Mild conditions for the synthesis of functionalized pyrrolidines via Pd-catalyzed carboamination reactions

Article abstract of DOI:10.1021/ol062808f

The palladium-catalyzed carboamination of N-protected y-aminoalkenes with aryl bromides and triflates has been achieved under new, mild reaction conditions using the weak base Cs₂CO₃ in dioxane solvent. These reactions tolerate a wid

Full text of DOI:10.1021/ol062808f

ORGANIC
LETTERS
2007
Vol. 9, No. 3
457-460
Mild Conditions for the Synthesis of
Functionalized Pyrrolidines via
Pd-Catalyzed Carboamination Reactions
Myra Beaudoin Bertrand, Matthew L. Leathen, and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 N. UniVersity AVenue,
Ann Arbor, Michigan, 48109-1055
jpwolfe@umich.edu
Received November 18, 2006
ABSTRACT
The palladium-catalyzed carboamination of N-protected
γ-aminoalkenes with aryl bromides and triflates has been achieved under new, mild
reaction conditions using the weak base Cs2CO3 in dioxane solvent. These reactions tolerate a wide variety of functional groups, including
enolizable ketones, nitro groups, methyl esters, and acetates, which are not compatible with previously described conditions.
The development of synthetic methods for the construction
of substituted pyrrolidines has been of longstanding impor-
tance in organic chemistry as a result of the prevalence of
this moiety in biologically active molecules and natural
products.1 Over the past several years, the palladium-
catalyzed carboamination of γ-aminoalkenes with aryl
bromides has emerged as an efficient and stereoselective
method for the construction of substituted pyrrolidine deriva-
tives.2,3 These transformations effect tandem cyclization and
coupling in a process that generates a C-N bond, a C-C
bond, and up to two stereocenters in one step. For example,
treatment of Boc-protected amine 1 with 4-bromoanisole in
the presence of NaOtBu and catalytic amounts of Pd2(dba)3
and dppb afforded pyrrolidine 2 in 60% yield with >20:1
dr (eq 1).2c
Despite the synthetic utility of these transformations, the
reactions are typically conducted in the presence of the strong
Table 1. Optimization Summarya
(1) For recent reviews, see: (a) Bellina, F.; Rossi, R. Tetrahedron 2006,
62, 7213-7256. (b) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765-
2810.
(2) (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605-
3608. (b) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906-
13907. (c) Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447-
6459. (d) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644-
8651. (e) Yang, Q.; Ney, J. E.; Wolfe, J. P. Org. Lett. 2005, 7, 2575-
2578. (f) Ney, J. E.; Hay, M. B.; Yang, Q.; Wolfe, J. P. AdV. Synth. Catal.
2005, 347, 1614-1620. (g) Bertrand, M. B.; Wolfe, J. P. Org. Lett. 2006,
8, 2353-2356.
(3) For a review on other Pd-catalyzed alkene carboamination reactions
that afford pyrrolidine products, see: (a) Wolfe, J. P. Eur. J. Org. Chem.
2007, in press. See also: (b) Harayama, H.; Abe, A.; Sakado, T.; Kimura,
M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1997, 62, 2113-
2122. (c) Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251-3254.
(d) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org. Lett. 2004,
6, 1573-1575. (e) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J.
Org. Chem. 1994, 59, 4172-4178.
entry
base
Pd
solvent
yield (%)
1
2
3
4
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
toluene
toluene
toluene
dioxane
81
38
63
82b
a Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 2.3 equiv base, 1 mol
% Pd2(dba)3 (2 mol % Pd) or 2 mol % Pd(OAc)2, 2 mol % Dpe-phos (with
Pd2(dba)3) or 4 mol % Dpe-Phos (with Pd(OAc)2), solvent (0.25 M), 105
°C. b The reaction was conducted at 100 °C.
10.1021/ol062808f CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/10/2007

Table 2. Palladium-Catalyzed Carboamination of N-Protected γ-Aminoalkenes with Functionalized Aryl Bromidesa
a Conditions: 1.0 equiv amine, 1.2 equiv ArBr, 2.3 equiv Cs2CO3, 2 mol % Pd(OAc)2, 4 mol % Dpe-phos, dioxane (0.2-0.25 M), 100 °C. b Yield refers
to average isolated yield obtained in two or more experiments. c Dppe used in place of Dpe-phos. d NaOtBu used in place of Cs2CO3. e The reaction was
conducted at 85 °C in DME solvent.
base NaOtBu, which limits the scope of this method. For
example, the use of NaOtBu restricts the functional group
tolerance of these reactions, and transformations of aryl
triflate electrophiles, which decompose in the presence of
strong base, have not been reported. Additionally, Cbz
protecting groups, which are frequently employed in the
synthesis of complex alkaloids, are incompatible with the
strongly basic conditions. In this Letter we describe the
development of new conditions that replace NaOtBu with
weaker bases (Cs2CO3 or K3PO4), which significantly
expands the scope of the carboamination method.
In our preliminary studies on palladium-catalyzed car-
boamination reactions of γ-(N-Boc-amino)- or γ-(N-acyl-
amino)alkenes, our attempts to conduct the transformations
using bases other than NaOtBu were met with limited
success.2c For example, the Pd2(dba)3/Dpe-phos4 catalyzed
carboamination of 3 with 4-bromo-tert-butylbenzene afforded
4 in 81% yield when the reaction was conducted in toluene
solvent with NaOtBu as base (Table 1, entry 1). However,
use of Cs2CO3 in place of NaOtBu provided only a 38%
isolated yield of 4 and led to the formation of large amounts
of side products (entry 2).5,6
To improve the yields obtained in Pd-catalyzed carboami-
nation reactions that employ mild bases, the effect of
palladium source and solvent were systematically examined;
the key results of these studies are summarized in Table 1.
After some experimentation, it was discovered that use of
Pd(OAc)2 in place of Pd2(dba)3 leads to significantly
improved yields of 4 (63%, entry 3), and replacement of
(5) The use of Cs2CO3 and other weak bases in Pd-catalyzed N-arylation
reactions of amines with aryl halides has been reported. For reviews, see:
(a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-209.
(b) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed., Wiley-
VCH: Weinheim, 2002; pp 107-168. (c) Schlummer, B.; Scholz, U. AdV.
Synth. Catal. 2004, 346, 1599-1626.
(6) Lower yields were obtained with other weak bases including K2CO3
and Et3N.
(4) Dpe-phos ) bis(2-diphenylphosphinophenyl)ether.
458
Org. Lett., Vol. 9, No. 3, 2007

toluene with dioxane as solvent provides optimal results
(82%, entry 4).7,8
Scheme 1. Stereoselective Synthesis of 25
As shown in Table 2, the new reaction conditions
described above are effective for the transformation of a
number of different substrate combinations. A variety of
functional groups are tolerated under these mild conditions,
including aldehydes (entry 3), enolizable ketones (entry 4),
nitro groups (entries 6 and 11), methyl esters (entries 8 and
14), and alkyl acetates (entry 9). In addition, the carboami-
nation reactions of electron-rich (entry 10), electron-neutral
(entries 1, 2, 5, 7, and 13), and heterocyclic (entry 12) aryl
bromides proceed with good chemical yields. The mild
conditions also are effective for stereoselective reactions and
provide selectivities that are comparable to those observed
in reactions that use NaOtBu as base. For example, trans-
formations of starting materials 1 and 9, which bear a
substituent adjacent to the nitrogen atom, provide cis-2,5-
disubstituted products 20 and 21 with excellent (>20:1)
diastereoselectivity (entries 11 and 12). Similarly, substrates
7 and 8, which are substituted at the allylic position, are
transformed to trans-2,3-disubstituted products 18 and 19
with good stereocontrol (12-15:1).
The main limitations of these new reaction conditions
involve transformations of sterically encumbered substrate
combinations.10 For example, attempts to convert substrates
bearing internal alkenes to pyrrolidines were unsuccessful
under these conditions. In addition, the reaction of methyl
2-bromobenzoate with 1, which bears a substituent on C-1
(adjacent to the nitrogen atom), was not effective. However,
as noted above, this ortho-substituted aryl bromide was
effectively coupled with the less hindered carbamate 8
(Scheme 1).
In addition to providing increased tolerance of base-
sensitive functional groups, the new reaction conditions also
allow the efficient carboamination of substrates bearing Cbz
protecting groups. For example, the Pd-catalyzed coupling
of 6 with 2-bromonaphthalene using Cs2CO3 as base provided
the desired product 16 in 88% isolated yield (entry 7). In
contrast, cleavage of the Cbz group from the substrate was
problematic when reactions were conducted with NaOtBu
as base; these conditions provided only a 17% yield of 16.
More complex γ-aminoalkene substrates are also ef-
ficiently transformed using the new reaction conditions. As
shown in Table 2 (entries 13 and 14), Pd-catalyzed reactions
of 10 with bromobenzene or methyl-4-bromobenzoate pro-
ceeded smoothly to provide 22 and 23 with excellent
stereoselectivity. Trisubstituted pyrrolidine 22 has been
previously employed as an intermediate in the synthesis of
the natural product (+)-preussin.2g,9
Table 3. Palladium-Catalyzed Carboamination of Aryl
Triflatesa
The high degree of functional group tolerance of this
method also allows straightforward access to 1-substituted
tetrahydropyrroloisoquinolin-5-ones. As shown in Scheme
1, the Pd-catalyzed reaction of 8 with methyl-2-bromoben-
zoate afforded pyrrolidine 24 in 73% yield with 14:1 dr.
Treatment of this product with trifluoroacetic acid followed
by an alkaline workup gave 25 in 95% yield.
a Conditions: 1.0 equiv amine, 1.2 equiv ArOTf, 2.3 equiv K3PO4, 4
mol % Pd(OAc)2, 8 mol % Dpe-phos, dioxane (0.25 M), 100 °C. b Yield
refers to average isolated yield obtained in two or more experiments.
c NaOtBu used in place of K3PO4.
(7) In some cases use of DME as solvent provided results comparable
to those obtained with dioxane (Table 2, entries 3, 4, 6, and 8.)
(8) The differences in reactivity between Pd2(dba)3 and Pd(OAc)2 are
not fully understood, but may result from coordination of dba (dibenzyli-
deneacetone) to the metal at key stages in the catalytic cycle, or through
the formation of dba-ligated complexes that lie outside of the catalytic cycle.
Dba has previously been demonstrated to have a large impact on the rates
of Pd-catalyzed or -mediated process. For lead references, see: (a) Shekhar,
S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter,
E. R.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 3584-3591. (b)
Amatore, C.; Broeker, G.; Jutand, A.; Khalil, F. J. Am. Chem. Soc. 1997,
119, 5176-5185.
In addition to greatly expanding the scope of Pd-catalyzed
carboamination reactions involving aryl bromide substrates,
the use of mildly basic reaction conditions also allows the
first Pd-catalyzed carboamination reactions with aryl triflates.
(9) (a) Huang, P.-Q.; Wu, T.-J.; Ruan, Y.-P. Org. Lett. 2003, 5, 4341-
4344. (b) Kadota, I.; Saya, S.; Yamamoto, Y. Heterocycles 1997, 46, 335-
348. (c) Yoda, H.; Yamazaki, H.; Takabe, K. Tetrahedron: Asymmetry
1996, 7, 373-374.
(10) These conditions were also less effective for carboamination
reactions of γ-(N-arylamino)alkenes; the desired N-arylpyrrolidine products
were obtained in low to moderate yield (35-55%).
Org. Lett., Vol. 9, No. 3, 2007
459

Our preliminary efforts to conduct these transformations with
the strong base NaOtBu were unsuccessful as a result of
competing cleavage of the trifluoromethanesulfonate ester,
which resulted in conversion of the aryl triflate to the
corresponding phenol. For example, treatment of 3 with
4-formylphenyl triflate in the presence of catalytic Pd(OAc)2/
Dpe-phos and stoichiometric NaOtBu failed to generate the
desired pyrrolidine product 12. However, subsequent experi-
ments demonstrated that use of K3PO4 as base provides the
desired pyrrolidine 12 in 67% yield (Table 3, entry 1). These
conditions are effective with both Boc- and Cbz-protected
substrates, and diastereoselectivities are similar to those
obtained in related reactions with aryl bromide electrophiles
(entries 3 and 4).
base NaOtBu, tolerate the presence of a broad array of
functional groups and significantly expand the scope of this
method. Applications of these new conditions to the synthesis
of complex pyrrolidine alkaloids are currently being pursued.
Acknowledgment. The authors thank the NIH-NIGMS
(GM071650) for financial support of this work. Additional
support was provided by the Camille and Henry Dreyfus
Foundation (New Faculty Award, Camille Dreyfus Teacher
Scholar Award), Research Corporation (Innovation Award),
Eli Lilly, Amgen, and 3M.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, 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.
In conclusion, we have developed new conditions for
palladium-catalyzed carboamination reactions of N-protected
γ-aminoalkenes with aryl bromides and triflates. These
conditions, which use Cs2CO3 or K3PO4 in place of the strong
OL062808F
460
Org. Lett., Vol. 9, No. 3, 2007