Addition of arylboronic acids to symmetrical and unsymmetrical azo compounds

Article abstract of DOI:10.1021/ol052403f

(Chemical Equation Presented) The addition of aryl- and heteroarylboronic acids to azo compounds is described. Copper salt catalysis was necessary to perform the reaction under mild conditions and high yields. Excellent regioselectivity was observed in addition to unsymmetrical azo compounds.

Full text of DOI:10.1021/ol052403f

ORGANIC
LETTERS
2006
Vol. 8, No. 1
43-45
Addition of Arylboronic Acids to
Symmetrical and Unsymmetrical Azo
Compounds
Ksenija Kisseljova,† Olga Tsˇubrik,† Rannar Sillard,‡ Sirje Ma
1
eorg,† and
Uno Ma
1
eorg*,†
Institute of Organic and Bioorganic Chemistry, UniVersity of Tartu, Jakobi 2, 51014,
Tartu, Estonia, and Department of Medical Biochemistry and Biophysics, Karolinska
Institutet SE 171-77, Stockholm, Sweden
uno@chem.ut.ee
Received October 4, 2005
ABSTRACT
The addition of aryl- and heteroarylboronic acids to azo compounds is described. Copper salt catalysis was necessary to perform the reaction
under mild conditions and high yields. Excellent regioselectivity was observed in addition to unsymmetrical azo compounds.
N-Arylation still remains one of the most challenging C-X
couplings. Despite the revolutionary achievements of pal-
ladium catalysis,1 classical Ullmann and Goldberg reactions
are still very useful2 since remarkable improvements have
been made to the method in recent years. Copper(I) and -(II)
catalysis enables the use of wide scope of reagents as aryl
sources. Besides arylhalogenides, the examples include
aryltrialkylstannanes,3 arylleadtriacetates,4 triarylbismuthanes/
triarylbismuth diacetates,4,5 and boron derivatives, such as
readily available arylboronic acids6 or aryltrifluoroborate
salts.7
pharmaceutical importance. Both organobismuth reagents5b,8
and aryl iodides9 were recently used in the preparation of
substituted hydrazines, whereas Lan’s and Lam’s works
involved arylboronic acids.3,6 All these methods start with a
N-H compound, although substituted hydrazines can also
be obtained by addition of an aryl-containing nucleophile to
azo compound. The analogy is clearly recognized in both
the Petasis-Mannich10 and Liebeskind methods,11 where an
NdC or NdO electrofile is used in reaction with arylboronic
acids.
Therefore, we decided to combine a copper-catalyzed
N-arylation process with addition to the NdN bond in azo
Arylation of hydrazines, which are a special class of
nitrogen compounds, is of high interest because of their
(5) (a) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron 1997, 53,
4137. (b) Tsˇubrik, O.; Ma¨eorg, U.; Sillard, R.; Ragnarsson, U. Tetrahedron
2004, 60, 8363. (c) Sorenson, R. J. J. Org. Chem. 2000, 65, 7747. (d) Chan,
D. M. T. Tetrahedron Lett. 1996, 37, 9013.
(6) Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.;
Xie, R.-G. Synlett 2004, 6, 1095.
(7) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397.
(8) Loog, O.; Ma¨eorg, U.; Ragnarsson, U. Synthesis 2000, 1591.
(9) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(10) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445. (b) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron Lett.
2002, 43, 6845.
† University of Tartu.
‡ Karolinska Institutet.
(1) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (c) Hartwig, J. F. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: Hoboken,
NJ, 2002; Vol. 1, pp 1051-1096.
(2) (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428. (b) Ley,
S. V.; Thomas, A. W. Angew. Chemie., Int. Ed. 2003, 42, 5400.
(3) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.;
Chan, D. M. T.; Combs, A. Synlett 2000, 5, 674.
(4) Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683.
(11) Yu, Y.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631.
10.1021/ol052403f CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/13/2005

compounds. The parallel work was very recently reported
by Chatani and included azodicarboxylates as electrofile.12
However, as we were interested in more complicated
hydrazine derivatives, our studies are not confined to
symmetrical azo compounds.
The starting materials were easily obtained from the
corresponding disubstituted hydrazines via oxidation with
Br2/Py13 or activated MnO2 in dichloromethane at room
temperature. The reaction is outlined in Scheme 1, and the
results are presented in Table 1.
substantially increase the yield to quantitative and to decrease
the reaction time (2 h in methanol at rt, 1.5 h under reflux).
The same arylation in CH2Cl2 was complete in 16 h at rt,
giving the product in 93% yield. After refluxing the reaction
mixture in acetonitrile for 6 days the starting material was
recovered in 31% and 45% of product was obtained.
Therefore, methanol was considered to be the solvent of
choice for this reaction.
The regioselectivity of addition to ArNdNBoc is con-
1
firmed by the analysis of H NMR spectra. The signal at
7.0 ppm corresponds to BocNH, and no hypothetical PhNH
was detected in the range 5-6 ppm. The melting point of
the product Ph2NNHBoc (122-123.5 °C, from hexane) was
in agreement with data reported previously (122.5-124 °C,
from cyclohexane).15 Coupling of PhB(OH)2 and DNPNd
NBoc was the only reaction, where we have isolated the other
isomer in 21% yield. The products were distinguished by
the signal at 9.46 ppm in 1H NMR, which belongs to DNPNH
in DNPNHNHBoc and DNPNHNPhBoc.
Scheme 1. Reaction between Arylboronic Acids and Different
Azo Compounds
BocNdNBoc was found to be more reactive than PhNd
NBoc since all arylations except in the case of with 3-PyB-
(OH)2 did not require elevated temperatures and were
complete in less than 45 min. On the other hand, coupling
of PhNdNPh with phenylboronic acid was extremely slow
under the described conditions.
The addition is not very sensitive to steric hindrance as
judged from the short reaction times of 1-naphthylboronic
acid. Still, low yields and longer reactions times in the case
of 3-PyB(OH)2 suggest some dependence on the electronic
effect of the aryl group. The results obtained with 3-thien-
ylboronic acid are also quite different from those with the
isomeric 2-thienylboronic acid.
PhNdNBoc was used as model compound.14 The addition
of phenylboronic acid (1.1 equiv) proceeded even without
catalyst in refluxing methanol (24 h), yielding 71% of Ph2-
NNHBoc with traces of PhNHNHBoc as detected on TLC.
Catalytic 5 mol % of Cu(OAc)2‚H2O was essential to
Coupling of PhNdNBoc with 1-naphthylboronic acid was
the only case where we observed positive influence of inert
atmosphere (77% under argon versus 55% in the presence
of air). BocNdNBoc yielded exactly the same results with
2- and 3-thienylboronic acids under both air and argon
atmosphere. In several reactions between thienylboronic acids
and azo compounds, the corresponding hydrazines were
detected in traces by TLC as the result of a reductive side
reaction.
Table 1. Copper-catalyzed Addition of Arylboronic Acids to
Azo Compounds
entry
1a PhNdNBoc
1b PhNdNBoc
1c PhNdNBoc
1d PhNdNBoc
1e PhNdNBoc
azo compd
aryl
reaction time yield, %
Ph
1.5 ha
45 min
6 h
100
77
65
b
1-naphthyl
3-Py
2-thienyl
3-thienyl
Ph
1- naphthyl
3-Py
2-thienyl
3-thienyl
Ph
The possible reaction mechanism, as derived from gener-
ally accepted considerations, is depicted in Scheme 2.
7 h
7 h
b
2a BocNdNBoc
2b BocNdNBoc
30 min
30 min
15 min
20 min
40 min
7-8 min
22 h
1 h
4 h
8 h
16 h
91
60
43
45
100
It is interesting that the addition of alkyl/aryl organo-
metallic nucleophiles to a row of unsymmetrical azo
2c
BocNdNBoc
2d BocNdNBoc
(12) Uemura, T.; Chatani, N. J. Org. Chem. 2005, 70, 8361.
(13) Starr, J. T.; Rai, G. S.; Dang, H.; McNelis, B. J. Synth. Commun.
1997, 27, 3197.
2e
BocNdNBoc
3a DNPNdNBocc
3b DNPNdNBoc
57d
3-Py
18
100
94
78
b
(14) A typical procedure is given, using 1a as example. The mixture of
PhNdNBoc (100 mg, 0.4854 mmol), PhB(OH)2 (95 mg, 1.6 equiv), and
Cu(OAc)2‚H2O (6 mg, 0.05 equiv) was refluxed in methanol (2 mL). The
reaction was monitored by TLC (1: 4 EtOAc-hexane). After starting
material was consumed in 1.5 h, silica gel (0.5 g) was added to the mixture
and the solvent was removed under reduced pressure. The obtained residue
was chromatographed (1:10 EtOAc-hexane), yielding 138 mg (quantitative
yield) of white solid Ph2NNHBoc, pure by TLC and NMR: IR (KBr) ν )
4a 4-NO2C6H4NdNBoc Ph
4b 4-NO2C6H4NdNBoc 1- naphthyl
4c
4d 4-NO2C6H4NdNBoc 2-thienyl
4e 4-NO2C6H4NdNBoc 3-thienyl
4-NO2C6H4NdNBoc 3-Py
36 h
59
a Experiments 1a-e, 2c, and 3a-4e were conducted at reflux, the rest
at rt. b Only decomposition products. c DNP: 2,4-dinitrophenyl. d 21% of
DNPNHNPhBoc and 21% of DNPNHNHBoc were isolated.
1
3317 (NH), 1704 (CO) cm-1; H NMR δ ) 1.48/1.31 (s, 9H, Boc), 6.87/
6.71 (broad s, 1H, NH), 6.9-7.4 (m, 10H, Ph); 13C NMR δ ) 28.3 (Boc),
81.3 (Cq, Boc), 119.4, 122.7, 129.1, 146.4 (Ph), 155.3 (CO, Boc).
(15) Koga, N.; Anselme, J.-P. J. Org. Chem. 1968, 33, 3963.
44
Org. Lett., Vol. 8, No. 1, 2006

addition of the arylboronic acid to the resulting azo com-
pound. In contrast, slow progress of arylation in the presence
of 5% of catalyst can be attributed to the typical direct
catalytic NH arylation by PhB(OH)2 occurring instead of
addition to azo compound.
Scheme 2. Proposed Reaction Mechanism
In conclusion, this work reports a systematic study of
coupling between arylboronic acids and azo compounds of
different structure. Regarding to the recently described
regioselective addition of organometallic nucleophiles to
unsymmetrical azo compounds, the current reaction can be
considered as its useful alternative.16 Since the practical
procedure is very convenient, the method is expected to find
applications in the synthesis of multisubstituted protected/
arylated hydrazines.
compounds (PhNdNBoc, PhNdNAc, o-CH3C6H4NdNBoc)
revealed exactly the same regiospecificity.16
The same regioselectivity was observed in direct arylation
of PhNHNHBoc by PhB(OH)2/Cu(OAc)2 in methanol. In the
presence of a stoichiometric amount of Cu(OAc)2, the
reaction was complete in 2 h (98% yield). A catalytic amount
of Cu(OAc)2 prolonged the reaction time to 70 h. We have
also found that PhNHNHBoc is readily oxidized by
Cu(OAc)2 to the azo compound (half of the material reacted
in 30 min, TLC). Thus, we have concluded that arylation of
PhNHNHBoc by PhB(OH)2 proceeds in two steps. First, the
oxidation of hydrazine by copper(II) occurs, followed by the
Acknowledgment. This work was financially supported
by the Estonian Science Foundation (No. 5255). Elemental
analyses were performed at Latvian Institute of Organic
Synthesis.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Tsˇubrik, O.; Sillard, R.; Ma¨eorg, O. Synthesis 2005, in press.
OL052403F
Org. Lett., Vol. 8, No. 1, 2006
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