The synthesis of aminopyridines: A method employing palladium-catalyzed carbon-nitrogen bond formation

Full text of DOI:10.1021/jo9612739

7240
J . Org. Chem. 1996, 61, 7240-7241
Sch em e 1
Th e Syn th esis of Am in op yr id in es: A
Meth od Em p loyin g P a lla d iu m -Ca ta lyzed
Ca r bon -Nitr ogen Bon d F or m a tion
Seble Wagaw‡ and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
amidopalladium intermediate and the formation of bis-
(amine) complexes that lead to products of hydrodebro-
mination. We have found that this catalyst system is
also effective with pyridine-containing substrates for a
different reason. We have found that the chelating bis-
(phosphine) does not undergo ligand exchange with
excess pyridine, and consequently, the formation of bis-
(pyridine) complexes, which terminate the catalytic cycle,
is prevented.22a Here, we report the use of these chelat-
ing bis(phosphine)/Pd complexes as catalysts for the
amination of halopyridines to form 2-, 3-, or 4-substituted
aminopyridines under mild conditions and in good to
excellent yields. This work constitutes the first example
of a palladium-mediated amination of haloheteroaromatic
substrates.
Mixtures of the chelating bis-(phosphine) ligand 1,3-
bis(diphenylphosphino)propane (dppp) and Pd2(dba)3 gen-
erated an effective catalyst for coupling 2-bromopyridine
with primary amines that do not contain R-hydrogens
and with secondary amines (Table 1, entries 1-3). For
example, the reaction of 2-bromopyridine with N-benzyl-
methylamine (1.2 equiv) and sodium tert-butoxide (1.4
equiv) employing a catalytic mixture of Pd2(dba)3 (2 mol
%) and dppp (4 mol %) in toluene at 70 °C for 3 h gave,
after workup and purification, 2-(N-benzyl-N-methylami-
no)pyridine in 86% yield (Table 1, entry 1). However,
this catalyst system was not completely general. Neither
3-bromopyridine nor primary amines that contained
R-hydrogen atoms were effectively cross-coupled.23 In
contrast to the dppp-derived catalyst, the catalyst gener-
ated from Pd2(dba)3 and (()-2,2′-bis(diphenylphosphino)-
1,1′-binaphthyl [(()-BINAP] was generally effective for
the cross-coupling of a wide variety of substrates includ-
ing that of 3-bromopyridine with both primary and
secondary amines (Table 1, entries 5-9). In the case of
unbranched primary amines such as n-hexylamine, both
the mono- or diarylated amine could be obtained selec-
tively. For example, the procedure employing a 3:1 ratio
of n-hexylamine:2-bromopyridine produced the monoary-
lated product in 74% yield (Table 2, entry 1). In contrast,
the procedure which used a 2-fold excess of 2-bromopy-
ridine relative to amine, gave the diarylated compound
in 71% yield (Table 2, entry 2). Additionally, trans-1,2-
diaminocyclohexane, upon treatment with excess 2-bro-
mopyridine (3 equiv) gives the triarylated diamine (Table
2, entry 3), without formation of the corresponding
tetrapyridyl derivative. Clean formation of 2,2′-dianili-
nopyridine occurred when 2,2′-dibromopyridine was heated
with excess aniline. In thiscase the initial coupling step
is considerably more facile than the second addition
(Table 2, entry 5).
Received J uly 9, 1996
Aminopyridines are important in various fields of
chemistry. They have been used as acyl transfer re-
agents in organic chemistry1,2 and as ligands in inorganic
and organometallic chemistry.3-7 Additionally, amino-
pyridine derivatives have been used as fluorescent dyes8,9
and are biologically important as central nervous system
stimulants.10 Current methods for the preparation of
aminopyridines generally involve nucleophilic aromatic
substitution of a pyridine substrate. However, these
methods typically produce only modest yields of the
desired aminopyridine, require activated substrates, and
often require harsh reaction conditions.11-15
Palladium(0)/P(o-tolyl)3 complexes are effective cata-
lysts for the cross-coupling of aryl bromides and ami-
nostannanes and for the cross-coupling of aryl halides
and amines in the presence of sodium tert-butoxide.16-18
Unfortunately, attempts to extend this protocol to the
amination of bromopyridines were unsuccessful. It has
been shown that pyridine inhibits the Pd(0)/P(o-tolyl)3-
catalyzed amination of aryl bromides19 and also displaces
a P(o-tolyl)3 ligand from key catalytic intermediates such
as the oxidative addition product 1 to form complexes
such as bis(pyridyl) derivative 2 (Scheme 1).20
We have recently reported a palladium-catalyzed pro-
cedure for the cross-coupling of aryl bromides and
primary amines that employed chelating bis-(phosphine)
ligands.21 The efficiency of this system is presumably due
to the ability of the chelating phosphine ligand to inhibit
side reactions such as â-hydride elimination from an
‡ Ford Foundation Predoctoral Fellow.
(1) Steglich, W.; Ho¨fle, G. Angew. Chem., Int. Ed. Engl. 1969, 8,
981.
(2) Ho¨fle, G.; Steglich, W. Synthesis 1972, 619.
(3) Kempe, R.; Arndt, P. Inorg. Chem. 1996, 35, 2644-2649.
(4) Nagao, N.; Mukaida, M.; Tachiyashiki, S.; Mizumachi, K. Bull.
Chem. Soc. J pn. 1994, 67, 1802.
(5) Maekawa, M.; Munakata, M.; Sow, T. K.; Hachiya, K. Inorg.
Chim. Acta 1994, 227, 137.
(6) Ranninger, M. C. N. Acta. Crystallogr. 1985, C41, 21.
(7) Alvila, L.; Pakkanen, T. A. J . Mol. Catal. 1993, 84, 145.
(8) Sathyamoorthi, G.; Soong, M. L.; Ross, T. W.; Boyer, J . H.
Heteroatom. Chem. 1993, 4, 603.
(9) Araki, K.; Mutai, T.; Shigemitsu, Y.; Yamada, M.; Nakajima, T.;
Kuroda, S.; Shimao, I. J . Chem. Soc., Perkin Trans. 2 1996, 613-617.
(10) Lechat, P.; Tesleff, S.; Bownan, W. C. Aminopyridines and
Similarly Acting Drugs; Pergamon Press: Oxford, NY, 1982.
(11) Vorbruggen, H. Advances in Amination of Nitrogen Heterocycles;
Academic Press: San Diego, 1990; Vol. 49.
(12) Gupton, J . T.; Idoux, J . P.; Baker, G.; Colon, C.; Crews, A. D.;
J urss, C. D.; Rampi, R. C. J . Org. Chem. 1983, 48, 2933.
(13) Pedersen, E. B.; Carlsen, D. Synthesis 1978, 844.
(14) Patel, K. M.; Sparrow, J . T. Synth. Commun. 1979, 9, 251.
(15) Vorbruggen, H. Synthesis 1973, 301.
(16) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.
(17) Paul, F.; Patt, J .; Hartwig, J . F. J . Am. Chem. Soc. 1994, 116,
5969.
(18) Guram, A. S.; Rennels, R. R.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348.
(19) Wagaw, S.; Buchwald, S. L. Unpublished results.
(20) Paul, F.; Pratt, J .; Hartwig, J . Organometallics 1995, 14, 3030.
(21) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215-7216.
(22) (a) In an NMR tube pyridine (2.1 µL, 0.26 mmol) was added to
a solution of [(R)-Tol-BINAP]Pd(4-benzonitrile)(Br)22b (10 mg, 1 × 10-3
mmol) in CDCl3. The 1H NMR spectrum of the [(R)-tol-BINAP]Pd(4-
benzonitrile)(Br) complex remained unchanged. (b) Widenhoefer, R.
A.; Buchwald S. L. Unpublished results.
(23) These substrates instead afforded predominantly imine and
pyridine, presumably formed from â-hydride elimination of the corre-
sponding palladium-amido intermediate.
S0022-3263(96)01273-X CCC: $12.00 © 1996 American Chemical Society

Communications
Ta ble 1. P a lla d iu m -Ca ta lyzed F or m a tion of
J . Org. Chem., Vol. 61, No. 21, 1996 7241
Ta ble 2. Mu ltip le P a lla d iu m -Ca ta lyzed Cou p lin g
Rea ction s
Am in op yr id in es
i Yields refer to the average of two isolated yields of >95% purity
ii
as determined by GC, 1H NMR, and elemental analyses. Entry
iii-v
3 was run with 3 equiv of n-hexylamine.
Entries 2-4 were
vi
run with 2, 3, and 4 equiv of 2-bromopyridine. Two equiv of
aniline was used. Reaction conditions A employ 2 mol % Pd2(dba)3
and 4 mol % dppp. Reaction conditions B employ 2 mol %
Pd2(dba)3 and 4 mol % (()-BINAP.
amines. For example, attempts to couple di-n-butyl-
amine with 2-, 3-, or 4-bromopyridine or 2-chloropyridine
using various chelating bis(phosphine) ligands provided
only low yields of the (di-n-butylamino)pyridine.
In summary, palladium(0) complexes with chelating
bis(phosphines) effectively catalyze the amination of
halopyridines to form aminopyridines. This procedure24
represents a significant improvement relative to existing
procedures for the synthesis of aminopyridines. Acti-
vated substrates are not required, and relatively non-
nucleophilic amines such as primary amines and anilines
are efficiently arylated. This work also demonstrates a
second, distinct, scenario in which the use of catalysts
containing chelating bisphosphines in aromatic amina-
tions procedures is superior to employing those contain-
ing (o-tolyl)3P. In this instance, the chelating ligands
prevent formation of bis-pyridyl complexes that terminate
the catalytic cycle.
i Yields refer to the average of two isolated yields of >95% purity
ii
as determined by GC, 1H NMR, and elemental analysis. Three
equiv of n-hexylamine was used. Reaction conditions A employ 2
mol % Pd2(DBA)3 and 4 mol % dppp. Reaction conditions B employ
2 mol % Pd2(DBA)3 and 4 mol % (() BINAP. Reaction conditions
C employ 4 mol % Pd(OAc)2 and 4 mol % dppp. Reaction
conditions D employ 4 mol % Pd(OAc)2 and 4 mol % (()-BINAP.
Ack n ow led gm en t. We thank the National Science
Foundation and Pfizer for their support of this research
and Strem Chemicals for their generous gift of (()-
BINAP. S.W. is the recipient of a Ford Foundation
Fellowship. We thank Dr. Ross Widenhoefer for helpful
discussions.
Attempts to couple 4-bromopyridine hydrochloride or
2-chloropyridine with amines employing mixtures of Pd2-
(DBA)3 and either dppp or (()-BINAP were unsuccessful.
However, these substrates were efficiently transformed
when Pd(OAc)2 was employed as the palladium source.
For example, mixtures of Pd(OAc)2 and dppp catalyzed
the cross-coupling of 4-bromopyridine hydrochloride and
morpholine (Table 1, entry 11), while mixtures of Pd-
(OAc)2 and (()-BINAP effectively cross-coupled 2-chlo-
ropyridine and cyclohexylamine (Table 1, entry 4) and
also 4-bromopyridine hydrochloride and hexylamine (Table
1, entry 12). Pd(OAc)2 also served as a suitable pal-
ladium source for coupling reactions involving 2- and
3-bromopyridines.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all compounds (9 pages).
J O9612739
(24) A general procedure is as follows: Bromopyridine (1 mmol),
amine (1.2 mmol), Pd2(DBA)3 (0.02 mmol, 4 mol % Pd, 18 mg), 1,3-
bis(diphenylphosphino)propane (dppp, 0.04 mmol, 16 mg), NaO-t-Bu
(1.4 mmol, 134 mg), and toluene (0.11 M with 2-bromopyridine, 9 mL)
were added to an oven-dried Schlenk flask that was purged with argon
for approximately 5 min. The reaction mixture was then heated to 70
°C under argon until the bromopyridine was consumed as determined
by GC analysis. The reaction mixture was then allowed to cool to room
temperature, taken up in diethyl ether (10 mL), washed three times
with saturated brine (10 mL), dried over MgSO4, and concentrated in
vacuo to give the crude product. Purification by flash column chroma-
tography afforded the analytically pure product.
The major limitation of the Pd/(()-BINAP or dppp-
catalyzed amination protocol is the inability of this
system to cross-couple halopyridines with acyclic dialkyl-