Synthesis of polycyclic nitrogen heterocycles via alkene aminopalladation/carbopalladation cascade reaction

Article abstract of DOI:10.1021/ol100033s

Chemical equation presented A new method for the synthesis of tricyclic nitrogen heterocycles from N/,2-diallylaniline derivatives Is described. These transformations proceed via sequential alkene amlnopalladation of an Intermediate L_nPd(Ar)(NRR') species followed by alkene carbopalladatlon of the resulting L_nPd(Ar)(R) complex. Both alkene insertion steps occur in preference to C-N or C-C bond-forming reductive elimination. An unusual 1,3palladium shift occurs when 2-Allyl-N-(2-vinylphenyl) aniline Is employed as substrate, which yields a tetracyclic molecule with three contiguous stereocenters.

Full text of DOI:10.1021/ol100033s

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1028-1031
Synthesis of Polycyclic Nitrogen
Heterocycles via Alkene
Aminopalladation/Carbopalladation
Cascade Reactions
Danielle M. Schultz and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan, 48109-1055
jpwolfe@umich.edu
Received January 6, 2010
ABSTRACT
A new method for the synthesis of tricyclic nitrogen heterocycles from N,2-diallylaniline derivatives is described. These transformations
proceed via sequential alkene aminopalladation of an intermediate LnPd(Ar)(NRR′) species followed by alkene carbopalladation of the resulting
LnPd(Ar)(R) complex. Both alkene insertion steps occur in preference to C-N or C-C bond-forming reductive elimination. An unusual 1,3-
palladium shift occurs when 2-Allyl-N-(2-vinylphenyl)aniline is employed as substrate, which yields a tetracyclic molecule with three contiguous
stereocenters.
Over the past several years, our group has developed a
method for the construction of nitrogen heterocycles via Pd-
Scheme 1. Cascade Aminopalladation/Carbopalladation
catalyzed carboamination reactions between aryl bromides
and amines bearing pendant alkenes.1 For example, treatment
of an N-substituted 2-allylaniline derivative (e.g., 1) with
an aryl bromide in the presence of NaOtBu and a palladium
catalyst leads to the formation of a 2-benzylindoline product
(4).2 These reactions proceed via intramolecular alkene
aminopalladation of palladium(aryl)(amido) complex 2 to
yield 3a, which undergoes reductive elimination to give 4
(Scheme 1).
It seemed plausible that this method could be extended to
cascade cyclization processes that yield tricyclic products if
an intermediate related to 3a could be intercepted with a
(1) Reviews: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe,
J. P. Synlett 2008, 2913.
pendant alkene. For example, if N,2-diallylaniline were
employed as a substrate, alkene aminopalladation of 2 (R
(2) (a) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906. (b)
Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447.
10.1021/ol100033s  2010 American Chemical Society
Published on Web 02/08/2010

) allyl) would yield 3b, which could undergo intramo-
lecular carbopalladation to give 5. Reductive elimination
would then yield 6. Overall, this transformation would
generate three bonds, two rings, and two stereocenters in
a single step from a simple starting material. Importantly,
this method would provide a new means to access benzo-
fused 1-azabicyclo[3.3.0]octanes (6) and related 1-azabi-
cyclo[4.3.0]nonanes. These scaffolds are a prominent
feature of several natural products3 and have also served
as key intermediates in the synthesis of analogous fully
saturated ring systems.4
Although the cascade aminopalladation/carbopalladation
sequence could have considerable utility, to achieve our
desired transformation, we would need to overcome a
significant obstacle that is not present in the cascade Heck
reactions. The key intermediates in the Heck cascades (8
and 9) contain only a single C-Pd bond. Thus, premature
termination of the cascade via competing reductive elimina-
tion from 8 or 9 cannot occur, as C-X bond forming
reductive elimination from Pd(II) is thermodynamically
unfavorable.9 In contrast, intermediate 3b contains two
Pd-C bonds and can potentially undergo competing
irreversible C-C bond-forming reductive elimination to
afford undesired monocyclized product 4. In addition, the
catalyst employed for the cascade cyclization must not
only favor alkene insertion over reductive elimination from
3b but also must allow the requisite reductive elimination
from 5 to proceed.
The approach outlined in Scheme 1 sharply contrasts with
related palladium-catalyzed cascade Heck reactions between
polyalkene substrates bearing pendant alkenyl (or aryl)
halides (Scheme 2).5-7 The Heck cascades occur through
In our initial experiments, we sought to find a catalyst that
would facilitate the desired cascade reaction. To this end,
we examined the coupling of 1 (R ) allyl) with bromoben-
zene using catalysts generated in situ from mixtures of
palladium acetate and phosphine ligands (Table 1). As
Scheme 2. Comparison to Cascade Alkene Carbopalladation
Table 1. Optimization Studiesa
sequential intramolecular alkene carbopalladation reactions
of R-Pd-X intermediates such as 8 or 9 (X ) halide or
pseudohalide) and are usually terminated by ꢀ-hydride
elimination from the final R-Pd-X species (10) to generate
an alkene (11). Thus, elements of molecular complexity
present in 10 are removed in the terminal step, as the
ꢀ-elimination leads to loss of a stereocenter and an organo-
metallic functional group. In comparison, the final step of
the aminopalladation/carbopalladation cascade shown in
Scheme 1 (reductive elimination from 5 to yield 6) would
produce a C-Ar bond, and the stereocenters generated in
each alkene insertion step would be retained in the
product.8
(3) (a) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.;
Zhang, X.-M.; Ma, Y.-B. Org. Lett. 2007, 9, 4127. (b) Kariba, R. M.;
Houghton, P. J.; Yenesew, A. J. Nat. Prod. 2002, 65, 566.
(4) (a) Ito, Y.; Nakajo, E.; Natatsuka, M.; Saegusa, T. Tetrahedron Lett.
1983, 24, 2881. (b) Pearson, W. H.; Fang, W.-K. J. Org. Chem. 2000, 65,
7158.
a Conditions: Reactions were conducted on a 0.11 mmol scale using
1.0 equiv 1, 1.5 equiv PhBr, 1.5 equiv NaOtBu, xylenes (0.2 M), 125 °C,
14 h. b Yields were determined by 1H NMR analysis of crude reaction
mixtures that contained phenanthrene as an internal standard. The mass
balance of these reaction mixtures was composed of products resulting from
ꢀ-hydride elimination of intermediate 2, 3b, or 5. c Isolated yield.
(5) (a) Negishi, E.-i.; Wang, G.; Zhu, G. Top. Organomet. Chem. 2006,
19, 1. (b) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay, B. A.
J. Am. Chem. Soc. 1996, 118, 10766. (c) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379. (d) Zeni, G.; Larock, R. C. Chem.
ReV. 2006, 106, 4644
.
(6) For cascade reactions of enynes that proceed through similar
intermediates, see: (a) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115,
9421. (b) Meyer, F. E.; Parsons, P. J.; de Meijere, A. J. Org. Chem. 1991,
56, 6487
.
(7) For Pd(II)-catalyzed oxidative cascade reactions that generate
heterocycles through aminopalladation of LnPdX2 alkene complexes fol-
lowed by alkene carbopalladation, see: Yip, K.-T.; Zhu, N.-Y.; Yang, D.
anticipated, these reactions afforded two major products: 12
and 13.10 After some exploration, we discovered that bulky
triaryl phosphines 14 and 15 provided 12 in acceptable
chemical yields and diastereoselectivities.
Org. Lett. 2009, 11, 1911, and references cited therein
.
(8) To the best of our knowledge, only two reports of intermolecular
cascade Heck reactions between aryl or alkenyl halides and 1,n-dienes have
appeared in the literature. In these cases, the transformations were terminated
by aryl C-H activation followed by C-C bond formation; all alkene
insertion steps proceed through R-Pd-X intermediates. See: (a) Hu, Y.;
Ouyang, Y.; Qu, Y.; Hu, Q.; Yao, H. Chem. Commun. 2009, 4575. (b) Hu,
Y.; Song, F.; Wu, F.; Cheng, D.; Wang, S. Chem.sEur. J. 2008, 14, 3110.
(9) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232.
(10) The formation of N-(prop-1-enyl)-2-methylindoline was observed
in some instances. The origin of this side product is not entirely clear, but
it may result from reduction or protonolysis of intermediate 3b.
Org. Lett., Vol. 12, No. 5, 2010
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Having discovered a viable catalyst system for the cascade
cyclization reaction of 1, we proceeded to examine analogous
transformations of related substrates. As illustrated in Table
2, a number of N,2-diallylaniline derivatives (1, 16-17) were
Table 2. Cascade Reactionsa
To probe the origin of this unexpected regioisomer, we
conducted three experiments with deuterium-labeled sub-
strates 33a-c. As shown in eq 2, substrates 33a and 33b
were converted to 34a and 34b, with no migration of the
label observed in either case. In contrast, substrate 33c,
bearing deuterium atoms on the terminal carbon of the allyl
group, were transformed to 34c with migration of a deuterium
atom to the C5-methyl group.
On the basis of this data, we suggest that formation of
34c may proceed as illustrated in Scheme 3. An initial
Scheme 3. Proposed Mechanism for Formation of 34c
a Conditions: Reactions were conducted on a 0.3-0.5 mmol scale using
1.0 equiv substrate, 1.5 equiv ArBr, 1.5 equiv NaOtBu, xylenes (0.4 M),
125 °C, 14 h. b Ratio of bicyclic product:monocyclic product observed in
crude reaction mixtures. c Diastereomeric ratios are for isolated material.
Numbers in parentheses represent diastereomeric ratios observed in crude
reaction mixtures. In some instances the minor diastereomer was partially
or entirely removed during isolation. d Isolated yield (average of two or
more experiments).
converted to benzo-fused-1-azabicyclo[3.3.0]octanes 20-25
in moderate yields with moderate to good diastereoselec-
tivities. Substitution at the benzylic position was tolerated,
as illustrated by the conversion of 18 to 26 and 27. The
conversion of N-allyl-2-(but-3-enyl)aniline (19) to benzo-
fused-1-azabicyclo[4.3.0]nonanes 28-29 was also achieved
with moderate to good yields and selectivities. However,
efforts to transform substrates bearing disubstituted alkenes
have been unsuccessful. In addition, the coupling of 2-bro-
motoluene with 1 afforded monocyclic N-allyl-2-(2-meth-
ylbenzyl)indoline (4, Ar ) 2-methylphenyl) as the major
product, which was isolated in 72% yield. Only a small
amount of the desired bicyclic compound was generated in
this reaction.
aminopalladation followed by carbopalladation could effect
the conversion of 33c to key intermediate 35 as outlined
above (Scheme 1). A surprising and unprecedented 1,3-
palladium/hydride shift would then yield 36, which could
undergo reductive elimination to afford 34c. Although
through-space palladium migrations have previously been
observed,11 only a single report has described Pd-migration
from one sp3-hybridized carbon to another.12 The conversion
of 35 to 36 is particularly surprising given the fact that 35
also contains hydrogen atoms that could potentially undergo
ꢀ-elimination.
(11) (a) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C.
J. Am. Chem. Soc. 2004, 126, 7460. (b) Kesharwani, T.; Verma, A. K.;
Emrich, D.; Ward, J. A.; Larock, R. C. Org. Lett. 2009, 11, 2591, and
references cited therein. (c) Ma, S.; Gu, Z. Angew. Chem., Int. Ed. 2005,
44, 7512.
Although most substrates examined afforded the antici-
pated products, reactions of 30 with aryl bromides provided
surprising results (eq 1). The expected products 32a-c were
not obtained, but instead 31a-c were generated in moderate
yield with excellent diastereoselectivity.
(12) For rare examples of 1,5-Pd migration of alkylpalladium intermedi-
ates, which occur under oxidative conditions, see: Heumann, A.; Ba¨ckvall,
J. E. Angew. Chem., Int. Ed. Engl. 1985, 24, 207.
1030
Org. Lett., Vol. 12, No. 5, 2010

In conclusion, we have developed a new cascade reaction
for the synthesis of polycyclic nitrogen heterocycles that
proceeds by way of sequential aminopalladation and carbo-
palladation. These transformations illustrate that catalyst
tuning can allow alkene insertion processes to occur in
preference to C-N or C-C bond-forming reductive elimina-
tion in LnPd(Ar)(NR2) or LnPd(Ar)(R) complexes. In addi-
tion, we have observed the first occurrence of 1,3-palladium
migration of an alkylpalladium intermediate. Studies on the
scope of this method and the application of these concepts
to the development of new catalytic reactions are underway.
funding was provided by GlaxoSmithKline, 3M, Amgen, and
Eli Lilly. We thank prior Wolfe group member Dr. Josephine
S. Nakhla (currently at Sigma-Aldrich) for conducting initial
experiments in this area.
Supporting Information Available: Experimental pro-
cedures, characterization data for all new compounds,
descriptions of stereochemical assignments with supporting
1
crystallographic structural data, and copies of H and 13C
NMR spectra for all new compounds reported in the text.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We acknowledge the NIH-NIGMS for
financial support of this work (GM-071650). Additional
OL100033S
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