Synthesis of chiral N,N'-disubstituted 1,2-benzenediamines from o- dibromobenzene

Article abstract of DOI:10.1016/S0957-4166(00)00124-5

Palladium-catalyzed amination of o-dibromobenzene provided chiral N,N'- disubstituted 1,2-benzenediamines in good to excellent yields. The amination was executed stepwise and in one pot to give unsymmetrically and symmetrically substituted 1,2-benzenediamines. Incorporation of chiral primary amines was possible without racemization using catalytic Pd₂dba₃- BINAP. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00124-5

Tetrahedron: Asymmetry 11 (2000) 1703±1707
Synthesis of chiral N,N0-disubstituted 1,2-benzenediamines
from o-dibromobenzene
Felix M. Rivas, Uzma Riaz and Steven T. Diver*
Department of Chemistry, State University of New York at Bu€alo, Bu€alo, NY 14260-3000, USA
Received 22 March 2000; accepted 23 March 2000
Abstract
Palladium-catalyzed amination of o-dibromobenzene provided chiral N,N0-disubstituted 1,2-benzene-
diamines in good to excellent yields. The amination was executed stepwise and in one pot to give unsymmetrically
and symmetrically substituted 1,2-benzenediamines. Incorporation of chiral primary amines was possible
without racemization using catalytic Pd2dba3±BINAP. # 2000 Elsevier Science Ltd. All rights reserved.
Many advances have been made in the palladium-catalyzed amination reaction since it was
reported by Buchwald et al.1a and by Driver and Hartwig.1b Dicult substrates, usually sterically
hindered aromatic halides, have generally yielded to amination thanks to a variety of ligand±
palladium combinations available.1 Double amination of dihalobenzenes is an important area of
materials science and has seen a recent ¯urry of activity.2 1,2-Dibromobenzene has been coupled
with morpholine;3 however, the reaction of primary amines and the scope of the double amination
has not been fully explored. Due to our interest in the preparation of chiral benzimidazolium salts
beginning from 1,2-benzenediamines, we decided to explore this reaction in greater detail. The
synthesis of a variety of chiral 1,2-benzenediamines from o-dibromobenzene is reported herein
(Scheme 1).
Scheme 1.
* Corresponding author. E-mail: diver@acsu.bu€alo.edu
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00124-5

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Bisamination of 1,2-dibromobenzene was achieved in one pot by using Pd2dba3±(þ)-2,20-
bis(diphenylphosphino)-1,10-binaphthyl (BINAP) catalytic conditions (4 mol% Pd2dba3 and 8±12
mol% BINAP) and excess reagents at 135ꢀC. Since the rate-determining step is thought to be
deprotonation of the coordinated amine, a higher base concentration was used to accelerate the
amination of 3 to 4.1d The coupling of o-dibromobenzene with secondary amines was accelerated
at 135ꢀC, with reactants consumed in ca. 1 h (Scheme 2). Previous literature reports on the double
amination of 1,2-dibromobenzene with secondary amines contain contrasting data.3,4 Witulski et
al.3 obtained a 56 and 70% yield of 4A using BINAP or dppf as a ligand, respectively. In both
cases, the major by-product was reduction product 5. A similar coupling by Beletskaya et al.4b
using dppf as ligand failed with piperidine and gave the corresponding reduction product 5,
exclusively. Using our conditions, both morpholine and pyrrolidine were coupled smoothly
(Scheme 2).
Scheme 2.
These results indicate that nucleophilic secondary amines couple e€ectively with 1,2-dibromo-
benzene without adverse steric or electronic e€ects on the second amination. The reduction
product 5 likely originates from an intermediate palladium hydride, formed through b-hydride
elimination of a coordinated amine.5 Hydride elimination can be suppressed by chelating
diphosphines,1c,6 which may help explain the e€ectiveness of BINAP in this particular case.
Coupling of a chiral primary amine was also successful (Scheme 3).7 A further problem in the
synthesis of dianiline 8 is the formation of imine 9. In this demanding case, reduction and imine
formation could be suppressed, but not completely eliminated when complete conversion of
intermediate 7 was attained. The reactions were monitored by GC and stopped promptly when 7
was consumed. The by-products were separated by column chromatography to provide 8 in 61%
yield (91% de, >99% ee; HPLC, Chiracel OD column).8
Scheme 3.
The preparation of unsymmetrical 1,2-benzenediamines is also possible using a sequential
application of the amination.9 Coupling of enantiomerically enriched 7 to various amines10 is
illustrative (Table 1). Monobromide 7 (>99% ee) was readily prepared by Pd-catalyzed amination
of 1,2-dibromobenzene using 1 equiv. of amine 6. Based on prior literature,3,4 the coupling in
Scheme 4 was expected to be slow, and bene®ted from a higher catalyst loading (4 mol%

F. M. Rivas et al. / Tetrahedron: Asymmetry 11 (2000) 1703±1707
1705
Pd2dba3). Two di€erent sets of reaction conditions were used for Scheme 4. Condition A utilizes
Pd2dba3±BINAP heated in toluene (sealed tube) at 135ꢀC. That the higher temperature does not
result in racemization is borne out by the enantiomeric excess determinations (Table 1). The coupling
of primary and secondary amines is ecient using the Pd2dba3±BINAP±135ꢀC combination
(entries 1, 2, 4, 6, and 7). Longer reaction times were sometimes needed for the complete
conversion of 7. In contrast, condition B uses the electron rich mixed donor ligand 1211 which
gave shorter reaction times, although in some cases, reduction product 10 became a major
by-product (e.g. entry 3, 33% isolated 10). Each of the conditions produced imines (e.g. 9, Scheme 3),
but shorter reaction times minimized their formation. The imines are thought to arise by elimination
of coordinated diamines 11, since imine formation increased over time as the concentration of 11
was diminished. This was further supported by resubjecting 8 to the reaction conditions (condition
1
B) which indicated a formation of 9 evidenced by H NMR analysis. For the coupling with
aniline using mixed donor 12 (entry 5) a higher base concentration is not needed and actually
gave decreased yields (1.3 equiv. NaOtBu, 92% yield 15; 2.0 equiv. NaOtBu, 65% yield 15 after
30 min and complete consumption of 7). The lower yield using 2 equiv. base was accompanied by
a deep purple±red color, possibly a result of oxidation to the o-quinone diimine.12 Benzophenone
Scheme 4.
Table 1
Synthesis of unsymmetrical N,N0-disubstituted 1,2-benzenediamines

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F. M. Rivas et al. / Tetrahedron: Asymmetry 11 (2000) 1703±1707
imine (1.3 equiv.) was coupled smoothly (entry 9) providing 17. Hydrolysis13 of imine 17 would
provide access to monosubstituted 1,2-benzenediamines.
The synthesis of C2-symmetrical diamine 8 (entries 7 and 8) is noteworthy. Longer reaction
times had to be avoided since imine by-product 9 was produced. Monitoring this reaction by GC±
MS indicated complete conversion to diamine after 1.5 h; however, the isolated yield of 8 was
70%. The amination using ligand 12 was complete in only 0.5 h (entry 8), but dianiline 8 was found
to be a mixture of stereoisomers, 2.4:1 ratio (S,S)-8 to meso-8. The major diastereomer was found
to be of >99% ee and recovered 7 had >99% ee. Using excess amine, unreacted 6 was recovered
and found to be 60% ee (after conversion to its benzoate; HPLC), suggesting that racemization of
the amine is competitive with coupling.6 To our knowledge, racemization of a-chiral primary
amines has not been documented using ligand 12. The dr did not change signi®cantly (1H NMR)
over time even as more imine was produced.
In conclusion, direct amination of 1,2-dibromobenzene has been used to prepare a variety of
1,2-benzenediamines using the BINAP±Pd2dba3 system. A combination of elevated reaction
temperature and excess base accelerated the reaction suciently for one-pot bisamination. Chiral,
unsymmetrical dianilines were eciently prepared by a sequential application of the amination.
The couplings were successful for a range of aliphatic amines. The incorporation of an a-chiral
primary amine can likewise be accomplished using this protocol without racemization. We have
successfully converted the substituted 1,2-benzenediamines into benzimidazoles and benzimidazolium
salts, the full details of which will be reported soon.
Acknowledgements
The authors express their gratitude to the National Science Foundation (CHE-9725002), the
donors of the Petroleum Research Fund administered by the ACS (33298G1) and SUNY Bu€alo
for ®nancial support of this work. F.M.R. is a fellow of the Ford Foundation for which a
predoctoral fellowship is gratefully acknowledged.
References
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F. M. Rivas et al. / Tetrahedron: Asymmetry 11 (2000) 1703±1707
1707
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7. General procedure for `double amination': Preparation of 8 (Scheme 3): an oven-dried, sealable Schlenk tube
equipped with a threaded te¯on plug and magnetic stirbar was cooled under Ar and charged with Pd2dba3 (Strem,
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was degassed, back®lled with Ar and then heated at 135ꢀC in an oil bath for 15 min. After cooling to room
temperature, the reaction vessel was charged with NaOt-Bu (192 mg, 2.03 mmol, 4.05 equiv.), (S)-a-
methylbenzylamine (0.32 mL, 2.5 mmol, 5 equiv.), 1,2-dibromobenzene (60 mL, 0.5 mmol, 1.00 equiv.), and
toluene (1.0 ml). The mixture was degassed, back®lled with Ar, sealed and then heated in an oil bath at 135ꢀC with
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then allowed to cool to room temperature, diluted with ether, ®ltered through a pad of Celite and concentrated in
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