Synthesis of N,N-dialkyl-N′-arylhydrazines via palladium-catalyzed N-arylation by using N,N-dialkylhydrazines/2LiCl adducts

Article abstract of DOI:10.1021/ol050130i

(Chemical Equation Presented) The reaction of N,N-dialkylhydrazine/2LiCl adducts with aryl bromides in the presence of Pd₂(dba)₃ as the palladium source, Xantphos or X-phos as the ligands, toluene as the solvent, and NaOBu-t as the b

Full text of DOI:10.1021/ol050130i

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1497-1500
Synthesis of
N,N-Dialkyl-N
′
-arylhydrazines via
Palladium-Catalyzed N-Arylation by
Using N,N-Dialkylhydrazines/2LiCl
Adducts
Sandro Cacchi,*,† Giancarlo Fabrizi,† Antonella Goggiamani,† Emanuela Licandro,‡
Stefano Maiorana,‡ and Dario Perdicchia‡
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy, and
Dipartimento di Chimica Organica e Industriale, UniVersita` degli Studi di Milano,
Via C. Golgi 19, 20133 Milano, Italy
sandro.cacchi@uniroma1.it
Received January 20, 2005
ABSTRACT
The reaction of N,N-dialkylhydrazine/2LiCl adducts with aryl bromides in the presence of Pd2(dba)3 as the palladium source, Xantphos or
X-phos as the ligands, toluene as the solvent, and NaOBu-t as the base provides an efficient route to N,N-dialkyl-N
′-arylhydrazines. Best
results were obtained by using N,N-dialkylhydrazine/2LiCl adducts prepared in situ, omitting their isolation.
The development of the palladium-catalyzed N-arylation
process by Buchwald1 and Hartwig2 has provided a powerful
tool for the functionalization of a wide range of nitrogen-
containing derivatives from readily available aryl halides and
triflates. However, despite the huge amount of work done
in this area,3 the utilization of this procedure for the
N-arylation of hydrazines has received little attention. To
the best of our knowledge, hydrazines have been subjected
to palladium-catalyzed N-arylation processes in intra-
molecular cyclizations to give 2-aryl-2H-indazoles,4 1-aryl-
1H-indazoles,5 and indole[1,2-b]indazoles.6 An intermolecu-
lar N-arylation of N-substituted and N,N-disubstituted hy-
drazines has also been reported.7 However, whereas the
reaction of aryl halides with N-aryl and N,N-diarylhydrazines
has usually been found to give arylation products in good to
high yields, unsatisfactory results were obtained with N,N-
dialkylhydrazines. For example, bromobenzene and N,N-
dimethylhydrazine gave the desired N,N-dimethyl-N′-phen-
ylhydrazine in only 24% yield.7 Other work involving
(3) For some reviews, see: (a) Shlummer, B.; Sholz, U. AdV. Synth. Catal.
2004, 346, 1599. (b) Prim, D.; Campagne, J. M.; Joseph, D.; Andrioletti,
B. Tetrahedron 2002, 58, 2041. (c) Hartwig, J. F. Pure Appl. Chem. 1999,
71, 1417. (d) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125. (e) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (f) Wolfe, J.
P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805. (g) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (h) Hartwig,
J. F. Synlett 1997, 329. (i) Baranano, D.; Mann, G.; Hartwig, J. F. Curr.
Org. Chem. 1997, 1, 287. For some recent references on the substitution of
Caryl-halogen bonds with Caryl-N bonds, see: (j) Ferreira, I. C. F. R.;
Queiroz, M.-J. R. P.; Kirsch, G. Tetrahedron 2003, 59, 3737. (k) Urgaonkar,
S.; Nagarajan, M.; Verkade, J. G. J. Org. Chem. 2003, 68, 452. (l) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (m) Maes, B. U. W.;
Loones, K. T. J.; Jonckers, T. H. M.; Lemiere, G. L. F.; Dommisse, R. A.;
Haemers, A. Synlett 2002, 1995.
† Universita` degli Studi “La Sapienza”.
(4) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519.
‡ Universita` degli Studi di Milano.
(5) Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937.
(6) Zhu, J.-m.; Kiryu, Y.; Katayama, H. Tetrahedron Lett. 2002, 43, 3577.
(7) Buchwald, S. L.; Wagaw, S.; Geis, O. WO 9943643, 1999; Chem.
Abstr. 1999, 131, 199501.
(1) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348.
(2) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
10.1021/ol050130i CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/18/2005

hydrazine derivatives that could be used to prepare N,N-
dialkyl-N′-arylhydrazines has been described,8 but in those
cases, two or more steps would be needed. On the other hand,
N,N-dialkyl-N′-arylhydrazines are useful synthetic intermedi-
ates,9 and most of them exhibit important biological activities,
acting as inhibitors of ileal bile acid transport,10 herbicides,11
interleukine-8 receptor antagonists,12 antibacterial agents,13
and inhibitors of the coagulation cascade.14
Thus, the development of a simple and general procedure
for the direct preparation of this class of compounds would
be greatly desirable. Hereafter, we report just such a process,
involving the palladium-catalyzed reaction of aryl bromides
2 with N,N-dialkylhydrazine/2LiCl adducts 1 (Scheme 1).
Scheme 1
Figure 1.
to be clearly superior to Cs2CO3 (Table 1, compare entry 4
with entry 5) and to give higher yields than KOBu-t (Table
1, compare entry 4 with entry 6). However, even under the
best conditions, the desired hydrazine derivative was isolated
in moderate yields, one of the main side reactions being the
formation of biphenyl, derived from the reduction of p-
(phenyl)bromobenzene. Though further studies are needed
to provide a detailed mechanism for this reduction reaction,
on the basis of previous studies on the formation of arenes
in palladium-catalyzed amination of aryl bromides16 and the
reduction of σ-alkylpalladium intermediates by tertiary
amines,17 we surmised that the main reaction pathway for
the formation of reduction byproducts might involve coor-
dination of the disubstituted nitrogen atom to the σ-aryl-
palladium intermediate formed in situ. According to this
Initial studies were directed toward finding a general set
of reaction conditions that could be applied to a variety of
N,N-dialkylhydrazines and aryl bromides. N,N-Dimethyl-
hydrazine and p-(phenyl)bromobenzene were selected as the
model system, and the influence of ligands, bases, and LiCl
was examined. Some results from that study are summarized
in Table 1.
Table 1. Ligands, Bases, and LiCl in the Palladium-Catalyzed
Synthesis of N,N-Dimethyl-N′-(p-phenylphenyl)hydrazine 3aa
% yieldb
entry
ligand
dppf
BINAP
MOP
base
hydrazine (equiv) time (h)
of 3a
(10) (a) Lee, L. F.; Banerjee, S. C.; Huang, H. C.; Li, J. J.; Miller, R.
E.; Reitz, D. B.; Tremont, S. J. U.S. Patent 831, 284, 2004; Chem. Abstr.
2004, 140, 111291. (b) Keller, B. T.; Glenn, K. C.; Manning, R. E. U.S.
Patent 831,284, 2001; Chem. Abstr. 2001, 135, 137410. (c) Lee, L. F.;
Banerjee, S. C.; Huang, H.-C.; Li, J. J.; U.S. Patent 109,551, 2000; Chem.
Abstr. 2000, 133, 193089. (d) Reitz, D. B.; Lee, L. F.; Li, J. J.; Huang,
H.-C.; Tremont, S. J.; Miller, R. E.; Baneriee, S. C.; Manning, R. E.; Glenn,
K. C.; Keller, B. T. WO 9840375, 1998; Chem. Abstr. 1998, 129, 260353.
(e) Reitz, D. B.; Lee, L. F.; Li, J. J.; Huang, H.-C.; Tremont, S. J.; Miller,
R. E.; Banerjee, S. C. WO 9733882, 1997; Chem. Abstr. 1997, 127, 307312.
(11) (a) Kajita, S.; Ishii, M.; Satoh, A.; Koguchi, M. WO 2003062195,
2003; Chem. Abstr. 2003, 139, 279230. (b) Sanemitsu, Y.; Tohyama, Y.
WO 2000021936, 2000; Chem. Abstr. 2000, 132, 279230.
(12) Low, J. E.; Trivedi, B. K. WO 9942464, 1999; Chem. Abstr. 1999,
131, 179809.
(13) Ascher, G.; Berner, H.; Hildebrandt, J. WO 2001009095, 2001;
Chem. Abstr. 2001, 134, 147722.
(14) South, M. S.; Parlow, J. J. WO 2001079155, 2001; Chem. Abstr.
2001, 135, 318330.
1
2
3
4
5
6
7
8
9
NaOBu-t Me2NNH2 (1.2)
NaOBu-t Me2NNH2 (1.2)
NaOBu-t Me2NNH2 (1.2)
24
7
8
4
24
12
24
6.5
7
c
50d
11
Xantphos NaOBu-t Me2NNH2 (1.2)
Xantphos Cs2CO3 Me2NNH2 (1.2)
55e
traces
32
Xantphos KOBu-t Me2NNH2 (1.2)
Xantphos NaOBu-t Me2NNH2 (2)
Xantphos NaOBu-t Me2NNH2/2LiCl (2)
40
75f
BINAP
NaOBu-t Me2NNH2/2LiCl (2)
54g
a Unless otherwise stated, reactions were carried out on a 0.563 mmol
scale in 2 mL of toluene at 80 °C under argon using 1 equiv of
p-(phenyl)bromobenzene, N,N-dimethylhydrazine (as shown in table), 0.025
equiv of Pd2(dba)3, 0.05 equiv of bidentate ligand, and 1.4 equiv of base.
b Yields are given for isolated products. c Pd(OAc)2 (0.05 equiv) was used.
d Starting bromide was recovered in 16% yield. e Biphenyl was isolated in
30% yield. f Biphenyl was isolated in 4% yield. g Starting bromide was
recovered in 42% yield.
(15) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kramer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081. For recent reviews on the use of Xantphos ligands in transition metal-
catalyzed reactions, see: (b) van Leeuwen, P. W. N. M.; Kramer, P. C. J.;
Reek, J. N. H.; Dierkes, P. Chem ReV. 2000, 100, 2741. (c) Kramer, P. C.
J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc. Chem. Res. 2001, 34,
895.
(16) For some references, see: (a) Beletskaya, I. P.; Bessmertnykh, A.
G.; Guilard, R. Tetrahedron Lett. 1999, 40, 6393. (b) Hamann, B. C.;
Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 3694. (c) Marcoux, J.-F.;
Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1568. (d) Driver, M.
S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217. (e) Hartwig, J. F.;
Richards, S.; Baran˜ano, D.; Paul, F. J. Am. Chem. Soc. 1996, 118, 3626.
(f) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1348.
The reaction of N,N-dimethylhydrazine with p-(phenyl)-
bromobenzene in the presence of Pd2(dba)3, NaOBu-t, and
BINAP or Xantphos15 (Figure 1) in toluene at 80 °C afforded
similar results (Table 1, entries 2 and 4). NaOBu-t proved
(8) (a) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 10252. (c) Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett.
1999, 40, 3543.
(9) Hojo, M.; Masuda, R.; Okada, E.. Synthesis 1990, 481.
1498
Org. Lett., Vol. 7, No. 8, 2005

working hypothesis, preventing this coordination could
minimize the observed side reaction.
involved in the reaction as reactive species. The efficiency
of N,N-dialkylhydrazine/2LiCl adducts, however, was found
to decrease on standing, very likely because of the hygro-
scopic nature of the adducts. For example, when the reaction
reported in entry 7 (Table 2) was repeated after 3 days using
the same batch of 1-aminopiperidine/2LiCl adduct, com-
pound 3g was isolated only in 37% yield.
Therefore, on the basis of the results obtained by some of
us in the reaction of hydrazine/2LiCl adducts with tungsten
and chromium Fischer-type carbene complexes,18 wherein
it was shown that the reduced nucleophilic character of the
â-nitrogen of dialkylhydrazines has a beneficial effect on
the hydrazinolysis of Fischer-type oxacarbenes, we decided
to investigate the use of N,N-dimethylhydrazine/2LiCl ad-
duct. This adduct was prepared according to the previously
described protocol,18 adding 1 equiv of N,N-dimethylhydra-
zine to an anhydrous THF solution of LiCl (2 equiv) at room
temperature. The resulting white solid was subjected to
N-arylation conditions. We were pleased to find that, with
Xantphos as the ligand, compound 3a could be isolated in
75% yield (Table 1, entry 8). Biphenyl was isolated only in
4% yield (30% yield under the same conditions using N,N-
dimethylhydrazine; Table 1, entry 4). Interestingly, in contrast
to reactions carried out with N,N-dimethylhydrazine (Table
1, entries 2 and 4), with the N,N-dimethylhydrazine/2LiCl
adduct BINAP gave results significantly different from
Xantphos. In fact, the use of BINAP afforded the desired
product in a yield similar to that obtained with N,N-
dimethylhydrazine (Table 1, compare entry 2 with entry 9).
Other hydrazine/2LiCl adducts and aryl bromides were
subjected to the best conditions found (Table 1, entry 8),
and the results obtained are shown in Table 2. Entries 7 and
Consequently, we turned our attention to exploring the use
of N,N-dialkylhydrazine/2LiCl adducts generated in situ,
Table 3. Palladium-Catalyzed Synthesis of
N,N-Dialkyl-N′-arylhydrazines 3 Omitting the Isolation of
N,N-Dialkylhydrazine/2LiCl Adducts 1a
Table 2. Palladium-Catalyzed Synthesis of
N,N-Dialkyl-N′-arylhydrazines 3 from Aryl Bromides 2 and
N,N-Dialkylhydrazine/2LiCl Adducts 1a
a Reactions were carried out on a 0.563 mmol scale in 2 mL of toluene
at 80 °C under argon using 1 equiv of aryl bromide, 2 equiv of hydrazine/
2LiCl adduct, 0.025 equiv of Pd2(dba)3, 0.05 equiv of Xantphos, and 1.4
equiv of NaOBu-t. b Yields are given for isolated products. c When the
reaction was carried out with 1-aminopiperidine, 3g was isolated in 41%
yield after 28 h. d When the reaction was carried out with 4-aminomor-
pholine, 3h was isolated in 51% yield after 24 h.
a Unless otherwise stated, reactions were carried out on a 0.563 mmol
scale as follows: 1 equiv of N,N-dialkylhydrazine and 2 equiv of LiCl in
3 mL of anhydrous THF for 1 h at room temperature, and then 2 mL of
toluene, 1 equiv of aryl bromide, 0.025 equiv of Pd2(dba)3, 0.05 equiv of
Xantphos, and 1.4 equiv of NaOBu-t were added under argon and the
temperature was raised to 80 °C. b Yields are given for isolated products.
c With 0.1 equiv of X-phos. d With 0.1 equiv of 4. e With 0.1 equiv of 5.
f Corresponding N,N-diarylaminopiperidine was isolated in 40% yield.
g Corresponding N,N-diarylaminomorpholine was isolated in 15% yield.h In
the absence of LiCl, the yield was 51%.
8 (see also Table 1 footnotes c and d) highlight further the
efficiency of the protocol based on the use of N,N-
dialkylhydrazine/2LiCl adducts, which, most probably, are
Org. Lett., Vol. 7, No. 8, 2005
1499

omitting their isolation. N,N-Dialkylhydrazine/2LiCl adducts
were prepared as usual. After evaporation of THF, toluene,
the aryl bromide, the catalyst system, and the base were
immediately added to the resulting white solid, and the
reaction mixture was warmed to 80 °C.
the use of some commercially available Buchwald biaryl
phosphines (Figure 1) and observed that the air stable X-phos
can provide higher yields than ligands 4, 5, and Xantphos
(Table 3, compare entry 5 with entries 4, 6, and 7; compare
also entry 4 of Table 2 with entry 3 of Table 3). Clearly,
there is room for optimization, and this further experimenta-
tion showed that an appropriate choice of the stabilizing
ligand for a particular case of importance may lead to a
significant increase of the yields.
Under these conditions, aryl bromides reacted efficiently
with adducts derived from 1-aminopiperidine and 1-amino-
morpholine. As shown in Table 3, the corresponding N,N-
dialkyl-N′-arylhydrazines were usually isolated in good to
high yields. The reaction proceeds efficiently with aryl
bromides containing both electron-donating and electron-
withdrawing substituents. Notably, the one-pot protocol
affords higher yields than the stepwise protocol (compare
entries 8 and 14 of Table 3 with entries 7 and 8 of Table 2,
respectively). In some cases, N,N-dialkyl-N′,N′-diaryl deriva-
tives were isolated in significant yield (Table 3, entries 9
and 17). With the N,N-dimethylhydrazine/2LiCl adduct,
compounds 3 were isolated in yields similar to those achieved
in the stepwise protocol (compare entries 2 and 4 of Table
3 with entries 3 and 6 of Table 2, respectively). We then
went back and examined the influence of additional ligands
on the reaction outcome. Particularly, we briefly explored
In summary, we have demonstrated that the reaction of
N,N-dialkylhydrazine/2LiCl adducts with aryl bromides in
the presence of Pd2(dba)3 as the palladium source, Xantphos
or X-phos as the ligands, toluene as the solvent, and NaOBu-t
as the base provides an efficient route to N,N-dialkyl-N′-
arylhydrazines. The method merits attention because of the
good to high yields usually observed, the use of simple and
readily available starting materials, and the simplicity of the
experimental procedure.
Acknowledgment. This work was supported by the
Ministero dell’Istruzione, dell’Universita` e della Ricerca
(MIUR) and the Universita` degli Studi “La Sapienza”.
(17) For some examples, see: (a) Cacchi, S.; Fabrizi, G.; Gasparrini,
F.; Pace, P.; Villani, C. Synlett 2000, 650. (b) Friestad, G. K.; Branchaud,
B. P. Tetrahedron Lett. 1995, 36, 7047. (c) Stokker, G. E. Tetrahedron
Lett. 1987, 28, 3179. (d) Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi,
S.; Cerrini, S.; Fedeli, W.; Ortar, G. Tetrahedron 1989, 45, 813. (e) Cacchi,
S.; Arcadi, A. J. Org. Chem. 1983, 48, 4236
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Licandro, E.; Maiorana, S.; Papagni, A.; Perdicchia, D.; Manzotti,
R. Chem. Commun. 1999, 925.
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