C-H activation in S-alkenyl sulfoximines: An endo 1,5-hydrogen migration

Article abstract of DOI:10.1002/anie.201203258

Intramolecular redox reaction: Heating N-alkyl, N-allyl-, and N-benzyl-substituted S-alkenyl sulfoximines under appropriate conditions results in the formation of NH-S-alkyl sulfoximines. The intramolecular redox reaction involves a hydride transfer that occurs by a 6-endo-trig process. The intermediates in the reaction can also give access to four- and six-membered heterocyclic rings and a new class of chiral dienes. Copyright

Full text of DOI:10.1002/anie.201203258

Angewandte
Chemie
DOI: 10.1002/anie.201203258
Hydrogen Transfer
À
C H Activation in S-Alkenyl Sulfoximines: An Endo 1,5-Hydrogen
Migration**
Xuefeng Gao, Vikram Gaddam, Erich Altenhofer, Rama Rao Tata, Zhengxin Cai,
Nattawut Yongpruksa, Aswin K. Garimallaprabhakaran, and Michael Harmata*
In memory of Richard N. Loeppky
À
The concept of C H activation has fascinated chemists for
quite a long time. It has been studied with a variety of
substrates using metal catalysis, and research in this area
continues unabated.[1] Metal-free processes are also known.[2]
on the nitrogen atom of the sulfoximine.[5] An attempt to
prepare 6, however, resulted in the formation of 5 by a process
À
we assumed to be an intramolecular redox/C H activation
process (Scheme 2). This result stimulated our interest in this
process as a general phenomenon.
À
One particular example of such a C H activation proceeds
through a mechanism that, at least formally, involves the 1,5-
sigmatropic shift of a hydride to an electron-deficient site,
with concomitant formation of some reactive ionic or
zwitterionic species, depending on the nature of the species
that undergoes the process.
This interesting and important reaction is part of a process
that involves the so-called “tert-amino effect”.[3] For example,
heating a compound, such as A, results in a hydride shift in
what appears to be a pericyclic process to produce zwitterion
B (Scheme 1). Collapse of B produces C. There are a number
of other transannular and related carbocationic 1,5-hydride
Scheme 2. Intramolecular redox reaction.
À
shifts that are not pericyclic, but result in C H activation via
ionic intermediates.[4]
Around the same time, we were interested in producing
the cyclic sulfoximine 8a through an intramolecular ring-
closing metathesis process. We thus heated sulfoximine 7a[6]
in the presence of Grubbsꢀ second generation catalyst in
toluene, but obtained only recovered starting material.[7] We
subsequently heated 7a in toluene for 3.5 hours and obtained
the cyclic species 9a in 41% yield of isolated product
(Scheme 3) along with 7a (8%), 10a (26%), and 10a’
(6%).[8] The structure and stereochemistry of 9a were
Scheme 1. Tert-amino effect.
1
established by H NMR and NOE experiments. The thermal
We recently reported the synthesis of a series of S-alkynyl
sulfoximines 2 by dehydration of the corresponding b-
ketosulfoximines 1 [Eq. (1)], all of which bore a TBS group
[*] X. Gao, V. Gaddam, E. Altenhofer, R. R. Tata, Z. Cai, N. Yongpruksa,
A. K. Garimallaprabhakaran, Prof. M. Harmata
Department of Chemistry, University of Missouri–Columbia
601 S. College Ave., Columbia, MO 65211 (USA)
E-mail: harmatam@missouri.edu
Homepage: http://www.chem.missouri.edu/Harmata/synthe-
sis.html
[**] This work was supported by a grant from the National Science
Foundation to whom we are grateful. We thank Dr. Charles L. Barnes
(Missouri–Columbia) for the acquisition of X-ray data.
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203258.
Scheme 3. Intramolecular redox reaction and C C bond formation with
vinyl sulfoximines.
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Table 1: Formation of N H sulfoximines.
process also worked with 7b, affording 9b in 43% yield.
Interestingly, if the reaction was allowed to proceed for
around 24 hours, thiazines 10 were isolated as a mixture of
diastereomers. The stereochemistry of 10a was verified by X-
ray crystallography. To the best of our knowledge, cyclic
sulfoximines, such as 9a/b, are unknown. It also appears that
dihydrothiazines, such as 10a/b, have not been reported.
The mechanism for this reaction presumably begins with
an intramolecular hydride migration in 7a to generate 11a
(Scheme 4). This type of hydride shift appears to be unique.
Generally, examples of the tert-amino effect and related
reactions with ethers involve 6-exo-trig or 7-endo-trig migra-
tions, if one includes the migrating hydrogen atom in the
Entry 12 R1
R2
13 Yield [%] 14 Yield [%]
1[a,h]
2[b]
a
a
a
b
b
c
d
e
f
H
H
H
nPr
nPr
Ph
Me
Me
Me
Ph
Ph
Ph
a
a
a
b
b
c
d
a
a
a
a
a
–
a
a
a
b
b
b
c
d
b
b
e
f
–
–
–
–
–
72
34
–
3[c,i]
4[a,j]
5[b]
42
52
39
83
81
62
86
82
6[d]
–
–
7[e]
2-furyl vinyl
8[f]
H
H
H
H
H
PhCHCH
Ph
Ph
4-OMe-C6H4
4-Br-C6H4
76
60
–
80
34
9[f]
10[g]
11[f]
12[f]
f
g
h
[a] MeOH, microwave, 1308C, 30 min. [b] nPrOH, microwave, 1708C,
20 min. [c] nPrOH, microwave, 1308C, 2 h. [d] nPrOH, microwave,
1708C, 1.5 h. [e] Toluene/H2O, microwave, 1908C, 2.5 h. [f] Toluene/
nBuOH, reflux, 4 h. [g] THF/MeOH, microwave, 1308C, 20 min. [h] 15a
(R3 =Me) was produced in 77% yield. [i] 15a’ (R3 =nPr) was isolated in
50% yield. [j] 15b (R3 =Me) was produced in 62% yield (d.r.=1:1).
Scheme 4. Proposed mechanism for the formation of 9a from 7a.
count, regardless of the specific mechanism.[9] However, 6-
endo-dig migrations are proposed in pericyclic processes, such
as those that occur in the Crabbe homologation.[10] Further-
more, processes that can be characterized as a 6-endo-trig
hydride transfer are known, but not common.[11] Lastly, there
are other types of hydride transfer that are 6-exo-dig,[12] 5-exo-
trig,[13] 8-exo-trig,[14] and 7-exo-trig[15] processes and others,[16]
the characterization of which is vague using this nomencla-
ture.
Ring closure can be formulated as the intramolecular
collapse of the zwitterion 11a or an electrocyclization.
Though at present we favor the former explanation, a more
definitive answer must await mechanistic studies. For reasons
that remain unclear, no other example of cyclization has been
observed in our studies of other substrates under similar
conditions.
To further explore the scope of the hydride shift, we
examined several changes in the substrate as well as the
reaction conditions (Table 1). At lower temperatures, con-
jugate addition of a nucleophilic solvent could be observed, as
in the conversion of 12a to 15a (entry 1). However, at 1708C
or with a longer reaction time, the product of an intra-
molecular redox reaction, 13a, was produced (entries 2 and
3). This behavior was reproduced in one other system
(entries 4 and 5). Polar solvents facilitate the reaction, as in
the examples already mentioned. The redox process occurs
with alkenyl sulfoximines that are disubstituted (entries 4–6),
but proceeds better with simple vinyl sulfoximines. We note
that N-allylic substituents participate in the reaction
(entries 7–8), and in these cases no cyclization to heterocycles
was observed. Interestingly, three different benzyl substitu-
ents afforded products in nearly the same yield (entries 9, 11,
and 12). Finally, we recorded the yield of aldehydes produced
in this process in several cases. Whether these aldehydes are
formed as a result of adventitious water or a different
mechanism is not clear at present (entries 8, 9, 11, and 12).
Some aspects of the mechanism of this reaction have been
evaluated. Heating 12 f at 1308C in deuterated methanol
afforded [D1]-13a as a 1:1 mixture of diastereomers, as
expected based on the formation of a zwitterionic intermedi-
ate [Eq. (2)]. When the dideuterated sulfoximine [D2]-12 f
was heated in a mixture of toluene and butanol for 8 hours,
the expected deuterated product [D1]-13a’ was produced in
64% yield [Eq. (3)]. Interestingly, under the same reaction
conditions, 12 f required less than 2 hours to give 13a in 81%
yield (Table 1, entry 9). Though this is a very qualitative
observation, it suggests a kinetic isotope effect of around 4, in
keeping with a rate-determining step in which hydride
transfer occurs.[17,18]
In order to assess the stereochemistry of the hydride
transfer, we heated [D2]-12b at 1708C in a mixture of toluene
and water[19] to afford [D1]-13b in 83% yield with a 3:1 ratio
of diastereomers [Eq. (4)].
In an effort to trap the putative sulfoximine-stabilized
carbocation formed in this process, we used ethylene glycol as
the polar cosolvent. Heating a solution of 12e in a 1:1 mixture
of toluene/ethylene glycol produced the expected sulfoximine
2
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In summary, we have disclosed an intramolecular redox
C H activation process of alkenyl sulfoximines. The process
is proposed to proceed through a 6-endo-trig hydride transfer
to produce a zwitterionic intermediate. This intermediate can
À
À
close to novel heterocycles, produce N H alkyl sulfoximines,
or form novel, chiral, N-dienyl sulfoximines. This preliminary
work raises many questions about the scope of the reaction
and how it may be catalyzed. Further results will be reported
in due course.
Received: April 27, 2012
Revised: May 11, 2012
Published online: && &&, &&&&
À
Keywords: C H activation · hydrogen transfer ·
.
intramolecular redox reaction · tert-amino effect ·
vinyl sulfoximines
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4
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Communications
Hydrogen Transfer
X. Gao, V. Gaddam, E. Altenhofer,
R. R. Tata, Z. Cai, N. Yongpruksa,
A. K. Garimallaprabhakaran,
M. Harmata*
&&&& — &&&&
Intramolecular redox reaction: Heating
N-alkyl, N-allyl-, and N-benzyl-substituted
S-alkenyl sulfoximines under appropriate
conditions results in the formation of
NH-S-alkyl sulfoximines. The intramolec-
ular redox reaction involves a hydride
transfer that occurs by a 6-endo-trig
process. The intermediates in the reac-
tion can also give access to four- and six-
membered heterocyclic rings and a new
class of chiral dienes.
À
C H Activation in S-Alkenyl
Sulfoximines: An Endo 1,5-Hydrogen
Migration
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