Synthesis of N-aryl hydrazides by copper-catalyzed coupling of hydrazides with aryl iodides.

Article abstract of DOI:10.1021/ol0168216

[reaction--see text] A convenient method for intermolecular N-arylation of hydrazides with substituted aryl iodides in the presence of a copper catalyst and Cs(2)CO(3) is reported. The C-N coupling of N-Boc hydrazine with para- and meta-substituted aryl iodides afforded the N-arylated products A, regioselectively. A reversal in regioselectivity is observed for the arylation of benzoic hydrazide with ortho-substituted aryl iodides, providing the N'-arylated products B.

Full text of DOI:10.1021/ol0168216

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3803-3805
Synthesis of N-Aryl Hydrazides by
Copper-Catalyzed Coupling of
Hydrazides with Aryl Iodides
Martina Wolter, Artis Klapars, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received September 26, 2001
ABSTRACT
A convenient method for intermolecular N-arylation of hydrazides with substituted aryl iodides in the presence of a copper catalyst and
Cs2CO is reported. The C−N coupling of N-Boc hydrazine with para- and meta-substituted aryl iodides afforded the N-arylated products A,
3
regioselectively. A reversal in regioselectivity is observed for the arylation of benzoic hydrazide with ortho-substituted aryl iodides, providing
the N′-arylated products B.
N-Aryl hydrazides form an important class of organic
compounds with many applications in organic synthesis and
in industry.1 They are useful starting materials for the
synthesis of biologically active heterocycles, such as indoles,
carbazoles, pyrazoles, triazines, indazolones, and indazoles.2
N-Aryl hydrazides have traditionally been prepared by
reduction of N-nitrosoarylamines,3 formed by nitrosation of
anilines, or by electrophilic aminations of aryl Grignard
reagents,4b aryllithium reagents,4b,4c aryl zinc halides,4a and
electron-rich arenes5 with azodicarboxylates. These methods
often employ expensive reagents or substrates requiring
multistep syntheses and/or require harsh conditions, which
limit the functional group tolerability.
Recently, a Pd/BINAP-catalyzed coupling of N-Boc hy-
drazine with aryl bromides has been reported.6 However, high
yields were obtained only with substrates having electron-
withdrawing substituents in the para position. A copper-
mediated N′-arylation of benzoic hydrazide, affording low
yields of N′,N′-diarylated products,7 and the arylation of
(1) (a) Enders, E. In Methoden der Organischen Chemie; Stroh, R., Ed.;
Georg Thieme Verlag: Stuttgart, 1967; Vol. 10/2, p 546. (b) Dekeyser,
M.; McDonald, P. T.; Angle, G. W., Jr. J. Agric. Food Chem. 1994, 42,
1358-1360. (c) Chee, G.-L.; Park, S. B.; Dekeyser, M. A. U.S. Patent
6,093,843, 2000. (d) Dekeyser, M. A.; McDonald, P. T. U.S. Patent
5,367,093, 1994. (e) Reich, M. F.; Fabio, P. F.; Lee, V. J.; Kuck, N. A.;
Testa, R. T. J. Med. Chem. 1989, 32, 2474-2485.
(2) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
(b) King, F. D. J. Chem. Soc., Perkin Trans. 1 1988, 3381-3385. (c) Carlin,
R. B.; Moores, M. S. J. Am. Chem. Soc. 1962, 84, 4107-4112. (d) Barnish,
I. T., Gibson, M. S. J. Chem. Soc. C 1970, 854-859. (e) Kulagowski, J. J.;
Moody, C. J.; Rees, M. J. Chem. Soc., Perkin Trans. 1 1985, 2725-2732.
(f) Oliva, A.; Ellis, M.; Fiocchi, L.; Menta, E.; Krapcho, A. P. J. Heterocycl.
Chem. 2000, 37, 47-55. (g) Tamura, Y.; Tsugoshi, T.; Mohri, S.-I.; Kita,
Y. J. Org. Chem. 1985, 50, 1542-1544. (h) Hughes, D. L. Org. Prep.
Proced. Int. 1993, 25, 607.
(3) (a) Enders, E. In Methoden der Organischen Chemie; Stroh, R., Ed.;
Georg Thieme Verlag: Stuttgart, 1967; Vol. 10/2, pp 224-231. (b)
Tschirret-Guth, R. A.; Ortiz de Montellano, P. R. J. Org. Chem. 1998, 63,
9711-9715.
(4) (a) Velarde-Ortiz, R.; Guijarro, A.; Rieke, R. D. Tetrahedron Lett.
1998, 39, 9157-9160. (b) Demers, J. P.; Klaubert, D. H. Tetrahedron Lett.
1987, 28, 4933-4934. (c) Katritzky, A. R.; Wu, J.; Verin, S. V. Synthesis
1995, 651-653.
(5) (a) Zaltsgendler, I.; Leblanc, Y.; Bernstein, M. A. Tetrahedron Lett.
1993, 34, 2441-2444. (b) Carlin, R. B.; Moores, M. S. J. Am. Chem. Soc.
1962, 84, 4107-4112.
(6) Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett. 1999, 40,
3543-3546.
(7) Suzuki, H.; Yamamoto, A. J. Chem. Res., Synop. 1992, 280-281.
10.1021/ol0168216 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/19/2001

trisubstituted hydrazines with triarylbismuthanes in the
presence of stoichiometric amounts of Cu(OAc)2 has also
been described.8
Table 1. Copper-Catalyzed Coupling of para-Substituted Aryl
Iodides with N-Boc Hydrazinea
Recently, we have described the copper-catalyzed amid-
ation of aryl halides.9 We reported an example of the
N-arylation of N-Boc hydrazine (Scheme 1, product A in
Scheme 1
moderate yield) and benzoic hydrazide (Scheme 1, product
B in moderate yield) at high temperature. We therefore set
out to look for an improved catalyst system for this
transformation and to demonstrate the generality with which
it can be employed.
Herein we describe our results in developing an improved
protocol. When DMF is used as a solvent, catalytic amounts
of CuI and 1,10-phenanthroline (1) in the presence of Cs2CO3
provide higher yields of N-arylated N-Boc hydrazine at 80
°C,10 as opposed to 110 °C in dioxane as reported in our
original investigations. We also show that reasonable yields
can be achieved using a ligandless catalyst system.
A series of para-substituted aryl iodides, shown in Table
1, were subjected to the reaction conditions described above.
Generally, 1-5 mol % of CuI and 10-20 mol % of 1,10-
phenanthroline (1) were sufficient to obtain the N-arylated
products (A in Scheme 1) in good to excellent yields. No
N′-arylated product (B in Scheme 1) could be detected by
GC. We were pleased to find that electron-withdrawing as
well as electron-donating substituents are tolerated under
these conditions. Moreover, substrates containing functional
groups that have been problematic in palladium-catalyzed
methology,11 such as a phenolic OH (entry 4) and an aromatic
NH2 (entry 5), were successfully transformed. The use of 5
mol % CuI (entries 6-9) as well as shorter reaction times
(entries 8 and 9) improved the isolated yield of the N-arylated
products 8-11. For example, the isolated yield of compound
a Reaction conditions: 1 equiv of aryl iodide, 1.2 equiv of hydrazide,
1.4 equiv of Cs2CO3, DMF (1 M in aryl iodide), under argon, for 21 h.
The reaction time is not optimized for each substrate. b Isolated yields are
1
the average of two runs and are estimated to be >95% pure by H NMR
and GC analysis. All previously unknown compounds gave satisfactory 1H
NMR, 13C NMR, IR, and combustion analysis data. c Yield for a reaction
time of 4 h. For 21 h: 61% yield of 10. d Yield for a reaction time of 4 h.
For 21 h: 34% yield of 11.
(8) Loog, O.; Ma¨eorg, U.; Ragnarsson, U. Synthesis 2000, 11, 1591-
1597.
(9) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727-7729.
(10) Typical Experimental Procedure. An oven-dried resealable Schlenk
tube was charged with CuI (1-5 mol %), ligand (10-20 mol %), and
Cs2CO3 (1.4 mmol), evacuated, and backfilled with argon. Hydrazide (1.2
mmol), aryl iodide (1.0 mmol), and DMF (1.0 mL) were added under argon.
The Schlenk tube was sealed, and the reaction mixture was stirred
magnetically at 80 °C for 21 h. The resulting suspension was cooled to
room temperature and filtered through a 0.5 × 1 cm2 pad of silica gel eluting
with ethyl acetate. The filtrate was concentrated. Purification of the residue
by flash chromatography on silica gel gave the desired product (see
Supporting Information).
10, which seemed to be more sensitive under the coupling
conditions, could be improved from 61% to 78%, using a
reaction time of 4 h instead of 21 h.
The reaction was also carried out with a series of meta-
substituted aryl iodides. As shown in Table 2, the N-arylated
products 12-16 were obtained regioselectively and in good
yields. Again, both electron-donating (entries 1-3) and
electron-withdrawing (entries 4 and 5) substituents, as well
as a free OH group (entry 3), were tolerated.
The transformation was also carried out in absence of 1,10-
phenanthroline (1) for some aryl iodides (Table 1, entries 3
(11) Deng, B.-L.; Lepoivre, J. A.; Lemie`re, G. Eur. J. Org. Chem. 1999,
2683-2688.
3804
Org. Lett., Vol. 3, No. 23, 2001

Table 2. Copper-Catalyzed Coupling of meta-Substituted Aryl
Iodides with N-Boc Hydrazinea
Table 3. Copper-Catalyzed Coupling of ortho-Substituted Aryl
Iodides with N-Boc Hydrazine and Benzoic Hydrazidea,d
entry
R1
R2
ligandc % yield (A)b % yield (B)b
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
CO2Et
CO2Et
CO2Et
Boc
Boc
1
none
1
none
1
35 (17)
13 (17)
4 (18)
11 (18)
57 (19)
69 (19)
8 (GC)
32 (21)
34 (21)
46 (22)
56 (23)
63 (23)
COPh
COPh
Boc
COPh
COPh
Boc
23 (20)
2
none
2
2
COPh
COPh
10
none
a See Table 1. b See Table 1. c 1: 1,10-phenanthroline, 2: picolinic acid.
d Reduction of aryl iodides to substituted arenes was detected by GC in
amounts of ∼30%.
moderate yields (entries 3, 6, 9). An increase in isolated
yields was seen in some instances under ligandless conditions
(entries 4 and 10).
In summary, we have developed a general and efficient
catalyst system for the N-arylation of N-Boc hydrazine. We
have shown that aryl iodides with electron-withdrawing as
well as with electron-donating substituents in meta or para
position undergo the coupling reaction in good to excellent
yield. We have also demonstrated a reversal of the regio-
selectivity for the C-N coupling of certain ortho-substituted
aryl iodides when benzoic hydrazide is used in place of
N-Boc hydrazine, providing the corresponding N′-arylated
products in moderate yield. The advantages of this method
include good substrate generality, the use of the air-stable,
inexpensive CuI under mild conditions, and experimental
ease.
a See Table 1. b See Table 1. c Yield for a reaction time of 4 h. For 21
h: 65% yield of 16. d 7% of the N′-arylated product 24 was also isolated.
e 5% of the N′-arylated product 25 was also isolated.
and 7; Table 2, entries 2 and 4). While the reaction still
proceeds fairly well, the yields of the N-arylated products
are 10-20% lower for both meta- and para-substituted aryl
iodides. Moreover, for the meta-substituted examples, 5-7%
of N′-arylated products (B) were isolated, along with the
N-arylated products 13 and 15.
The arylation of N-Boc hydrazine with ortho-substituted
aryl iodides is detailed in Table 3. As can be seen in entries
1 and 5, modest yields of the N-Boc N-aryl hydrazines 17
and 20 were obtained, and we observed a drop in regio-
selectivity with N′-arylation products (B) now being formed
in 4-8% yield. In the absence of 1 (entry 2), a complete
loss of regioselectivity is observed. Using a substrate with
an electron-withdrawing substituent (entry 8), the N′-arylated
product 22 was formed exclusively. For this substrate
picolinic acid (2) was found to be a better ligand than 1.
Switching to benzoic hydrazide further improved the yield
of the coupling, and we observed a reversal in the regio-
selectivity with all ortho-substituted substrates. In these cases
the N′-arylated products 19, 21, and 23 were produced in
Acknowledgment. We thank the National Institutes of
Health (GM 58160) for support of this work. We gratefully
acknowledge unrestricted support from Pfizer, Merck, and
Bristol-Myers Squibb. M.W. thanks the Deutsche Fors-
chungsgemeinschaft (DFG) for a postdoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization data for all unknown com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0168216
Org. Lett., Vol. 3, No. 23, 2001
3805