Palladium-catalyzed hydroamination of 1,3-dienes: A colorimetric assay and enantioselective additions [16]

Full text of DOI:10.1021/ja005881o

4366
J. Am. Chem. Soc. 2001, 123, 4366-4367
Palladium-Catalyzed Hydroamination of 1,3-Dienes:
A Colorimetric Assay and Enantioselective Additions
Oliver Lo¨ber, Motoi Kawatsura, and John F. Hartwig*
Department of Chemistry, Yale UniVersity
P.O. Box 208107, New HaVen, Connecticut 06520-8107
ReceiVed December 14, 2000
Mild, selective 1:1 reactions of amines with dienes to form
allylic amines are rare1 and limited to the reaction of cyclic
dialkylamines catalyzed by nickel.2 Late transition metal-
catalyzed, amine-induced telomerizations of butadiene1 and
oxidative 1,4 addition of nucleophiles to dienes3 are now well
known, and the palladium-catalyzed additions of amines to more
reactive eneynes4 and allenes5 have been reported. However,
reactions of dienes with amines generally occur at high temper-
atures and produce isomeric mixtures.1c,f,g We report the use of a
high-throughput colorimetric assay to identify catalysts for the
regioselective 1:1 hydroamination of dienes at room tempera-
ture.6,7 The scope of the diene hydroamination is broad and
includes enantioselective examples.
Figure 1. Use of a simple spot test to screen catalysts for the
hydroamination of cyclohexadiene with aniline. A red color indicates
remaining aniline reactant.
Table 1. Pd-Catalyzed Addition of Arylamines to Cyclohexadienea
To evaluate simultaneously a large number of potential catalysts
for the hydroamination, we developed a colorimetric method to
monitor the presence or absence of anilines. Furfural undergoes
a condensation and ring opening with 2 equiv of aniline, but not
with the allylic amine product, in the presence of acid to create
a red product.8 Thus, addition of furfural and acid to catalytic
reactions of aromatic amines will reveal which catalysts are most
active; reactions that consume the largest amount of aniline will
show an absence of the red color. Typically, the reactions were
diluted to distinguish the colors.
Figure 1 displays the results of this colorimetric assay for the
reaction of aniline with cyclohexadiene. A set of potential catalysts
generated from commercially available coordination complexes
and common phosphines was assembled from stock solutions in
a 96-well glass plate prior to the addition of reactants. Acids have
been shown to inhibit telomerization of butadiene, eneynes, and
allenes. Thus, we conducted reactions in the presence and absence
of 10 mol % of TFA. After 4 h, some reactions conducted in the
presence of acid showed, by the colorimetric assay, complete
conversion of aniline, while reactions in the absence of acid
required longer times to observe reaction. GC/MS analysis of
solutions showing conversion of aniline indicated formation of
(1) (a) For a review on telomerizations, see: Behr, A. Aspects of
Homogeneous Catalysis; Kluwer: Dordrecht, The Netherlands, 1984; Vol. 5,
pp 3-73. (b) Takahashi, S.; Shibano, T.; Hagihara, N. Bull. Chem. Soc. Jpn.
1968, 41, 454-460. (c) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem.
Soc. Jpn. 1972, 45, 1183-1191. (d) Patel, B. A.; Dickerson, J. E.; Heck, R.
F. J. Org. Chem. 1978, 43, 5018-5020. (e) Beger, J.; Meier, F. J. Prakt.
Chem. 1980, 322, 69-80. (f) Armbruster, R. W.; Morgan, M. M.; Schmidt,
J. L.; Lau, C. M.; Riley, R. M.; Zabrowski, D. L.; Dieck, H. A. Organome-
tallics 1986, 5, 234-237. (g) Petrushkina, E. A.; Zakharkin, L. I. IzV. Akad.
Nauk Ser. Khim. 1992, 8, 1794-1798. (h) For a recent contribution on
telomerizations, see: Maddock, S. M.; Finn, M. G. Organometallics 2000,
19, 2684-2689.
a Reaction conditions: 0.5 mmol amine, 2 mmol cyclohexadiene, 2
mol % Pd(PPh3)4, 10 mol % TFA, toluene, 25 °C, 24 h. bYields are for
c
pure, isolated compounds and are an average of two runs. Reaction
time: 48 h. dReaction conditions: 2.5 mol % [Pd(π-allyl)Cl]2, 10 mol
% PPh3, toluene, 100 °C, 24 h.
1:1 adducts without telomerization. These experiments showed
that complexes formed from [Pd(π-allyl)Cl]2 and PPh3 were the
most active (Figure 1). These two materials are known to form
PPh3-ligated Pd(0),9 and NMR experiments in THF showed
formation of Pd(PPh3)4 immediately upon mixing. Thus, we used
the readily available Pd(PPh3)4 for preparative-scale reactions.
Table 1 shows results from preparative reactions containing 2
mol % Pd(PPh3)4 and 10 mol % TFA as catalyst and cocatalyst.
Reactions were typically run at room temperature in toluene for
24 h, but shorter times could be used. All reactions occurred in
high yield regardless of the presence of an electron-withdrawing,
electron-donating, or ortho substituent on the aniline. Both the
electron-rich (entries 7, 9) and electron-poor anilines (entries 5,
6) gave the addition products in high yields, although reactions
(2) (a) Andell, O. S.; Ba¨ckvall, J.-E.; Moberg, C. Acta Chem. Scand. B
1986, 40, 184-189. (b) Dzhemilev, U. M.; Yakupova, A. Z.; Tolstikov, G.
A. IzV. Akad. Nauk. SSSR, Ser. Khim. 1976, 2346-2348.
(3) Ba¨ckvall, J. E. Acc. Chem. Res. 1983, 16, 335-342.
(4) Radhakrishnan, U.; Al-Masum, M.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 1037-1040.
(5) Al-Masum, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1997,
38, 6071-6075.
(6) For a review on Combinatorial Chemistry in Material Science and
Catalysis, see: Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem., Int. Ed. Engl. 1999, 38, 2494-2532.
(7) Lavastre, O.; Morken, J. P. Angew. Chem., Int. Ed. Engl. 1999, 38,
3163-3165.
(8) Feigl, F. In QualitatiVe Analysis by Spot Tests; Elsevier: New York,
Amsterdam, 1946; p 383.
(9) Barnard, C. F. J.; Russell, M. J. H. In ComprehensiVe Organometallic
Chemistry; G. Wilkinson, Gillard, R. D., McCleverty, J. A., Eds.; Pergamon
Press: Oxford, 1987; Vol. 5, p 1101.
10.1021/ja005881o CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/13/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 18, 2001 4367
Table 2. Reactions of Arylamines with Various Dienes
Table 3. Enantioselective Addition of Arylamines to
Cyclohexadiene
a Yields are for pure, isolated compounds and are an average of two
runs. bReaction conditions: 0.5 mmol amine, 2 mmol diene, 1 mol %
entry
amine
ligand
(R,R)-1
(R,R)-Trost 1.2
(R)-BINAP 1.2
(S,S)-DIOP 1.2
(S,S)-BDPPe 1.2
(R,R)-1
(R,R)-1
(R,R)-1
(R,R)-1
(R,R)-1
M
time (h) yielda(%) eeb(%)
c
Pd(PPh3)4, 50 mol % acetic acid. Same reaction conditions except 2
1c PhNH2
1.2
72
72
61
65
99
84
31
94
87
63
78
59
83
73
91 (S)
11 (S)
7 (R)
d
mol % Pd(PPh3)4, 10 mol % TFA. 6% of diallylamine obtained for
2c PhNH2
3c PhNH2
e
this reaction with excess diene. Four-fold excess of aniline used.
72
72
4c PhNH2
4 (R)
5c PhNH2
72
72
34 (R)
50 (S)
89 (S)
92 (S)
86 (S)
90 (S)
95 (S)
95 (S)
of the electron-poor anilines required longer times. Reaction of
o-toluidine, o-anisidine, o-bromoaniline, and 1-aminonaphthalene
showed that ortho substituents are tolerated. Addition of N-
alkylanilines also occurred under standard conditions (entries 15,
16). However, pyridylamines reacted only in the absence of acid
cocatalyst. Reactions at 100 °C containing [Pd(π-allyl)Cl]2/PPh3
as catalyst gave high yields of the pyridylamine products (entries
13, 14). Anisyl groups can be removed by oxidation;10 thus, the
reactions of anisidine and N-alkyl anisidine are the synthetic
equivalent of adding ammonia or primary alkylamines.
The scope of the process for different 1,3-dienes is provided
in Table 2. Cycloheptadiene reacted slower than cyclohexadiene
but gave good yields. Cyclooctadiene did not react under the
standard conditions. Reactions of acyclic dienes occurred in good
yields in many cases, but the scope was less straightforward than
that for cyclic dienes. The reaction of aniline with 2,3-dimethyl-
1,3-butadiene formed the 1:1-adduct as the major product, and
formation of the competing N,N-diallylamine product was sup-
pressed by adding a four-fold excess of aniline. Isoprene reacted
with aniline and N-methylaniline to give almost exclusively a
single product from reaction at the less hindered end of the diene,
whereas butadiene gave complex reaction mixtures.
6c PhNH2
neat
1.2
0.6
1.2
1.2
1.2
1.2
7d PhNH2
120
120
120
120
120
120
8d PhNH2
9d p-MeC6H4NH2
10d o-MeC6H4NH2
11d p-EtO2CC6H4NH2 (R,R)-1
12d p-F3CC6H4NH2
(R,R)-1
a Yields are for pure, isolated compounds. bValues for ee were
determined by chiral HPLC; assignment of absolute configuration by
comparison with retention time of product synthesized by arylation of
commercially available (S)-2-cyclohexen-1-amine with phenyl bromide
applying a previously reported method (arylation of chiral amines:
Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 8451-8458; of allylic amines: Wolfe, J. P.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1144-1157). cReaction conditions: 0.25 mmol
aniline, 1 mmol cyclohexadiene, 2.5 mol % [Pd(π-allyl)Cl]2, 5 mol %
ligand, RT. dReaction conditions: 0.125 mmol aniline, 0.5 mmol
cyclohexadiene, 5 mol % [Pd(π-allyl)Cl]2, 11 mol % ligand, RT.
e(2S,4S)-(-)-2,4-Bis(diphenylphosphino)pentane.
Scheme 1. Possible Mechanisms for the Hydroamination in
the Absence and Presence of Acid
Studies at low catalyst loadings showed complete conversion
after 24 h at room temperature when using only 0.5 mol % Pd
and 1 mol % TFA. Complete conversion was even observed when
we used 0.01 mol % Pd and 0.02 mol % TFA at room
temperature, although after the long reaction time of 7 d.
With a catalyst system for reaction of a broad range of
arylamines in hand, we sought an enantioselective version of this
process. Preliminary experiments with added TFA, various
optically active phosphines instead of PPh3, and [Pd(π-allyl)Cl]2
as catalyst precursors showed good conversions but little or no
stereoselection. Although slower, the reaction without added acid
containing a catalyst comprised of [Pd(π-allyl)Cl]2 and Trost’s
ligand 1,11a a naphthyl version of the parent ligand in entry 2,11b
showed a promising combination of stereoselection and conver-
sion. Optimization of reaction conditions showed that 5 mol %
[Pd(π-allyl)Cl]2 and 11 mol % ligand 1 at 1.25 mM in THF
solvent at room temperature provided the highest combination
of yield and enantioselectivity for a broad range of arylamines
(entries 7, 9-12). Higher temperatures provided lower final
conversions, presumably because of catalyst deactivation. Moni-
toring of the reaction by HPLC showed that the enantioselectivity
was constant throughout the reaction, demonstrating that the
process is favorable enough thermodynamically, even without
telomerization, to be irreversible. Applying the same conditions
to the reaction of cycloheptadiene gave the 1,4 addition product
in 22% yield with 66% ee (Table 3).
acid could be initiated by formation of an allylic acetate or
benzoate, which would undergo a well-known allylic amination.12
However, benzoic, acetic, and trifluoroacetic acids do not react
with cyclohexadiene at room temperature in the presence of amine.
Moreover, hydroamination occurred without acid cocatalyst when
the catalyst contained PPh3 or 1 as ligand, although the reactions
were slower. Thus, the reactions do not involve allylic carboxylate
intermediates. We present two plausible pathways in Scheme 1;
some different steps have been proposed for telomerizations. The
first path involves attack on an η2-diene complex by amine to
form an allylpalladium product that can undergo proton transfer
to produce free allylic amine. This mechanism is related to one
presented and supported by unpublished data in a review by
Jolly.13 The second mechanism involves insertion of diene into a
palladium hydride and nucleophilic attack on the resulting allyl.
Perhaps the first mechanism occurs in the absence of acid
cocatalyst, while the second occurs with acid cocatalyst.
Experiments to distinguish these mechanisms, to develop
catalysts for additions of aliphatic amines, and to use organic spot
tests for reaction discovery will be performed in the future.
Initial mechanistic studies have evaluated the role of the acid
cocatalyst. We considered that the reaction in the presence of
Acknowledgment. We thank the NIH (R29-GM55382), DOE (DE-
FG02-96ER14678), and DuPont for support of this work. O.L. also thanks
the Deutsche Forschungsgemeinschaft for a postdoctoral fellowship.
(10) Yao, S.; Saaby, S.; Hazell, R. G.; Jørgensen, K. A. Chem. Eur. J.
2000, 6, 2435-2448.
Supporting Information Available: Spectroscopic and analytical data
of new compounds and information on procedures (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) (a) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996, 35,
99-102. (b) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed. Engl.
1992, 31, 228-230.
(12) Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689-1708.
(13) Jolly, P. W. Angew. Chem., Int. Ed. Engl. 1985, 24, 283-295.
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