Cascade intramolecular N-arylation/intermolecular carboamination reactions for the construction of tricyclic heterocycles

Article abstract of DOI:10.1021/ol201123b

A new method for the stereoselective synthesis of tetrahydropyrroloindoles and hexahydropyrroloquinolines of general structure 8 is described. These products are formed through cascade Pd-catalyzed coupling reactions between aryl chlorides and unsaturated

Full text of DOI:10.1021/ol201123b

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3218–3221
Cascade Intramolecular N-Arylation/
Intermolecular Carboamination Reactions
for the Construction of Tricyclic
Heterocycles
Georgia S. Lemen and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan, 48109-1055, United States
jpwolfe@umich.edu
Received April 27, 2011
ABSTRACT
A new method for the stereoselective synthesis of tetrahydropyrroloindoles and hexahydropyrroloquinolines of general structure 8 is described.
These products are formed through cascade Pd-catalyzed coupling reactions between aryl chlorides and unsaturated amine substrates 5. A single
catalyst effects an intramolecular N-arylation reaction followed by an intermolecular alkene carboamination reaction to generate two rings, three
bonds, and one stereocenter with good chemoselectivity, diastereoselectivity, and chemical yield.
Cascade reaction sequences that involve two fundamen-
tally different metal-catalyzed transformations are power-
ful tools for organic synthesis.1,2 These processes typically
proceed via two or more different types of bond-forming
events and lead to a rapid buildup of molecular complex-
ity. Thus, the development of new sequential reaction
cascades that provide stereocontrolled access to useful
structural motifs remains of considerable merit.
We have previously described a cascade Pd-catalyzed
intermolecular N-arylation/intermolecular carboamina-
tion reaction between γ-aminoalkenes and aryl bromides
that affords 2-(arylmethyl)indolines or -pyrrolidines.3,4
For example, treatment of 1 with 2 equiv of bromobenzene
in the presence of NaOtBu and a catalyst composed of
Pd2(dba)3 and Dpe-Phos (4) afforded N-phenyl-2-benzy-
lindoline 2 in 92% yield (eq 1). Although this method
provides an efficient approach to saturated nitrogen het-
erocycles, it suffers from two significant limitations. First
of all, a rather cumbersome experimental protocol is
necessary to achieve the chemoselective sequential cou-
pling of two different aryl bromides to generate products
such as 3 (eq 2).3 The N-arylation reaction is conducted at
80 °C until the first aryl bromide is consumed. The reaction
mixture is then cooled to rt, a second ligand is introduced
to effect in situ ligand exchange, the second aryl bromide is
then added, and heating is continued until the reaction
proceeds to completion.5 In addition to the complexity of
the experimental procedure, this sequence of two inter-
molecular reactions is not amenable to the construction of
€
(1) For reviews, see: (a) D’Souza, D. M.; Muller, T. J. J. Chem. Soc.
Rev. 2007, 36, 1095. (b) Bruneau, C.; Derien, S.; Dixneuf, P. H. Top.
Organomet. Chem. 2006, 19, 295.
(2) For selected recent examples, see: (a) Ohmura, T.; Kijima, A.;
Suginome, M. Org. Lett. 2011, 13, 1238. (b) Gollner, A.; Koutentis, P. A.
Org. Lett. 2010, 12, 1352. (c) Wang, X.; Liu, L.; Chang, W.; Li, J. Eur. J.
Org. Chem. 2010, 5391. (d) Pinto, A.; Neuville, L.; Zhu, J. Tetrahedron
Lett. 2009, 50, 3602. (e) Thansandote, P.; Raemy, M.; Rudolph, A.;
Lautens, M. Org. Lett. 2007, 9, 5255.
(3) (a) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906. (b)
Yang, Q.; Ney, J. E.; Wolfe, J. P. Org. Lett. 2005, 7, 2575.
(4) For reviews on Pd-catalyzed carboamination reactions between
aryl/alkenyl halides and amines bearing pendant alkenes, see: (a) Wolfe,
J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe, J. P. Synlett 2008, 2913.
(5) This limitation is due to the fact that: (a) aryl bromides with
similar steric and electronic properties (e.g., bromobenzene and
2-bromonaphthalene) undergo oxidative addition to Pd(0) with com-
parable rates; and (b) the rate of the carboamination step exceeds that of
the N-arylation step with most catalyst systems. The sequential addition
of the aryl halides avoids the first problem, and the in situ ligand
exchange addresses the second. The ligand (o-biphenyl)P(tBu)2 pro-
motes rapid N-arylation and disfavors carboamination. When Dpe-
Phos is added, a new catalyst is generated that facilitates the carboami-
nation step. For further discussion, see ref 3a.
r
10.1021/ol201123b
Published on Web 05/23/2011
2011 American Chemical Society

tricyclic heterocycles, which are an important class of
compounds.
Scheme 2. Synthesis of Enantiomerically Enriched Substrates
We reasoned that both of these limitations could be
addressed through development of a related cascade reac-
tion between aryl chlorides and γ-aminoalkenes 5 that
contain pendant o-bromophenyl groups. As shown
in Scheme 1, the chemoselective intramolecular N-aryla-
tionofa substratesuchas5 wouldyield 6, which couldthen
undergo a stereoselective intermolecular carboamination
reaction with an exogenous aryl chloride via chairlike
transition state 7 to afford 8.6 Given the differences in
reactivity between aryl bromides and aryl chlorides toward
Pd(0) complexes,7 it seemed that chemoselectivity in the
cascade could be achieved in a straightforward manner.
Intramolecular amination of an aryl bromide should be
considerably faster than intermolecular carboamination
with an aryl chloride electrophile.8 As such, it appeared
that the desired sequential intramolecular N-arylation/
intermolecular alkene carboamination reactions could
potentially be effected using a single catalyst system, with
both electrophiles present in the reaction mixture from the
outset. In addition, the scaffolds generated via this strategy
are displayed in a number of interesting biologically active
compounds,9 and similar fused tricyclic heterocycles have
also been used as intermediates en route to bioactive
molecules.10,11
Table 1. Optimization of Reaction Conditionsa
a Conditions: 1.0 equiv of 5b, 1.2 equiv of PhCl, 2.4 equiv of
NaOtBu, 1 mol % Pd2(dba)3, 4 mol % ligand, toluene (0.25 M), 100
°C, 5À24 h. b Product ratios were determined by 1H NMR analysis
of crude reaction mixtures. c The reaction was conducted using 2 mol %
ligand. d The product was isolated with 25:1 dr, although analysis of
the crude reaction mixture indicated the product had been formed with
8:1 dr.
Scheme 1. Cascade Intramolecular N-Arylation/Intermolecular
Carboamination Strategy for Tricyclic Heterocycle
Synthesis
2134. (c) Hayashi, S.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int.
Ed. 2009, 48, 7224.
ꢀ
(9) (a) Hajıcek, J.; Taimr, J.; Budesınsky, M. Tetrahedron Lett. 1998,
´
´
39, 505. (b) 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.
(10) (a) Jones, K.; Storey, J. M. D. J. Chem. Soc., Perkin Trans. 1
2000, 769 and references cited therein. (b) Ito, Y.; Nakajo, E.; Nakatsu-
ka, M.; Saegusa, T. Tetrahedron Lett. 1983, 24, 2881.
(11) For other recent complementary approaches to the synthesis of
hexahydropyrroloquinolines and tetrahydropyrroloindoles structurally
related to 8aÀl, see: (a) Kip, K.-T.; Yang, D. Org. Lett. 2011, 13, 2134.
(b) Krogsgaard-Larsen, N.; Begtrup, M.; Herth, M. M.; Kehler, J.
Synthesis 2010, 4287. (c) Beemelmanns, C.; Blot, V.; Gross, S.; Lentz,
D.; Reissig, H. ÀU. Eur. J. Org. Chem. 2010, 2716. (d) Kang, Y. K.; Kim,
S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847. (e) Li, X.; Li, C.;
Zhang, W.; Lu, X.; Han, S.; Hong, R. Org. Lett. 2010, 12, 1696. (f)
Scarborough, C. C.; Bergant, A.; Sazama, G. T.; Guzei, I. A.; Spencer,
L. C.; Stahl, S. S. Tetrahedron 2009, 65, 5084. (g) Sherman, E. S.;
Chemler, S. R. Adv. Synth. Catal. 2009, 351, 467.
(6) For further discussion of transition states leading to fused bicyclic
compounds in Pd-catalyzed alkene carboamination reactions, see:
Lemen, G. S.; Wolfe, J. P. Org. Lett. 2010, 12, 2322.
(7) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
(8) For Pd-catalyzed carboamination reactions involving aryl chlor-
ide electrophiles, see: (a) Rosen, B. R.; Ney, J. E.; Wolfe, J. P. J. Org.
Chem. 2010, 75, 2756. (b) Bagnoli, L.; Cacchi, S.; Fabrizi, G.;
Goggiamani, A.; Scarponi, C.; Tiecco, M. J. Org. Chem. 2010, 75,
Org. Lett., Vol. 13, No. 12, 2011
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Table 2. Cascade Intramolecular N-Arylation/Intermolecular Carboamination Reactionsa
a Conditions: Reactions were conducted on a 0.25 mmol scale using 1.0 equiv of substrate, 1.2 equiv of ArCl, 2.4 equiv of NaOtBu, catalyst (4 mol %
[Pd]), toluene (0.25 M), 100 °C. b Catalyst A: Pd(OAc)2 (4 mol %), Cy4Dpe-Phos 15 (4 mol %). Catalyst B: Pd2(dba)3 (2 mol % complex), PCy3•HBF4
(4 mol %). Catalyst C: Pd2(dba)3 (2 mol % complex), X-Phos 14 (8 mol %). c Diastereomeric ratiosare reported for the isolated products. Diastereomeric
ratios in parentheses were observed in crude reaction mixtures. d Isolated yield (average of two experiments). e The reaction was conducted using 8 mol %
PCy3•HBF4.
The starting materials required for the cascade reactions
were accessible in either racemic or optically active form
using concise (3À4 step) sequences. For example, the
enantiomerically enriched substrates 5aÀb were prepared
in 3 steps from aldehydes 9 via conversion to the corre-
sponding sulfinyl imines 10 followed by addition of but-3-
enylmagnesium bromide and cleavage of the N-Bus group
from the resulting product 11 (Scheme 2).12 A similar
strategy was used for the generation of enantiomerically
enriched ketimine-derived substrates 5dÀe (Table 2). Al-
ternatively, substrates 5aÀc were synthesized as racemates
via reductive amination of the corresponding ketones.13,14
In our preliminary studies we examined a number of
different phosphine ligands for the Pd-catalyzed coupling
of 5b with chlorobenzene. Initial results obtained with
S-Phos (13), which has been shown to provide optimal
yields in many other carboamination reactions of aryl
chlorides,8a were very promising (Table 1, entry 1). Sub-
stantial amounts of desired product 8g were formed, along
with a small amount of side product 12, which results from
competing N-arylation of intermediate 6a. However, other
(12) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600.
(13) Hydrazine substrate 16 was prepared in four steps from 2-bro-
mobenzyl bromide, tert-butyl carbazate, benzaldehyde, and allylmag-
nesium bromide.
(14) See the Supporting Information for complete experimental
details.
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Org. Lett., Vol. 13, No. 12, 2011

related biaryl(dialkyl)phosphine ligands failed to provide
improved results (entries 2À5). As noted above, we have
previously shown that Dpe-Phos (4) affords good results in
sequential N-arylation/carboamination reactions that give
2-(arylmethylindoline) products.3a However, this ligand is
not very reactive toward aryl chlorides, and use of this
ligand in an attempted coupling of 5b with chlorobenzene
afforded only 6a, which results from intramolecular N-
arylation of the substrate. To address this problem, we
examined the more electron-rich Cy4Dpe-Phos ligand
(15)15 and were gratified to observe the product 8g was
generated in good yield using these conditions. In addition,
the simple trialkyl phosphine PCy3 (which was introduced
to the reaction mixture as an air-stable tetrafluoroborate
salt) also provided good selectivity for product 8g. How-
ever, small amounts of several other unidentified side
products were formed in the Pd/PCy3 catalyzed reaction,
so Cy4Dpe-Phos was selected as the ligand of choice for
our exploration of reaction scope.
As shown in Table 2, the cascade intramolecular
N-arylation/intermolecular carboamination reactions are
effective for the preparation of several different substituted
tetrahydropyrroloindole and hexahydropyrroloquinoline
derivatives. The products were formed with good to
excellent levels of diastereoselectivity and in moderate to
good chemical yield. Importantly, enantiomerically en-
riched starting materials are converted to the heterocyclic
products with no erosion of optical purity.16 The construc-
tion of fused tricycles bearing two heteroatoms (entries 7
and 14) was also achieved, although yields for these
products were moderate.17
or electron-neutral aryl chlorides. Attempts to employ
this catalyst for reactions of electron-poor aryl chloride
substrates led to the formation of large amounts of side
products analogous to 12, which result from sequential
intramolecular and intermolecular N-arylation reactions.
However, the use of a catalyst composed of Pd2(dba)3 and
PCy3•HBF4 provided good results in the coupling of
4-chlorobenzotrifluoride with 5b (entry 10). This latter
catalyst system also provided optimal results in transfor-
mations involving chlorinated aromatic nitrogen hetero-
cycles (entries 4, 5, 11, and 13). However, efforts to employ
2-chlorothiophene and 3-chlorothiophene as electrophiles
in these transformations were unsuccessful.
In summary, cascade intramolecular N-arylation/
intermolecular carboamination reactions provide a
concise new approach to the generation of fused tri-
cyclic nitrogen heterocycles. The reaction sequence
leads to the formation of two rings, three bonds, and
one stereocenter in a chemo- and stereoselective fash-
ion. In addition, these experiments also illustrate the
utility of the generally unexplored Cy4Dpe-Phos ligand
(15) for Pd-catalyzed cascade reactions involving both
aryl bromide and aryl chloride electrophiles.18
Acknowledgment. The authors acknowledge the NIH-
NIGMS for financial support of this work (GM-071650).
Additional funding was provided by GlaxoSmithKline,
Amgen, and Eli Lilly. G.S.L. thanks Novartis for a
Graduate Research Fellowship.
Supporting Information Available. Experimental pro-
cedures, characterization data for all new compounds,
descriptions of stereochemical assignments, and copies of
1H 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.
The Pd(OAc)2/Cy4Dpe-Phos catalyst proved to be ef-
fective for transformations of several different electron-rich
(15) (a) Veits, Y. A.; Mutsenek, E. V.; Neganova, E. G.; Beletskaya,
I. P. Russ. J. Org. Chem. 2001, 37, 1583. (b) Veits, Y. A.; Mutsenek, E. V.
Russ. J. Gen. Chem. 2005, 75, 207.
(16) Small differences in enantiopurity between substrates and
products are attributed to experimental error resulting from a neces-
sary use of Mosher amide NMR analysis to assay substrate enantio-
purities. The enantiopurities of products were assayed by HPLC
analysis.
(17) The cascade reaction of 16 with 3-bromoanisole was most
effective when X-Phos (14) was employed as a ligand. A complex
mixture of products was obtained when Cy4Dpe-Phos or PCy3•HBF4
was used as a ligand for this transformation.
(18) To date, only a single report has appeared describing the utility
of Cy4Dpe-Phos in metal-catalyzed reactions (the Pd-catalyzed N-
arylation of 4-bromoacetophenone with five different amines). See ref
15b. In general, the reactivity of electron-rich wide bite angle phosphine
ligands in catalytic transformations has rarely been examined. For
additional discussion, see: Birkholz, M.-N.; Freixa, Z.; van Leeuwen,
P. W. N. M. Chem. Soc. Rev. 2009, 38, 1099.
Org. Lett., Vol. 13, No. 12, 2011
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