(O)C6H4Me)+, 50]; HRMS m/z calcd
1
40%) as a pale yellow oil, RF (4 : 1 petrol–EtOAc) 0.2; H NMR for C22H21NO3S (M + Na)+ 402.1134, found 402.1124 (+2.5 ppm
(400 MHz, CDCl3) δ 8.94 (br s, 1H, NH), 7.88 (dd, J = 7.0, error).
1.5 Hz, 2H, o-Ph), 7.67 (d, J = 8.5 Hz, 2H, Ar), 7.52 (tt, J = 7.0,
N-(4-Methoxyphenyl)-N-p-tolylsulfinylmethyl thiobenzamide
1.5 Hz, 1H, p-Ph), 7.45 (td, J = 7.0 1.5 Hz, 2H, m-Ph), 6.98 (d, 24. m-CPBA (141 mg of ∼70% purity, 0.57 mmol, 1.1 eq.) was
J = 8.5 Hz, 2H, Ar), 3.86 (s, 3H, OMe); MS (ESI) m/z 266 added to a stirred solution of sulfanyl thiobenzamide 22
[(M + Na)+, 20], 244 [(M + H)+, 100], 159 (30), 141 (30), 125 (30); (200 mg, 0.52 mmol, 1.0 eq.) in CH2Cl2 (3.5 mL) at −40 °C
HRMS m/z calcd for C14H13NOS (M + H)+ 244.0791, found under Ar. The resulting solution was stirred at −40 °C for 1 h.
244.0786 (+2.0 ppm error).
Then, saturated Na2SO3(aq) (7 mL) and CH2Cl2 (10 mL) were
N-(4-Methoxyphenyl)-N-p-tolylsulfanylmethyl thiobenzamide added and the two layers were separated. The aqueous layer
22. A 90 : 10 mixture (by 1H NMR spectroscopy) of chloro- was extracted with CH2Cl2 (2 × 10 mL). The combined organic
methyl p-tolylsulfide and methyl p-tolylsulfide (481 mg, layers were dried (Na2SO4) and evaporated under reduced
2.48 mmol of chloromethyl p-tolylsulfide, 2.5 eq.) was added pressure to give the crude product. Purification by flash
to a stirred solution of tetraethylammonium iodide (112 mg, column chromatography on silica with 7 : 3 EtOAc–petrol as
0.50 mmol, 0.5 eq.) and thiobenzamide 20 (240 mg, eluent gave sulfoxide 24 (158 mg, 77%) as a viscous orange
0.99 mmol, 1.0 eq.) in CH2Cl2 (4.5 mL) at rt. The resulting foam, RF (7 : 3 EtOAc–petrol) 0.2; IR (CHCl3) 2833, 1613 (CvS),
solution was cooled to 0 °C and then 50% NaOH(aq) (2.5 mL) 1502, 1443, 1242, 1178, 1047, 956, 832 cm−1
;
1H NMR
was added. The resulting solution was stirred and heated at (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H, m-C6H4Me),
50 °C for 18 h. Then, the solution was allowed to cool to rt and 7.34–7.19 (m, 7H, Ar), 6.69 (d, J = 8.0 Hz, 2H, Ar), 6.51 (d, J =
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8.5 Hz, 2H, Ar), 4.57 (d, J = 13.0 Hz, 1H, NCHAHB), 4.45 (d, J = 137.9 (ipso-Ar), 136.4 (ipso-Ar), 135.4 (Ar), 134.4 (Ar), 131.0 (Ar),
13.0 Hz, 1H, NCHAHB), 3.74 (s, 3H, OMe), 2.40 (s, 3H, Me); 13C 130.1 (Ar), 129.7 (Ar), 129.6 (Ar), 129.0 (Ar), 128.0 (Ar), 127.8
NMR (100.6 MHz, CDCl3) (rotamers) δ 208.1 (CvS), 156.1 (Ar), 126.8 (Ar), 124.3 (Ar), 114.1 (Ar), 113.3 (Ar), 80.1 (CMe3),
(ipso-C6H4OMe), 141.7 (ipso-Ar), 140.1 (ipso-Ar), 135.1 (br, ipso- 55.5 (OMe or NCH), 55.2 (OMe or NCH), 28.3 (CMe3), 28.1
Ar), 130.0 (ipso-Ar), 129.6 (Ar), 128.5 (Ar), 128.0 (Ar), 127.5 (Ar), (CMe3), 21.3 (Me), 21.2 (Me); MS (ESI) m/z 474 [(M + Na)+, 2],
124.7 (Ar), 122.7 (Ar), 113.9 (Ar), 60.4 (NCH2), 55.8 (OMe), 55.3 452 [(M + H)+, 1], 393 (20), 352 (50), 312 (100), 256 (20); HRMS
(OMe), 21.4 (Me), 14.6 (Me); MS (ESI) m/z 396 [(M + H)+, 100]; (ESI) m/z calcd for C26H29NO4S (M + H)+ 452.1890, found
HRMS m/z calcd for C22H21NO2S2 (M + H)+ 396.1086, found 452.1919 (+5.5 ppm error) and sulfoxide 28b (92 mg, 20%) as a
396.1092 (−0.4 ppm error).
N-(tert-Butoxycarbonyl)methylamine 26. n-BuLi (100 μL of a Et3N) 0.1; IR (CHCl3) 2964, 1691 (CvO), 1494, 1224, 1143,
2.5 M solution in hexanes, 0.26 mmol, 1.3 eq.) was added 1042, 817 cm−1 1H NMR (400 MHz, CDCl3) δ 7.27–7.17 (m,
yellow solid, mp 68–70 °C, RF (98 : 2 CH2Cl2–acetone with 0.5%
;
dropwise to a stirred solution of diisopropylamine (26 mg, 3H, Ar), 7.17–7.03 (m, 6H, Ar), 6.88–6.76 (m, 4H, Ar), 6.33–5.93
36 μL, 0.26 mmol, 1.3 eq.) in THF (1 mL) at −78 °C under Ar. (m, 1H, NCH), 3.84 (s, 3H, OMe), 2.31 (s, 3H, Me), 1.74–1.27
The resulting solution was warmed to 0 °C and stirred for (m, 9H, CMe3); 13C NMR (100.6 MHz, CDCl3) (rotamers)
15 min and then cooled to −78 °C. Then, a solution of sulfox- δ 158.3 (CvO), 155.6 (ipso-Ar), 153.1 (ipso-Ar), 142.1 (ipso-Ar),
ide 18 (67 mg, 0.22 mmol, 1.0 eq.) in THF (2 mL) was added 141.0 (ipso-Ar), 140.8 (ipso-Ar), 137.9 (ipso-Ar), 136.4 (ipso-Ar),
dropwise over 10 min. The resulting mixture was stirred at 135.4 (Ar), 134.4 (Ar), 131.4 (Ar), 131.0 (Ar), 130.1 (Ar), 129.7
−78 °C for 1 h. Then, Me2SO4 (42 mg, 31 μL, 0.49 mmol, 1.5 (Ar), 129.6 (Ar), 129.0 (Ar), 128.0 (Ar), 127.8 (Ar), 126.8 (Ar),
eq.) was added and the mixture was allowed to warm to rt over 124.3 (Ar), 114.1 (Ar), 113.3 (Ar), 80.1 (CMe3), 55.5 (OMe or
2 h. Then, saturated NH4Cl(aq) (4 mL) and Et2O (5 mL) were NCH), 55.2 (OMe or NCH), 28.3 (CMe3), 28.1 (CMe3), 21.5 (Me),
added and the two layers were separated. The aqueous layer 21.2 (Me); MS (ESI) m/z 474 [(M + Na)+, 10], 452 [(M + H)+, 5],
was extracted with Et2O (3 × 5 mL) and the combined organic 393 (40), 352 (60), 312 (100), 256 (20); HRMS (ESI) m/z calcd for
layers were dried (MgSO4) and evaporated under reduced C26H29NO4S (M + H)+ 452.1890, found 452.1902 (+4.1 ppm
pressure to give the crude product. Purification by flash error).
column chromatography on silica with 96 : 4 CH2Cl2–acetone
Subsequent attempts to repeat this lithiation-trapping reac-
with 1% Et3N as eluent gave N-Boc methylamine 26 (17 mg, tion were unsuccessful and sulfoxides 28a and 28b were not
59%) as a colourless oil, RF (96 : 4 CH2Cl2–acetone with 1% isolated probably due to their instability on silica.
Et3N) 0.2; 1H NMR (400 MHz, CDCl3) δ 4.80 (br s, 1H, NH),
N-tert-Butoxycarbonyl-5-(p-tolylsulfinyl)-2,3-dihydropyrrole
2.83 (br s, 3H, NMe), 1.46 (s, 9H, CMe3); 13C NMR (100.6 MHz, 32. s-BuLi (1.50 mL of
1.3 solution in hexanes,
a
M
CDCl3) (rotamers) δ 156.2 (CvO), 155.9 (CvO), 80.1 (CMe3), 1.95 mmol, 1.3 eq.) was added dropwise to a stirred solution of
79.8 (CMe3), 32.7 (Me), 32.5 (Me), 28.3 (CMe3). Spectroscopic N-Boc pyrrolidine 30 (257 mg, 1.50 mmol, 1.0 eq.) in THF
data consistent with those reported in the literature.40
(6 mL) at −78 °C under Ar. The resulting solution was stirred
tert-Butyl 4-methoxyphenyl(phenyl(p-tolylsulfinyl)methyl) at −78 °C for 1 h. Then, methyl p-toluenesulfinate 17 (510 mg,
carbamate 28a and 28b. s-BuLi (1.0 mL of a 1.3 M solution in 3.0 mmol, 2.0 eq.) was added and the solution was allowed to
hexanes, 1.3 mmol, 1.3 eq.) was added dropwise to a stirred warm to rt over 2 h and stirred at rt for 16 h. Saturated
solution of N-Boc N-benzyl p-anisidine 27 (313 mg, 1.0 mmol, NH4Cl(aq) (10 mL) was added and the two layers were separ-
1.0 eq.) and TMEDA (151 mg, 194 μL, 1.3 mmol, 1.3 eq.) in ated. The aqueous layer was extracted with Et2O (3 × 10 mL).
Et2O (2 mL) at −78 °C under Ar. The resulting solution was The combined organic layers were dried (Na2SO4) and evapor-
stirred at −78 °C for 30 min. Then, methyl p-tolylsulfinate 17 ated under reduced pressure to give the crude product. Purifi-
(255 mg, 1.5 mmol, 1.5 eq.) was added. The resulting solution cation by flash column chromatography on silica with 1 : 1
was stirred at −30 °C for 10 min and then allowed to warm to petrol–EtOAc as eluent gave dihydropyrrole 32 (145 mg, 31%)
rt over 1 h. Then, MeOH (1 mL), saturated NH4Cl(aq) (2 mL) as a colourless oil, RF (1 : 1 petrol–EtOAc) 0.3; IR (CHCl3) 2980,
and Et2O (5 mL) were added and the two layers were separated. 1678 (CvO), 1369, 1306, 1153, 1093, 901, 809, 722 cm−1 1H
;
The aqueous layer was extracted with Et2O (3 × 5 mL) and the NMR (400 MHz, CDCl3) δ 7.68 (br d, J = 8.0 Hz, 2H,
combined organic layers were dried (MgSO4) and evaporated m-C6H4Me), 7.24 (d, J = 8.0 Hz, 2H, o-C6H4Me), 5.96 (t, J =
under reduced pressure to give the crude product. Purification 3.0 Hz 1H, vCH), 3.97 (br s, 1H, NCH), 3.85–3.76 (m, 1H,
by flash column chromatography on silica with 98 : 2 CH2Cl2– NCH), 2.84–2.74 (m, 1H, CH), 2.64 (dddd, J = 17.0, 11.5, 6.0,
acetone with 0.5% Et3N as eluent gave sulfoxide 28a (135 mg, 3.0 Hz, 1H, CH), 2.37 (s, 3H, Me), 1.37 (s, 9H, CMe3); 13C NMR
30%) as a yellow solid, mp 65–68 °C, RF (98 : 2 CH2Cl2–acetone (100.6 MHz, CDCl3) (rotamers) δ 174.3 (CvO), 150.2 (CvO),
with 0.5% Et3N) 0.2; IR (CHCl3) 2963, 1691 (CvO), 1494, 1347, 142.1 (ipso-Ar), 140.9 (vC), 140.8 (vC), 136.5 (Ar), 135.4 (Ar),
1
1224, 1142, 1018, 817 cm−1; H NMR (400 MHz, CDCl3) δ 7.61 130.2 (Ar), 129.6 (Ar), 127.7 (Ar), 126.6 (ipso-Ar), 126.2 (ipso-Ar),
(d, J = 8.0 Hz, 2H, Ar), 7.33–7.22 (m, 7H, Ar), 6.68 (d, J = 9.0 Hz, 124.3 (vCH), 82.7 (CMe3), 46.4 (NCH2), 32.9 (CH2), 28.1
2H, Ar), 6.56 (br d, J = 8.0 Hz, 2H, Ar), 5.57 (s, 1H, NCH), 3.77 (CMe3), 28.0 (CMe3), 21.5 (br, Me), 17.4 (CH2); (MS (ESI) m/z
(s, 3H, OMe), 2.43 (s, 3H, Me), 1.34 (s, 9H, CMe3); 13C NMR 330 [(M + Na)+, 100], 208 (40), 238 (100); HRMS (ESI) m/z calcd
(100.6 MHz, CDCl3) (rotamers) δ 158.3 (CvO), 155.6 (ipso-Ar), for C16H21NO3S (M
153.1 (ipso-Ar), 142.1 (ipso-Ar), 140.9 (ipso-Ar), 140.7 (ipso-Ar), (+3.7 ppm error).
+
Na)+ 330.1134, found, 330.1122
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s-BuLi (1.92 mL of a 1.3 M solution in hexanes, 2.50 mmol, gave dihydropyrrole 42 (178 mg, 72%) as a yellow oil, RF (9 : 1
2.5 eq.) was added to a stirred solution of N-Boc pyrrolidine 30 petrol–Et2O) 0.2; 1H NMR (400 MHz, CDCl3) δ 7.33–7.22
(171 mg, 1.00 mmol, 1.0 eq.) in THF (6 mL) at −78 °C under (m, 5H, Ph), 5.23 (t, J = 3.0 Hz, 1H, CvCH), 4.05 (t, J = 9.0 Hz,
Ar. The resulting solution was stirred at −78 °C for 1 h. Then, 2H, NCH2), 2.62 (td, J = 9.0, 3.0 Hz, 2H, CH2), 1.19 (s, 9H,
methyl p-toluenesulfinate 17 (510 mg, 3.0 mmol, 3.0 eq.) was CMe3). On standing, this compound was unstable and con-
added and the two layers were separated. The aqueous layer verted into N-Boc aminophenone 43 (158 mg, 60%) as an off-
1
was extracted with Et2O (3 × 10 mL). The combined organic white solid, H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.5 Hz,
layers were dried (Na2SO4) and evaporated under reduced 2H, o-Ph), 7.55 (t, J = 7.5 Hz, 1H, p-Ph), 7.45 (t, J = 7.5 Hz, 2H,
pressure to give the crude product. Purification by m-Ph), 4.75 (br s, 1H, NH), 3.22 (q, J = 7.0 Hz, 2H, NCH2), 3.02
flash column chromatography on silica with 1 : 1 petrol–EtOAc (t, J = 7.0 Hz, 2H, CH2CO), 1.93 (quin, J = 7.0 Hz, 2H, CH2),
as eluent gave dihydropyrrole 32 (136 mg, 44%) as
colourless oil.
a
1.41 (s, 9H, CMe3). Spectroscopic data of 43 consistent with
those reported in the literature.30
N-tert-Butylcarbonyl-6-(phenylsulfinyl)-3,4-dihydro-2H-pyri-
N-tert-Butylcarbonyl-2-(phenylsulfanyl)pyrrolidine 44. s-BuLi
dine 36. s-BuLi (2.50 mL of a 1.3 M solution in hexanes, (2.62 mL of a 1.3 M solution in hexanes, 3.40 mmol, 1.3 eq.)
3.25 mmol, 1.3 eq.) was added dropwise to a stirred solution of was added dropwise to a stirred solution of N-Boc pyrrolidine
N-Boc piperidine 33 (463 mg, 2.50 mmol, 1.0 eq.) and TMEDA 30 (445 mg, 2.60 mmol, 1.0 eq.) in THF (10 mL) at −78 °C
(378 mg, 0.49 mL, 3.25 mmol, 1.3 eq.) in Et2O (8 mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 h.
under Ar. The resulting solution was stirred at −78 °C for 3 h. Then, a solution of diphenyl disulfide (1.14 g, 5.2 mmol,
Then, methyl benzenesulfinate 34 (624 mg, 4.00 mmol, 2.0 eq.) in THF (2 mL) was added and the solution was allowed
1.6 eq.) was added and the solution was allowed to warm to rt to warm to rt over 2 h and stirred at rt for 16 h. Saturated
over 2 h and stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) NH4Cl(aq) (10 mL) was added and the two layers were separ-
was added and the two layers were separated. The aqueous ated. The aqueous layer was extracted with Et2O (3 × 10 mL).
layer was extracted with Et2O (3 × 10 mL). The combined The combined organic layers were dried (Na2SO4) and evapor-
organic layers were dried (Na2SO4) and evaporated under ated under reduced pressure to give the crude product. Purifi-
reduced pressure to give the crude product. Purification by cation by flash column chromatography on silica with 98 : 2
flash column chromatography on silica with 1 : 1 petrol–EtOAc CH2Cl2–acetone as eluent gave sulfide 44 (301 mg, 44%) as a
as eluent gave tetrahydropyridine 36 (100 mg, 13%) as a col- colourless oil, RF (98 : 2 CH2Cl2–acetone) 0.7; IR (film) 2976,
ourless oil, RF (1 : 1 petrol–EtOAc) 0.30; IR (Film) 2975, 1693 2931, 1695 (CvO), 1444, 1406, 1367, 1143, 1078, 1049,
1
(CvO), 1511, 1454, 1391, 1366, 1246, 1166, 1033, 700 cm−1; 1H 750 cm−1; H NMR (400 MHz, CDCl3) (60 : 40 mixture of rota-
NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H, o-Ph), mers) δ 7.55–7.42 (m, 2H, Ph), 7.31–7.29 (m, 3H, Ph), 5.39 (br
7.41–7.40 (m, 3H, Ph), 6.37 (t, J = 3.5 Hz, 1H, vCH), 3.97 (br d, s, 0.4H, NCH), 5.29–5.28 (m, 0.6H, NCH), 3.51–3.34 (m, 1.2H,
J = 11.5 Hz, 1H, NCH), 2.71 (br s, 1H, NCH), 2.39 (ddt, J = 18.5, NCH), 3.33–3.22 (m, 0.8H, NCH), 2.20–1.98 (m, 2.4H, CH),
6.5, 3.5 Hz, 1H, CH), 2.28 (dddd, J = 18.5, 10.0, 7.0, 3.5 Hz, 1H, 1.93–1.83 (m, 1.6H, CH), 1.45 (s, 3.6H, CMe3), 1.35 (s, 5.4H,
CH), 1.86–1.69 (m, 2H, CH), 1.37 (s, 9H, CMe3); 13C NMR (rota- CMe3); 13C NMR (100.6 MHz, CDCl3) (rotamers) δ 153.4
mers) (100.6 MHz, CDCl3) δ 152.3 (CvO), 144.7 (ipso-Ph), (CvO), 134.4 (ipso-Ph), 134.1 (ipso-Ph), 133.9 (Ph), 128.9 (Ph),
143.5 (vC) 131.0 (Ph), 128.9 (Ph), 128.7 (Ph), 126.4 (Ph), 126.1 128.7 (Ph), 127.8 (Ph), 127.6 (Ph), 127.3 (Ph), 82.6 (CMe3), 79.8
(Ph), 113.7 (br, vCH), 82.1 (br, CMe3), 44.9 (NCH2), 28.1 (CMe3), 66.9 (NCH), 66.6 (NCH), 46.1 (NCH2), 45.4 (NCH2),
(CMe3), 23.2 (CH2), 22.0 (CH2); MS (ESI) m/z 330 [(M + Na)+, 33.8 (CH2), 33.1 (CH2), 28.3 (CMe3), 28.0 (CMe3), 22.8 (CH2),
100], 308 [(M + H)+, 30], 252 (70); HRMS m/z calcd for 22.1 (CH2); MS (ESI) m/z 302 [(M + Na)+, 100], 208 (25), 114
C16H21NO3S (M + Na)+ 330.1134, found 330.1127 (+2.2 ppm (50); HRMS m/z calcd for C15H21NO2S (M + Na)+ 302.1185,
error).
tert-Butyl 5-phenyl-2,3-dihydro-1H-pyrrole-1-carboxylate 42
found, 302.1181 (+1.4 ppm error).
N-tert-Butylcarbonyl-2-(p-tolylsulfanyl)pyrrolidine 45. s-BuLi
and tert-butyl 4-oxo-4-phenylbutylcarbamate 43. n-BuLi (1.50 mL of a 1.3 M solution in hexanes, 1.95 mmol, 1.3 eq.)
(520 μL of a 2.5 M solution in hexanes, 1.3 mmol, 1.3 eq.) was was added dropwise to a stirred solution of N-Boc pyrrolidine
added dropwise to a stirred solution of N-Boc 2-phenylpyrroli- 30 (257 mg, 1.50 mmol, 1.0 eq.) in THF (6 mL) at −78 °C
dine 40 (247 mg, 1.0 mmol, 1.0 eq.) in THF (10 mL) at 0 °C under Ar. The resulting solution was stirred at −78 °C for 1 h.
under Ar. The resulting mixture was stirred at 0 °C for 5 min. Then, a solution of p-tolyl disulfide (739 mg, 3.0 mmol,
Then, methyl p-tolylsulfinate 17 (340 mg, 2.0 mmol, 2.0 eq.) 2.0 eq.) in THF (2 mL) was added and the solution was allowed
was added. The reaction was stirred at 0 °C for 10 min and to warm to rt over 2 h and stirred at rt for 16 h. Saturated
then allowed to warm to rt over 30 min. Then, MeOH (0.6 mL), NH4Cl(aq) (10 mL) was added and the two layers were separ-
saturated NH4Cl(aq) (5 mL) and Et2O (5 mL) were added and ated. The aqueous layer was extracted with Et2O (3 × 10 mL).
the two layers were separated. The aqueous layer was extracted The combined organic layers were dried (Na2SO4) and evapor-
with Et2O (3 × 5 mL) and the combined organic layers were ated under reduced pressure to give the crude product. Purifi-
dried (MgSO4) and evaporated under reduced pressure to give cation by flash column chromatography on silica with 98 : 2
the crude product. Purification by flash column chromato- CH2Cl2–acetone as eluent gave sulfide 45 (319 mg, 52%) as a
graphy on silica with 9 : 1 petrol–Et2O with 0.5% Et3N as eluent colourless oil, RF (98 : 2 CH2Cl2–acetone) 0.40; IR (film) 2974,
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2933, 1710 (CvO), 1527, 1390, 1366, 1165 cm−1
;
1H NMR 79.4 (CMe3), 60.7 (NCH), 45.0 (br, NCH2), 43.1 (br, NCH2), 36.7
(400 MHz, CDCl3) (60 : 40 mixture of rotamers) δ 7.43 (d, J = (CH2), 35.6 (CH2), 31.5 (CMe3), 28.5 (CMe3); MS (ESI) m/z 282
7.5 Hz, 0.8H, o-C6H4Me), 7.38 (d, J = 7.5 Hz, 1.2H, o-C6H4Me), [(M + Na)+, 90], 210 (50), 114 (100); HRMS m/z calcd for
7.12 (d, J = 7.5 Hz, 2H, m-C6H4Me), 5.32 (br s, 0.4H, NCH), C13H25NO2S (M + Na)+ 282.1498, found 282.1477 (+7.7 ppm
5.22 (br d, J = 5.5 Hz, 0.6H, NCH), 3.46–3.39 (m, 1.2H, NCH), error).
3.30–3.27 (m, 0.8H, NCH), 2.34 (s, 3H, Me), 2.21–2.03 (m,
N-tert-Butyl
carbonyl-2-hydroxypyrrolidine
48. mCPBA
2.4H, CH), 2.01–1.86 (m, 1.6H, CH), 1.45 (s, 3.6H, CMe3), 1.36 (77 mg of ∼77% purity, 0.35 mmol, 1.0 eq.) was added to a
(s, 5.4H, CMe3); 13C NMR (100.6 MHz, CDCl3) δ 153.7 (CvO), stirred solution of phenylsulfanyl pyrrolidine 44 (100 mg,
138.3 (ipso-Ar), 135.1 (Ar), 130.3 (ipso-Ar), 129.8 (Ar), 80.1 0.35 mmol, 1.0 eq.) and Na2CO3 (80 mg, 0.74 mmol, 2.1 eq.) in
(CMe3), 67.1 (NCH), 45.6 (NCH2), 33.8 (CH2), 32.5 (CH2), 28.5 CH2Cl2 (5 mL) at rt under Ar. The resulting solution was
(CMe3), 21.3 (Me); MS (ESI) m/z 316 [(M + Na)+, 100]; HRMS stirred at rt for 30 min. Then, saturated Na2SO3(aq) (7 mL) and
m/z calcd for C16H23NO2S (M + Na)+ 316.1342, found 316.1342 CH2Cl2 (7 mL) was added. The two layers were separated and
(0.0 ppm error).
N-tert-Butylcarbonyl-2-(p-methoxyphenylsulfanyl)pyrrolidine combined organic layers were dried (Na2SO4) and evaporated
46. s-BuLi (1.50 mL of 1.3 solution in hexanes, under reduced pressure to give the crude product. Purification
the aqueous layer was extracted with CH2Cl2 (3 × 7 mL). The
a
M
1.95 mmol, 1.3 eq.) was added dropwise to a stirred solution of by flash column chromatography on silica with 9 : 1 CH2Cl2–
N-Boc pyrrolidine 30 (257 mg, 1.50 mmol, 1.0 eq.) in THF acetone as eluent gave recovered sulfanyl pyrrolidine 44
(6 mL) at −78 °C under Ar. The resulting solution was stirred (26 mg, 26%) as a colourless oil and hydroxy pyrrolidine 48
at −78 °C for 1 h. Then, p-methoxyphenyldisulfide (745 mg, (21 mg, 31%) as a colourless oil, RF (9 : 1 CH2Cl2–acetone) 0.3;
3.0 mmol, 2.0 eq.) was added and the solution was allowed to IR (Film) 3452 (OH), 2976, 1695 (CvO), 1478, 1392,
warm to rt over 2 h and stirred at rt for 16 h. Saturated 1254, 1163, 1112, 1041, 916 cm−1
;
1H NMR (400 MHz,
NH4Cl(aq) (10 mL) was added and the two layers were separ- CDCl3) (60 : 40 mixture of rotamers) δ 5.48 (br s, 0.6H,
ated. The aqueous layer was extracted with Et2O (3 × 10 mL). NCH), 5.39 (br m, 0.4H, NCH), 3.56–3.46 (m, 1H, NCH),
The combined organic layers were dried (Na2SO4) and evapor- 3.34–3.17 (m, 1H, NCH), 2.11–1.78 (m, 4H, CH), 1.50 (s, 3.6H,
ated under reduced pressure to give the crude product. Purifi- CMe3), 1.47 (s, 5.4H, CMe3); 13C NMR (100.6 MHz, CDCl3)
cation by flash column chromatography on silica with 98 : 2 δ 155.1 (CvO), 81.8 (NCHOH), 80.0 (CMe3), 45.9 (NCH2),
CH2Cl2–Et2O as eluent gave sulfide 46 (65 mg, 14%) as a col- 32.6 (CH2), 28.4 (CMe3), 22.7 (CH2); MS (ESI) m/z 379
ourless oil, RF (98 : 2 CH2Cl2–Et2O) 0.30; 1H NMR (400 MHz, [(M Dimer + Na)+, 100], 266 (50), 210 [(M + Na)+, 20]; HRMS
CDCl3) (60 : 40 mixture of rotamers) δ 7.48 (d, J = 8.0 Hz, 0.8H, m/z calcd for C9H17NO3 (M + Na)+ 210.1101, found 210.101
o-C6H4OMe), 7.42 (d, J = 8.0 Hz, 1.2H, o-C6H4OMe), 6.84 (d, J = (−0.1 ppm error). Spectroscopic data consistent with those
8.0 Hz, 2H, m-C6H4OMe), 5.25 (br s, 0.4H, NCH), 5.16 (br d, J = reported in the literature.31
6.0 Hz, 0.6H, NCH), 3.80 (s, 3H, C6H4OMe), 3.45–3.28 (m, 2H,
mCPBA (89 mg of ∼77% purity, 0.41 mmol, 1.1 eq.) was
NCH), 2.14–1.99 (m, 2.4H, CH), 1.89–1.81 (m, 1.6H, CH), 1.43 added to a stirred solution of KF (40 mg, 0.69 mmol, 1.8 eq.)
(s, 3.6H, CMe3), 1.36 (s, 5.4H, CMe3); MS (ESI) m/z 332 [(M + in 4 : 1 MeCN–water (3 mL) at 0 °C. The resulting solution was
Na)+, 100]; HRMS m/z calcd for C16H23NO3S (M + Na)+ stirred at 0 °C for 30 min. Then, phenylsulfanyl pyrrolidine 44
332.1291, found 332.1289 (+0.5 ppm error).
(107 mg, 0.38 mmol, 1.0 eq.) was added. The resulting solution
N-tert-Butylcarbonyl-2-(tert-butylsulfanyl)pyrrolidine 47. was stirred at 0 °C for 30 min. Then, saturated Na2SO3(aq)
s-BuLi (1.50 mL of a 1.3 M solution in hexanes, 1.95 mmol, 1.3 (7 mL) and Et2O (7 mL) was added. The two layers were separ-
eq.) was added dropwise to a stirred solution of N-Boc pyrroli- ated and the aqueous layer was extracted with Et2O (3 × 7 mL).
dine 30 (257 mg, 1.50 mmol, 1.0 eq.) in THF (6 mL) at −78 °C The combined organic layers were dried (Na2SO4) and evapor-
under Ar. Then, tert-butyldisulfide (535 mg, 3.0 mmol, 2.0 eq.) ated under reduced pressure to give the crude product. Purifi-
was added and the solution was allowed to warm to rt over 2 h cation by flash column chromatography on silica with 9 : 1
and stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) was CH2Cl2–acetone as eluent gave hydroxy pyrrolidine 48 (40 mg,
added and the two layers were separated. The aqueous layer 57%) as a colourless oil.
was extracted with Et2O (3 × 10 mL). The combined organic
mCPBA (208 mg of ∼77% purity, 1.20 mmol, 1.1 eq.) was
layers were dried (Na2SO4) and evaporated under reduced added to a stirred solution of phenylsulfanyl pyrrolidine 44
pressure to give the crude product. Purification by flash (309 mg, 1.10 mmol, 1.0 eq.) in CH2Cl2 (2.2 mL) at −40 °C
column chromatography on silica with 4 : 1 petrol–Et2O as under Ar. The resulting solution was stirred at −40 °C for 1 h.
eluent gave sulfide 47 (230 mg, 59%) as a colourless oil, RF Then, saturated Na2SO3(aq) (7 mL) and CH2Cl2 (10 mL) were
(4 : 1 petrol–Et2O) 0.40; IR (film) 2979, 1689 (CvO), 1393, added and the two layers were separated. The aqueous layer
1367, 1254, 1163, 1117, 1042, 921, 870 cm−1
;
1H NMR was extracted with CH2Cl2 (2 × 10 mL). The combined organic
(400 MHz, CDCl3) (50 : 50 mixture of rotamers) δ 5.22 (br s, layers were dried (Na2SO4) and evaporated under reduced
0.5H, NCH), 5.03 (br s, 0.5H, NCH), 3.39–3.34 (m, 1H, NCH), pressure to give the crude product. Purification by flash
3.30–3.22 (m, 1H, NCH), 2.20–2.03 (m, 2H, CH), 1.99–1.85 (m, column chromatography on silica with 9 : 1 CH2Cl2–acetone as
2H, CH), 1.44 (br s, 9H, CMe3), 1.38 (br s, 9H, CMe3); 13C NMR eluent gave hydroxy pyrrolidine 48 (179 mg, 86%) as a colour-
(100.6 MHz, CDCl3) (rotamers) δ 153.4 (CvO), 82.7 (CMe3), less oil.
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The above procedure was repeated using p-tolylsulfanyl pyr- organic layer was washed with water (2 × 30 mL) and brine
rolidine 45 (81%), p-methoxyphenylsulfanyl pyrrolidine 46 (30 mL), dried (MgSO4) and evaporated under reduced
(74%), t-butylsulfanyl pyrrolidine 47 (77%).
pressure. The residue was dissolved in CH2Cl2 (50 mL) and
H2O2 (0.07 mL of a 30% aqueous solution, 0.61 mmol, then DMAP (47 mg, 0.39 mmol, 0.1 eq.), benzoyl chloride
1.8 eq.) was added dropwise to a stirred solution of sulfanyl (0.49 mL, 4.3 mmol, 1.1 eq.) and Et3N (0.81 mL, 5.8 mmol, 1.5
pyrrolidine 45 (100 mg, 0.34 mmol, 1.0 eq.) in hexafluoroiso- eq.) were added. The resulting solution was stirred at rt for
propanol (0.7 mL) at rt under Ar. The resulting solution was 20 h. Then, NaHCO3(aq) (50 mL) and CH2Cl2 (50 mL) were
stirred at rt for 10 min. Then, saturated Na2SO3(aq) (5 mL) and added and the two layers were separated. The organic layer
Et2O (5 mL) was added. The two layers were separated and the was washed with NH4Cl(aq) (2 × 50 mL) and brine (50 mL),
aqueous layer was extracted with Et2O (3 × 5 mL). The com- dried (MgSO4) and evaporated under reduced pressure to give
bined organic layers were dried (Na2SO4) and evaporated the crude product. Purification by flash column chromato-
under reduced pressure to give the crude product. Purification graphy on silica with 80 : 20 petrol–Et2O as eluent gave pyrroli-
by flash column chromatography on silica with 9 : 1 CH2Cl2– dine 50 (1.27 g, 70%) as a colourless oil, RF (98 : 2 petrol–
acetone as eluent gave recovered sulfanyl pyrrolidine 45 EtOAc) 0.3; IR (CHCl3) 2911, 2881, 1653 (CvO), 1526, 1427,
(42 mg, 42%) and hydroxy pyrrolidine 48 (26 mg, 43%) as a col- 1380, 1342, 707, 623 cm−1
;
1H NMR (400 MHz, CDCl3) δ
ourless oil. 7.50–7.45 (m, 2H, Ph), 7.41–7.36 (m, 3H, Ph), 3.57 (t, J = 8.5
A solution of Me3SiCl (47 µL, 0.37, 1.1 eq.) in MeCN (1 mL) Hz, 1H, NCH), 3.50 (ddd, J = 11.0, 7.0, 4.5 Hz, 1H, NCH), 3.39
was added dropwise to a stirred solution of KO2 (52 mg, 0.73, (dt, J = 11.0, 7.0 Hz, 1H, NCH), 2.26 (dquin, J = 12.5, 7.0 Hz,
2.15 eq.) and sulfanyl pyrrolidine 45 (100 mg, 0.34 mmol, 1.0 1H, CH), 2.05–1.93 (m, 1H, CH), 1.93–1.77 (m, 2H, CH),
eq.) in MeCN (3 mL) at −15 °C under Ar. The resulting solution 1.68–1.42 (m, 6H, CH2), 1.32 (sextet, J = 7.5 Hz, 6H, CH2Me),
was stirred at −15 °C for 5 h. Then, 1M HCl(aq) (5 mL) was 0.97–0.91 (m, 6H, CH2), 0.89 (t, J = 7.5 Hz, 9H, CH2Me); 13C
added and the solution was extracted with EtOAc (3 × 15 mL). NMR (100.6 MHz, CDCl3) δ 167.8 (CvO), 137.3 (ipso-Ph), 129.5
The combined organic layers were dried (Na2SO4) and evapor- (Ph), 128.2 (Ph), 127.1 (Ph), 50.1 (NCH2), 47.7 (NCH), 29.6
ated under reduced pressure to give the crude product. Purifi- (CH2), 29.2 (CH2), 27.8 (CH2), 27.6 (CH2), 13.8 (Me), 10.2
cation by flash column chromatography on silica with 9 : 1 (CH2); MS (ESI) m/z 466 [(M + H)+, 100], 408 (70); HRMS (ESI)
CH2Cl2–acetone as eluent gave hydroxy pyrrolidine 48 (31 mg, m/z calcd for C23H39NOSn (M + H)+ 466.2130, found 466.2122
52%) as a colourless oil.
(+1.1 ppm error).
2-(Tributylstannyl)pyrrolidine-1-carboxylic acid tert-butyl
2,2,2-Triphenyl-1-(2-(tributylstannyl)pyrrolidin-1-yl)ethanone
ester 49. s-BuLi (10.0 mL of a 1.3 M solution in hexanes, 51. Me3SiI (790 μL, 5.5 mmol, 1.3 eq.) was added to a stirred
13.0 mmol, 1.3 eq.) was added dropwise to a stirred solution of solution of N-Boc stannyl pyrrolidine 49 (1.97 g, 4.3 mmol, 1.0
N-Boc pyrrolidine 30 (1.71 g, 10.0 mmol, 1.0 eq.) and TMEDA eq.) in CH2Cl2 (32 mL) at rt under Ar. The resulting solution
(1.51 g, 1.94 mL, 13.0 mmol, 1.3 eq.) in Et2O (56 mL) at −78 °C was stirred at rt for 30 min. Then, water (6 mL) and CH2Cl2
under Ar. The resulting solution was stirred at −78 °C for (75 mL) were added and the two layers were separated. The
15 min. Then, Bu3SnCl (4.0 mL, 15.0 mmol, 1.5 eq.) was organic layer was washed with water (2 × 30 mL) and brine
added. The resulting solution was stirred at −78 °C for 10 min (30 mL), dried (MgSO4) and evaporated under reduced
and then allowed to warm to rt over 16 h. Then, saturated pressure to give the deprotected stannyl pyrrolidine, which was
1
NH4Cl(aq) (40 mL) and Et2O (100 mL) were added and the two sufficiently pure (by H NMR spectroscopy) for use in the next
layers were separated. The aqueous layer was extracted with step. In a separate flask, oxalyl chloride (870 mg, 580 μL,
Et2O (3 × 40 mL) and the combined organic layers were dried 6.8 mmol, 1.6 eq.) was added to a stirred suspension of triphe-
(MgSO4) and evaporated under reduced pressure to give the nylacetic acid (1.36 g, 4.7 mmol, 1.1 eq.) in CH2Cl2 (8 mL) at rt
crude product. Purification by flash column chromatography under Ar. Then, DMF (1 drop) was added and the reaction
on silica with 98 : 2 petrol–EtOAc as eluent gave stannyl pyrroli- mixture was stirred and heated at 35 °C for 2 h until a brown
dine 49 (3.64 g, 79%) as a colourless oil, RF (98 : 2 petrol– solution was formed and effervescence ceased. Then, the
1
EtOAc) 0.3; H NMR (400 MHz, CDCl3) (75 : 25 mixture of rota- solvent was evaporated under reduced pressure to give a light
mers) δ 3.69 (dd, J = 8.5, 2.0 Hz, 0.25H, NCH), 3.45–3.23 (m, brown solid. The solid was dissolved in CH2Cl2 (8 mL) and
2H, NCH), 3.22–3.12 (m, 0.75H, NCH), 2.27–2.03 (m, 1H, CH), added to a stirred solution of the deprotected stannyl pyrroli-
1.97–1.75 (m, 2H, CH), 1.56–1.40 (m, 6H, CH), 1.48 (s, 2.25H, dine (1.54 g, 4.3 mmol, 1.0 eq.) and DMAP (52 mg, 0.4 mmol,
CMe3), 1.43 (s, 6.75H, CMe3), 1.35–1.23 (m, 6H, CH), 0.95–0.81 0.1 eq.) in CH2Cl2 (50 mL) at rt under Ar. Then, Et3N (1.29 g,
(m, 15H, CH). Spectroscopic data consistent with those 1.79 mL, 12.8 mmol, 3.0 eq.) was added and the reaction
reported in the literature.6
mixture was stirred at rt for 60 h. Then, saturated NaHCO3(aq)
Phenyl(2-(tributylstannyl)pyrrolidin-1-yl)methanone
50. (15 mL) and CH2Cl2 (15 mL) were added and the two layers
Me3SiI (0.71 mL, 5.0 mmol, 1.3 eq.) was added to a stirred were separated. The organic layer was washed with saturated
solution of N-Boc stannyl pyrrolidine 49 (1.78 g, 3.9 mmol, 1.0 NH4Cl(aq) (15 mL) and brine (15 mL), dried (MgSO4) and evap-
eq.) in CH2Cl2 (30 mL) at rt under Ar. The resulting solution orated under reduced pressure to give the crude product. Puri-
was stirred at rt for 30 min. Then, water (6 mL) and CH2Cl2 fication by flash column chromatography on silica with 95 : 5
(100 mL) were added and the two layers were separated. The petrol–Et2O as eluent gave stannyl pyrrolidine 51 (1.93 g, 71%)
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as a white solid, mp 121–123 °C; RF (95 : 5 petrol–Et2O) 0.3; IR (232 mg, 0.5 mmol, 1.0 eq.) in THF (2 mL) at −78 °C under Ar.
(CHCl3) 2971, 2912, 1585 (CvO), 1470, 1424, 1379, 1196, 763, The resulting solution was stirred at −78 °C for 5 min. Then,
1
731, 691 cm−1; H NMR (400 MHz, CDCl3) δ 7.30–7.23 (m, 6H, methyl p-tolylsulfinate 17 (340 mg, 2.0 mmol, 2.0 eq.) was
Ph), 7.23–7.16 (m, 9H, Ph), 3.68 (t, J = 8.5 Hz, 1H, NCH), 2.79 added. The resulting solution was stirred at −78 °C for 10 min
(ddd, J = 11.0, 7.0, 4.0 Hz, 1H, NCH), 2.29 (ddd, J = 11.0, 8.5, and then allowed to warm to rt over 1 h. Then, MeOH (1 mL),
6.5 Hz, 1H, NCH), 2.10–1.97 (m, 1H, CH), 1.80–1.69 (m, 1H, saturated NH4Cl(aq) (2 mL) and Et2O (5 mL) were added and
CH), 1.65–1.55 (m, 1H, CH), 1.55–1.40 (m, 7H, CH + CH2), 1.31 the two layers were separated. The aqueous layer was extracted
(sextet, J = 7.5 Hz, 6H, CH2Me), 1.00–0.82 (m, 6H, CH2), 0.89 (t, with Et2O (3 × 5 mL) and the combined organic layers were
J = 7.5 Hz, 9H, CH2Me); 13C NMR (100.6 MHz, CDCl3) δ 169.0 dried (MgSO4) and evaporated under reduced pressure to give
(CvO), 143.3 (ipso-Ph), 130.5 (Ph), 127.5 (Ph), 126.3 (Ph), 67.6 the crude product. Purification by flash column chromato-
(CPh3), 49.6 (NCH), 48.7 (NCH2), 29.3 (CH2), 28.5 (CH2), 27.7 graphy on silica with 1 : 1 petrol–EtOAc with 1% Et3N as eluent
(CH2), 27.6 (CH2), 13.8 (Me), 10.4 (CH2); MS (ESI) m/z 654 gave pyrrolidine 53 (44 mg, 62%) as a white solid, mp
[(M + Na)+, 100], 632 [(M + H)+, 80]; HRMS (ESI) m/z calcd for 93–95 °C; RF (1 : 1 petrol–EtOAc) 0.2; IR (CHCl3) 2962, 2835,
C36H49NOSn (M + H)+ 632.2916, found 632.2891 (+2.9 ppm 1667 (CvO, ketone), 1598 (CvO, amide), 1553, 1400, 1208,
1
error).
690 cm−1; H NMR (400 MHz, CDCl3) δ 8.10–8.06 (m, 2H, Ph),
2-(Tributylstannyl) N-(2,4,6-triisopropylphenylsulfonyl) pyr- 7.65–7.57 (m, 3H, Ph), 7.54–7.48 (m, 2H, Ph), 7.45–7.39 (m,
rolidine 52. Me3SiI (467 μL, 3.25 mmol, 1.3 eq.) was added to 3H, Ph), 5.72 (dd, J = 8.5, 5.0 Hz, 1H, NCH), 3.75 (dt, J = 10.5,
a stirred solution of N-Boc stannyl pyrrolidine 49 (1.15 g, 7.0 Hz, 1H, NCH), 3.63 (dt, J = 10.5, 6.5 Hz, 1H, NCH),
2.5 mmol, 1.0 eq.) in CH2Cl2 (25 mL) at rt under Ar. The result- 2.45–2.36 (m, 1H, CH), 2.09–1.90 (m, 3H, CH); 13C NMR
ing solution was stirred at rt for 30 min. Then, water (6 mL) (100.6 MHz, CDCl3) δ 198.3 (CvO), 169.7 (CvO), 136.6 (ipso-
and CH2Cl2 (75 mL) were added and the two layers were separ- Ph), 135.6 (ipso-Ph), 133.5 (Ph), 130.3 (Ph), 128.9 (Ph), 128.8
ated. The organic layer was washed with water (2 × 30 mL) and (Ph), 128.4 (Ph), 127.5 (Ph), 61.2 (NCH), 49.9 (NCH2), 29.2
brine (30 mL), dried (MgSO4) and evaporated under reduced (CH2), 25.1 (CH2); MS (ESI) m/z 302 [(M + Na)+, 40], 280 [(M +
pressure to give the deprotected stannyl pyrrolidine, which was H)+, 100]; HRMS (ESI) m/z calcd for C18H17NO2 (M + H)+
1
sufficiently pure (by H NMR spectroscopy) for use in the next 280.1332, found 280.1329 (+1.2 ppm error).
step. The residue was dissolved in CH2Cl2 (29 mL) and 2,4,6-
2,2,2-Triphenyl-1-(pyrrolidin-1-yl)ethanone 55 and 2,2,2-Tri-
triisopropylsulfonyl chloride (832 mg, 2.75 mmol, 1.1 eq.), phenyl-1-(5-(p-tolylsulfinyl)-2,3-dihydro-1H-pyrrol-1-yl)ethanone
DMAP (30 mg, 0.25 mmol, 0.1 eq.) and Et3N (769 mg, 1.04 mL, 56. n-BuLi (260 μL of a 2.5 M solution in hexanes, 0.65 mmol,
7.5 mmol, 3.0 eq.) were added sequentially at rt under Ar. The 1.3 eq.) was added dropwise to a stirred solution of stannyl
resulting solution was stirred at rt for 20 h. Then, saturated pyrrolidine 51 (315 mg, 0.5 mmol, 1.0 eq.) in THF (5 mL) at
NaHCO3(aq) (30 mL) and CH2Cl2 (30 mL) were added and the −78 °C under Ar. The resulting solution was stirred at −78 °C
two layers were separated. The organic layer was washed with for
5 min. Then, methyl p-tolylsulfinate 17 (128 mg,
saturated NH4Cl(aq) (30 mL) and brine (30 mL), dried (MgSO4) 0.75 mmol, 1.5 eq.) was added. The resulting solution was
and evaporated under reduced pressure to give the crude stirred at −78 °C for 10 min and then allowed to warm to rt
product. Purification by flash column chromatography on over 1 h. Then, MeOH (0.5 mL), saturated NH4Cl(aq) (5 mL)
silica with 98 : 2 petrol–Et2O as eluent gave sulfonyl pyrrolidine and Et2O (5 mL) were added and the two layers were separated.
52 (781 mg, 50%) as a colourless oil, RF (98 : 2 petrol–Et2O) 0.3; The aqueous layer was extracted with Et2O (3 × 5 mL) and the
IR (CHCl3) 2913, 2882, 2827, 1575, 1439, 1272, 1128, 1055, combined organic layers were dried (MgSO4) and evaporated
1
651 cm−1; H NMR (400 MHz, CDCl3) δ 7.15 (s, 2H, Ar), 4.25 under reduced pressure to give the crude product. Purification
(septet, J = 7.0 Hz, 2H, ArCH), 3.48 (t, J = 7.5 Hz, 1H, NCH), by flash column chromatography on silica with 9 : 1 to 1 : 1
3.13 (dt, J = 10.0, 7.0 Hz, 1H, NCH), 3.03 (dt, J = 10.0, 7.0 Hz, petrol–EtOAc with 0.5% of Et3N gave pyrrolidine 55 (74 mg,
1H, NCH), 2.90 (septet, J = 7.0 Hz, 1H, ArCH), 2.30–2.13 (m, 43%) as a white solid, mp 175–177 °C (lit.,41 188.5 °C); RF (7 : 3
1
1H, CH), 1.99–1.80 (m, 3H, CH), 1.61–1.46 (m, 6H, CH2), 1.33 petrol–EtOAc) 0.3; H NMR (400 MHz, CDCl3) δ 7.32–7.18 (m,
(sextet, J = 7.5 Hz, 6H, CH2), 1.26 (d, J = 7.0 Hz, 6H, CHMe2), 15H, Ph), 3.66 (t, J = 6.5 Hz, 2H, NCH2), 2.44 (t, J = 6.5 Hz, 2H,
1.25 (d, J = 7.0 Hz, 6H, CHMe2), 1.24 (d, J = 7.0 Hz, 6H, NCH2), 1.72 (quin, J = 6.5 Hz, 2H, CH2), 1.57 (quin, J = 6.5 Hz,
CHMe2), 1.00–0.93 (m, 6H, CH2), 0.91 (t, J = 7.5 Hz, 9H, 2H, CH2); 13C NMR (100.6 MHz, CDCl3) δ 170.7 (CvO), 142.9
CH2Me); 13C NMR (100.6 MHz, CDCl3) δ 152.6 (ipso-Ar), 151.1 (ipso-Ph), 130.5 (Ph), 127.7 (Ph), 126.6 (Ph), 54.8 (CPh3), 48.3
(ipso-Ar), 137.7 (ipso-Ar), 123.7 (Ar), 48.1 (NCH2), 47.1 (NCH), (NCH2), 47.8 (NCH2), 26.6 (CH2), 23.2 (CH2) and sulfoxide 56
34.1 (ArCH), 31.0 (CH2), 29.4 (Me), 29.2 (CH2), 27.6 (CH2), 26.2 (50 mg, 21%) as a white solid, mp 160–163 °C; RF (1 : 1 petrol–
(CH2), 25.0 (Me), 24.8 (Me), 23.6 (Me), 13.7 (Me), 10.0 (CH2); EtOAc with 0.5% of Et3N) 0.3; IR (CHCl3) 2962, 1612 (CvO),
1
MS (ESI) m/z 650 [(M + Na)+, 40], 628 [(M + H)+, 100]; HRMS 1363, 1212, 1020, 691 cm−1; H NMR (400 MHz, CDCl3) δ 7.65
(ESI) m/z calcd for C31H57NO2SSn (M + H)+ 628.3209, found (d, J = 8.0 Hz, 2H, Ar), 7.27 (d, J = 8.0 Hz, 2H, Ar), 7.22–7.15 (m,
628.3206 (−0.5 ppm error).
9H, Ar), 6.93–6.87 (m, 6H, Ar), 6.30 (dd, J = 3.5, 2.0 Hz, 1H,
Pyrrolidine-1,2-diylbis(phenylmethanone) 53. n-BuLi (210 μL vCH), 3.45–3.37 (m, 1H, NCH), 2.67–2.42 (m, 2H, NCH and
of a 2.5 M solution in hexanes, 0.5 mmol, 1.0 eq.) was added CH), 2.47 (s, 3H, Me), 2.41–2.29 (m, 1H, CH); 13C NMR
dropwise to a stirred solution of stannyl pyrrolidine 50 (100.6 MHz, CDCl3) δ 169.7 (CvO), 152.3 (ipso-Ar), 142.3 (ipso-
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Ar), 141.7 (vC), 141.5 (ipso-Ar), 130.0 (Ar), 129.4 (Ar), 127.8 (400 MHz, CDCl3) δ 7.50–7.48 (m, 2H, m-C6H4Me), 7.28 (d, J =
(Ar), 127.4 (Ar), 126.7 (Ar), 116.3 (vCH), 66.7 (CPh3), 51.7 8.0 Hz, 2H, o-C6H4Me), 3.47 (br s, 1H, NCHAHB), 2.84 (br s, 1H,
(NCH2), 29.4 (CH2), 21.5 (Me); MS (ESI) m/z 500 [(M + Na)+, NCHAHB), 2.41 (s, 3H, Me), 2.28 (br s, 1H, CH), 1.93–1.90 (m,
100], 478 [(M + H)+, 50]; HRMS (ESI) m/z calcd for C31H27NO2S 1H, CH), 1.77–1.74 (m, 2H, CH), 1.52 (br s, 9H, CMe3),
(M + H)+ 478.1835, found 478.1855 (−4.4 ppm error). Spectro- 1.16–1.13 (m, 1H, CH); 13C NMR (100.6 MHz, CDCl3) (rota-
scopic data for 55 consistent with those reported in the mers) δ 155.0 (br, CvO), 141.9 (ipso-Ar), 141.6 (ipso-Ar), 141.1
literature.41
2,2-Dimethyl-1-(2-(p-tolylsulfinyl)azetidin-1-yl)propane-1-thione 81.2 (br, CMe3), 61.2 (NCS(O)Ar), 61.1 (NCS(O)Ar), 52.3 (br,
58. s-BuLi (0.92 mL of 1.3 solution in hexanes, NCH2), 28.5 (CMe3), 26.1 (br, CH2), 23.7 (CH2), 22.3 (CH2), 21.6
(ipso-Ar), 139.5 (ipso-Ar), 129.7 (br, Ar), 125.5 (Ar), 124.8 (Ar),
a
M
1.20 mmol, 1.2 eq.) was added dropwise to a stirred solution of (Me), 11.9 (CH), 11.7 (CH); MS (ESI) m/z 344 [(M + Na)+, 30],
N-thiopivaloyl azetidine 57 (157 mg, 1.00 mmol, 1.0 eq.) and 322 [(M + H)+, 100]; HRMS m/z calcd for C17H23NO3S (M + Na)+
TMEDA (358 μL, 2.40 mmol, 2.4 eq.) in THF (6 mL) at −78 °C 344.1291, found 344.1286 (+1.5 ppm error) and sulfoxide anti-
under Ar. The resulting solution was stirred at −78 °C for 60 (144 mg, 36%) as a colourless oil, RF (3 : 2 petrol–EtOAc)
30 min. Then, methyl p-toluenesulfinate 17 (340 mg, 0.2; IR (film) 2977, 2932, 1696 (CvO), 1477, 1384, 1335, 1257,
1
2.0 mmol, 2.0 eq.) and the solution was allowed to warm to rt 1168, 1083, 1048, 810 cm−1; H NMR (400 MHz, CDCl3) δ 7.48
over 2 h and stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.26 (d, J = 8.0 Hz, 2H,
was added and the two layers were separated. The aqueous o-C6H4Me), 3.79–3.72 (m, 1H, NCHAHB), 3.61 (br s, 1H,
layer was extracted with Et2O (3 × 10 mL). The combined NCHAHB), 2.37 (s, 3H, Me), 2.27–2.18 (m, 1H, CH), 2.05 (dtd,
organic layers were dried (Na2SO4) and evaporated under J = 8.0, 7.0, 1.5 Hz, 1H, NCCH), 1.83–1.75 (m, 1H, CH), 1.49 (s,
reduced pressure to give the crude product which contained a 9H, CMe3), 1.09 (t, J = 7.0 Hz, 1H, CH), 1.05–1.01 (br m, 1H,
1
91 : 9 mixture of diastereoisomers by H NMR. Purification by CH); 13C NMR (100.6 MHz, CDCl3) δ 155.5 (CvO), 141.4 (ipso-
flash column chromatography on silica with 8 : 2–1 : 1 petrol– Ar), 138.0 (ipso-Ar), 129.5 (Ar), 124.8 (Ar), 80.9 (CMe3), 69.9 (br,
EtOAc as eluent gave sulfoxide 58 (27 mg, 9%) as a colourless NCS(O)Ar), 52.5 (br, NCH2), 29.9 (br, CH2), 28.4 (CMe3), 26.8
oil, RF (7 : 3 petrol–EtOAc) 0.2; IR (film) 2987, 2954, 1502, 1480, (CH2), 24.3 (br, CH), 21.3 (Me); MS (ESI) m/z 344 [(M + Na)+,
1424, 1395, 1240, 1140, 1025, 728 cm−1 1H NMR (400 MHz, 40], 322 [(M + H)+, 100]; HRMS m/z calcd for C17H23NO3S (M +
;
CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.32 (d, J = 8.0 Hz, Na)+ 344.1291, found 344.1286 (+1.3 ppm error). Spectroscopic
2H, o-C6H4Me), 5.55 (dd, J = 9.0, 4.5 Hz, 1H, NCH), 4.50 (dt, J = data consistent with those reported in the literature.8
9.0, 7.0 Hz, 1H, NCHAHB), 4.34 (dt, J = 9.0, 4.5 Hz, 1H,
NCHAHB), 2.83 (ddt, J = 12.0, 9.0, 4.5 Hz, 1H, CH), 2.41 (s, 3H,
Me), 2.06 (dtd, J = 12.0, 9.0, 7.0 Hz, 1H, CH), 1.39 (s, 9H,
Acknowledgements
CMe3); 13C NMR (100.6 MHz, CDCl3) δ 213.5 (CvS), 141.3
(ipso-Ar), 137.3 (ipso-Ar), 129.9 (Ar), 123.9 (Ar), 86.0 (NCH), 56.5 We are grateful to the EPSRC (CASE award to P. J. R.), Univer-
(NCH2), 43.8 (CMe3), 29.7 (CMe3), 21.3 (Me) 17.3 (CH2); MS sity of York (Partner Award to G. G.), GlaxoSmithKline and
(ESI) m/z 318 [(M + Na)+, 100], 296 [(M + H)+, 50]; HRMS m/z Pfizer for funding.
calcd for C15H21NOS2 (M + Na)+ 318.0962, found 318.0960
(−0.5 ppm error) and recovered N-thiopivaloyl azetidine 57
(113 mg, 72%). Diagnostic signal for other diastereoisomer: 1H
NMR (400 MHz, CDCl3) δ 5.72 (dd, J = 9.0, 4.0 Hz, 1H, NCH).
Notes and references
tert-Butyl 1-(p-tolylsulfinyl)-2-azabicyclo[3.1.0]hexane-2-car-
boxylate syn-60 and anti-60. s-BuLi (2.11 mL of a 1.3 M solu-
tion in hexanes, 2.75 mmol, 2.2 eq.) was added dropwise to a
stirred solution of N-Boc 4-chloro piperidine 59 (275 mg,
1.25 mmol, 1.0 eq.) and TMEDA (319 mg, 2.75 mmol, 2.2 eq.)
in Et2O (8 mL) at −78 °C under Ar. The resulting solution was
stirred at −78 °C for 1 h. Then, methyl p-toluenesulfinate 17
(468 mg, 2.75 mmol, 2.2 eq.) was added and the solution was
allowed to warm to rt over 2 h and stirred at rt for 16 h. Satu-
rated NH4Cl(aq) (10 mL) was added and the two layers were
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10 mL). The combined organic layers were dried (Na2SO4) and
evaporated under reduced pressure to give the crude product.
Purification by flash column chromatography on silica with
3 : 2 petrol–EtOAc with 1% Et3N as eluent gave sulfoxide syn-60
(142 mg, 35%) as a white solid, mp 161–163 °C; RF (3 : 2
petrol–EtOAc) 0.3; IR (CHCl3) 2975, 2931, 1703 (CvO), 1492,
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