Regioselective [5,5]-sigmatropic rearrangement reactions of aryl hydrazides

Article abstract of DOI:10.1021/ol060451+

N,N′-Aryl hydrazides with substituents at the ortho or meta positions undergo highly regioselective [5,5]-sigmatropic rearrangement reactions to furnish benzidines in good to excellent isolated yields. The presence of single substituent at either the ortho or meta position provides sufficient bias, effectively suppressing the formation of diphenylene, the major byproduct of the conventional benzidine rearrangement reaction.

Full text of DOI:10.1021/ol060451+

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2047-2050
Regioselective [5,5]-Sigmatropic
Rearrangement Reactions of Aryl
Hydrazides
Hong-Min Kang, Young-Kwan Lim, In-Jee Shin, Hee-Yeon Kim, and
Cheon-Gyu Cho*
Department of Chemistry, Hanyang UniVersity, Seoul, Korea 133-791
ccho@hanyang.ac.kr
Received February 21, 2006
ABSTRACT
N,N′-Aryl hydrazides with substituents at the ortho or meta positions undergo highly regioselective [5,5]-sigmatropic rearrangement reactions
to furnish benzidines in good to excellent isolated yields. The presence of single substituent at either the ortho or meta position provides
sufficient bias, effectively suppressing the formation of diphenylene, the major byproduct of the conventional benzidine rearrangement reaction.
The acid-catalyzed rearrangement of hydrazobenzenes, known
as the benzidine rearrangement, affords 4,4′-diaminobiaryls
(benzidines).1 Benzidines are useful synthetic building blocks
to polyimides, polyfluorenes, and other aromatics.2 In addi-
tion, their N-arylated compounds are important hole-trans-
porting materials in the fabrication of light-emitting displays
for their π-electron-donating properties.3 Despite their long
history and extensive mechanistic studies, the synthetic utility
of the benzidine rearrangement has been collectively disre-
garded in the literature because it gives a substantial amount
of byproducts, mostly diphenylene 3, along with o- and
p-semidines, not separable with flash column chromatogra-
phy (Scheme 1).4
Scheme 1. Benzidine Rearrangement of Hydrazobenzene 1
N,N′-Diaryl hydrazides are readily available from the Pd-
catalyzed coupling reactions of N-aryl hydrazides and aryl
halides and are effective synthetic equivalents of hydra-
zobenzenes, undergoing [3,3]-sigmatropic rearrangement to
provide 2,2′,-diamino-1,1′-biaryls, when heated in the pres-
ence of an acid.6 In light of this, we explored the benzidine
rearrangement reactions of N,N′-diaryl hydrazides with
particular interest in controlling the regiochemical outcome
of the reaction. For this venture, we prepared a series of N,N′-
diaryl hydrazides with substituents at the ortho position,
anticipating that the ortho substituent would suppress the
The lack of adequate synthetic methods to the starting
hydrazobenzenes5 further limited the reaction as a synthetic
protocol for the generation of benzidines and related
products.
(1) (a) Hoffman, A. W. Proc. R. Soc. (London) 1863, 12, 576. (b) Dewar,
M. J. S. In Molecular Rearrangement; de Mayo, P., Ed.; Interscience: New
York, 1969; Vol. 1, p 323. (c) Banthorpe, D. V. Chem. ReV. 1970, 70, 295.
(d) Olah, G. A.; Dunne, K.; Kelly, D. P.; Mo, Y. K. J. Am. Chem. Soc.
1972, 94, 7438. (e) Cox, R. A.; Buncel, E. In The Chemistry of the Hydrazo,
Azo, and Azoxy Groups; Patai, S., Ed.; Wiley: New York, 1975; p 775. (f)
Bunton, C. A.; Rubin, R. J. J. Am. Chem. Soc. 1976, 98, 4236. (g) Park, K.
H.; Kang, J. S. J. Org. Chem. 1997, 62, 3794. (h) Benniston, A. C.; Clegg,
W.; Harriman, A.; Harrington, R. W.; Li, P.; Craig, S. Tetrahedron Lett.
2003, 44, 2665.
(3) (a) Popovic, Z. D.; Aziz, H. J. Appl. Phys. 2005, 98, 13510. (b) Tung,
C.-H.; Zhang, L.-P.; Li, Y.; Cao, H.; Tanimoto, Y. J. Am. Chem. Soc. 1997,
119, 5348.
(2) (a) Chen, R.-F.; Fan, Q.-L.; Zheng, C.; Huang, W. Org. Lett. 2005,
8, 203. (b) Chan, K. L.; McKiernan, M. J.; Towns, C. R.; Holmes, A. B. J.
Am. Chem. Soc. 2005, 127, 21, 7662.
(4) (a) Cheng, J. D.; Shine, H. J. J. Org. Chem. 1975, 40, 703. (b) Zhu-
Ohlbach, A.; Gleiter, R.; Bleiter, R.; Schmidt, H. L.; Reda, T. Eur. J. Org.
Chem. 1998, 11, 2409. (c) Buncel, E. Can. J. Chem. 2000, 78, 1251.
10.1021/ol060451+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/12/2006

formation of diphenylenes, the major byproduct of the
benzidine rearrangement reaction.
Shown in Table 1 are the Pd-catalyzed coupling reactions
Table 2. Benzidine Rearrangement of Aryl Hydrazides
Table 1. Synthesis of Aryl Hydrazides
entry
6
R
R1
R2
7 (% yield)a
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
H
H
H
7a (89)b
7b (76)
7c (81)
7d (72)
7e (91)
7f (88)
Me
H
H
Me
Me
Me
Me
Me
H
Me
Me
Me
H
OMe
entry
R
R1
R2
6 (% yield)a
CO2Et
1
2
3
4
5
6
4a (R ) H)
H
H
H
Me
Me
Me
H
6a (96)
6b (99)
6c (99)
6d (74)
6e (64)
6f (94)
a Isolated yields. b Combined yield of the 2:1 inseparable product mixture
of 2/3.
4b (R ) Me)
4b (R ) Me)
4b (R ) Me)
4c (R ) OMe)
4d (R ) CO2Et)
H
H
Me
Me
Me
bearing electron-donating and electron-withdrawing groups,
in terms of the yield and rate (entries 5 and 6). Notably, the
presence of single methyl group at the ortho position (entry
2) provides sufficient bias to effectively suppress the
formation of the diphenylene byproduct, affording the
benzidine product 7b in 86% isolated yield.
a Isolated yield.
of N-aryl hydrazides 4 with aryl halides 5, which provided
various ortho-substituted N,N′-diaryl hydrazides 6.
The coupling reactions proceeded in good to excellent
yields, even in the cases with three ortho substituents.7
We next examined reaction conditions to effect the [5,5]-
sigmatropic rearrangement. Heating at reflux in EtOH with
a catalytic amount of aqueous HCl proved optimal for both
product yield and operational ease. The product yields peaked
mostly after 1-2 h and gradually decreased thereafter, owing
to decomposition of the benzidine products. The results are
summarized in Table 2.8
Gratified with the successful control of the regiochemical
outcomes, we extended our protocol to multiple benzidine
rearrangement reactions. Tables 3 and 4 summarize the
Table 3. Synthesis of Bis-aryl Hydrazides
The unsubstituted hydrazide 6a (entry 1, Table 2) furnished
an inseparable 2:1 mixture of the benzidine 2 and diphe-
nylene 3, the [3,5]-sigmatropic rearrangement product, along
with small amounts of other byproducts, similar to hydra-
zobenzene. However, the N,N′-diaryl hydrazides with ortho
substituents (entries 2-6) cleanly rearranged to afford the
corresponding benzidines 7b-f in good to excellent isolated
yields. No difference was observed between the substrates
entry
5
time (h)
9 (% yield)a
1
2
3
4
5a (R ) R1 ) H)
3
3
3
2
9a (57)
9b (59)
9c (57)
9d (64)
5b (R ) H1, R1 ) Me)
5c (R ) R1 ) Me)
5d (R ) H1, R1 ) CO2Me)
a Isolated yields.
(5) They are generally prepared from nitroarenes via the reductive
coupling reaction with NaBH4 or from azobenzenes through Zn-mediated
reduction process that are moderately effective only for symmetric hydra-
zobenzenes. (a) Feiring, A. E.; Auman, B. C.; Wonchoba, E. R. Macro-
molecules 1993, 26, 2779. (b) Shine, H. J.; Trisler, J. C. J. Am. Chem. Soc.
1960, 82, 4054.
Table 4. Synthesis of Bis-aryl Hydrazides
(6) (a) Lee, K. S.; Lim, Y. K.; Cho, C. G. Tetrahedron Lett. 2002, 43,
7463. (b) Lim, Y. K.; Lee, K. S.; Cho, C. G. Org. Lett. 2003, 5, 979. (c)
Lim, Y. K.; Pang, S. J.; Paik, S. U, Cho, C. G. Bull. Korean Chem. Soc.
2003, 24, 543. (d) Lim, Y. K.; Choi, S.; Park, K. B.; Cho, C. G. J. Org.
Chem. 2004, 69, 2603. (e) Lim, Y. K.; Jung, J. W.; Lee, H. Cho, C. G. J.
Org. Chem. 2004, 69, 5778. (f) Kim, K. Y.; Shin, J. T.; Lee, K. S.; Cho,
C. G. Tetrahedron Lett. 2004, 45, 117.
(7) Representative Procedure. To a round flask were charged 329 mg
(1.58 mmol) of aryl hydrazide 4b, 267 mg (1.32 mmol) of iodobenzene, 5
mol % of Pd(OAc)2, 5 mol % of P(t-Bu)3‚HBF4, 602 mg (1.85 mmol) of
Cs2CO3, and 5 mL of anhydrous toluene at rt. The reaction mixture was
stirred for 30 min at rt and refluxed for 2 h. The resulting mixture was
concentrated and purified by flash column chromatography (hexanes/EtOAc
) 20: 1) to afford 389 mg of product 6b in 99% yield.
(8) Representative Procedure. To a round flask were charged 110 mg
(0.39 mmol) of N,N′-aryl hydrazide 6b, 3 mL of ethanol, and 3 drops of
concd HCl at rt. The reaction mixture was refluxed for 1 h, cooled to 0 °C,
neutralized with aq NaHCO3, filtered, concentrated, and purified by flash
column chromatography (CH2Cl2/EtOAc ) 2: 1) to afford 59 mg of 7b in
76% yield.
entry
4
time (h)
9 (% yield)a
1
2
3
4a (R ) H)
4b (R ) Me)
4c (R ) OMe)
2
3
2
9e (99)
9f (99)
9g (85)
a Isolated yields.
synthesis of the bis-aryl hydrazides employing two slightly
different strategies.
2048
Org. Lett., Vol. 8, No. 10, 2006

The corresponding compounds 9a-d (Table 3) were
prepared by reacting bis-hydrazide 89 with aryl iodide 5.
Mono-hydrazides 4 were coupled with 3,5-dibromotoluene
to afford 9e-g in excellent yields (Table 4).
The double-benzidine rearrangement reactions of 9a-g
were conducted under the conditions shown in Table 1 (Table
5).
Table 7. Triple Benzidine Rearrangement
Table 5. Double Benzidine Rearrangement
entry
11
12 (% yield)a
1
2
3
11a (R ) H)
11b (R ) Me)
11c (R ) OMe)
12a (46)
12b (56)
12c (45)
a Isolated yield.
Scheme 2. Benzidine Rearrangment Reactions of Aryl
Hydrazides with Substitutent at Meta-position
entry
9
R
R1
R2
10 (% yield)
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9f
H
H
H
10a (75)b
10b (56)
10c (61)
10d (N/A)c
10e (45)
10f (61)
H
H
Me
H
Me
H
Me
Me
Me
Me
Me
CO2Me
H
H
Me
H
H
OMe
9g
10g (54)
a Combined yield; 10a and traces of inseparable by-products. b Isolated
yield. c MeOH was used, the product decomposes upon standing.
Table 6. Synthesis of Tris-aryl Hydrazides
entry
4
time (h)
11 (% yield)a
1
2
3
4a (R ) H)
4b (R ) Me)
4c (R ) OMe)
2
3
2
11a (98)
11b (84)
11c (99)
a Isolated yield.
As in the cases of mono-benzidine rearrangement reac-
tions, the presence of ortho substituents suppressed the
formation of byproducts, yielding mainly the benzidines
10b-f in good isolated yields, except entry 4. The unsub-
stituted bis-aryl hydrazide 9a furnished 10a, which was
contaminated with small amounts of byproducts, not sepa-
rable with flash column chromatography, in a combined yield
of 75% (72% based on GC analysis with internal standard).
Further extension to triple benzidine rearrangement reac-
tions was made with tris-aryl hydrazides 11 which were
prepared from the coupling reactions of N-aryl hydrazides 4
with tribromobenzene in excellent yields (Table 6). Table 7
summarizes the rearrangement reactions providing novel
trisubstituted triaminobenzenes 12a-c in good isolated
yields.
The effect of a meta substituent on the benzidine rear-
rangement reaction was then investigated.10 Despite our initial
expectation that it might promote the [3,5]-sigmatropic
rearrangement product, i.e., diphenylene 3, the aryl hydrazide
(9) Compound 8 was prepared from the Cu(I)-mediated coupling reaction
of BocNHNH2 with 1,3-dibromobenzene according to Buchwald’s condi-
tions. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
Org. Lett., Vol. 8, No. 10, 2006
2049

13a, bearing a methyl group at the meta position, cleanly
provided the benzidines 14a in 90% yield (Scheme 2).
The aryl hydrazide 13b with bromine at the meta position
can be conceived as a chemical equivalent of aryl hydrazine
1 which can provide the parent benzidine 2, otherwise
difficult to be obtained in chemically pure form through the
two-step sequence involving the rearrangement to 14b and
the reductive removal of the bromine group (Scheme 2).11
In conclusion, we have shown that aryl hydrazides with
substituent(s) at the ortho or meta positions undergo highly
regioselective [5,5]-sigmatropic rearrangement reactions to
an array of structurally novel benzidines12 in good to
excellent isolated yields. Our new route would certainly shed
light on the synthetic utility of the long-standing and mostly
unexploited benzidine rearrangement reaction to its full
potential.
Acknowledgment. This work was supported by the grant
from the Korea Science and Engineering Foundation through
the Center for Bioactive Molecular Hybrids (CBMH), Yonsei
University. K.H.-M. is grateful for a BK21 fellowship.
Supporting Information Available: Experimental pro-
cedures and details of compound characterization for all
unknown aryl hydrazides and benzidines. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Park, K. H.; Park, M.-K.; Cho, Y. H. Bull. Korean. Chem. Soc.
1998, 19, 1090.
(11) The Pd-catalyzed coupling reaction of 4 with 1-bromo-3-iodoben-
zene gave the coupling product in only 47% yield.
1
(12) All of the new benzidines were completely characterized with H,
13C NMR, IR, and HRMS.
OL060451+
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Org. Lett., Vol. 8, No. 10, 2006