Synthesis of 3-(Arylsulfonyl)-3-pyrrolines from Allenyl Sulfonamides by Silver Ion Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02440

Treatment of allenyl sulfonamides with catalytic amounts of silver fluoride in acetonitrile at reflux afforded the corresponding 3-sulfonyl-3-pyrrolines in excellent yields by intramolecular hydroamination via a 5-endo-trig cyclization. The starting allenyl sulfonamides were prepared by lithiation of allenic sulfones and trapping with various N-sulfonylimines.

Full text of DOI:10.1021/acs.orglett.8b02440

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 3‑(Arylsulfonyl)-3-pyrrolines from Allenyl Sulfonamides
by Silver Ion Catalysis
Rama Rao Tata,† Chencheng Fu, Steven P. Kelley, and Michael Harmata*
Department of Chemistry, University of MissouriColumbia, Columbia, Missouri 65211, United States
S
* Supporting Information
ABSTRACT: Treatment of allenyl sulfonamides with catalytic amounts of silver
fluoride in acetonitrile at reflux afforded the corresponding 3-sulfonyl-3-pyrrolines
in excellent yields by intramolecular hydroamination via a 5-endo-trig cyclization.
The starting allenyl sulfonamides were prepared by lithiation of allenic sulfones
and trapping with various N-sulfonylimines.
The cyclization of aminoallenes to pyrrolines catalyzed or
ive-membered ring heterocycles comprise a vast number
Fof substructures that appear commonly in both natural mediated by various reagents has a long history, beginning with
products and man-made substances.1 Those containing a single
the first examples of aminoallene cyclizations catalyzed by
silver cations.11 This methodology continues to be inves-
nitrogen atom include indoles and pyrroles, as well as reduced
tigated, with base-mediated processes,12 phosphine-catalyzed
congeners of these compounds, and are significant enough to
processes,13 metal catalysis combined with halogenation,14
have attracted a great deal of attention from the synthetic
tandem metal-catalyzed cyclizations,15 and micellar catalysis16
being among the more recent developments in the area.17 In
spite of these important contributions, some gaps in the
possible tactics one might use in this area still remain. For
example, engaging substrates that might afford substituents on
the product alkene that are novel or may be used as handles for
further functionalization would be important. In undertaking
our research, we decided to examine the reaction of lithiated
allenic sulfones with sulfonyl imines and then assess the
product of this addition reaction in cyclization chemistry to
produce 3-pyrrolines.
community.2 One class of compounds in which we have an
interest are the 3-pyrrolines.3 3-Pyrroline-containing com-
pounds possess many important biological activities including
inhibitory activity against monoamine oxidase (MAO),4
anticancer activity,5 agonist activity at the NMDA receptor,6
and K-agonist activity.7 Owing to their pharmaceutical interest
and synthetic utility, there have been many methods developed
for the synthesis of 3-pyrrolines.8 Among them, the metal-
catalyzed cyclization of amino/amido allenes is of considerable
interest.9
In the context of the exploration of metal-catalyzed
cyclization of allenes, our group has recently reported the
synthesis of 2,5-dihydrofurans from α-hydroxy allenes or
hydroxy propargylic sulfinates by silver fluoride catalysis.10 For
example, treatment of 1 or 3 with silver fluoride under the
conditions noted afforded the dihydrofurans 2 and 4 in 99%
and 81% yields, respectively (Scheme 1). We envisaged that we
could synthesize 3-pyrrolines from α-amino/amido allenes.
Herein, we report the synthesis of 3-sulfonyl-2,5-disubstituted-
3-pyrrolines from α-sulfonamido allenes via a 5-endo-trig
cyclization.
The N-sulfonylimines needed for our studies were
synthesized by the condensation of corresponding aldehyde
and phenyl sulfonamide according to literature procedures.18
We synthesized various allenylsulfonamides by the lithiation of
allenyl sulfones and trapping with various N-sulfonylimines.
We investigated the lithiation step by using both n-BuLi and
LiHMDS as a base. Treatment of allenic sulfone 5a in THF
with n-BuLi followed by addition of N-sulfonylimine 6a
furnished the corresponding allenyl sulfonamide 7a in only
54% yield. However, when LiHMDS was used as the base, 7a
was obtained in 86% yield (Scheme 2). We used either n-BuLi
or LiHMDS for the preparation of all of our cyclization
substrates. The results are shown in Table 1.
Scheme 1. Dihydrofuran Formation
One result in this series was rather interesting and
unexpected. When 5d was treated with LiHMDS and then
trapped with 6a, a single stereoisomer of product was obtained
in 82% yield (Table 1, entry 12). The process is depicted in
Scheme 3. The organolithium obtained from deprotonation of
5d is not configurationally stable. The sole product obtained
resulted from inversion of configuration at the sulfone bearing
Received: July 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02440
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To evaluate the cyclization reaction, we began by examining
various catalysts using the substrate 7f. The results are
summarized in Table 2. We initially tested the cyclization
Scheme 2. Effect of Base Change on Lithiation and
Trapping of Allenic Sulfones
Table 2. Optimization of Cyclization Reaction Conditions
entry
catalyst (equiv)
solvent
CH2Cl2
THF/H2O
CH2Cl2
CH2Cl2
CH2Cl2
THF/H2O
THF/H2O
THF/H2O
CH3CN
CH3CN
CH3CN
time
yield (%)
Table 1. Synthesis of Sulfamido Allenes
1
2
3
4
5
6
7
8
AuCl3 (0.1)
HAuCl4·H2O (0.1)
Ph3PAuOTf (0.1)
AgSbF6 (0.1)
AgBF4 (0.1)
AgNO3 (0.1)
AgBr (0.1)
AgI (0.1)
AgF (0.1)
AgF(0.05)
10 h
4 d
9 h
60
88
20
32
99
99
nr
3
98
81
83
99
a
3 h
48 h
27 h
4 d
a
a
a
4 d
9
70 m
80 m
14 h
10 m
10
11
12
AgF (0.02)
b
AgF (0.02)
CH3CN
a
b
1:1 v/v. At reflux.
with gold (I and III) catalysts. Treatment of 7f with 10 mol %
of AuCl3 (Table 2, entry 1) produced the corresponding 3-
pyrroline 8f in 60% yield. The use of HAuCl4·H2O (Table 2,
entry 2) gave 8f in 88% yield. However, the use of gold(I)
catalysts such as 10 mol % of Ph3PAuOTf (generated in situ
from Ph3PAuCl and AgOTf) (Table 2, entry 3) afforded 8f in
only 20% yield. We then examined various silver salts.
Treatment of substrate 7f with AgSbF6 (Table 2, entry 4)
produced 8f in only 32% yield. However, when the substrate 7f
was treated with AgBF4 and AgNO3 (Table 2, entry 5 and 6),
8f was produced in an excellent 99% yield in 48 and 27 h,
respectively. The catalyst AgBr (Table 1, entry 7) showed no
reaction even after 4 days, and the catalyst AgI (Table 1, entry
8) gave 8f in only 3% yield. Silver fluoride (AgF) at levels of 10
and 5 mol % (Table 2, entries 9 and 10) afforded 8f in 98%
and 81% yields, respectively. The use of low catalyst loading (2
mol %, Table 2, entry 11) produced 8f in 83% yield, but the
reaction was slow compared to higher catalyst loading (Table
2, entries 9 and 10). Finally, we conducted the reaction using
AgF at only 2 mol % loading (Table 2, entry 12) under reflux.
This afforded the 3-pyrroline 8f in 99% yield in only 10 min,
and these conditions became what we used to produce
additional examples of the reaction.
a
b
c
n-BuLi used as base. Single stereoisomer. dr = 1:1
Scheme 3. Trapping an Allenic Organolithium with
Inversion of Configuration
Using the aforementioned optimized conditions, we
investigated the scope of 5-endo-trig cyclization of allenyl
sulfonamide. The results are summarized in Table 3. Allenyl
sulfonamides derived from the aliphatic substituted imines 7b
and 7c (Table 3, entries 2 and 3) furnished the corresponding
3-sulfonyl-3-pyrrolines 8b and 8c in 97% and 95% yield,
respectively, but relatively slowly, requiring 40 min for the
completion of the reactions. The cyclization of phenyl-
substituted allenyl sulfonamides 7d,e (Table 3, entries 4−5)
were completed within 5 min in excellent yields. To ascertain
the electronic effects on this cyclization, various substitutions
on the phenyl ring of the sulfonyl imine were examined. It
appears that electron-donating groups on the phenyl group,
such as a methyl or methoxy group (Table 3, entries 4 and 6),
carbon. We conjecture that the organolithium derived from 5d
is rapidly equilibrating. A difference in the rates of the reaction
of each diastereomer results in the formation of the product
observed, an example of the Curtin−Hammett principle.19 We
have a small amount of evidence in support of this basic idea,20
but we make no claim as to the veracity of our hypothesis.
B
DOI: 10.1021/acs.orglett.8b02440
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Heteroaromatic-substituted allenyl sulfonamide 7h (Table 3,
entry 8) gave 8h in 83% yield. An allenyl sulfonamide
possessing the cinnamyl group 7i (Table 3, entry 9) produced
8i in 78% yield. Cyclopentyl (7j) and cyclohexyl (7k and 7l)
systems afforded the desired cyclized products 8j−l in
excellent yields within 5 min (Table 3, entries 10−12).
These results indicate that there are no substantial steric effects
on this cyclization. Treatment of unsymmetrical allenyl
sulfonamides 7m and 7n (dr 1:1) (Table 3, entries 13 and
14) with AgF furnished 8m and 8n (dr 1:1) in excellent yields
(98% and 99%, respectively).
Table 3. Synthesis of Pyrrolines by Catalytic Ring Closure
A plausible mechanism for the cyclization of an α-allenyl
sulfonamide by silver(I) catalysis is shown in Scheme 4. First,
Scheme 4. Proposed Mechanism for Pyrroline Formation
silver ion coordinates to the distal, more electron-rich double
bond of allene 7 and forms the intermediate 9. The lone pair of
electrons on the nitrogen then attacks the distal bond of the
allene, undergoing a 5-endo-trig cyclization to give the 5-
membered vinyl silver intermediate 10. Finally, the loss of
silver through a proton transfer affords the final product
pyrroline 8.
In conclusion, we have developed a new method for the
synthesis of highly substituted, 3-(arylsulfonyl)-3-pyrrolines
from α-allenyl sulfonamides by silver ion catalysis. While the
vinyl sulfone group in the five-membered ring can be used to
create various functional groups on the ring,21 further
development of the chemistry of the vinyl sulfone is warranted.
Continuing studies of the scope of this process and the
chemistry of the products will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02440.
Experimental procedures and 1H and 13C spectra (PDF)
Accession Codes
CCDC 1855814−1855815 and 1858620 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
dr = 1:1.
AUTHOR INFORMATION
Corresponding Author
■
accelerated the reaction slightly, whereas an electron-with-
drawing group such as the nitro group (Table 3, entry 7)
slowed the reaction.
*E-mail: harmatam@missouri.edu.
C
DOI: 10.1021/acs.orglett.8b02440
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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1979, B33, 309−310.
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Lipshutz, B. H. Chem. Sci. 2017, 8, 6354−6358.
Rama Rao Tata: 0000-0002-4906-0712
Chencheng Fu: 0000-0002-5746-9438
Steven P. Kelley: 0000-0001-6755-4495
Michael Harmata: 0000-0003-3894-2899
Present Address
†(R.R.T.) Eurofins Biopharma Product Testing, 7200 E ABC
Lane, Columbia, MO 65202.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1463724). Thanks to the Alexander von Humboldt
Foundation for providing funds for a leave for M.H. at the
̈
Justus Liebig Universitat (Giessen) in the laboratories of
Professor Peter R. Schreiner, to whom we are also grateful.
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DOI: 10.1021/acs.orglett.8b02440
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