Diastereomerically and enantiomerically pure 2,3-disubstituted pyrrolidines from 2,3-aziridin-1-ols using a sulfoxonium ylide: A one-carbon homologative relay ring expansion

Article abstract of DOI:10.1021/ja065833p

An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for the preparation of pyrrolidines. The aza-Payne rearrangement under basic reaction conditions favors the formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion, which upon a 5-exo-tet ring-closure yields the desired pyrrolidine, thus completing the relay of the three-membered to the five-membered nitrogen-containing ring system. This process takes place with complete transfer of stereochemical fidelity and can be applied to sterically hindered aziridinols.

Full text of DOI:10.1021/ja065833p

Published on Web 01/27/2007
Diastereomerically and Enantiomerically Pure
2,3-Disubstituted Pyrrolidines from 2,3-Aziridin-1-ols Using a
Sulfoxonium Ylide: A One-Carbon Homologative Relay Ring
Expansion
Jennifer M. Schomaker, Somnath Bhattacharjee, Jun Yan, and Babak Borhan*
Contribution from the Department of Chemistry, Michigan State UniVersity,
East Lansing, Michigan 48824
Received August 17, 2006; E-mail: borhan@cem.msu.edu
Abstract: An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for
the preparation of pyrrolidines. The aza-Payne rearrangement under basic reaction conditions favors the
formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion,
which upon a 5-exo-tet ring-closure yields the desired pyrrolidine, thus completing the relay of the three-
membered to the five-membered nitrogen-containing ring system. This process takes place with complete
transfer of stereochemical fidelity and can be applied to sterically hindered aziridinols.
Introduction
3 + 2 cycloadditions of azomethine ylides with alkenes or
nitrones with cyclopropanes,4 oxidative decarboxylation-â-
Substituted pyrrolidines are important heterocycles by virtue
of their frequent appearance in a large number of biologically
active natural products and pharmaceuticals.1 Enantiomerically
pure pyrrolidines are also used as chiral auxiliaries for various
organic transformations.2 Conformationally restrained analogues
of proline are also being utilized in the synthesis of unnatural
oligomers as scaffolds for biological applications such as
antimicrobial activity.3 As such, much effort has been devoted
to the synthesis of pyrrolidines in enantiomerically and diaste-
reomerically pure form, including, but certainly not limited to,
iodination of amino acids,5 palladium-catalyzed carboamination
reactions,6 intramolecular cyclization of epoxy and halogenated
sulfones under basic conditions,7 acid-catalyzed cyclization of
vinylsilanes,8 intramolecular carbolithiation of homoallylic
amines,9 radical cyclizations,10 Brønsted acid-catalyzed intramo-
lecular hydroamination of alkenylamines,11 manipulations of
sugars from the chiral pool,12 various other metal-catalyzed
cyclizations,13 and ring-closing metathesis.14 Clearly, the im-
portance of pyrrolidines can be directly inferred from the
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1996
J. AM. CHEM. SOC. 2007, 129, 1996-2003
10.1021/ja065833p CCC: $37.00 © 2007 American Chemical Society

Pure 2,3-Disubstituted Pyrrolidines
A R T I C L E S
Scheme 1
Scheme 2
Scheme 3
significant amount of effort that has led to the development of
various methodologies for their synthesis. Our interest in the
synthesis of pyrrolidines stems from our desire to develop
methods that translate the stereochemistry embedded in simple
and easy-to-obtain starting materials into more complex products
with complete fidelity. As such, herein we report a general
methodology for conversion of hydroxy aziridines into pyrro-
lidines via a one-carbon homologative relay ring expansion that
is initiated by an aza-Payne rearrangement.
The Payne rearrangement is a base-mediated isomerization
of epoxy alcohols and has been well-utilized in organic synthesis
to reveal the latent electrophilicity at C-1 of a 2,3-epoxy-1-ol
such as 1 (Scheme 1).15 We have recently used this approach
to control attack at C-1 with dimethylsulfoxonium methylide
in the synthesis of a series of 2,3-substituted tetrahydrofurans
(Scheme 1).16a These reactions can be high-yielding and deliver
the THF ring in a regio- and stereocontrolled manner. The Payne
rearrangement of trans-epoxides is not as facile as that of cis-
epoxides (release of steric strain of cis-epoxides is the driving
force), as can be seen by comparing the yields of THF products
3 and 6, which originate from cis- and trans-epoxy diols 1 and
4, respectively (Scheme 1). However, the presence of an
electron-withdrawing atom at C-4 or C-5 of the epoxy alcohol
is sufficient for successful THF formation with 2,3-disubstituted
epoxy-1-ols. Certain substrates, mainly alkyl-disubstituted and
trisubstituted 2,3-epoxy-1-ols, do not undergo sufficient Payne
rearrangement to allow for successful nucleophilic attack on
the less hindered 1,2-epoxy-3-ol (structures analogous to 2b and
5b in Scheme 1). Mixtures of products often result from
competing nucleophilic attack at C-2 and C-3, as well as base-
mediated elimination reactions.
In contrast to the Payne rearrangement, the aza-Payne
rearrangement of activated 2,3-aziridin-1-ols (Scheme 2) has
not received as much attention, despite its great potential for
the synthesis of enantiomerically pure nitrogen-containing
compounds.17 Ibuka and co-workers have described the aza-
Payne rearrangement of a series of cis- and trans-2,3-disubsti-
tuted aziridin-1-ols, as well as the reaction of the resulting epoxy
amines with a few selected nucleophiles, including organocu-
prates and amines.17-19 A particularly useful feature of the aza-
Payne rearrangement is that, under aprotic conditions, the
equilibrium for both cis- and trans-disubstituted 2,3-aziridin-
1-ols lies exclusively toward the epoxy amine. This may result
from the greater ability of the activated amine to stabilize the
negative charge under the basic reaction conditions and/or the
greater thermodynamic stability of the epoxy amine vs the
aziridinol.20 Thus, it was envisaged that an ylide-based aza-
Payne rearrangement of 2,3-aziridin-1-ols could lead to an
efficient process for the preparation of pyrrolidines (Scheme
3).16b The aza-Payne rearrangement is expected to favor epoxide
7a over aziridine 7, and subsequent nucleophilic attack to yield
the bis-anion is anticipated. A 5-exo-tet ring-closure of the bis-
anion would yield the desired pyrrolidine 7b, thus completing
the relay of the three-membered to the five-membered nitrogen-
containing ring system.
Aza-Payne Rearrangment
To our knowledge, the facility of the aza-Payne rearrangement
in more highly substituted compounds, such as 2,3,3- or 2,2,3-
(17) (a) Ibuka, T. Chem. Soc. ReV. 1998, 27, 145-154. (b) Ibuka, T.; Nakai,
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N.; Yamamoto, Y. Tetrahedron Lett. 1995, 36, 6247-6250. (d) Ibuka, T.;
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(16) (a) Schomaker, J. M.; Reddy, P. V.; Borhan, B. J. Am. Chem. Soc. 2004,
126, 13600-13601. (b) During the submission of this manuscript, we were
made aware of a recent disclosure that bears some similarity to this work,
although clearly both our groups have pursued their efforts independently.
In the following paper the authors report the conversion of epoxy amines
to pyrrolidines with the use of sulfoxonium ylides: Hodgson, D. M.;
Fleming, M. J.; Xu, Z.; Lin, C.; Stanway, S. J. Chem. Commun. 2006,
3226-3228.
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1987, 1140-1142.
9
J. AM. CHEM. SOC. VOL. 129, NO. 7, 2007 1997

A R T I C L E S
Schomaker et al.
Table 1. Aza-Payne Rearrangement of 2,3-Aziridin-1-ols to Epoxy Aminesa
a Method A: a 0.1 M solution of the aziridinol was treated with 4.0 equiv of NaH in THF at room temperature. Method B: a 0.1 M solution of the
aziridinol in DMSO was treated with 4-8 equiv of dimethylsulfoxonium methylide at room temperature. Method C: a 0.1 M solution of the aziridinol was
treated with 4.0 equiv of NaH in 20:1 to 12:1 THF/HMPA at room temperature.
trisubstituted and tetrasubstituted aziridinols, has not been well-
studied. In order to utilize aziridinols for the synthesis of
pyrrolidines, a closer inspection of the aza-Payne rearrangement
for a variety of substituted aziridines was necessary. The desired
aziridinols could be accessed in several ways. Enantiomerically
pure 2,3-disubstituted aziridin-1-ols such as 8 and 9 (Table 1)
could be obtained via the asymmetric epoxides 1 and 4 using
literature procedures.21,22 Ring-opening of the corresponding
epoxide with sodium azide was followed by a one-pot Staudinger
reduction/cyclization and tosyl protection to give the desired
aziridine. The Sharpless asymmetric aminohydroxylation could
be used to synthesize disubstituted aziridinols.23 The use of a
VAPOL-catalyzed aziridination developed by the Wulff group
could be implemented to access cis-aryl-substituted com-
pounds.24 Tetrasubstituted aziridinols could be accessed via
stereoselective nucleophilic attack of an azirine, as described
by Davis and co-workers.25 The majority of the racemic
substrates were synthesized via treatment of the corresponding
allylic alcohols with Chloramine T and catalytic NBS.26
The aza-Payne rearrangement of tosylated aziridinols was
accomplished in excellent yields using 4.0 equiv of NaH in THF
or, in some cases, dimethylsulfoxonium methylide in dimeth-
ylsulfoxide (DMSO) (Table 1). Other bases and solvents that
could be utilized for the aza-Payne rearrangement include NaH
in toluene, DMSO or 12:1 THF/HMPA, as well as KH in either
THF or toluene. The use of NaHMDS or KHMDS in THF,
toluene, or DMSO was much less successful. In previous work
directed toward the synthesis of tetrahydrofurans (Scheme 1),
compounds containing an oxygen substituent at either C-4 or
C-5 of the epoxy alcohol were excellent substrates for the Payne
rearrangement/one-carbon homologative ring-opening/cycliza-
(21) Fujii, N.; Nakai, K.; Habashita, H.; Hotta, Y.; Tamamura, H.; Otaka, A.;
Ibuka, T. Chem. Pharm. Bull. 1994, 42, 2241-2250.
(22) (a) Nayak, S. K.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1999, 40,
981. (b) Andres, J. M.; de Elana, N.; Pedrosa, R.; Perez-Encabo, A.
Tetrahedron 1999, 55, 14137. (c) Nayak, S. K.; Thijs, L.; Zwandenburg,
B. Synlett 1998, 1187. (d) Hwang, G. I.; Chung, J. H.; Lee, W. K. J. Org.
Chem. 1996, 61, 6183.
(23) (a) Kolb, H. C.; Sharpless, B. K. Asymmetric aminohydroxylation. In
Transition Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 309-326. (b) Schlingloff,
G.; Sharpless, K. B. Asymmetric aminohydroxylation. In Asymmetric
Oxidation Reactions; Katsuki, T., Ed.; Oxford University Press: Oxford,
UK, 2001; pp 104-114.
(24) (a) Patwardhan, A. P.; Lu, Z.; Pulgam, V. R.; Wulff, W. D. Org. Lett.
2005, 7, 2201-2204. (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int.
Ed. 2000, 39, 4518-4521. (c) Antilla, J. C.; Wulff, W. D. J. Am. Chem.
Soc. 1999, 121, 5099-5100. (d) Patwardhan, A. P.; Pulgam, V. R.; Zhang,
Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2005, 44, 6169-6172.
(25) (a) Davis, F. A; Ramachandar, T.; Wu, Y. J. Org. Chem. 2003, 68, 6894-
6898. (b) Davis, F. A.; Deng, J.; Zhang, Y.; Haltiwanger, R. C. Tetrahedron
2002, 58, 7135-7143. (c) Davis, F. A.; Liu, H.; Liang, C.; Reddy, G. V.;
Zhang, Y.; Fang, T.; Titus, D. D. J. Org. Chem. 1999, 64, 8929-8935. (d)
Davis, F. A.; Liang, C.; Liu, H. J. Org. Chem. 1997, 62, 3796-3797.
(26) Thakur, V. V.; Sudalai, A. Tetrahedron Lett. 2003, 44, 989-992.
9
1998 J. AM. CHEM. SOC. VOL. 129, NO. 7, 2007

Pure 2,3-Disubstituted Pyrrolidines
A R T I C L E S
Table 2. Conversion of Epoxy Amines to 2,3-Substituted Pyrrolidinesa
a Reactions were run in a 0.1 M solution of epoxy amine in DMSO using 4-8 equiv of dimethylsulfoxonium methylide at 80-85 °C for 24 h.
tion sequence to yield 2,3-disubstituted tetrahydrofurans. Like-
wise, these substrates (entries 1-4, Table 1) performed well in
the aza-Payne rearrangement by treatment with NaH in THF,
as described by Ibuka.17 There were no notable disparities in
the yields of epoxy amines utilizing either cis- or trans-
disubstitituted aziridinols as substrates (Table 1, entries 1-8).
Alkyl epoxides analogous to 12 and 13 (entries 5 and 6) were
not good substrates for Payne rearrangement, but the corre-
sponding 2,3-aziridin-1-ols 12 and 13 gave only epoxy amine
products 12a and 13a, with no trace of the starting materials. It
was also of note that the 2,3,3-trisubstituted aziridinol 16 (entry
9) derived from geraniol was converted successfully to the epoxy
amine 16a in excellent yield, despite the fact that the analogous
geraniol epoxide was resistant to the Payne rearrangement and
gave only 14% of the tetrahydrofuran product.16a A cyclic 2,3,3-
trisubstituted substrate 19 (entry 12) was also successful in the
aza-Payne rearrangement, the analogous epoxy alcohol substrate
giving only 21% yield of the desired product in our previous
work.16a Gratifyingly, 2,2,3-trisubstituted aziridinols such 17 and
18 (entries 10 and 11) underwent facile rearrangement, even
though the electrophilic center was tertiary, to yield epoxy
amines 17a and 18a, respectively. Relief of steric strain in the
epoxide analogue of 17 on going from the fused ring system to
the spiro ring system has been cited as the reason for the 1:2
mixture of 1,2-epoxy-3-ol and 2,3-epoxy-1-ol in the Payne
rearrangement.27 In contrast, aziridinol 17 leads to the production
of only one isomer. A series of 2,2,3-trisubstituted aziridinols
bearing an aryl group at C-3 were also examined. An electronic
component to the facility of the aza-Payne rearrangement was
noted, as the p-methoxyphenyl-containing 21 gave a 93% yield
of the epoxy amine, while the trifluoromethylphenyl-containing
substrate 22 gave only a 66% yield of 22a. The 2,2,3-
trialkylsubstituted aziridinol 23 gave the epoxy amine 23a.
Finally, the tetrasubstituted aziridinols 24 and 25 (entries 17
and 18) also underwent successful aza-Payne rearrangement to
yield epoxy amines 24a and 25a. A small amount of HMPA
was necessary to improve the yield of the transformation.17 The
ability to use tri- and tetrasubstituted aziridinols in the aza-Payne
rearrangement allows transfer of the terminal oxygen to a
sterically congested tertiary center, yielding a quaternary hy-
droxyl center upon opening of the unhindered epoxide with
various nucleophiles. This can yield synthetically useful 1,2-
amino alcohols of various substitution patterns that might not
otherwise be easily accessible.
Pyrrolidines from Aza-Payne Rearranged Aziridinols
The data in Table 1 illustrate the efficiency of the aza-Payne
rearrangement for a number of aziridinols. In all cases the
epoxide is isolated in high yields; however, more importantly,
the rearrangement was facile using dimethylsulfoxonium meth-
ylide as the base. This is critical for the implementation of the
next series of transformations. As depicted in Scheme 3, it was
envisaged that epoxide 7a, obtained via the aza-Payne re-
arrangement of 7, could undergo nucleophilic trapping with the
sulfoxonium ylide to yield the bis-anion intermediate. Ring-
closure with loss of DMSO would yield the desired pyrrolidine
7b.
The epoxy amine products listed in Table 1 were treated with
dimethylsulfoxonium methylide in DMSO at 85 °C to afford
the 2,3-disubstituted pyrrolidine rings in good to excellent yields
and with complete control of diastereoselectivity (Table 2).
Epoxy amine 8a, generated from the cis-aziridinol 8, led to the
corresponding cis-disubstituted pyrrolidine ring 8b, while the
(27) Swindell, C. S.; Britcher, S. F. J. Org. Chem. 1986, 51, 793-797.
9
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A R T I C L E S
Schomaker et al.
Scheme 4
Figure 1. X-ray crystal structure of 9b. Most of the hydrogen atoms are
not shown for better clarity.
Scheme 5
epoxy amine 9a, obtained from the trans-aziridinol 9, gave the
trans-disubstituted pyrrolidine 9b, both in excellent yields (Table
2, entries 1 and 2). The relative stereochemistries were verified
by NOE experiments of the cis- and trans-pyrrolidines 8b and
9b that showed a greater enhancement of the H-2 proton when
H-3 of the cis compound was irradiated as compared to the
trans product. To further establish the relative stereochemistry
of the substituents at C-2 and C-3, an X-ray crystal structure of
compound 9b was obtained that clearly indicated the trans
orientation of the C-2 and C-3 substituents (Figure 1).
The remaining epoxy amines obtained from disubstituted
aziridinol substrates (Table 2, entries 3-8) gave the corre-
sponding pyrrolidines in high yields as single diastereoisomers.
Epoxy amines derived from 2,3,3-trisubstituted aziridinols
(Table 2, entries 9 and 12) also gave good yields of the
pyrrolidines bearing a quaternary nitrogen center. This is again
in contrast to the analogous reactions with similarly substituted
epoxy alcohols as substrates, which gave the THF products in
yields less than 30%. The steric hindrance of the nucleophilic
nitrogen of 19a in entry 12, along with the strain of the spiro
ring system, presumably led to a lower yield of pyrrolidine 19b.
Entries 10 and 11 illustrate the conversion of epoxy amines 17a
and 18a, derived from 2,2,3-trisubstituted aziridinols, to pyr-
rolidines that contain a chiral 3° hydroxyl group at C-3. The
relative stereochemistry of the trisubstituted pyrrolidine 18b was
established via NOE enhancements observed between the
benzyl-protected hydroxymethyl side chain at C-2 and the C-3
methyl group. This again verified the anticipated stereochemical
outcome of the reaction based on the mechanism depicted in
Scheme 3.
nucleophilicities of the oxygen and nitrogen anions to form
oxetanes, azetidines, tetrahydrofurans, or pyrrolidines (Scheme
4).28
In order to determine the facility of epoxide vs aziridine ring-
opening with dimethylsulfoxonium methylide, a competition
experiment was performed (Scheme 5). A 1:1 mixture of 36
and 38 was treated with 1.0 equiv of dimethylsulfoxonium
methylide in DMSO at room temperature for 1 h and then at
85 °C for 24 h. Epoxide 36 was recovered in 95% yield, while
aziridine 38 was consumed completely. The azetidine 39 was
obtained in 64% yield. Clearly, the higher reactivity of the
aziridine as compared to that of the epoxide toward nucleophilic
attack by the ylide could lead to the aforementioned mixture of
undesired products (Scheme 4). However, two factors were
crucial in our belief that a choreographed sequence of events
(aza-Payne; nucleophilic attack of epoxide; ring-closure) could
be achieved (Scheme 3). First, the aza-Payne rearrangement is
an intramolecular process and may compete favorably with the
intermolecular process of aziridine ring-opening with the ylide.
Second, the epoxide that undergoes attack by the ylide is less
hindered than the starting aziridine. Another important piece
of information obtained from the experiment shown in Scheme
5 was that heating to 85 °C was necessary to cause ylide ring-
opening of the aziridine. We reasoned that the aza-Payne
rearrangement could be accomplished at a lower temperature
and then the temperature could be raised to 85 °C to promote
epoxide ring-opening and subsequent ring-closure to the pyr-
rolidine. In this manner, the undesired ring-opening of the
aziridine should not compete with the desired epoxide ring-
opening by the ylide.
One-Pot Conversion of Aziridinols to Pyrrolidines
Having established high efficiency in the preparation of
pyrrolidines from aziridinols in two steps, i.e., aza-Payne
rearrangement of aziridinols followed by treatment of products
isolated from the latter reaction with dimethylsulfoxonium
methylide, we directed our attention toward a one-pot prepara-
tion of pyrrolidines. As such, the ylide itself would serve as
the base to promote aza-Payne rearrangement (already shown
to be effective, Table 1), leading to an epoxide that would
undergo attack with the ylide (Scheme 3). Ring-closure to the
pyrrolidine would deliver the desired product. An issue of
particular concern was competing ring-opening of the aziridine
at either C-2 or C-3 by the ylide prior to aza-Payne rearrange-
ment, particularly since excess ylide is used to compensate for
its degradation at the elevated reaction temperatures. Several
products could then be obtained, depending on the relative
In the first successful attempt at a one-pot reaction to form
pyrrolidines, the ylide generated from trimethylsulfoxonium
iodide and NaH was added to the aziridinol, stirred at room
temperature for 30 min, and heated to 85 °C for 24 h.
Conversion of aziridinols 8 and 9 to pyrrolidines 8b and 9b
occurred with moderate yields of 67% and 61%, respectively.
We suspected that the lower yields might be caused by
(28) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
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Pure 2,3-Disubstituted Pyrrolidines
A R T I C L E S
Table 3. One-Pot Conversion of 2,3-Aziridin-1-ols to 2,3-Substituted Pyrrolidines
a Reactions were run by stirring a 0.1 M solution of the aziridinol with excess dimethylsulfoxonium methylide in DMSO for 4 h, followed by heating at
80 °C for 24 h.
competitive ring-opening of the aziridine at the elevated reaction
temperatures prior to complete aza-Payne rearrangement.
The effect of the ylide counterion on the efficacy of the aza-
Payne/ring-opening/ring-closure reaction was briefly examined.
Dimethylsulfoxonium methylide was generated using both NaH
and KH as bases in DMSO. Varying amounts of the ylide were
added to solutions of 8 in DMSO, and the reactions were stirred
for 4 h at room temperature to ensure aza-Payne rearrangement
was complete. After an additional 4 h, the reactions were
analyzed by HPLC. The reactions utilizing potassium as the
counterion were reanalyzed at 22 h. The results indicate that
the sodium counterion is more effective for ring-closure to the
desired pyrrolidine 8b, with a 90% conversion to product after
8 h. The potassium cation was less effective, resulting in a 40%
conversion to 8b after 8 h. However, high conversions were
obtained using KH by running the reaction overnight. As
expected, increasing the amount of ylide from 2 to 10 equiv
greatly increased the rate, although this effect leveled out after
8 equiv.
With these results in hand, we repeated the one-pot reaction
with 8 using 8.0 equiv of ylide generated from NaH as the base
in DMSO. The reaction was stirred at room temperature
overnight, and pyrrolidine 8b was obtained in 82% yield.
However, the reaction was often not complete for trans and
more hindered aziridinols, resulting in a mixture of pyrrolidine,
epoxy amine, and N-methylated products. Prolonged heating
of the more stubborn reactions proved to be a general solution,
and thus heating of all reactions at 80-85 °C for 24 h was
adopted as standard protocol. These reactions could also be
performed in THF with a small amount of DMSO (5 equiv).
Substrate 8 (Table 3) was treated with dimethylsulfoxonium
methylide (generated by refluxing trimethylsulfoxonium iodide
with NaH in THF for 4 h), stirred at room temperature for 4 h,
and heated to 80 °C overnight in a sealed tube. In this manner,
the pyrrolidine 8b could be obtained in 82% yield.
The general reaction conditions discussed above were adopted
for the one-pot conversion of 2,3-aziridin-1-ols to pyrrolidines
(Table 3). The cis-substituted aziridinols tended to give slightly
higher yields than the corresponding trans analogues. As
previously described in the discussion of Table 2, substrates
containing alkyl substituents (entries 5 and 6) or trisubstituted
aziridines (entries 9-12) proceeded under the reaction condi-
tions to give pyrrolidines in good yields, in contrast to our
analogous work using 2,3-epoxy-1-ols to prepare THFs. Aryl
aziridines 14 and 15 (entries 7 and 8) were also successfully
converted to pyrrolidines 14b and 15b, respectively, without
any indication of C-3 ring-opening by the ylide. The major
byproduct in the trans-aziridine substituted with an aryl group
at C-3 (entry 10) was N-methylated epoxy amine. Other trans-
aziridinols were also prone to N-methylation if the temperature
was lowered below 75 °C or any extra trimethylsulfoxonium
iodide was present. The ee’s of selected aziridinols and
pyrrolidines were determined by preparing the corresponding
MPA esters to ensure that racemization had not occurred under
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A R T I C L E S
Schomaker et al.
Table 4. Use of a Bus Protecting Groupa
Table 5. Deprotection of Pyrrolidine Products
a Epoxy amines were prepared by treating a 0.1 M solution of the
aziridinol in THF with 4.0 equiv of NaH and stirring at room temperature
for 4-6 h. The pyrrolidines were prepared by treating a 0.1 M solution of
the aziridinol in DMSO with 4-8 equiv of dimethylsolfoxonium methylide,
stirring at room temperature for 4 h, and heating to 80 °C for 24 h.
the reaction conditions (entries 1, 2, 7, and 9).21 Thus, a
successful one-pot strategy for the synthesis of pyrrolidines from
2,3-aziridin-1-ols was developed by decoupling the roles of the
ylide as a base and a nucleophile by judicious modulation of
temperature.
Lengthy reaction times for some of the sterically demanding
aziridinols prompted a quick screen of possible remedies.
Microwave reactions have the potential to decrease reaction
times dramatically while increasing the yield.29 Aziridinols 8,
13, and 16 were subjected to microwave irradiation studies to
ascertain the potential reduction in reaction time for the
preparation of pyrrolidines. The ylide was prepared as usual,
and the aziridinols were allowed to stir initially at room
temperature for 4 h to ensure that aza-Payne rearrangement was
complete. The reactions were then subjected to microwave
irradiation (30 pulses, 15 s/pulse). Gratifyingly, the reaction
times of 8 and 13 decreased substantially (24 h vs ∼8 min),
and the yields of their corresponding products 8b and 13b
increased to 91% (from 82%) and 79% (from 71%), respec-
tively. Microwave-assisted reaction of aziridinol 16 produced
a yield similar to that obtained under the typical conditions at
a fraction of the time required with conventional heating. Further
microwave studies are ongoing, and the results will be reported
in due course.
a 6.0 equiv of Mg metal in MeOH, sonicate 30 min, room temperature
overnight. b TfOH, p-anisole, CH2Cl2, -78 °C, then NaOH/EtOAc.
Payne rearrangement. The yield of the aza-Payne rearrangement
was lower as compared to that obtained with the Ts-activated
counterpart, perhaps due to the sterics of the bulky tert-butyl
group or the decreased ability of the tert-butylsulfonyl group
to stabilize the resulting negative charge on nitrogen following
rearrangement. The lower yield of pyrrolidine in the one-pot
reaction to give 40b and 41b reflects the lower yield of the in
situ aza-Payne rearrangement compared to that of the Ts-
protected analogues. We also attempted the use of a -P(O)Ph2
protecting group that has been documented to activate aziridines
toward nucleophilic ring-opening but can be removed under mild
acidic conditions.31 However, we could not obtain aza-Payne
rearranged products, much less the pyrrolidines.
Removal of the Nitrogen Protecting Group
Having established the viability of generating substituted
pyrrolidines in a stereocontrolled fashion, it was important to
ensure that the activating groups could be removed efficiently
to give the free pyrrolidine. The use of an electron-withdrawing
group on the aziridine nitrogen was necessary to activate the
ring toward nucleophilic ring-opening, but tosyl (Ts) groups
can be difficult to remove under acidic or basic conditions. We
wanted to examine other activating groups that allow for easier
deprotection of the pyrrolidine products. Typical nitrogen
protecting groups such as acetyl, Boc, and benzyl did not
facilitate aza-Payne rearrangement. The use of the tert-butyl-
sulfonamide (Bus) group as an activating/protecting group for
aziridines has been documented and provides a complementary
alternate to the Ts group, as it can be easily removed under
acidic conditions.30 As depicted in Table 4, Bus analogues of
aziridinols 8 and 15 (40 and 41 in Table 4) were synthesized
and subjected to treatment with NaH in THF to effect the aza-
Finally, the pyrrolidine products were subjected to various
deprotection conditions in order to ascertain the efficiency in
removal of the nitrogen activating group (Table 5). The Ts-
protected pyrrolidines could be deprotected with sodium naph-
thalide in glyme in moderate to good yields, but a substantial
amount of debenzylated product was also formed for benzyl-
protected substrates.32 In contrast, the Ts group was easily
removed under mild conditions using Mg metal in MeOH (Table
5) to provide the free amines.33 TBS-protected alcohols under
the tosyl deprotection conditions were stable, as can be seen in
conversion of 42 to 42c. The p-methoxy variant of the Ts
protecting group (see structure 43 in Table 5) was also utilized;
however, it was less efficient. The Bus group in 40b was easily
removed using conditions previously described by Weinreb
(31) Sweeney, J. B.; Cantrill, A. A. Tetrahedron 2003, 79, 3677-3690.
(32) (a) Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455. (b)
Casadei, M. A.; Gessner, A.; Inesi, A.; Achille, J.; Werner, M.; Micheletti,
F. J. Chem. Soc., Perkin Trans. 1 1992, 122, 7-9.
(29) MicrowaVe Assisted Organic Synthesis; Tierney, J. P., Lidstrom, P., Eds.;
Blackwell Publishing: Oxford, 2005.
(30) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783-786.
(33) Pak, C. S.; Kim, T. H.; Ha, S. J. J. Org. Chem. 1998, 63, 10006-10010.
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2002 J. AM. CHEM. SOC. VOL. 129, NO. 7, 2007

Pure 2,3-Disubstituted Pyrrolidines
A R T I C L E S
ammonium chloride (10 mL) and extracted three times with portions
of ethyl acetate. The combined organics were washed with brine and
dried over sodium sulfate, and the volatiles evaporated. The residue
was purified by column chromatography (hexanes/ethyl acetate gradient)
to give the desired pyrrolidine 8b in 99% yield as a thick oil that
eventually crystallized to a low-melting solid.
(solution of triflic acid in MeOH with p-anisole as a cation
scavenger) in good yields to provide the free amine.34 The
benzyl protecting group was also removed under these condi-
tions, giving a highly polar product that was acetylated to
facilitate isolation of 40c. Thus, we can remove the nitrogen
protecting group under either acidic or basic conditions, provided
care is taken in the protection of hydroxyls in the molecule.
Synthesis of Pyrrolidines from Aziridinols. DMSO was dried by
stirring overnight over CaH2 and distilled under high vacuum into a
flame-dried flask containing activated molecular sieves. Trimethylsul-
foxonium iodide was dried overnight at room temperature under high
vacuum. Dimethylsulfoxonium methylide was prepared fresh for each
reaction. Sodium hydride (0.32 g as a 60% dispersion in mineral oil,
8.0 mmol, 8.0 equiv, washed twice with pentane dried over sodium
metal) was placed in a flame-dried flask, and dry DMSO (10 mL) was
added via syringe. Trimethylsulfoxonium iodide (1.77 g, 8.0 mmol,
8.0 equiv) was added in small portions over 20-30 min. After addition
of the trimethylsulfoxonium iodide was complete, the reaction was
stirred for an additional 30 min until the bubbling of the milky-white
suspension ceased. The aziridinol 8 (0.35 g, 1.0 mmol, 1.0 equiv),
dissolved in a small amount of DMSO, was added dropwise, and the
reaction was stirred at room temperature for 4 h to complete the aza-
Payne rearrangement. The reaction was then covered with aluminum
foil and heated to 80-85 °C for 24 h. The dark brown mixture was
cooled and diluted with 2× volume of water and saturated ammonium
chloride (1 mL). The reaction was extracted several times with ethyl
acetate, and the combined organics were washed with brine and dried
over sodium sulfate. After evaporation of the solvent, the residue was
column chromatographed using a hexane/ethyl acetate gradient to give
compound 8b in 82% yield as a thick oil that eventually crystallized
to a low-melting solid.
Conclusion
In conclusion, we have developed a new method for the
synthesis of 2,3-disubstituted, 2,2,3- and 2,3,3-trisubstituted, and
2,2,3,3-tetrasubstituted pyrrolidine rings. The stereochemistry
present in the asymmetric aziridinol is translated fully to the
final product. Since it is simple to access these substrates in
high enantiomeric excess via the Sharpless asymmetric epoxi-
dation, Sharpless aminohydroxylation, or Wulff VAPOL-
catalyzed aziridination, this can be a powerful methodology for
gaining entry into 2,3-substituted pyrrolidines with stereodefined
substituents. Future work includes efforts to further functionalize
the pyrrolidine ring via the use of aziridinols substituted at C-1
and utilization of substituted ylides.
Experimental Section
General Procedures. Aza-Payne Rearrangement. The aziridinol
8 (1.0 g, 2.9 mmol, 1.0 equiv) dissolved in a small amount of THF
was added to a suspension of NaH (0.46 g as a 60% dispersion in
mineral oil, 4.0 equiv, 11.5 mmol) in dry THF (30 mL). The reaction
was stirred at room temperature for 4 h and then cooled to 0 °C and
quenched carefully with saturated ammonium chloride. The aqueous
layer was extracted three times with portions of ethyl acetate, and the
combined organics were washed with brine. The organics were dried
over sodium sulfate and the volatiles removed via rotary evaporation.
The residue was purified by column chromatography (hexanes/ethyl
acetate gradient) to give the epoxy amine 8a in 90% yield.
Synthesis of Pyrrolidines from Epoxy Amines. A suspension of
NaH (58.2 mg as a 60% dispersion in mineral oil (washed twice with
dry pentane), 1.45 mmol, 5.0 equiv) in DMSO (3 mL, 0.1 M in
aziridinol) was treated with trimethylsulfoxonium iodide (0.32 g, 1.45
mmol, 5.0 equiv) and the reaction stirred at room temperature for 30
min to give a milky-white solution. The epoxy amine 8a (0.1 g, 0.29
mmol, 1.0 equiv), dissolved in a small amount of DMSO, was added
to the ylide, stirred at room temperature for 30 min, and heated to 80
°C for 24 h. The cooled reaction mixture was quenched with saturated
Acknowledgment. Generous support was provided in part
by the Michigan Economic Development Corporation (GR-183).
J.M.S. also thanks the ACS Division of Organic Chemistry for
a Graduate Fellowship sponsored by Eli Lilly, Michigan State
University for a University Distinguished Fellowship, and a
graduate fellowship sponsored by the Dow Chemical Company
Foundation. The authors thank Ms. Zheijie Lu for help in
preparing substrate 14 and Rui Huang for X-ray crystallography
of 9b.
Supporting Information Available: Experimental procedures
and spectral data for compounds 8-43c. This material is
available free of charge via the Internet at http://pubs.acs.org.
(34) Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604.
JA065833P
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