Pd-Catalyzed [3+2] cycloaddition of ketoimines with alkynes via directed sp3 C-H bond activation

Article abstract of DOI:10.1039/c4cc04676e

The Pd(ii)-catalyzed oxidative [3+2] cycloaddition of N-(2-pyridyl) ketoimines with internal alkynes has been developed. The transformation is tolerant of extensive substitution on halogen, alkene, alkyne, hydroxyl, aryl and acyl groups, and allows facile assembly of multisubstituted pyrroles. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04676e

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Pd-Catalyzed [3+2] cycloaddition of ketoimines
with alkynes via directed sp3 C–H bond
activation†
Cite this: Chem. Commun., 2014,
50, 10699
Received 19th June 2014,
Accepted 17th July 2014
Ying Xie,a Tengfei Chen,a Shaomin Fu,a Xing-Shu Li,b Yuanfu Deng,a
Huanfeng Jianga and Wei Zeng*a
DOI: 10.1039/c4cc04676e
www.rsc.org/chemcomm
The Pd(II)-catalyzed oxidative [3+2] cycloaddition of N-(2-pyridyl)
ketoimines with internal alkynes has been developed. The transfor-
mation is tolerant of extensive substitution on halogen, alkene,
alkyne, hydroxyl, aryl and acyl groups, and allows facile assembly of
multisubstituted pyrroles.
Pyrroles are among the most commonly used heterocyclic feed-
stocks for assembling complex biologically active molecules and
pharmaceuticals.1 Therefore, a myriad of catalytic reactions have
been developed for the functionalization of pyrroles.2 Among the
different synthetic strategies, transition-metal catalyzed direct
oxidative coupling reactions by the selective activation of C–H
bonds have emerged as a powerful method for constructing
pyrroles.3 For example, the Pd(II), Ru(II) or Rh(III)-catalyzed cross-
coupling cyclization of C–H/N–H bonds with internal alkynes
could give pyrroles via cyclometalated intermediates.4 However,
Scheme 1 The direct C–C coupling strategies of ketoimines.
despite enormous progress in this field, all methods for instal- of ketoimines instead of imine carbon (a-C) or imine nitrogen5c,8
ling different types of substituents into specific positions of could be directly coupled with unsaturated carbon–carbon bonds via
pyrroles cannot be accessed by a single type of transformation. a C–H activation process. Although the direct C(sp3)–C(sp) coupling
Developing a new, more concise approach to multisubstituted between unfunctionalized alkanes and alkynes has remained a
pyrroles is a subject of great importance.
considerable challenge,9 inspired by earlier studies,6,7,9 and in
Imines are of great importance in organic chemistry, and their combination with the fact that pyridine could be used as a directing
corresponding C–X coupling reactions (X = C and N) are widely group to realize versatile C–H functionalization,5i,k,10 we reasoned
utilized in constructing various kinds of nitrogen-containing com- that a metallacyclic species (B) could be achieved via b-C(sp3)–H
pounds.5 Recently, Yoshikai reported that Co(II)-catalyzed C(sp2)–C(sp) activation if a pyridyl group from ketoimine (A) is employed as an
coupling of aryl ketoimines with alkynes could furnish trisubstituted anchor (Scheme 1c), then the corresponding cyclometalated species
olefins via a C–H activation process, in which ketoimines were (B) will be possibly trapped by C(sp)-containing alkyne (C) through
employed as directing groups (Scheme 1a).6 Very recently, they further inserting into the carbon–carbon triple bond. To identify this
found that Pd(II) could directly enhance the intramolecular cyclization hypothesis, herein we report a novel Pd-catalyzed [3+2] cycloaddition
of N-aryl ketoimines to give benzopyrroles through aryl C (sp2)–alkyl of 2-ketoiminopyridines with alkynes; this protocol can be readily
C (sp3) coupling (Scheme 1b);7 these results imply that b-C(sp3) used for constructing multisubstituted pyrroles (D).
Initially we focused on investigating whether the palladium-
a School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510641, China. E-mail: zengwei@scut.edu.cn
b Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China
catalyzed cycloaddition of imine 1a with diphenylacetylene 2a could
lead to the corresponding pyrrole 3a. Reactions were usually carried
out in the presence of n-Bu4NBr and PhI(OAc)2. After an initial
screening of various palladium catalysts (Table 1, entries 1–5),
we quickly found that Pd(OAc)2 (10 mol%) could afford 13% yield
of the desired product 3a by using toluene as a solvent at 60 1C for
† Electronic supplementary information (ESI) available. CCDC 1004595. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc04676e
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Table 1 Optimization of the reaction parametersa
corresponding five-substituted pyrrole 3l could be produced in 52%
yield (entry 3), and its structure was already unambiguously assigned
by its single crystal X-ray analysis [see the ESI† for more details]. Then,
we investigated the substitution effects of the pyridine ring on this
transformation, and found that the electron-rich pyridine offered
higher yield of product (3o), while electron-deficient substrates
inhibited cycloaddition performance (entry 5, compare 3o with
3p–3r). In addition, 2-ketoiminopyrimidine was also a suitable
substrate for this transformation and provided 48% yield of the
desired pyrrole 3s (entry 6).
Subsequently, the scope of the procedure with regard to various
internal alkynes was additionally explored with 1a particularly. Gratify-
ingly, we found that alkyl, aryl, alkoxycarbonyl, hydroxymethyl, acyl,
alkenyl and alkynyl substituted alkynes were all tolerated for this
transformation, and provided good to excellent yield of the desired
products 3t–3z (Table 2, entries 7–9). Notably, when ketoimine 1l and
alkenylalkyne 2i were used as the substrates in this reaction system,
the desired 1, 2, 3, 4, 5-differently substituted group-containing pyrrole
3za was obtained in 43% yield (entry 10). Finally, the pyridyl
moiety of 3a could be very easily removed under basic condi-
tions (MeOTf–NaOH, 0 1C–r.t) to provide the free N–H pyrrole
4a in 75% yield [eqn (1)].
Entry
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
PdCl2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
Ag2CO3
Cu(OAc)2
BQc
O2
O2
O2
O2
O2
O2
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
Dioxane
EtOAc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
5
Pd(TFA)2
PdCl2(CH3CN)2
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Trace
Trace
Trace
13
21
Trace
10
22
13
11
57
9
10
11
12
13
14
15
16
17
18
59
83d
91e
78 f
43e,g
62e,h
a
Unless otherwise noted, all the reactions were carried out using ketoimine
(1a) (0.10 mmol) and alkyne (2a) (0.10 mmol) with Pd catalysts (10 mol%) in
the presence of an oxidant (1.0 equiv.) and a solvent (1.0 mL) at 60 1C for
24 h under Ar in a sealed reaction tube, followed by flash chromatography
c
on SiO2. b Isolated yield. BQ stands for 1, 4-benzoquinone. d The reaction
(1)
temperature is 80 1C. e The reaction temperature is 100 1C. f The reaction
temperature is 120 1C. g The additive is n-Bu4NCl instead of n-Bu4NBr.
h The additive is n-Bu4NI instead of n-Bu4NBr.
To further probe the reaction mechanism, several controlled
experiments were carried out. First, we tried the [3+2] cyclo-
addition of N-phenyl imine (1t) with diphenylacetylene (2a)
under our standard conditions. Unfortunately, we only got
65% yield of indole derivative 4d which was from the oxidative
cyclization of 1t, and no pyrrole product 4c was observed
[eqn (2)]. These results clearly indicated that the pyridyl group
played a significant directing role in forming pyrroles. Second,
when the H/D exchange of N-pyridyl ketoimine 1a was conducted
in the Pd(II)–CD3OD system for 24 h in the absence of alkyne 2a,
91% deuterium incorporation was observed at the imino methyl
group of 1a (see the ESI for more details), and no 1H NMR trace
from enamine d-1aa was detected [eqn (3)];11 this experiment
suggested that the Csp3–H insertion step was involved in the
transformation in this reaction system. Finally, the intermole-
cular isotope effect (KH/KD = 1.52) suggested Csp3–H bond
cleavage occurred in the rate-limiting step [eqn (4)] (see the
ESI† for more details).12
24 h (entry 5). Subsequently, further improvement of the reaction
(22% yield of 3a) was achieved when DMSO was employed as the
solvent (compare entries 5–8 with 9). Considering that a proper
oxidant is essential for enhancing this transformation, various
oxidants were evaluated in the DMSO solvent system. To our delight,
the yield of product 3a could be significantly increased to 59% using
molecular oxygen as an oxidant (compare entries 9–12 with 13).
Finally, the best yield (91% yield of 3a) was obtained by increasing the
reaction temperature to 100 1C (compare entries 13 and 14 with 15),
while higher temperature (120 1C) gave a slightly lower yield (compare
entry 15 with 16). It is worth noting that switching additives from
n-Bu4NBr to n-Bu4NCl or n-Bu4NI could not further improve the yield
of 3a (entries 17 and 18).
Having established an efficient reaction protocol that enables the
smooth Pd-catalyzed [3+2] cycloaddition of 1a with 2a, we next
investigated the scope and generality of this transformation under
the optimized conditions. As shown in Table 2, common functional
groups on the benzene rings (Ar) attached to the imine carbon,
including alkyl, alkoxy, hydroxyl, ester, nitro, halogen, and acetal
groups, were all compatible with this cycloaddition and gave moderate
to excellent yields of pyrroles (entries 1 and 2). The meso or the ortho-
substituted benzene ring (Ar) led to a lower yield presumably due to
the increased steric hindrance around the ketoimine (entry 1, compare
3e with 3f and 3g). Moreover, aromatic heterocycle (Ar) substituted
ketoimines (such as Ar = 2-thiophene and 2-furan) could also give the
desired pyrroles 3m and 3n in 47–56% yields (entry 4). Worthy of note
was that when R2 was changed to the methyl group (CH3–), the
(2)
(3)
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Table 2 Substrate scope for the Pd(II)-catalyzed [3+2] cycloaddition of
ketoimines with alkynesa
Table 2 (continued)
Entry Ketoimine (1)
Alkyne (2)
Product (3)b (yield)
Entry Ketoimine (1)
Alkyne (2)
Product (3)b (yield)
2e: R1 = Ph,
R2 = CH2OH
2f: R1 = Ph,
R2 = PhCO
3w: R1 = Ph,
1a
1a
R2 = CH2OH (61%)
3x: R1 = Ph,
R2 = PhCO (80%)
1
1a: R = H
2a
2a
2a
2a
2a
2a
2a
2a
3a: R = H (91%); (87%)c
3b: R = p-Me (93%)
3c: R = p-MeO (93%)
3d: R = o-OH (44%)
3e: R = p-Cl (78%)
3f: R = m-Cl (59%)
3g: R = o-Cl (54%)
3h: R = p-Br (84%)
3i: R = p-CO2Me (70%)
3j: R = p-NO2 (67%)
8
9
1a
1a
1b: R = p-Me
1c: R = p-MeO
1d: R = o-OH
1e: R = p-Cl
1f: R = m-Cl
1g: R = o-Cl
1h: R = p-Br
1i: R = p-CO2Me 2a
1j: R = p-NO2
2a
10
2
2a
a
All the reactions were carried out using ketoimine (1) (0.10 mmol) and
alkyne (2) (0.10 mmol) with Pd(OAc)2 (10 mol%) in DMSO (1.0 mL) at
100 1C for 24 h under 1 atm of O2 in a sealed reaction tube, followed by
3
4
2a
2a
b
c
flash chromatography on SiO2. Isolated yield. The yield for a larger
d
scale coupling product of 1a (8.0 mmol) with 2a (8.0 mmol). Regio-
isomeric ratio (r.r) determined by 1H NMR spectroscopy. e 1H–1H NOE
NMR spectra of 3y is available in the ESI.
1m: X = O
1n: X = S
2a
2a
3m: X = O (47%)
3n: X = S (56%)
(4)
From the above-mentioned experimental results, we proposed
a possible mechanism that involved a Pd(II)/Pd(0) redox process
(Scheme 2). At first, enamine 1-E derived from imine/enamine-
isomerization 7 would be electrophilically attacked by Pd(II) to
form a six-membered palladacycle A via an intramolecular Csp3–H
palladation. Subsequently, the reactive palladium intermediate
A will be inserted into an equivalent of alkyne 2 to form an
8-membered palladacycle B, which would further result into a
six-membered ring cyclopalladated D through a N-ligand shift
process.13 Finally, Pd(II) intermediate D can reductively eliminate
to form pyrrole 3 and generate a Pd(0) species which can be
oxidized by O2 to generate the catalytically active Pd(II) complex.
In summary, we have developed a facile palladium-catalyzed
oxidative [3+2] cycloaddition reaction to assemble a multi-
substituted pyrrole skeleton from readily available N-pyridyl
substituted ketoimines and internal alkynes. This new approach
tolerates a variety of useful functionalities including halogen,
hydroxyl, alkyloxycarbonyl, alkenyl and alkynyl substituents
which have not been easily accessible through existing synthetic
methods. Since the pyridyl moiety could be removed under mild
5
2a
1o: R = 5-Me
1p: R = 5-Cl
1q: R = 5-Br
1r: R = 5-CN
2a
2a
2a
2a
3o: R = 5-Me (82%)
3p: R = 5-Cl (61%)
3q: R = 5-Br (62%)
3r: R = 5-CN (40%)
6
7
2a
1a
2b: R1 = Et,
3t: R1 = Et,
1a
1a
1a
R2 = Ph
R2 = Ph (80%) (r.r = 9 : 1)d
2c: R1 = R2 = n-Pr 3u: R1 = R2 = n-Pr (66%)
2d: R1 = Ph,
3v: R1 = Ph,
R2 = CO2Me
R2 = CO2Me (71%)
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Scheme 2 Possible mechanism for the reaction.
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12 The KIE value was also determined via a competition experiment
using a 50 : 50 mixture of the D- and H-isotopomer (d-1a/H-1a) under
standard conditions, and the corresponding KIE value (KH/KD = 3.0)
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10702 | Chem. Commun., 2014, 50, 10699--10702
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