Diverse reactivity in a rhodium(III)-catalyzed oxidative coupling of N-allyl arenesulfonamides with alkynes

Article abstract of DOI:10.1002/anie.201206918

Olefinic CiH activation of N-allyl sulfonamides in the presence of [{RhCpCl₂}₂] (Cp=Me₅C₅) enabled their oxidative coupling with alkynes to generate 1,2-dihydropyridines, pyridines, and cyclopentenones (see scheme; Ts=p-toluenesulfonyl). The type of highly substituted product formed was controlled by the substitution of the allyl group and the reaction conditions. Copyright

Full text of DOI:10.1002/anie.201206918

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DOI: 10.1002/anie.201206918
À
C H Activation
Diverse Reactivity in a Rhodium(III)-Catalyzed Oxidative Coupling of
N-Allyl Arenesulfonamides with Alkynes**
Dongqi Wang, Fen Wang, Guoyong Song, and Xingwei Li*
À
Metal-catalyzed C H activation has been explored widely for
[1,2]
À
À
À
the construction of C C, C N, and C O bonds.
This
À
process is advantageous in that C H bonds are ubiquitous,
and the direct functionalization of C H bonds is a step-
economical approach to bond formation. Although, arguably,
palladium compounds are most well-known for the activation
of C H bonds for coupling reactions,
À
[1b,d,j,l]
À
stable rhodium-
(III) complexes have been used increasingly in the past five
À
years and stand out as highly active catalysts for C H
activation with high selectivity, broad substrate scope, and
high functional-group compatibility.[2] Furthermore, rhodium-
(III) can complement other metals in terms of selectivity and
reactivity.[3]
Scheme 1. Diverse reactivity in the oxidative coupling of N-allyl sulfon-
amides with alkynes. Ts=p-toluenesulfonyl.
Chelation assistance is a common strategy in rhodium-
dienyl) was used as a catalyst, both Ag2CO3 and Cu(OAc)2
failed to effect this coupling reaction with high conversion
and high selectivity. In contrast, AgOAc (4.5 equiv) proved to
be an efficient oxidant. When the reaction was carried out in
the presence of AgOAc (4.5 equiv) and the catalyst in acetone
at 1008C, product 3aa was isolated in 71% yield (Table 1).
The yield of 3aa was much lower (32%) when only
2.1 equivalents of AgOAc were used, which suggests that
a twofold oxidation process occurs. Indeed, product 3aa was
characterized as a 3-sulfonylpyridine on the basis of NMR
spectroscopic analysis (see the Supporting Information).
Under the optimal coupling conditions, a series of dialkyl-
substituted alkynes readily underwent coupling with N-allyl
[2]
(III)-catalyzed C H activation. Various nitrogen[4] and
À
oxygen directing groups have been successfully employed[2]
for the construction of a variety of heterocycles, such as
isocoumarin,[5] indole or pyrrole,[6] pyridine,[7] isoquinoline,[8]
lactam,[9] and 2-pyridone derivatives.[10] Although readily
available, sulfonamides have found limited application as
directing groups for C H activation.[11] If sulfonamides could
À
be used effectively as directing groups, it would significantly
expand the synthetic utility of RhIII catalysis for the con-
struction of heterocyclic cores. In continuation of our interest
À
in rhodium(III)-catalyzed C H activation, we now report the
efficient construction of pyridine and cyclopentenone rings in
a rhodium(III)-catalyzed oxidative coupling of N-allyl sulfo-
namides with alkynes (Scheme 1). To the best of our knowl-
edge, cyclopentenone scaffolds have not been constructed
Table 1: Synthesis of 3-sulfonylated pyridines.[a,b]
À
previously by C H activation.
III
À
The activation of olefinic C H bonds under Rh catal-
ysis[7,10,12] has been studied less than the activation of aryl C
H bonds. We embarked on our studies with the coupling of N-
allyl p-tolylsulfonamide (1a) with 3-hexyne (2a). When
[{RhCp*Cl2}2] (4 mol%; Cp* = pentamethylcyclopenta-
À
[*] D. Wang, F. Wang, Dr. G. Song, Prof. X. Li
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
Dalian 116023 (China)
E-mail: xwli@dicp.ac.cn
D. Wang
State Key Laboratory of Pharmaceutical Biotechnology
School of Life Sciences, Nanjing University
Nanjing 210093 (China)
[**] This research was supported by the Dalian Institute of Chemical
Physics, Chinese Academy of Sciences and the NSFC (No.
20172188). We thank Prof. Yong-Gui Zhou for insightful discus-
sions.
[a] Reaction conditions: sulfonamide (0.3 mmol), alkyne (0.36 mmol),
[{RhCp*Cl2}2] (4 mol%), AgOAc (1.35 mmol), acetone (3 mL), 30 h.
[b] The yield of the isolated product is given. [c] The reaction was carried
out at 1008C. [d] The reaction was carried out at 1308C.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206918.
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sulfonamides. The resulting substituted pyridines were iso-
lated in 63–73% yield. When the unsymmetrical alkyne
ꢀ
MeC CEt was used, two separable regioisomers, 3ad and
3ad’, were obtained. The regioisomers were characterized by
NOESY spectroscopy, which showed a slight preference of
the bulkier Et group to be distal to the nitrogen atom (as in
3ad’). Unsymmetrical alkynes bearing an alkyl and an aryl
group are also suitable substrates, but only at an elevated
temperature (1308C). Thus, products 3ae–3bf were isolated
in good yield as a single regioisomers. NOESY analysis of
these products revealed that the phenyl group of the alkyne
unit is oriented closed to the pyridine nitrogen atom.
To establish which intermediates are formed in this
twofold oxidation process, we carried out the coupling of 1a
ꢀ
and PhC CMe (2e) at a lower temperature in the presence of
2.1 equivalents of AgOAc (Scheme 2). The 1,2-dihydropyr-
Scheme 3. Mechanism of the formation of 3-sulfonated pyridines.
of TsÀ generates a carbocation, and an SN1-type substitution
affords an isomeric 2,3-dihydropyridine intermediate. Subse-
quent oxidative aromatization furnishes the final product of
a formal oxidative 1,3-shift of the sulfonyl group.[14] We
carried out cross-over experiments to probe the intermole-
cularity of the sulfonyl 1,3-shift (Scheme 3c).[15,16] When an
equimolar mixture of 4ae and 4bf was heated at 1308C under
the catalytic conditions, the four expected products 3ae, 3af,
3be, and 3bf were detected by GC in a 1.1:1.4 :1:1.1 ratio,
which is consistent with our proposed mechanism. An
intermolecular 1,3-shift of TsÀ in a pyrrole synthesis was
also reported recently.[16]
Scheme 2. Intermediacy of a 1,2-dihydropyridine.
idine 4ae, a product at a low oxidation level, was isolated in
77% yield and fully characterized. The formation of 4ae
corresponds to oxidative coupling through C H and N H
À
À
bond cleavage and C C and C N bond formation.[2,4] The use
of diphenylacetylene as the alkyne led to 4ah in 83% yield.
When an isolated sample of 4ae was stirred at 1308C in the
presence of AgOAc and the Rh catalyst, pyridine 3ae was
obtained in 82% yield (Scheme 2). This result indicates that
dihydropyridine 4ae is an intermediate in the overall reaction
of 1a with alkyne 2e to form pyridine 3ae. Furthermore, in
the absence of the catalyst, 3ae was formed from 4ae in
a slightly lower yield. In contrast, no reaction occurred when
dihydropyridine 4ah was subjected to the above conditions,
which suggests that the second oxidation step is kinetically
favored by an electron-donating alkyl group in the alkyne
À
À
À
To better define the scope of the C H activation with
respect to the allyl moiety, we treated N-methallyl p-
ꢀ
tolylsulfonamide (1c) with PhC CnPr (2h) under the con-
ditions for twofold oxidation [Eq. (1)]. As the 1,3-migration
of the sulfonyl group would no longer be possible owing to the
introduction of a methyl (blocking) group into the olefin unit,
the formation of a 1,2-dihydropyridine product was expected.
Surprisingly, 13C NMR and IR spectroscopic analysis of the
major product, 5ch, isolated from this reaction pointed to
a ketone functionality, although a small amount (< 5%) of
1,2-dihydropyridine 4ch was also generated [Eq. (1)]. In
particular, 13C NMR spectroscopy revealed a carbonyl group
(d = 207.6 ppm, CDCl3). No regioisomers of 5ch were
observed. The identity of cyclopentenone 5ch was unambig-
uously confirmed by X-ray crystallography.[17] The methyl and
NHTs groups are in a trans arrangement. In this reaction, the
ketone oxygen atom most likely originates from adventitious
water. Indeed, when water (3 equiv) was added to the
reaction mixture, 5ch was isolated in reproducibly good
ꢀ
ꢀ
unit. Thus, the reactivity order MeC CMe > PhC CMe >
ꢀ
PhC CPh was established for the one-pot synthesis of 3-
sulfonylated pyridines.
We carried out several experiments to probe the mech-
anism of oxidation of the 1,2-dihydropyridine. When 2,3-
diethylpyridine was treated with p-tolylsulfinic acid (TsH)
under the standard conditions, none of the desired pyridine
but only decomposition was detected (Scheme 3a). This
result ruled out a pathway of TsH elimination[13] of the
À
dihydropyridine, followed by oxidative C S bond formation.
A likely mechanism is proposed in Scheme 3b: Dissociation
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Table 2: Rhodium(III)-catalyzed synthesis of cyclopentenones.[a,b]
yield. In sharp contrast, 4ch was the major product isolated
(65% yield) when 2.1 equivalents of AgOAc were used
[Eq. (1)]. Thus, the reaction selectivity is controlled by the
amount of AgOAc used.
Despite the successful synthesis of 5ch, we failed to obtain
ꢀ
the corresponding cyclopenteneone product for PhC CPh or
ꢀ
PhC CMe. Instead, only the dihydropyridine product
formed. Gratifyingly, when AgOAc was replaced with
AgOPiv (4.2 equiv; Piv = pivalate), the desired cyclopente-
none product was isolated in consistently high yield and with
high selectivity. Under these optimal conditions, different
diaryl-, dialkyl-, and mixed alkyl- and aryl-substituted alkynes
reacted with 1c with high efficiency (63–84% yield) and high
regio- and diastereoselectivity (Table 2). The substituent in
the olefin unit is not restricted to a methyl group. Thus, the
introduction of Et, nPr, and aryl groups in the 2-position of
ꢀ
the olefin was well-tolerated in the coupling with PhC CnPr,
with the corresponding products formed in 72–86% yield.
However, no reaction occurred in the attempted coupling of
ꢀ
N-crotyl p-tolylsulfonamide with PhC CnPr. Nevertheless,
this methodology provides efficient and expedient access to
a wide range of functionalized cyclopentenones from readily
available starting materials under operationally simple con-
ditions.
[a] Conditions: sulfonamide (0.3 mmol), alkyne (0.36 mmol),
[{RhCp*Cl2}2] (4 mol%), AgOPiv (1.26 mmol), H2O (0.9 mmol), acetone
(3 mL), 1008C, 20 h. [b] The yield of the isolated product is given.
When an isolated sample of 4ch was exposed to our
standard reaction conditions, essentially no reaction occurred.
We could thus rule out the intermediacy of this dihydropyr-
idine in the formation of 5ch. Therefore, these two products
must be generated by two competitive pathways. We propose
a mechanism in which the cyclometalation of 1c first affords
a five-membered rhodacycle A, which undergoes regioselec-
tive alkyne insertion to generate a seven-membered metal-
lacycle B (Scheme 4). The fate of this metallacycle inter-
mediate is determined by two possible pathways: intermedi-
role of the excess AgI oxidant in shifting the selectivity of the
reaction is unclear at this stage, it might act as a base to
facilitate HX elimination from C so as to shift the equilibrium
between B and C toward C. It might also interact with the N-
Ts imine to enhance the electrophilicity of the imine.
Amine-assisted cyclometalation is not the only possible
mechanistic pathway. Alternatively, amine 1c might initially
be oxidized to an N-Ts imine (either by AgI or by acetone;
Scheme 5). Cyclometalation of this unsaturated imine[19] and
insertion of an alkyne would afford a seven-membered
rhodacyclic intermediate analogous to C (Schemes 4 and
5a). To probe this possibility, we prepared the N-Ts imine 6;
however, no coupling occurred when 6 was treated with
various alkynes under the usual catalytic conditions
(Scheme 5b). Thus, the amine-cyclometalation pathway is
more likely.
À
ate B undergoes C N reductive elimination to give a dihy-
dropyridine 4 when a smaller amount of AgI is present;
alternatively, in the presence of a larger amount of AgI, a b-
hydride-elimination pathway to afford a cyclometalated
imine C is preferred. Intermediate C should readily undergo
migratory insertion of the alkenyl rhodium ligand into the N-
Ts imine[18] to afford a rhodium(III) hydride species D. A
second b-hydrogen-atom elimination[18c] generates an imine E
and a rhodium(III) dihydride species, which can be oxidized
to regenerate the RhIII active catalyst (4 equivalents of AgI
are needed). The final product 5 could be formed from imine
E in a sequence involving the conjugate addition of water (to
give F), followed by cyclopentadiene isomerization and
ketone–enol tautomerization (via G). Although the exact
In summary, we have demonstrated the oxidative syn-
thesis of several important cyclic scaffolds, including pyridines
and cyclopentenones, from readily available N-allyl sulfon-
À
amides and alkynes through rhodium(III)-catalyzed C H
activation. The reactions have broad scope in terms of both
substrates. The selectivity of the reaction is determined by the
allyl moiety of the sulfonamide, the identity of the alkyne, and
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À
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Received: August 27, 2012
Published online: October 29, 2012
À
Keywords: alkynes · C H activation · pyridines · rhodium ·
sulfonamides
.
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À
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