Aerobic synthesis of pyrroles and dihydropyrroles from imines: Palladium(II)-catalyzed intramolecular C-H dehydrogenative cyclization

Article abstract of DOI:10.1002/anie.201300477

sp³ectacularly mild! An efficient Pd^II-catalyzed intramolecular dehydrogenative cyclization of imines affords (dihydro)pyrrole products using molecular oxygen as the sole oxidant. This mild formal sp ³-C-H functionalization allows rapid and atom-economical assembly of (dihydro)pyrrole rings from inexpensive and readily available allylamines and ketones. A broad range of functional groups are tolerated. Copyright

Full text of DOI:10.1002/anie.201300477

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DOI: 10.1002/anie.201300477
Synthetic Methods
Aerobic Synthesis of Pyrroles and Dihydropyrroles from Imines:
À
Palladium(II)-Catalyzed Intramolecular C H Dehydrogenative
Cyclization**
Zhuangzhi Shi, Mamta Suri, and Frank Glorius*
Imines and enamines are useful building blocks in organic
synthesis, and especially in the synthesis of nitrogen hetero-
cycles, such as in the Bischler indole, Hantzsch, or Paal–Knorr
using (3,5-(CF3)2C6H3)3P as ligand (Scheme 1c).[9] In view of
the importance of pyrroles and related scaffolds, we were
prompted to consider an effective and direct route to
construct pyrroles from imine substrates. We hypothesized
that N-allylimines prepared by condensation of the corre-
sponding allylamines and ketones may undergo intramolec-
pyrrole synthesis.[1] During the past years, C H functionali-
À
zation has emerged as an attractive and powerful strategy for
À
the generation of C C and carbon–heteratom bonds in a step-
and atom-economical fashion.[2] Among these, a number of
ular C H dehydrogenative cyclization
(dihydro)pyrroles in an atom-economical approach
(Scheme 1d).
to form the
[10,11]
À
À
novel C H functionalization strategies for the synthesis of
azaheterocycles using imines and enamines as starting
materials have been reported.[3] In 2008, a PdII-catalyzed
oxidative cyclization of N-aryl enamines was developed
(Scheme 1a).[4] The mechanism starts with the attack of the
enamine onto the Pd2+ catalyst (electrophilic substitution)
The initial reaction of (E)-N-(1-phenylethylidene)prop-2-
en-1-amine 3a was carried out in the presence of 10 mol%
Pd(OAc)2 as the catalyst at 808C under an O2 atmosphere in
DMSO. Interestingly, the desired pyrrole product 4a was
observed in 15% yield and was accompanied by an unex-
pected pyridine product 4a’ in 33% yield (Table 1, entry 1).[12]
À
and proceeds with an intramolecular C H activation of the
aniline ring, affording the corresponding indoles. Recently,
the group of Yoshikai made a significant breakthrough for
indole synthesis by PdII-catalyzed oxidative cyclization of
common N-aryl imines under mild conditions (Scheme 1b).[5]
In contrast to previous reports, this process works with imine
substrates and thus possesses a broader scope.
The pyrrole-based scaffold is one of the most abundant
and relevant units in natural products and pharmaceuticals.[6]
The Pd-catalyzed cyclization of oxime esters (usually O-
perfluorobenzoyl oximes) with olefins was first reported by
Narasaka et al. and provides an efficient approach to
(dihydro)pyrroles by Heck-type reactions.[7] The “Narasaka–
Heck” method has been applied to natural product synthesis,
such as in the synthesis of butylcycloheptylprodigiosin by
Fꢀrstner et al.[8] Very recently, Faulkner and Bower reported
a highly efficient Pd-catalyzed “Narasaka–Heck” cyclization
[*] Dr. Z. Shi,[+] M. Suri,[+] Prof. Dr. F. Glorius
NRW Graduate School of Chemistry, Organisch-Chemisches
Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
index.html
[+] These authors contributed equally to this work.
[**] We thank Karl Collins for helpful discussions. This work was
supported by the Alexander von Humboldt Foundation (Z.S.) and
the International NRW Graduate School of Chemistry (M.S.).
Generous financial support by the European Research Council
under the European Community’s Seventh Framework Program
(FP7 2007-2013)/ERC Grant agreement no. 25936 is gratefully
acknowledged.
Scheme 1. a,b) Palladium(II)-catalyzed synthesis of indoles from enam-
ines and imines; c) palladium(0)-catalyzed “Narasaka–Heck” reac-
tions; d) Palladium(II)-catalyzed synthesis of (dihydro)pyrroles from
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300477.
À
imines by C H dehydrogenative cyclization.
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Table 1: Reaction development.[a]
With a set of optimized conditions in hand, we examined
the scope of this dehydrogenative cyclization process
(Table 2). The effect of substituents on the arene undergoing
the cyclization reaction was first examined. This aromatic ring
was found to be tolerant of both electron-rich groups, such as
methyl (4b, 4j and 4l) and methoxy (4c), and electron-
deficient groups, such as trifluoromethyl (4d and 4k), cyano
(4h), and nitro (4i). Notably, the halogen-containing motifs,
such as F (4e), Cl (4 f), and even I (4g) work well in this
transformation. The naphthaldehyde substrate 3m can be
Entry Pd source (equiv) Additive (equiv)
T [8C] Yield [%][b]
4a
4a’
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.1)
Pd(OTFA)2 (0.1)
Pd(acac)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
–
–
–
–
80
80
80
60
30
30
30
30
30
15
6
8
33
27
18
8
26
46
51
56
66
82
85 (83)
82
60
21
0
–
8
Table 2: Palladium(II)-catalyzed cyclization of imines to pyrroles.[a]
1,10-Phen (0.1)
Diazafluoreno (0.1)
TBAB (2.0)
10
15
0
0
0
0
0
0
0
9
TBAB (2.0)+4 ꢂ MS
10
11
12
TBAB (2.0)+4 ꢀ M.S. 30
TEAB (2.0)+4 ꢂ M.S. 30
TMAB (2.0)+4 ꢂ M.S. 30
TBAB (2.0)+4 ꢂ M.S. 30
TBAB (2.0)+4 ꢂ M.S. 30
13[c] Pd(OAc)2 (0.05)
14
–
[a] Conditions: 3a (0.2 mmol), 10.0 mol% Pd(OAc)2, dry solvent
(1.0 mL), 24 h, under O2 (1 atm). TBAB=nBu4NBr, TEAB=Et4NBr,
TMAB=Me4NBr. [b] Determined by GC using an internal standard; value
in parentheses indicate yield of isolated product. [c] Using DCE (1,2-
dichloroethane) as solvent.
The efficiency of several palladium sources was tested, and
Pd(OAc)2 was found to be the best for this cyclization
(entries 2 and 3). Lowering the reaction temperature
improved the conversion into the pyrrole product (entries 4
and 5), with 308C being optimum. We explored different N-
based ligands in this aerobic palladium-catalyzed system, and
observed that diazafluoreno was the most efficient ligand,
affording 4a in 56% (entries 6 and 7). When using 2.0 equiv
of TBAB instead of the ligand, 4a was increased to 66%, and
the pyridine by-product was completely inhibited (entry 8).[13]
The yield of 4a was further improved by the addition of 4 ꢁ
M.S. molecular sieves (entry 9). Under these conditions, when
Pd(OAc)2 was decreased to 5 mol%, a slightly higher yield of
83% was observed (entry 10). Note that freshly activated,
powdered 4 ꢁ M.S. and TBAB stored in a glovebox were
found to be key for obtaining optimal results. Besides TBAB,
TEAB also showed a similar effect, though TMAB gave the
reduced yield (entries 11 and 12). The choice of DMSO as
solvent is crucial for the success of the present catalytic
reaction,[14] and of other solvents, only DCE gave some
product (entry 13). Control reactions confirmed that the
transformation does not occur in the absence of the Pd(OAc)2
(entry 14). Furthermore, to simplify the operations, this
pyrrole synthesis could be easily started directly from
acetophenone (1a) and allylamine (2a) and scaled up to
gram quantity without difficulty [Eq. (1)].
[a] Reaction conditions: 3 (0.2–1.0 mmol), Pd(OAc)2 (5.0 mol%), TBAB
(2.0 equiv), 4 ꢂ M.S. (0.2–1.0 g), in DMSO (1.0–5.0 mL) at 308C for 24 h
under O2 (1 atm). [b] Yield of isolated product. [c] At 608C.
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Table 3: Palladium(II)-catalyzed cyclization of imines to dihydropyrro-
ture, the present method can be applicable to the enamines
such as ethyl 3-allylamino-3-phenylacrylate (3u), resulting in
the formation of ethyl 4-methyl-2-phenyl-1H-pyrrole-3-car-
boxylate (4w) in 46% yield.
les.[a]
Further exploration into substrate scope revealed that
imines derived from acetophenone (1a) and cyclic allyl-
amines were selectively proceeding as a 5-exo cyclization to
form dihydropyrroles (Table 3). Cyclization of 5a and 5b,
which involves a five- and six-membered-ring allylamine,
generated the dihydropyrroles 6a and 6b in good yield with
a small amount of olefin isomerization byproduct by chain
walk.[15] Seven-membered-ring substrate 5c generated a mix-
ture of cyclization products with poor selectivity. Interest-
ingly, eight-membered-ring substrate 5d selectively afforded
6d’’ as the major product. It is important to note that, besides
cyclic allylamines, imine substrates bearing g-substituents
(containing H) on the allyl group such as imine 5e can also
deliver dihydropyrrole products in good yield (such as 6e;
entry 5). The rigid N-heterobicyclic products arising from this
transformation can easily be accessed in good yield, suggest-
ing that this method might open up a convenient entry to the
core of some scaffolds such as prodigiosin[16] and the
aeruginosin skeleton.[17]
On the basis of these results, a mechanistic proposal is
outlined in Scheme 2. The transformation begins with an
electrophilic palladation of the nucleophilic enamine 3’, which
is generated in situ by tautomerization of imine 3. The
resulting palladium complex A is followed by olefin activa-
tion, olefin insertion to form C. At this stage, when R is the H
atom, subsequent b-H elimination gives the intermediate D.
On the other hand, in case with the alkyl groups (containing
b-H) on R, b-H elimination from R is a preferable way to
form the dihydropyrrole product 6. Subsequent isomerization
[a] Reaction conditions: 5 (0.2 mmol), Pd(OAc)2 (5.0 mol%), TBAB
(2.0 equiv), 4 ꢂ M.S. (0.2 g), in DMSO (1.0 mL) at 308C for 24 h under
O2 (1 atm). [b] The reaction mixture analyzed by 1H NMR to determine
the ratio of regioisomers; yield of isolated product. [c] These isomers are
difficult to distinguish by NMR spectroscopy.
converted into the desired product
in 76% yield. Heteroaryl groups,
such as 2-furyl and 4-pyridyl groups,
could also be tolerated to give the
biheteroaryl products in moderate
yield (4n and 4o). 2-tert-Butyl-pyr-
role (4p) was also obtained in good
yields from the alkyl substituted
imine. Next, the effect of the sub-
stituents on the allyl moiety in the
synthesis of the corresponding
imines using acetophenone (1a) as
partner was examined. The reaction
of imines 3q and 3r under the
standard
reaction
conditions
afforded the tri-substituted pyrroles
4q and 4r in good yield. However,
the imines 3s and 3t failed to afford
the corresponding products 3s and
4t. Enamines proved to be less
reactive than imines in this trans-
formation; under higher tempera- Scheme 2. Plausible reaction mechanism.
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possible way for this step involving olefin insertion into the
À
Pd H bond affording E followed by b-H elimination gives the
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À
relies on C H functionalization and uses molecular oxygen
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products.
Received: January 18, 2013
Revised: March 4, 2013
Published online: April 8, 2013
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[18] For selected reviews on PdII-catalyzed reactions using molecular
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[19] R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981.
[20] For a detailed mechanistic discussion, see the Supporting
Information.
[12] Two pathways can be considered for the formation of 4a’,
involving PdII-catalyzed 6-endo cyclization of 3a’ or dehydro-
genation of 3a’ to form an azatriene, which then undergoes 6p
cyclization.
[13] TBAB may play a role in stabilizing Pd0 complexes from forming
Pd0 aggregates or it might promote the reoxidation to PdII; see:
a) V. Calꢆ, A. Nacci, A. Monopoli, L. Lopez, A. di Cosmo,
4896 www.angewandte.org
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