Asymmetric palladium-catalyzed carboamination reactions for the synthesis of enantiomerically enriched 2-(Arylmethyl)- and 2-(Alkenylmethyl)pyrrolidines

Article abstract of DOI:10.1021/ja106989h

The enantioselective synthesis of 2-(arylmethyl)- and 2-(alkenylmethyl) pyrrolidine derivatives via Pd-catalyzed alkene carboamination reactions is described. These transformations generate enantiomerically enriched products with up to 94% ee from readily

Full text of DOI:10.1021/ja106989h

Published on Web 08/18/2010
Asymmetric Palladium-Catalyzed Carboamination Reactions for the Synthesis of
Enantiomerically Enriched 2-(Arylmethyl)- and 2-(Alkenylmethyl)pyrrolidines
Duy N. Mai and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received March 2, 2010; E-mail: jpwolfe@umich.edu
ligands with relatively large bite angles (e.g., dpe-phos or dppb)2b
provided satisfactory yields of racemic products. Thus, we examined
a series of chiral bis-phosphines for the carboamination of 3a.
Unfortunately, ligands such as (S)-BINAP (5) or (S)-Phanephos (7),
Abstract: The enantioselective synthesis of 2-(arylmethyl)- and
2-(alkenylmethyl)pyrrolidine derivatives via Pd-catalyzed alkene
carboamination reactions is described. These transformations
generate enantiomerically enriched products with up to 94% ee
which possess bite angles similar to dpe-phos and dppb, provided
from readily available alkenyl or aryl bromides and N-boc-pent-
poor yields of 4a, low enantioselectivities, or both.10 We then
4-enylamines. The application of this method to a concise
asymmetric synthesis of (-)-tylophorine is also discussed.
elected to investigate chiral phosphoramidite ligands for this
transformation, as several recent studies have illustrated these
ligands are highly effective in other enantioselective Pd-catalyzed
addition reactions.11 Promising results were obtained with BINOL-
The syn-insertion of alkenes into palladium-nitrogen bonds has
been implicated as a key step in a number of important metal-
catalyzed processes,1 including alkene carboaminations,2 diamina-
tions,3 and oxidative aminations.4 In many instances these trans-
formations proceed with high levels of diastereoselectivity. However,
enantioselective variants of transformations that involve syn-
aminopalladation are extremely rare.5 For example, enantioselective
Pd-catalyzed carboamination reactions between aryl/alkenyl halides
and alkenes bearing pendant amines have not previously been
described, and only two reports of Pd-catalyzed asymmetric
diaminations that likely proceed via syn-aminopalladation have
appeared in the literature.5
derived phosphoramidites 8-9, and further exploration led to the
discovery that (R)-Siphos-PE12 (10) provided useful levels of
enantioselectivity. After further optimization of reaction conditions
we found that use of 2.5 mol % of Pd2(dba)3 as precatalyst, a ligand:
metal ratio of 1.5:1, and a lower reaction temperature of 90 °C
produced 4a in 78% yield and 82% ee (Table 2, entry 1).
Table 1. Chiral Ligand Screena
Over the past several years our group has developed a practical
and efficient method for the synthesis of substituted pyrrolidines
via Pd-catalyzed carboamination reactions between aryl/alkenyl
bromides and γ-aminoalkene derivatives.1a,b,2 Our success in this
endeavor prompted us to investigate an asymmetric variant of these
transformations that would generate enantiomerically enriched
2-(arylmethyl)pyrrolidines. These structures are prominent features
of many natural products (e.g., (-)-tylophorine, 1) and pharma-
ceutical leads (e.g., 2), and their absolute stereochemistry can have
striking effects on biological activity. For example, the R-enantiomer
of pyrrolidine 2 is a potent 5-HT6 agonist, whereas the S-enantiomer
displays antagonistic activity.6 In this communication we report our
preliminary studies on the enantioselective synthesis of 2-(arylmethyl)-
or 2-(alkenylmethyl)pyrrolidines via asymmetric Pd-catalyzed alkene
carboamination reactions.7-9 These reactions proceed with good levels
of asymmetric induction and constitute rare examples of transforma-
tions that involve enantioselective syn-aminopalladation.
a Conditions: Reactions were conducted on a 0.15 mmol scale with
1.0 equiv of substrate, 1.2 equiv of ArBr, 1.2 equiv of NaOtBu, 2 mol
% Pd(OAc)2, 4 mol % ligand, toluene (0.15 M), 110 °C, 14 h.
The optimized conditions described above are effective for
carboamination reactions between substrates 3a-c and several
different aryl or alkenyl bromides. As shown in Table 2, these
transformations proceeded in moderate to good yield and provided
the desired products with ee’s ranging from 72-94%. Although
most experiments were conducted on a small scale (0.20 mmol),
the coupling of 3a with 2-bromonaphthalene gave nearly identical
results on both small (0.2 mmol) and large (1.0 mmol) scales
(entries 1-2). The best enantioselectivities were obtained with
ꢀ-bromostyrene as the electrophilic coupling partner (entries 12,
13, and 22). Electron-donating groups on the aryl bromide were
In our initial experiments we examined the coupling of N-(boc)-
pent-4-enylamine (3a) with 2-bromonaphthalene (Table 1). Our
prior studies with achiral catalysts indicated that chelating phosphine
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J. AM. CHEM. SOC. 2010, 132, 12157–12159 12157

C O M M U N I C A T I O N S
Scheme 1. Synthesis of (-)-Tylophorine
well tolerated, although this method is less generally effective with
electron-poor aryl bromides. For example, reactions of tert-butyl
p-bromobenzoate (entry 10), p-bromofluorobenzene (entry 11), and
m-bromobenzotrifluoride (entries 20-21) proceeded in acceptable
yields, but efforts to employ 3-bromobenzonitrile or 4-bromoben-
zophenone were unsuccessful. Substrate 3b bearing gem-dimethyl
substitution at C2 was transformed in similar yields and selectivities
as in the case of 3a, although use of a substrate bearing a diethyl
acetal at C2 (3c) gave a product with lower ee (entry 23). Use of
aryl iodide electrophiles gave product yields and enantioselectivities
similar to those obtained with aryl bromides. However, aryl
chlorides were unreactive under these conditions, and low yields
were obtained with aryl triflate substrates due to competing base-
mediated cleavage of the sulfonate ester.13
Our enantioselective synthesis of (-)-tylophorine employs a route
analogous to that developed by Herr for the construction of (()-
tylophorine.18 Aryl bromide 11 was prepared in four steps18 and
then coupled with N-boc-pent-4-enylamine (3a) using the Pd/(R)-
Siphos-PE catalyst system (Scheme 1). We were gratified to find
this reaction yielded the desired pyrrolidine 12 in 69% yield and
88% ee. Intermediate 12 was converted to (-)-tylophorine (1) in
two steps18 and nearly quantitative yield.
Table 2. Catalytic Asymmetric Synthesis of Pyrrolidinesa
Scheme 2. Syn-Aminopalladation Mechanism
The mechanism of Pd/phosphine catalyzed alkene carboamination
reactions is believed to involve intramolecular alkene insertion into
the Pd-N bond of an intermediate LnPd(Ar)(NRR′) complex (e.g.,
13),1a,2c which generates the new C-N bond and forms 1-2
stereocenters depending on the degree of alkene substitution
(Scheme 2). Carbon-carbon bond-forming reductive elimination
from 14 then leads to generation of pyrrolidine products 4 that result
from net suprafacial addition of the aryl group and the nitrogen
atom across the alkene.20 In the enantioselective transformations,
it appears reasonably likely that product stereochemistry is deter-
mined during the C-N bond-forming step. However, the Siphos-
PE ligand has considerably different steric and electronic properties
than those of phosphine ligands such as dpe-phos, dppf, and
xantphos, which were employed in the generation of racemic
pyrrolidine products.1a,20 Thus, we sought to determine if the Pd/
Siphos-PE-catalyzed reactions also occur with suprafacial selectivity
(via a syn-aminopalladation pathway). To this end, we examined
the coupling of deuterated substrate 3d with bromobenzene. As
shown in eq 1, the pyrrolidine product results from suprafacial
addition, which suggests both the asymmetric and nonasymmetric
variants of the carboamination reactions proceed through similar
mechanisms.
a Conditions: Reactions were conducted on a 0.2 mmol scale with 1.0
equiv of substrate, 2.0 equiv of ArBr or alkenylBr, 1.0-2.0 equiv of
NaOtBu, 2.5 mol % Pd2(dba)3, 7.5 mol % (R)-Siphos-PE, toluene (0.2
M), 90 °C, 12-15 h. b Enantiomeric excess was determined by chiral
HPLC analysis. c Isolated yield (average of two or more experiments).
d This reaction was conducted on a 1.0 mmol scale.
In general, side products were not observed in crude reaction
mixtures, and it is likely that modest yields result from competing
base-mediated substrate decomposition.2b,14,15 Substrate decom-
position was also observed in attempted asymmetric carboamination
reactions of substrates bearing 1,1- or 1,2-disubstituted alkenes.
In order to illustrate the utility of the enantioselective carboami-
nation reactions, and to establish the absolute configuration of the
pyrrolidine products,16 a short synthesis of the natural product (-)-
tylophorine was undertaken. This molecule exhibits potent antitumor
and antiviral activities,17 and there has been considerable interest
in the development of synthetic routes to tylophorine and other
related phenanthroindolizidine alkaloids.7b,18,19
Although the precise structure of the transition state leading to the
major enantiomer is not clear, our data provide some information about
the enantiodetermining step of these reactions. The enantioselectivity
obtained in the conversion of 3a to 4a did not change when ligand/
metal ratios were varied from 1:1 to 2:1, which suggests a monoligated
palladium complex is involved in the stereochemistry determining step.
The poor asymmetric induction obtained with chelating bis-phosphines
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C O M M U N I C A T I O N S
(7) Chemler has previously described enantioselective Cu-catalyzed intramo-
lecular carboamination reactions of N-(arylsulfonyl)-N-(pent-4-enyl)amines
that generate substituted tetrahydro-1H-benzo[e]pyrrolo[1,2-b][1,2]thia-
zinedioxides. These products can be transformed to enantiomerically
enriched 2-(arylmethyl)pyrrolidines through reductive desulfonylation. See:
(a) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948. (b)
Zeng, W.; Chemler, S. R. J. Org. Chem. 2008, 73, 6045.
(8) For enantioselective intramolecular alkene carboamination reactions that
proceed via Pd-catalyzed oxidative tandem cyclization of N-(2-allylphe-
nyl)acrylamide derivatives, see: (a) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu,
N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130. (b) He, W.; Yip,
K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 5626.
(9) For oxidative Pd-catalyzed aminocarbonylation reactions of alkenylureas,
see: Tsujihara, T.; Shinohara, T.; Takenaka, K.; Takizawa, S.; Onitsuka,
K.; Hatanaka, M.; Sasai, H. J. Org. Chem. 2009, 74, 9274.
(10) A complete table of results from our ligand screening experiments is
provided in the Supporting Information.
(e.g., 5-7) may be due to dissociation of one arm of the chelate to
provide a four-coordinate complex analogous to 13 prior to amino-
palladation. This would place much of the chiral ligand steric bulk at
a large distance away from the reactive site, which could diminish
asymmetric induction.21 In contrast, the monodentate phosphoramidite
ligands should provide relatively facile access to reactive L1 complexes.
The high selectivities obtained with these ligands may arise from the
steric bulk and chiral elements on both the amine group and the diol
portion, which appear to be projected around the metal center to a
much greater degree than the substituents on ligands such as 5-7 when
bound through a single P-atom.22
In conclusion, we have developed enantioselective Pd-catalyzed
alkene carboamination reactions that afford 2-(arylmethyl)- or 2-(alk-
enylmethyl)pyrrolidines in good yields and enantioselectivities. These
transformations provide a new means for the asymmetric construction
of this important class of nitrogen heterocycles and a new route to
enantiomerically enriched phenanthroindolizidine alkaloids such as
tylophorine. Further studies on the design of more efficient chiral
catalysts for these transformations are currently underway.
(11) (a) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde,
E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.;
Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Hubertus, H. J. W.; de Vries,
J. G. AdV. Synth. Catal. 2003, 345, 308. (b) Imbos, R.; Minnaard, A. J.;
Feringa, B. L. Dalton. Trans. 2003, 2017–2023. (c) Trost, B. M.; Silverman,
S. M.; Stambuli, J. P. J. Am. Chem. Soc. 2007, 129, 12398. (d) Yasui, Y.;
Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303. (e) Reddy, V. J.;
Douglas, C. J. Org. Lett. 2010, 12, 952.
(12) Guo, X.-X.; Xie, J.-H.; Hou, G.-H.; Shi, W.-J.; Wang, L.-X.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2004, 15, 2231.
(13) Efforts to employ weak bases such as Cs2CO3 or K3PO4 led to low reactivity.
(14) Secondary tert-butyl carbamates have been shown to undergo elimination
reactions to afford reactive isocyanates when heated in the presence of
NaOtBu. Aqueous workup affords the corresponding primary amines. See:
Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M. Tetrahedron Lett. 2004,
45, 905.
Acknowledgment. The authors acknowledge the NIH-NIGMS
(GM071650) for financial support of this work. Additional unre-
stricted funding was provided by GlaxoSmithKline, Amgen, and
Eli Lilly. The authors thank Dr. Qifei Yang for conducting
preliminary experiments in this area.
(15) When a solution of 3a and NaOtBu (1:1) in toluene-d8 was heated to 90
°C for 3 h, ca. 35% decomposition to the corresponding isocyanate was
observed. This isocyanate likely is converted to the volatile pent-4-
enylamine upon aqueous workup.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) The absolute stereochemistry of 4a-t was assigned based on analogy to 12.
(17) (a) Zeng, W.; Chemler, S. R. Curr. Bioact. Cmpds. 2009, 5, 2. (b) Li, Z.;
Jin, Z.; Huang, R. Synthesis 2001, 2365.
(18) A recent syntheses of racemic tylophorine was reported that employed a
Pd-catalyzed alkene carboamination reaction between 3a and 11 to generate
the heterocyclic ring. See: Rossiter, L. M.; Slater, M. L.; Giessert, R. E.;
Sakwa, S. A.; Herr, R. J. J. Org. Chem. 2009, 74, 9554.
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