Cobalt-catalyzed hydrohydrazination of dienes and enynes: Access to allylic and propargylic hydrazides

Article abstract of DOI:10.1021/ol0517473

(Chemical Equation Presented) The cobalt-catalyzed hydrohydrazination reaction of dienes and enynes is presented. Allylic and propargylic hydrazines were obtained in synthetically useful yields (allylic amines, 60-90%; propargylic amines, 47-83%) and good chemo- and regioselectivity.

Full text of DOI:10.1021/ol0517473

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4249-4252
Cobalt-Catalyzed Hydrohydrazination of
Dienes and Enynes: Access to Allylic
and Propargylic Hydrazides
Je´roˆme Waser, Jose´ C. Gonza´lez-Go´mez, Hisanori Nambu, Pascal Huber, and
Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg,
HCI H335 8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received July 22, 2005
ABSTRACT
The cobalt-catalyzed hydrohydrazination reaction of dienes and enynes is presented. Allylic and propargylic hydrazines were obtained in
synthetically useful yields (allylic amines, 60 90%; propargylic amines, 47 83%) and good chemo- and regioselectivity.
−
−
Allylic and propargylic amines and their derivatives are
useful building blocks for the synthesis of biologically active
compounds.1 Consequently, a number of new methodologies
detailing the preparation of these building blocks have
recently been disclosed, largely involving the direct addition
of alkynyl or alkenyl nucleophiles to imines.2,3 The introduc-
tion of amine functionality via C-N bond formation
constitutes a fundamentally different disconnection,4 and it
has been achieved via allylic substitution reactions,4e-h ene
reactions,4i Overman rearrangement,4j or the hydroamination
reaction of dienes.4k-m This latter strategy has been success-
fully employed for the synthesis of allylic amines, but there
are only a few reports for the synthesis of propargylic amines
using this approach.5 During our recent studies on the cobalt-
catalyzed hydrohydrazination reaction of olefins,6 we ob-
served an important accelerating effect of olefin conjugation
to an aromatic ring (styrene derivatives) on the reaction rate
of the process. We speculated that if a similar effect was
present with alkenes and alkynes as substituents (i.e., dienes
or enynes as substrates), it would be possible to achieve a
monohydrazination of dienes and enynes. Herein, we wish
to report the successful realization of this strategy, culminat-
ing in a new efficient synthesis of allylic and propargylic
hydrazines (Figure 1).
In prior work, we have documented the reaction of olefins
and azodicarboxylates in the presence of silanes mediated
(4) (a) DuBois, J.; Hong, J.; Carreira, E. M.; Day, M. W. J. Am. Chem.
Soc. 1996, 118, 915. (b) DuBois, J.; Tomooka, C. S.; Hong, J.; Carreira, E.
M. Acc. Chem. Res. 1997, 30, 364. (c) DuBois, J.; Tomooka, C. S.; Hong,
J.; Carreira, E. M.; Day, M. W. Angew. Chem., Int. Ed. Engl. 1997, 36,
1645. (d) DuBois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. J. Am.
Chem. Soc. 1997, 119, 3179. (e) Vonmatt, P.; Loiseleur, O.; Koch, G.; Pfaltz,
A.; Lefeber, C.; Feucht, T.; Helmchen, G. Tetrahedron: Asymmetry 1994,
5, 573. (f) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164.
(g) Shu, C. T.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43,
4797. (h) Yamagishi, T.; Ohnuki, M.; Kiyooka, T.; Masui, D.; Sato, K.;
Yamaguchi, M. Tetrahedron: Asymmetry 2003, 14, 3275. (i) Brimble, M.
A.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5261. (j) Anderson, C. E.;
Overman, L. E. J. Am. Chem. Soc. 2003, 125, 12412. (k) Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546. (l) Lober, O.; Kawatsura,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366. (m) Pawlas, J.;
Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
3669.
(1) Enders, D.; Schankat, J. HelV. Chim. Acta 1995, 78, 970.
(2) (a) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319. (b) Fassler,
R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002,
41, 3054. (c) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497. (d)
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41,
2535. (e) Knopfel, T. E.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (f) Wei, C.; Li,
C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (g) Wipf, P.; Kendall, C.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761. (h) Patel, S. J.;
Jamison, T. F. Angew. Chem., Int. Ed. 2004, 43, 3941.
(5) An, D. K.; Hirakawa, K.; Okamoto, S.; Sato, F. Tetrahedron Lett.
1999, 40, 3737.
(6) (a) Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676.
(b) Waser, J.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
8294.
(3) Hirabayashi, R.; Ogawa, C.; Sugiura, M.; Kobayashi, S. J. Am. Chem.
Soc. 2001, 123, 9493.
10.1021/ol0517473 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/19/2005

Table 1. Hydrohydrazination Reaction of Dienes
Figure 1. Hydrohydrazination of conjugated olefins.
by a simple Co-catalyst to afford alkylhydrazides.6 Expansion
of the scope of the monohydrazination process to include
dienes would require that a number of key criteria be met.
First, the reactivity difference between the diene starting
material and the product monoalkene would have to be
sufficiently large to minimize the formation of products
corresponding to double hydrohydrazination. Given the lack
of reactivity of alkynes under the conditions we have
examined, this first concern did not apply to the enyne
starting materials. Second, competitive semireduction of the
reactive dienes or enynes would need to be prevented. Third,
additional side reactions such as Diels-Alder cycloaddition
reaction of the azodicarboxylate with dienes, a well-prece-
dented transformation at ambient temperature, would need
to be slow relative to the hydrohydrazination process.7 With
respect to the last of these, as a control experiment, treatment
of di-tert-butyl azodicarboxylate (3) with 2,3-dimethyl-1,3-
butadiene (2) led to the formation of cycloadduct 4 in 85%
yield in 24 h (23 °C). By contrast, a mixture of diene 2 and
azodicarboxylate 3 in the presence of cobalt catalyst 1 and
phenylsilane led to the selective and preferential formation
of hydrohydrazination product 5 in 60% yield in the span of
1 h (Scheme 1).
Scheme 1. Test Case for the Hydrohydrazination of Dienes
a Isolated yield after chromatography. b 5 mol% of catalyst 1 was used.
rather unexpected, because the results of previous studies
with olefins had indicated a strong preference for formation
of Markovnikov products.6 To further assess the scope and
the regioselectivity of the reaction, we first examined acyclic
olefins (Table 1, entries 2-4). Isoprene (entry 2) gave a 4:1
mixture of products consistent with the preferential hydro-
cobaltation of the R,R-disubstituted double bond followed
Subsequent optimization studies highlighted the benefits
of TMDSO (tetramethyldisiloxane) and lower catalyst load-
ing (2.5 mol%) in the reaction, allowing the isolation of 5
in 83% yield as a single regioisomer (Table 1, entry 1). The
selective formation of the primary hydrazine derivative 5 is
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Org. Lett., Vol. 7, No. 19, 2005

by amination at the primary center. The reaction of 2,5-
dimethylhexa-2,4-diene (entry 3) underscores the unusual
regioselectivity of the reaction of conjugated dienes, in which
formation of the secondary allylic amination product was
favored over the tertiary one (7:1). In the case of myrcene
(entry 4), the reaction showed impressive regio- and chemose-
lectivity, allowing the isolation of one major isomer in 65%
yield and a small amount (3%) of the Diels-Alder adduct.
We then turned to cyclic substrates. These are some of the
best substrates for the hydrohydrazination reaction. The
desired cyclic allylic hydrazines were obtained in good yields
(entry 5-7), even for 1,3-cyclooctadiene, which has proven
to be unreactive or much less reactive in other methods.4k-m
Cyclopentadiene could be converted to the desired hydrazine
(entry 8), although in this case background cycloaddition
reaction of cyclopentadiene and the azodicarboxylate leads
to formation of the Diels-Alder adduct in 23% yield. Finally,
we observed the selective formation of an exocyclic hydra-
zine (entries 9 and 10). Entry 10 is especially interesting, as
in this case complete selectivity is observed. As similar
dienes are easily accessible via enyne metathesis,8 the high
yield and selectivity observed is promising for further
applications of the reaction (Scheme 2).
selective reactions with the double bond are very scarce.11d,e
To the best of our knowledge, there is only one report of a
hydroamination reaction of conjugated enynes; however,
under the reaction conditions, multiaminated products are
observed.11f
We decided to focus initially on enynes bearing an
unsubstituted double bond and a bulky protecting group on
the alkyne (TMS or an acetone-derived protecting group
(Table 2, entries 1 and 2)). It was indeed possible to obtain
Table 2. Hydrohydrazination Reaction of Enynes
Scheme 2. Application of the Hydrohydrazination Reaction
Having successfully developed the hydrohydrazination of
dienes, we were interested in examining enynes as substrates.
Enynes are interesting substrates because the presence of the
alkyne triple bond alleviates any potential difficulties as-
sociated with the stereoselective synthesis of dienes and
potentially leads to the question of chemoselectivity of the
process. Furthermore, advances in the Sonogashira reaction9
and development of alkyne-alkyne coupling processes10
provide fast and modular access to these compounds. Yet,
the selective functionalization of enynes has proven to be a
challenging task.11 Although there are some reports on
the selective functionalization of the triple bond,2g,11b,c
(7) (a) Gillis, B. T.; Beck, P. E. J. Org. Chem. 1962, 27, 1947. (b) Allred,
E. L.; Anderson, C. L.; Smith, R. L. J. Org. Chem. 1966, 31, 3493. (c)
Stout, D. M.; Takaya, T.; Meyers, A. I. J. Org. Chem. 1975, 40, 563. (d)
Luna, A. P.; Ceschi, M. A.; Bonin, M.; Micouin, L.; Husson, H. P.;
Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George, P.
J. Org. Chem. 2002, 67, 3522. (e) Bentz, D.; Laschat, S. Synthesis 2000,
1766.
(8) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(10) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G. J.
Am. Chem. Soc. 1997, 119, 698.
a Isolated yield after chromatography. b TMDSO (2.5 equiv) was used
instead of phenylsilane. c 1 mol% catalyst was used.
(11) (a) Aksela, R.; Oehlschlager, A. C. Tetrahedron 1991, 47, 1163.
(b) Zaidlewicz, M.; Meller, J. Collect. Czech. Chem. Commun. 1999, 64,
1049. (c) Backvall, J. E.; Ericsson, A. J. Org. Chem. 1994, 59, 5850. (d)
Wang, X. H.; Ni, Z. J.; Lu, X. J.; Smith, T. Y.; Rodriguez, A.; Padwa, A.
Tetrahedron Lett. 1992, 33, 5917. (e) Smit, W. A.; Schegolev, A. A.; Gybin,
A. S.; Mikaelian, G. S.; Caple, R. Synthesis 1984, 887. (f) Radhakrishnan,
U.; Al-Masum, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 1037.
propargylic hydrazides as the only isolable products in the
presence of catalyst 1 (5 mol%), phenylsilane (1.5 equiv),
and di-tert-butylazodicarboxylate (3) (2 equiv). TMS proved
to be optimal as a protecting group, furnishing the desired
Org. Lett., Vol. 7, No. 19, 2005
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product in 83% yield under these conditions. Phenyl- (entry
3) and butyl-substituted (entry 4) alkynes were also tolerated.
However, for these products, quenching of the reaction
immediately after full consumption of the starting material
was crucial to prevent reduction of the triple bond. In the
case of phenyl, this reduction side-reaction could only be
suppressed by the use of TMDSO as the silane.
obtain useful yields (66-67%) with these substrates (entries
11 and 12).
In summary, we have documentated a new approach
toward allylic and propargylic hydrazines based on the
cobalt-catalyzed hydrohydrazination reaction of dienes and
enynes. For dienes, our method is mechanistically distinct
from existing approaches and displays useful yields and
regioselectivities. For enynes, the selective amination of the
double bond is unprecedented and opens a new perspective
for the selective functionalization of enynes en route to useful
building blocks and biologically active compounds. Further
studies are ongoing in our laboratory in order to extend this
strategy and to examine the transformation of the obtained
hydrazines into other useful compounds.
Substrates incorporating alkene substitution were inves-
tigated. A methyl (entry 5) and an ester (entry 6) substituent
at the â-position of the double bond were tolerated, but the
products were obtained in moderate yields (54 and 47%
1
respectively). H NMR analysis of the crude reaction mix-
ture showed signals corresponding to allenic side products,
but, unfortunately, these compounds could not be isolated.
We were pleased to observe that the introduction of an
hydroxy (entry 7) or silyl ether group (entry 8) in the
â-substituent led to product formation in 77 and 63% yield,
respectively.
Enynes with an R-substituted or an R,â-disubstituted
double bond were examined next. The products from the
hydrohydrazination of these could only be isolated in low
yields using the conditions described above (entries 9 and
10). In both cases, we also isolated considerable quantities
of product resulting from dimerization at the propargylic
position. We reasoned that lower catalyst loadings and the
use of sterically less hindered azodicarboxylates would
increase the yield of the desired hydrazines. Indeed, using 1
mol% catalyst 1 and diethyl azodicarboxylate allowed us to
Acknowledgment. We thank the Swiss National Founda-
tion for support of this research and the Roche Research
Foundation for the support of J.W. H.N. thanks the Japan
Society for the Promotion of Science (JSPS) for a postdoc-
toral fellowship. J.C. thanks the Xunta de Galicia for a
postdoctoral fellowship.
Supporting Information Available: General experimen-
tal procedures, specific details for representative reactions,
and isolation and spectroscopic information for the new
compounds prepared. This material is available free of charge
via the Internet at http://pubs.acs.org.
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