α-Palladation of imines as entry to dehydrogenative heck reaction: Aerobic oxidative cyclization of N-allylimines to pyrroles

Article abstract of DOI:10.1021/ol400638q

We report here a palladium(II)-catalyzed oxidative cyclization reaction of N-allylimines derived from methyl ketones, typically acetophenones, affording pyrrole derivatives at room temperature under oxygen atmosphere. The reaction likely proceeds through α-palladation of the imine followed by olefin migratory insertion and β-hydride elimination, thus representing a new example of aerobic dehydrogenative Heck cyclization.

Full text of DOI:10.1021/ol400638q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
r‑Palladation of Imines as Entry to
Dehydrogenative Heck Reaction:
Aerobic Oxidative Cyclization of
N‑Allylimines to Pyrroles
Zhiyuan Chen, Beili Lu, Zhenhua Ding, Ke Gao, and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
nyoshikai@ntu.edu.sg
Received March 11, 2013
ABSTRACT
We report here a palladium(II)-catalyzed oxidative cyclization reaction of N-allylimines derived from methyl ketones, typically acetophenones,
affording pyrrole derivatives at room temperature under oxygen atmosphere. The reaction likely proceeds through R-palladation of the imine
followed by olefin migratory insertion and β-hydride elimination, thus representing a new example of aerobic dehydrogenative Heck cyclization.
Catalytic oxidative linkage of two CꢀH bonds using
molecular oxygen as a sole oxidant, producing water as the
only byproduct, represents an ideal strategy for CꢀC bond
formation.1 With palladium catalysis, such transforma-
tions can be achieved through two major mechanistic
pathways. One involves sequential palladation of two
CꢀH bonds followed by reductive elimination (cross-
dehydrogenative coupling),2 and the other involves palla-
dation of a CꢀH bond, alkene insertion into the resulting
PdꢀC bond, and β-hydride elimination (dehydrogena-
tive Heck reaction).3,4 Recently, our group reported
an intramolecular example of the former type of trans-
formation, that is, an oxidative cyclization reaction of
N-arylimines to indoles with a catalytic system comprising
Pd(OAc)2, Bu4NBr, and molecular oxygen in DMSO
(Scheme 1a).5,6 The reaction was proposed to involve
palladation of the R-position of the imine through imineꢀ
enamine tautomerization,7 intramolecular palladation of
the aromatic ring, and reductive elimination. The same
catalytic system also proved effective for dehydrogenative
aromatization of cyclohexanone imines to arylamines,
which presumably goes through R-palladation/β-hydride
elimination sequences (Scheme 1b).8ꢀ10 These previous
studies guided us to find another type of dehydrogenative
(1) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Campbell,
A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (c) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (d) Liu, C.; Zhang, H.; Shi, W.; Lei, A.
Chem. Rev. 2011, 111, 1780.
(5) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098.
(6) See also: (a) Shi, Z.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
(2) For selected examples, see: (a) Brasche, G.; Garcıa-Fortanet, J.;
ꢀ
€
€
9220. (b) Neumann, J. J.; Rakshit, S.; Droge, T.; Wurtz, S.; Glorius, F.
€
Buchwald, S. L. Org. Lett. 2008, 10, 2207. (b) Liegault, B.; Lee, D.;
Chem.;Eur. J. 2011, 17, 7298. (c) Wurtz, S.; Rakshit, S.; Neumann,
J. J.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 7230.
Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022.
(c) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74,
4720. (d) Izawa, Y.; Stahl, S. S. Adv. Synth. Catal. 2010, 352, 3223. (e)
Campbell, A. N.; Meyer, E. B.; Stahl, S. S. Chem. Commun. 2011, 47,
10257–10259.
€
(7) (a) Liu, J.; Zhu, J.; Jiang, H.; Wang, W.; Li, J. Chem.;Asian J.
2009, 4, 1712. (b) Zhu, J.; Liu, J.; Ma, R.; Xie, H.; Li, J.; Jiang, H.; Wang,
W. Adv. Synth. Catal. 2009, 351, 1229.
(8) Hajra, A.; Wei, Y.; Yoshikai, N. Org. Lett. 2012, 14, 5488.
(9) Girard, S. A.; Hu, X.; Knauber, T.; Zhou, F.; Simon, M. O.;
Deng, G. J.; Li, C.-J. Org. Lett. 2012, 14, 5606.
(10) For related Pd-catalyzed dehydrogenation reactions, see ref 7
and the following: (a) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333,
209. (b) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566. (c)
Diao, T.; Wadzinski, T. J.; Stahl, S. S. Chem. Sci. 2012, 3, 887. (d) Gao,
W.; He, Z.; Qian, Y.; Zhao, J.; Huang, Y. Chem. Sci. 2012, 3, 883.
(3) (a) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170. (b) Ferreira,
E. M.; Zhang, H.; Stoltz, B. M. In The MizorokiꢀHeck Reaction;
Oestreich, M., Ed.; Wiley: Chichester, 2009; pp 345ꢀ382.
(4) For selected examples, see: (a) Ferreira, E. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2003, 125, 9578. (b) Zhang, Y.-H.; Shi, B.-F.; Yu,
J.-Q. J. Am. Chem. Soc. 2009, 131, 5072. (c) Engle, K. M.; Wang, D.-H.;
Yu, J. Q. Angew. Chem., Int. Ed. 2010, 49, 6169. (d) Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137.
r
10.1021/ol400638q
XXXX American Chemical Society

CꢀC bond formation reported herein, that is, an oxidative
cyclization reaction of N-allylimines to pyrroles (Scheme 1c).
The reaction would represent a new example of dehydro-
genative Heck reaction, which is triggered by imine
R-palladation and promoted with molecular oxygen as
the sole oxidant.
because of facile oxidation of allylamine under oxidative
palladium catalysis.
Table 1. Screening of Reaction Conditionsa
Scheme 1. Aerobic Palladium Catalysis Involving Imine
R-Palladation
yieldb (%)
entry
x
additive
temp (°C)
2a
3a
1
10 Bu4NBr (2 equiv)
10 None
60
80
60
80
80
60
rt
31
0
3
10
0
2
˚
3
10 Bu4NBr (2 equiv), MS3 A
62
0
˚
4
10 MS3 A
4
˚
5
10 Bu4NCl (2 equiv), MS3 A
60
76
76c
3
0
˚
6
5
5
5
5
5
5
5
Bu4NBr (2 equiv), MS3 A
0
˚
7
Bu4NBr (2 equiv), MS3 A
0
8d
9e
10f
11g
12h
13
Bu4NBr (2 equiv), MS3 A
rt
0
˚
˚
Bu4NBr (2 equiv), MS3 A
rt
4
0
˚
Bu4NBr (2 equiv), MS3 A
rt
6
0
˚
Bu4NBr (2 equiv), MS3 A
rt
25
2
0
˚
Bu4NBr (2 equiv), MS3 A
rt
0
˚
10 MS3 A
rt
11
0
The feasibility of the dehydrogenative Heck reaction
was initially examined using imine 1a derived from aceto-
phenone and allylamine (Table 1). Our catalytic system for
the indole synthesis, consisting of Pd(OAc)2 (10 mol %),
Bu4NBr (2 equiv), 1 atm O2, and DMSO, promoted the
oxidative cyclization reaction to produce 2-phenyl-4-
methylpyrrole 2a in 31% yield along with a trace amount
of 2-phenylpyridine 3a (entry 1). The products 2a and 3a
would have arisen from a common intermediate, i.e.,
R-palladated imine, through 5-exo- and 6-endo cyclizations,
respectively (vide infra). Bu4NBr turned out to be a critical
additive because in its absence the reaction did not afford
a The reaction was performed on a 0.4 mmol scale. E/Z ratio of 1a
was 12:1. The amount of MS3 A was 100 mg per 0.1 mmol of 1a.
˚
b Determined by GC using n-tridecane as an internal standard or by 1H
NMR using 1,3,5-trimethoxybenzene as an internal standard. c Isolated
yield. d DMF was used instead of DMSO. e 1,4-Dioxane was used instead
of DMSO. f Toluene was used instead of DMSO. g The reaction was
performed under air. h The reaction was performed under N2.
With the optimized catalytic system in hand, we explored
the scope of the present cyclization reaction (Scheme 2).
N-Allylimines derived from a series of aryl methyl ketones
participated in the reaction to afford the corresponding
2-aryl-4-methylpyrroles 2aꢀo in moderate to good yields.11
The reaction tolerated a wide range of substituents in-
cluding electron-donating methoxy and dimethylamino
groups (see 2b and 2c), electron-withdrawing trifluoro-
methyl, nitro, and cyano groups (see 2eꢀg,k), and halo-
gen atoms (I, Br, Cl, F; see 2hꢀj,m,n). The reaction of 1a
could be performed on a gram scale without significant
decrease in the yield of 2a (67%). The ortho-substituted
acetophenone imines reacted sluggishly at room tempera-
ture and thus needed heating at 60 °C to achieve reason-
able conversion (see 2l and 2m). This may be partly due to
much poorer E/Z ratios of these imines (1:3.2 and 1.9:1
for 1l and 1m, respectively) compared to that of the others
(>10:1 for most cases); for the Z-isomer to participate in
the cyclization reaction, isomerization of the CdN bond
is necessary prior to or after R-palladation. Imines de-
rived from heteroaryl methyl ketones cyclized to afford
pyrroles having 3-pyridyl, 2-furyl, and 3-indolyl groups
˚
2a but produced 3a in 10% yield (entry 2). Addition of 3 A
molecular sieves to the reaction using Bu4NBr improved
the yield of 2a while completely shutting down the forma-
tion of 3a (entry 3), while molecular sieves alone had only a
small effect (entry 4). Bu4NCl was similarly effective as
Bu4NBr (entry 5). Upon further optimization, the catalyst
loading and the reaction temperature could be reduced to
5 mol % and room temperature (ca. 25 °C), respectively,
with formation of the product 2a in 76% isolated yield
(entries 6 and 7). The use of DMSO as the solvent was also
critical because little pyrrole formation was observed in
DMF, 1,4-dioxane, and toluene (entries 8ꢀ10). The use of
air instead of molecular oxygen significantly decreased the
yield of 2a (entry 11). Not unexpectedly, only a trace
amount of 2a was obtained under a nitrogen atmosphere
(entry 12). In contrast to the results in entries 2 and 4, at
room temperature, the reaction in the absence of Bu4NBr
afforded 2a in a low yield but none of 3a (entry 13). Other
attempts to increase the yield of 3a were unsuccessful. Note
also that attempts on direct oxidative condensation of
acetophenone and allylamine into 2a failed, presumably
(11) TLC analysis typically showed full consumption of the starting
material and formation of the pyrrole product along with unindentified
polar byproducts (i.e., baseline spots).
B
Org. Lett., Vol. XX, No. XX, XXXX

(2pꢀr) in moderate yields. Pinacolone-derived imine was
also amenable to the present cyclization reaction, afford-
ing 2-(tert-butyl)-4-methylpyrrole 2s in a respectable
yield of 61%, whereas the reaction of cyclohexyl methyl
ketone-derived imine produced the desired pyrrole 2t in
only 6% yield (estimated by GC and GCMS analysis).
The allyl group on the imine substrate may have
R-branching substituent, as imine derived from 1-phenyl-
prop-2-en-1-amine and acetophenone afforded 2,5-
diphenyl-3-methylpyrrole 2u in 67% yield.
in 27% yield. The reaction did not tolerate the presence of
acidic protons. For example, imine 1ab bearing a primary
amide group did not give the pyrrole product at all. Note
also that imine 1ac derived from acetophenone and homo-
allylamine did not afford any (six- or seven-membered)
cyclization products.
Scheme 2. Pyrrole Synthesis from N-Allyliminesa
Figure 1. Substrates that failed to participate in the dehydro-
genative Heck cyclization.
A proposed catalytic cycle for the present oxidative
cyclization reaction is shown in Scheme 3. Tautomeriza-
tion of imine 1 to enamine 10 is followed by electrophilic
palladation to give rise to, on elimination of HOAc, an
R-palladated imine B. This intermediate then undergoes
5-exo-cyclization, the most common mode of cyclizations
in intramolecular Heck reaction,12,13 to give an alkylpalla-
dium species C. Subsequent β-hydride elimination of the
intermediate C affords 3-methylene-3,4-dihydro-2H-
pyrrole 20 and generates Pd(0). Isomerization and aro-
matization of 20 furnishes the pyrrole product 2, while
Pd(0) is reoxidized to Pd(II) with the aid of molecular
oxygen and acetic acid.1a,b As an alternative mechanistic
possibility, a Wacker-type process involving nucleophilic
Scheme 3. Proposed Catalytic Cycle
a Unless otherwise noted, the reaction was performed under the
conditions shown in the equation, and the E/Z ratio of the starting
material was >8:1. b The reaction was performed using 1.2 g of 1a for
36 h. c The reaction time was 36 h. d MS4 A was used instead of MS3 A.
e The reaction was performed at 60 °C for 30 h. f E/Z ratio of the imine
was 1:3.2. g E/Z ratio of the imine was 1.9:1. h E/Z ratio of the imine was
4.5:1. I The reaction was performed with 10 mol % of Pd(OAc)2 for 36 h.
j Estimated by GC and GCMS analysis. k The reaction was performed at
60 °C for 24 h.
˚
˚
Limitations of the present oxidative cyclization reaction
became clear through further exploration of imine sub-
strates (Figure 1). Imines derived from 1,1,1-trifluoro-
acetone (1v) and cyclopropyl methyl ketone (1w) did not
produce the expectedpyrrole products. N-Cinnamylimines
1x and 1y and R-phenylacetophenone-derived imine 1z also
failed to undergo the cyclization reaction. In these cases,
decomposition of the starting materials to unknown prod-
ucts was observed. Not unexpectedly, tetralone-derived
imine 1aa underwent dehydrogenation rather than oxi-
dative cyclization,8 affording N-allylnaphthalen-1-amine
Org. Lett., Vol. XX, No. XX, XXXX
C

addtion of enamine to the olefin moiety activated by
Pd(II) may not be excluded. We speculate that the role
of Bu4NBr is to stabilize Pd nanoclusters and molecular
Pd species through coordination of the bromide anion to
Pd and electrostatic interaction between the thus-formed
anionic species and the ammonium cation, as has been
proposed for Heck reaction under related conditions.14
In summary, we have demonstrated that R-pallada-
tion of imine serves as an entry to dehydrogenative
Heck cyclization, allowing facile conversion of aceto-
phenone N-allylimines and related imines to pyrroles
under mild aerobic conditions. While significant prog-
ress has been made in synthetic methods for pyr-
roles based on various transition metal-catalyzed CꢀH
functionalization and condensation approaches,15ꢀ18
the present dehydrogenative Heck reaction may serve
as a complementary method in light of the accessible
substitution patterns of such reactions. Further studies
to address the limitations of the present reaction as well
as to explore other types of transformations involving
R-metalloimine and related species19 are currently
underway.
(12) (a) Machotta, A. B.; Oestreich, M. In The MizorokiꢀHeck
Reaction; Oestreich, M., Ed.; Wiley: Chichester, 2009; pp 179ꢀ213. (b)
€
Muller, T.; Brase, S. In The MizorokiꢀHeck Reaction; Oestreich, M., Ed.;
Wiley: Chichester, 2009; pp 215ꢀ258.
(13) For related intramolecular Heck reactions onto N-allyl group
leading to pyrroles and indoles, see: (a) Yamagishi, M.; Nishigai, K.;
Hata, T.; Urabe, H. Org. Lett. 2011, 13, 4873. (b) Jensen, T.; Pedersen,
H.; Bang-Andersen, B.; Madsen, R.; Jørgensen, M. Angew. Chem., Int.
Ed. 2008, 47, 888.
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(15) (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Chem. Rev. 2013, 10.1021/cr300333u. (b) Chiba, S. Synlett 2012, 21.
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Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellman, R. A. Angew. Chem.,
Int. Ed. 2013, 52, 629. (b) Wang, L.; Ackermann, L. Org. Lett. 2013, 15,
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Yoshikai, N.; Wei, Y. Asian J. Org. Chem. 2013, 10.1002/ajoc.201300016.
(17) For dehydrogenative condensation of alcohol and amine start-
ing materials, see: (a) Michlik, S.; Kempe, R. Nat. Chem. 2013, 5, 140. (b)
Zhang, M.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2013, 52,
597. (c) Srimani, D.; Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed.
2013, 52, 4012. (d) Iida, K.; Miura, T.; Ando, J.; Saito, S. Org. Lett. 2013,
15, 1436.
Acknowledgment. This work was supported by the Na-
tional Research Foundation Singapore (NRF-RF2009-05
to N.Y.) and Nanyang Technological University. We
€
thank Prof. Frank Glorius (University of Munster) for
sharing with us the work of his group in this area prior to
publication.
Supporting Information Available. Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) For selected other examples, see: (a) Humenny, W. J.; Kyriacou,
P.; Sapeta, K.; Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed.
2012, 51, 11088. (b) Trost, B. M.; Lumb, J.-P.; Azzarelli, J. M. J. Am.
Chem. Soc. 2011, 133, 740. (c) Wang, H.-Y.; Mueller, D. S.; Sachwani,
R. M.; Londino, H. N.; Anderson, L. L. Org. Lett. 2010, 12, 2290.
(19) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX