Reductive carbodiazenylation of nonactivated olefins via aryl diazonium salts

Article abstract of DOI:10.1021/ol0611393

The reduction of aryl diazonium salts in the presence of nonactivated olefins provides rapid entry to carbodiazenylation products. The regioselective functionalization of double bonds is achieved in a one-pot process starting from aniline derivatives. Car

Full text of DOI:10.1021/ol0611393

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3323-3325
Reductive Carbodiazenylation of
Nonactivated Olefins via Aryl Diazonium
Salts
Markus R. Heinrich,* Olga Blank, and Sabrina Wo1lfel
Lehrstuhl fu¨r Organische Chemie 1, Technische UniVersita¨t Mu¨nchen,
Lichtenbergstr. 4, D-85747 Garching, Germany
markus.heinrich@ch.tum.de
Received May 10, 2006
ABSTRACT
The reduction of aryl diazonium salts in the presence of nonactivated olefins provides rapid entry to carbodiazenylation products. The
regioselective functionalization of double bonds is achieved in a one-pot process starting from aniline derivatives. Carboamination of olefins
is possible via a two-step carbodiazenylation−hydrogenation sequence in which one aniline equivalent is recovered.
Several attempts have been made to achieve carboamination
of nonactivated olefins and acetylenes recently. Among the
organometallic methods, substituted pent-4-enylamines have
been cyclized to give pyrrolidines via palladium catalysis.1
2-Alkynyl-substituted anilines2 as well as isocyanates3 have
served as precursors for indoles in the presence of transition
metals, and imines have been reacted with alkynes using
zirconium4 and titanium5 catalysts.
Among the radical methods, the carboazidation of olefins,
where sulfonyl azides are employed as nitrogen equivalents,
has found broader applications.6 In addition to sulfonyl
azides, diazirines,7 and thionitrosyl compounds,8 aryl dia-
zonium salts can serve as nitrogen-centered radical scaven-
gers. This ability of diazonium salts has so far rarely been
used for the functionalization of olefins.9
The principle of a carbodiazenylation, which can be
described as a combination of Meerwein arylation10 and
radical addition to diazonium salts, is depicted in Scheme
1. A large number of arylamines 1 can be converted to aryl
diazonium salts 2 via diazotization. When the diazonium salts
2 are treated with reductants in the presence of an olefin 3,
Scheme 1. Carbodiazenylation of Olefins
* To whom correspondence should be addressed. Fax: +49-89-289-
13329.
(1) (a) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006,
128, 2893-2901. (b) Ney, J. E.; Hay, M. B.; Yang, Q.; Wolfe, J. P. AdV.
Synth. Catal. 2005, 347, 1614-1620. (c) Yang, Q.; Ney, J. E.; Wolfe, J. P.
Org. Lett. 2005, 7, 2575-2578.
(2) Fu¨rstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024-
15025.
(3) Kamijo, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 3230-
3233.
(4) Ruck, R. T.; Zuckerman, R. L.; Krska, S. W.; Bergman, R. G. Angew.
Chem., Int. Ed. 2004, 43, 5372-5374.
(5) Basuli, F.; Aneetha, H.; Huffman, J. C.; Mindiola, D. J. J. Am. Chem.
Soc. 2005, 127, 17992-17993.
10.1021/ol0611393 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/23/2006

Table 1. Carbodiazenylation of Olefins
aniline
R1
R2
olefin
R3
R4
product
yielda (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1d
1d
1d
1d
H
o-Cl
m-Cl
p-CO2Me
o-CO2Me
p-CF3
p-CO2Me
p-CO2Me
p-CO2Me
p-CO2Me
H
H
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2CN
(CH2)2COMe
CH2OAc
CH2OH
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
47b
67 (61)b
p-CO2H
55b
80
59 (64)c
68
H
H
H
H
H
H
H
70
60
Me
Me
58d
10
4j
73d
a Yield according to method A (2.1 equiv of TiCl3) and column chromatography. b Yield according to method B (1.1 equiv of TiCl3 and 4.0 equiv of
FeSO4). c Reaction on a larger scale (5×). d Byproduct: 10-20% hydrazine.
azo compounds 4 are obtained. Both an aryl and an aryl
diazenyl substituent are added regioselectively to the double
bond during the course of the reaction.
This reaction so far seemed to be limited to suitably
substituted electron-deficient9a,b double bonds, which is not
surprising, since these olefins have also been reported to be
the most effective substrates in the Meerwein arylation.10 In
the case of electron-rich olefins, the process is disturbed by
electron-transfer which may overcome trapping.9c
Our goal now was to find conditions that would allow the
effective functionalization of nonactivated olefins. Such a
procedure could decisively enlarge the scope of the carbo-
diazenylation reaction. In fact, the carbodiazenylation of
nonactivated olefins was first observed by Levisalles and
Rudler.11 In mechanistic studies of the Meerwein arylation,
low yields around 10% (with one maximum yield of 28%)
were obtained with unsaturated alcohols and acetates under
copper(I) catalysis. For better evaluation and comparison of
our results, we chose similar olefins for the optimization.
When optimizing the reaction conditions, we found that
the use of 2.1 equiv of titanium(III) chloride often gave better
results than mixtures of titanium(III) and iron (II) (1.1 and
4.0 equiv). Iron(II) as the only reductant (5 equiv) leads to
a very slow conversion and numerous side products.
Since the main solvent of the reaction is water, solubility
of the organic reactants is a key issue. We thus varied the
amount of methanol added to the reaction mixture. As a
result, it became clear that small quantities of methanol are
favorable. In this way, the solubility of the olefin is enhanced,
but the azo compounds formed still remain mostly in-
soluble.12
The low solubility of the products was intended, as it helps
to protect the azo compounds from isomerization to hydra-
zones under acidic conditions and from further reduction to
hydrazines by the excess of reductant present in the reaction
mixture. An overview of reactants and substrates is presented
in Table 1. The described method allows the facile synthesis
of azo compounds 4 on a gram scale (entry 5). Only in some
rare cases were small amounts of the corresponding hydra-
zines, resulting from an excess of titanium(III) in the reaction
mixture, observed (entries 9 and 10). To explain the product
formation, the mechanism shown in Scheme 2 is plausible.9,11
Scheme 2. Mechanism of the Carbodiazenylation
(6) (a) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2000, 122, 6496-
6497. (b) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717-
4727. (c) Panchaud, P.; Renaud, P. J. Org. Chem. 2004, 69, 3205-3207.
(d) Panchaud, P.; Ollivier, C.; Renaud, P.; Zigmantas, S. J. Org. Chem.
2004, 69, 2755-2759. (e) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett.
2005, 7, 2587-2590. (f) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett.
2002, 4, 4257-4260.
(7) Barton, D. H. R.; Jaszberenyi, J. C.; Theodorakis, E. A.; Reibenspies,
J. H. J. Am. Chem. Soc. 1993, 115, 8050-8059.
(8) Girard, P.; Guillot, N.; Motherwell, W. B.; Potier, P. Chem. Commun.
1995, 2385-2386.
The diazonium salt 2 is first reduced to an aryl diazenyl
radical 5, which readily acts as a source of aryl radicals 6
with loss of nitrogen.13 After addition of radical 6 to olefin
3, the radical intermediate 7 is trapped by another aryl
(9) (a) Citterio, A.; Minisci, F.; Albinati, A.; Bruckner, S. Tetrahedron
Lett. 1980, 21, 2909-2910. (b) Citterio, A.; Minisci, F.; Vismara, E. J.
Org. Chem. 1982, 47, 81-88. (c) Minisci, F.; Coppa, F.; Fontana, F.;
Pianese, G.; Zhao, L. J. Org. Chem. 1992, 57, 3929-3933.
(10) (a) Rondestvedt, C. S. Org. React. 1976, 24, 225-259. (b) Citterio,
A.; Vismara, E. Synthesis 1980, 291-292.
(11) (a) Al Adel, I.; Salami, B. A.; Levisalles, J.; Rudler, H. Bull. Soc.
Chim. Fr. 1976, 930-933. (b) Al Adel, I.; Salami, B. A.; Levisalles, J.;
Rudler, H. Bull. Soc. Chim. Fr. 1976, 934-938.
(12) For details, see the Supporting Information
(13) Galli, C. Chem. ReV. 1988, 88, 765-792.
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Org. Lett., Vol. 8, No. 15, 2006

diazonium ion 2. The final azo compound 4 is formed from
the radical cation 8 via a further reductive step.9,14
As yet, we cannot exclude the possibility that the presence
of titanium has an activating effect on the double bonds of
the olefinic reactants so that the attack of the nucleophilic
aryl radical is facilitated. This could counterbalance the low
solubility and the lower reactivity of nonactivated olefins.
Despite the low solubility of allyl acetate, the yield of the
reaction with methyl 4-aminobenzoate (1d) (Table 1, entry
4) decreases only to 58% when the excess of olefin is
lowered to 2.0 equiv.
dihydroisoquinolone 10 is obtained. Heating azo compound
4h in hydrochloric acid in methanol leads to the formation
of pyrrole 11, and simple stirring of 4e with potassium
carbonate in methanol gave hydrazone 12.
Since all azo compounds 4 are obtained in good purity
from the carbodiazenylation process, the transformations
described above can be carried out without intermediate
purification.
Last, but not least, we found that the hydrogenation of
unsymmetric azo compounds to give the two amine com-
ponents proceeds cleanly with Raney nickel in methanol. By
this method, lactam 13 was obtained in 84% yield from 4e,
and 95% of the starting material methyl anthranilate (1e)
was recovered.15 Known literature methods for the reduction
of azo compounds using zinc and formic acid or palladium
on charcoal gave unsatisfactory results.16
The carbodiazenylation products 4 can serve as reactants
for numerous further transformations. Some examples are
shown in Figure 1. Hydrazine 9 is available from 4e via
In summary, we have found a simple and practical
procedure for the carbodiazenylation of nonactivated olefins.
Most aromatic amines are readily available, many of them
from commercial sources. Moreover, there is no need for
dry solvents or protecting gas atmospheres. The aryl diazo-
nium salts which occur as intermediates, do not have to be
isolated. The reaction can, therefore, be carried out on larger
scales without safety concerns, which is a certain advantage
over other nitrogen-centered radical traps. We have also
shown that the azo compounds obtained are valuable
precursors for many polyfunctionalized target molecules,
which are now accessible in good yields. The carboamination
products of the olefins are obtained via hydrogenation, and
1 equiv of the aniline, which was used as starting material,
is recovered.
Acknowledgment. The work was supported by the Fonds
der Chemischen Industrie (Liebig fellowship). The help of
Prof. Dr. Thorsten Bach (TU Mu¨nchen) and his group is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 1. Synthesis of consecutive products from 4e and 4h.
OL0611393
(15) Azo compound 4e was chosen for more convenient isolation of the
carboamination product 13.
hydrogenation with palladium on charcoal. When 4e is
treated with zinc powder in acetic acid at 80 °C the
(16) For hydrogenations of azo compounds, see: (a) Srinivasa, G. R.;
Abiraj, K.; Gowda, D. C. Synth. Commun. 2005, 35, 1161-1165. (b) Martin,
V. V.; Rothe, A.; Gee, K. R. Bioorg. Med. Chem. Lett. 2005, 15, 1851-
1855. (c) Alonso-Alija, C.; Michels, M.; Peilsto¨cker, K.; Schirok, H.
Tetrahedron Lett. 2004, 45, 95-98.
(14) (a) Citterio, A.; Ramperti, M.; Vismara, E. J. Heterocycl. Chem.
1981, 18, 763-766. (b) Citterio, A.; Minisci, F. J. Org. Chem. 1982, 47,
1759-1761.
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