A highly effective catalyst system for the Pd-catalyzed amination of vinyl bromides and chlorides

Article abstract of DOI:10.1021/ol051612x

(Chemical Equation Presented) A highly efficient synthesis of enamines and imines by Pd-catalyzed amination of vinyl bromides or chlorides with amines is described using the Pd₂(dba)₃/P(i-BuNCH₂CH ₂)₃N catalyst system.

Full text of DOI:10.1021/ol051612x

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4427-4430
A Highly Effective Catalyst System for
the Pd-Catalyzed Amination of Vinyl
Bromides and Chlorides
Chinta Reddy Venkat Reddy, Sameer Urgaonkar,† and John G. Verkade*
Department of Chemistry, Gilman Hall, Iowa State UniVersity, Ames, Iowa 50011
jVerkade@iastate.edu
Received July 12, 2005
ABSTRACT
A highly efficient synthesis of enamines and imines by Pd-catalyzed amination of vinyl bromides or chlorides with amines is described using
the Pd2(dba)3/P(i-BuNCH2CH2)3N catalyst system.
Palladium-catalyzed Buchwald-Hartwig amination is a
powerful method for constructing aromatic C-N bonds in
synthetically useful arylamines.1 Consequently, considerable
attention has been devoted to the development of ligand
supported palladium catalyst systems for this process.2,3 It
is important to note that most of these studies were performed
with a wide variety of aryl iodides, bromides, and chlorides
as electrophilic coupling partners. By contrast, examples of
amination of vinyl halides leading to enamines (or imines)
are rare.4
Enamines are important synthetic intermediates,5 especially
in the alkylation and acylation of ketones as pioneered by
Stork.6 Although several methods7 are known for synthesiz-
ing enamines (and imines), a palladium-catalyzed Buch-
wald-Hartwig amination could constitute a significant
† Present address: Chemical Biology Program, Broad Institute of Harvard
and MIT, 320 Bent Street, Cambridge, MA 02141.
(1) For reviews, see: (a) Schlummer, B.; Scholz, U. AdV. Synth. Catal.
2004, 346, 1599. (b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131. (c) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, Germany, 2000. (d) Yang, B. H.; Buchwald, S.
L. J. Organomet. Chem. 1999, 576, 125. (e) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (f) Hartwig,
J. F. Acc. Chem. Res. 1998, 31, 852. (g) Hartwig, J. F. Angew. Chem., Int.
Ed. 1998, 37, 2046.
(2) (a) Wolfe, J. P.; Tomori, J.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158. (b) Hartwig, J. F.; Kawatsura, M.; Hauck,
S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
5575. (c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144. (d)
Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617.
(e) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem. 2001,
66, 7729. (f) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig,
J. F. Org. Lett. 2000, 2, 1423. (g) Rataboul, F.; Zapf, A.; Jackstell, R.;
Harkal, S.; Riermeier, A.; Monsees, A.; Dingerdissen, U.; Beller, M. Chem.
Eur. J. 2004, 10, 2983. (h) Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser,
H.-U. Angew. Chem., Int. Ed. 2002, 41, 3668. (i) Li, G. Y. Angew. Chem.,
Int. Ed. 2001, 40, 1513. (j) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig,
J. F. Angew. Chem., Int. Ed. 2005, 44, 1371.
(3) (a) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. Org. Lett. 2003, 5,
815. (b) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. J. Org. Chem. 2003,
68, 452. (c) Urgaonkar, S.; Verkade, J. G. AdV. Synth. Catal. 2004, 346,
611. (d) Urgaonkar, S.; Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003, 68,
8416. (e) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135. (f)
Urgaonkar, S.; Verkade, J. G. Tetrahedron 2004, 60, 11837.
(4) For the palladium-catalyzed synthesis of enamines and enamides from
vinyl triflates, see: (a) Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002,
43, 9085. (b) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P.
Org. Lett. 2003, 5, 4749.
(5) (a) Whitesell, J. K. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Oxford: Pergamon: 1991. (b) Enamines: Synthesis,
Structure and Reactions, 2nd ed.; Cook, A. G., Ed.; Dekker: New York,
1988. (c) The Chemistry of Enamines, Part 1; Rappoport, Z., Ed.; Wiley:
New York, 1994.
(6) (a) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954,
76, 2029. (b) Stork, G.; Landesman, H. K. J. Am. Chem. Soc. 1956, 78,
5129. (c) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207.
10.1021/ol051612x CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/08/2005

advancement in the aforementioned methodology and it could
also overcome several limitations associated with the present
approaches. Surprisingly, it was only in 2002, almost a
decade after the first palladium-catalyzed amination of aryl
halides was reported,8 that Voskoboynikov9 reported for the
first time the cross-coupling of vinyl bromides with azoles
and phenothiazine using a Pd(dba)2/P(t-Bu)3 catalyst system.
Soon after Voskoboynikov’s report, Barluenga et al. dem-
onstrated that vinyl bromides can be effectively coupled with
a wide variety of amines using BINAP as a ligand in
combination with either Pd(OAc)2 or Pd2(dba)3.10 These
workers also demonstrated the suitability of vinyl chlorides
as coupling partners in the aforementioned process when
[2,2′-(biphenyl)P(t-Bu)2(NMe2)] was employed as the ligand.11
In recent years, we have reported on the palladium-
catalyzed cross-coupling of aryl halides with amines,3
arylboronic acids,12 and organostannanes.13 These processes
are successfully accomplished with the use of palladium
catalysts supported by ligand 1d (Figure 1). In a continuation
Table 1. Optimization of Reaction Conditions
entry
catalyst (mol %)
time (h)
T (°C)
yielda (%)
1
Pd(OAc)2 (0.25)
Pd2(dba)3 (0.25)
Pd2(dba)3 (0.25)
Pd2(dba)3 (0.25)
noned
7
8
3
8
12
80
80
80
rt
83
2
95
nrc
nrc
2b
3
4
5
80
a Isolated yields (average of two runs). b The reaction was performed in
the absence of 1d, and the yield was based on 1H NMR spectroscopic
integration. c nr ) no reaction. d In the absence of palladium but with 1d
present.
be suitable palladium sources. The reaction conditions shown
in entry 3 of Table 1 proved to be optimal. Thus, with 0.25
mol % of Pd2(dba)3 and 0.5 mol % of 1d (L/Pd ) 1), the
desired enamine 3a was obtained in 95% isolated yield in 3
h at 80 °C.
The NMR spectra (1H and 13C) of enamine 3a were very
clean after the workup. The crude reaction mixture was
filtered through Celite followed by removal of solvent under
reduced pressure. No silica gel column chromatography was
performed on any of the enamines described in this paper
owing to their acid-sensitive nature.10a Further control
experiments showed the need for palladium, ligand, and a
reaction temperature of 80 °C (Table 1, entries 2-5).
A screening study of proazaphosphatranes was also
performed (Table 2). Except for proazaphosphatrane 1a (R
Figure 1. Proazaphosphatranes used in this study.
of these studies, we document herein a highly active
palladium catalyst utilizing ligand 1d for the efficient
synthesis of enamines. Our process is effective for the
amination of both vinyl bromides and chlorides. The method
also uses much lower palladium and ligand loadings (in the
case of vinyl bromides), and it proceeds in shorter reaction
times compared with those in previous reports.
Table 2. Survey of Proazaphosphatranes
For the optimization of reaction conditions, we examined
the amination reaction of R-bromostyrene (2) with morpho-
line in toluene using 1d as the ligand and NaO-t-Bu as the
base (Table 1). Both Pd(OAc)2 and Pd2(dba)3 were found to
entry
ligand
time (h)
yielda (%)
1
2
3
4
5
1a
1b
1c
1d
1e
8
6
3.5
3
4
trace
94
93
95
93
(7) Using amine-substituted Wadsworth-Emmons reagents: (a) Martin,
S. F.; Gompper, R. J. Org. Chem. 1974, 39, 2814. Using condensation
reactions: (b) White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213.
(c) Hickmott, P. W. Tetrahedron 1982, 38, 1975. Via methylenation of
amides: (d) Petasis, N. A.; Lu, S. P. Tetrahedron Lett. 1995, 36, 2393. Via
hydroamination of alkynes: (e) Barluenga, J.; Aznar, F. Synthesis 1975,
704.
a Isolated yields (average of two runs).
(8) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348. (b) Louie, J.; Hartwig, J. F. Tetrahedron
Lett. 1995, 36, 3609.
(9) Lebedev, A. Y.; Izmer, V. V.; Kazyul’kin, Beletskaya, I. P.;
Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623.
(10) (a) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem.
Commun. 2002, 2362. (b) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.;
Valde´s, C. Chem. Eur. J. 2004, 494.
(11) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem.
Commun. 2004, 1400.
(12) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. Tetrahedron Lett. 2002,
43, 8921.
(13) (a) Su, W.; Urgaonkar, S.; McLaughlin, P. A.; Verkade, J. G. J.
Am. Chem. Soc. 2004, 126, 16433. (b) Su, W.; Urgaonkar, S.; Verkade, J.
G. Org. Lett. 2004, 6, 1421.
) R′ ) Me, entry 1), the other proazaphosphatranes
possessing varying degrees of additional steric hindrance [i.e.,
isopropyl (1b, entry 2), benzyl (1c, entry 3), isobutyl (1d,
entry 4), or a combination of benzyl and isobutyl groups
(1e, entry 5)] on the PN3 nitrogens provided active palladium
catalysts. High activity displayed by ligands 1b, 1c, and 1e
is surprising as they were either ineffective or showed only
moderate activity in the amination reactions performed on
aryl bromides and chlorides.3b,e
4428
Org. Lett., Vol. 7, No. 20, 2005

Barluenga.10a,b For example, reactions shown for the forma-
tion of 3b,c and 5a,c,d,f in Table 3 and for 3a in Table 1
when performed with the Pd/BINAP catalyst system required
3 mol % of Pd and 6 mol % of BINAP, compared with the
0.5 mol % of Pd and 0.5 mol % of 1d that provided these
enamines in comparable or higher yields.10
Table 3. Synthesis of Enamines from Vinyl Bromides Using
the Pd2(dba)3/1d Catalyst Systema
Next, we investigated the coupling of vinyl bromides with
primary amines (Scheme 1). Enamines initially formed in
Scheme 1. Synthesis of Imines from 2 Using the Pd2(dba)3/1d
Catalyst Systema
a Isolated yields (average of two runs) and reaction times appear
in parentheses.
these reactions tautomerized to give the more stable imine
form. In nearly all cases, excellent yields of the desired
imines were obtained. As expected, aromatic amines coupled
faster (30 min to 2 h) than aliphatic amines (3 h). The
reaction of a sterically hindered primary amine, such as 2,6-
dimethylaniline, also proceeded efficiently.
Enamine formation via the palladium-catalyzed amination
of a vinyl chloride was also briefly explored (Scheme 2).
Scheme 2. Synthesis of Enamines from the Vinyl Chloride 8
Using the Pd2(dba)3/1d Catalyst Systema
a Reaction conditions: Pd2(dba)3 (0.25 mol %), 1d (0.5 mol %), NaO-
t-Bu (1.4 equiv), toluene (4 mL), 80 °C. b Isolated yields (average of two
runs).
Further studies to establish the scope of the reaction were
performed with commercially available 1d as the ligand. As
is evident from Table 3, both R-bromostyrene and â-bro-
mostyrene were efficiently coupled with cyclic secondary
amines, acyclic secondary amines, and secondary aliphatic
amines, affording the desired enamines in excellent yields.
It is noteworthy that only very short reaction times (1-4 h)
are needed for these reactions to proceed to completion.
Another appealing aspect of our method is the catalyst
loading (0.5 mol % of Pd and 0.5 mol % of ligand 1d) which
is at least 2-fold (and in some cases 6-fold) less than was
used for the Pd/BINAP catalyst system reported by
a Isolated yields (average of two runs) and reaction times appear
in parentheses.
For these studies, 1-chlorocyclopentene (8) was chosen as a
prototypical substrate. Unfortunately, our standard conditions
proved inapplicable to vinyl chlorides. Pleasingly, however,
Org. Lett., Vol. 7, No. 20, 2005
4429

8 reacted efficiently with morpholine and N-methylaniline
at elevated temperature (115 °C) and higher catalyst loading
(5 mol % Pd and 5 mol % 1d). We are now focusing on
widening the scope of vinyl bromides and chlorides that can
employed in amination reactions to include deactivated and
sterically hindered examples.
Finally, we successfully extended our method to the
synthesis of the indole 11 by a cascade alkenyl amination
followed by an intramolecular Heck reaction in one pot
(Scheme 3). A yield comparable with that obtained using
In summary, an efficient and general catalyst system based
on commercially available Pd2(dba)3 and proazaphosphatrane
1d has been developed for the reaction of vinyl bromides
and chlorides with amines to afford enamines and imines in
excellent yields.15 The use of lower palladium and ligand
loading, shorter reaction times, and a relatively mild tem-
perature (80 °C for vinyl bromides) are salient features of
this method.
Acknowledgment. We are grateful to the Aldrich Chemi-
cal Co. for their generous support of this study by supplying
research samples. We also thank Dr. Weiping Su for kindly
providing ligands 1c and 1e. The National Science Founda-
tion is gratefully acknowledged for financial support of this
research in the form of a grant.
Scheme 3. Reaction of Vinyl Bromide 2 with o-Bromoaniline
10 for the Synthesis of 1H-Indole 11 Using the Pd2(dba)3/1d
Catalyst Systema
Supporting Information Available: Experimental pro-
cedures, references for known products, complete charac-
terization of previously unknown products, and copies of 1H
and 13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Isolated yield (average of two runs).
OL051612X
(14) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem. Eur.
J. 2005, 2276.
(15) While our manuscript was under review, a paper describing Pd-
catalyzed amination of vinyl bromides appeard. See: Willis, M. C.;
Chauhan, J.; Whittingham, W. G. Org. Biomol. Chem. 2005, 3, 3094.
the Pd/DavePhos system (64%)14 was achieved with lower
palladium and ligand loadings. Further efforts are underway
to determine the scope of such cascade reactions.
4430
Org. Lett., Vol. 7, No. 20, 2005