Transition-Metal-Catalyzed Aldehydic C-H Activation by Azodicarboxylates

Article abstract of DOI:10.1021/jo035456o

Rhodium acetate-catalyzed hydroacylation between aldehydes and an activated form of N=N bond was achieved under mild conditions to provide efficient access to a variety of hydrazino imides. Good selectivity for the aldehydic C-H activation relative to the ene-type reaction was observed with aldehydes having unsaturation both at terminal and internal positions.

Full text of DOI:10.1021/jo035456o

of aldehydes and an activated form of NdN bond under
mild conditions, thereby providing an efficient synthesis
of hydrazino imide functionality with good selectivity
between “paths c and d”.
Tr a n sition -Meta l-Ca ta lyzed Ald eh yd ic C-H
Activa tion by Azod ica r boxyla tes
Daesung Lee* and Ryan D. Otte
Department of Chemistry, University of Wisconsin,
Madison, Wisconsin 53706
dlee@chem.wisc.edu
Received October 3, 2003
Abstr a ct: Rhodium acetate-catalyzed hydroacylation be-
tween aldehydes and an activated form of NdN bond was
achieved under mild conditions to provide efficient access
to a variety of hydrazino imides. Good selectivity for the
aldehydic C-H activation relative to the ene-type reaction
was observed with aldehydes having unsaturation both at
terminal and internal positions.
Hu¨ckel MO theory indicates that the strong electron-
withdrawing azodicarboxylates possess a vacant bonding
orbital, which predicts these molecules to be good hydro-
gen and hydride acceptors.1 With 1, the C-H activation
at the R-position of amines and ethers (path a)2 and the
ene-type reaction (path b)3 are amply documented. It was
also reported that the reaction between 1 and acetalde-
hyde gave diacetyl under photolytic conditions,4 whereas
Huisgen reported that under thermal conditions2a the
corresponding addition product (path d) was formed. In
our effort to make adducts of unsaturated aldehydes with
1 via “path d”, competition between “paths c and d” was
noticed. In search for a solution to this problem, we were
intrigued by the possibility of accelerating the aldehydic
C-H activation (path d) relative to the ene-type reaction
(path c) by transition-metal catalysts. Herein, we report
a rhodium-catalyzed hydroacylation5 between a variety
For calibration, we first examined the uncatalyzed
reaction between hexanal and 1a in THF at 25 °C.
Complete consumption of azodicarboxylate along with
the formation of a 1:1 ratio of two major compounds
was observed after 3 days. Isolation and characteriza-
1
tion of these compounds by H NMR, 13C NMR, HRMS,
and IR clearly supports the structure of hexanal-1a
adduct (2) and the “path a”-derived THF adduct (3).
The reaction under neat conditions afforded only 2
but with much reduced reaction rate, requiring 14 days
for completion. In search for a catalyst providing higher
turnover, we screened various transition-metal catalysts
and Lewis acids. Remarkably, within 15 min, com-
plete consumption of 1a was observed with [Rh(OAc)2]2
(10 mol %, THF, 25 °C), generating roughly a 1:1 mix-
ture of 2 and the THF adduct 3. The relative conver-
sion rates of 1a and hexanal to 2 by other catalysts were
also shown in Figure 1. Other than [Rh(OAc)2]2, only
[RuCl2(benzene)]2 showed significant catalytic activ-
ity.6 Neither Pd complexes nor Lewis acids (EuFOD,
Sm(OTf)2, Sc(OTf)2, AgOTf) showed activity higher
than background level. Next, we tried different solvents
to suppress the formation of a solvent-adduct. When the
reaction was carried out in CH2Cl2 with [Rh(OAc)2]2 no
reaction occurred. In hexane and toluene, the reaction
was much slower. The reactions in Et2O and 1,4-dioxane
gave the expected solvent-adducts 4 and 5, respectively,
but to a lesser extent compared to that in THF; however,
in EtOAc, only the desired adduct 2 formed.7 The amount
of catalyst can be as low as 1.5-2.0 mol % without
affecting the yield significantly, although the reaction
time becomes longer.
(1) Hu¨ckel MO treatment of azodicarbonitrile, see: Marsh, F. D.;
Hermes, M. E. J . Am. Chem. Soc. 1965, 87, 1819. (b) Koga, G.; Anselme,
J . P. In The Chemistry of Hydrazo, Azo, and Azoxy Groups; Patai, S.,
Ed.; J ohn Wiley & Sons: New York, 1975; Part 2, p 903.
(2) (a) Diels, O.; Fisher, E. Ber. Dtsch. Chem. Ges. 1914, 47, 2043.
(b) Huisgen, R.; J akob, F. J utus Liebigs Ann. Chem. 1954, 590, 37. (c)
Askani, R. Chem. Ber. 1965, 98, 2551. (d) Cookson, R. C.; Stevens, I.
D. R.; Watt, C. T. Chem. Commun. 1965, 259. (e) Smissman, E. E.;
Makriyannis, A. J . Org. Chem. 1973, 38, 1652. (f) Grochowski, E.;
Boleskawska, T.; J urczak, J . Synthesis 1977, 718. (g) Doleschall, G.
Tetrahedron Lett. 1978, 19, 2131. (h) Abarca, B.; Ballesteros, R.;
Gonzalez, E.; Sancho, P.; Sepulveda, J .; Soriano, C. Heterocycles 1990,
31, 1811. (i) Denis, A.; Renou, C. Tetrahedron Lett. 2002, 43, 4171. In
related reactions, alcohols can be oxidized to the corresponding
aldehydes and ketones; see: (j) Yoneda, F.; Suzuki, K.; Nitta, Y. J .
Am. Chem. Soc. 1966, 88, 2328. (k) Yoneda, F.; Suzuki, K.; Nitta, Y.
J . Org. Chem. 1967, 32, 727.
(3) For a review, see: (a) Hoffmann, H. M. R. Angew. Chem., Int.
Ed. Engl. 1969, 8, 556. (b) Firl, J .; Sommer, S. Tetrahedron Lett. 1969,
10, 1137. (c) Raporterie, A.; Dubac, J .; Lesbre, M. J . Organomet. Chem.
1975, 101, 187. (d) Stephenson, L. M.; Mattern, D. J . Org. Chem. 1976,
41, 3614. (e) J enner, G.; Ben Salem, R. J . Chem. Soc., Perkin Trans. 2
1990, 1961. (f) Leblanc, Y.; Zamboni, R.; Bernstein, M. A. J . Org. Chem.
1991, 56, 1971. (g) Brimble, M. A.; Heathcock, C. H. J . Org. Chem.
1993, 58, 5261. (h) Desimoni, G.; Faita, G.; Righetti, P. P.; Sfulcini,
A.; Tsyganov, D. Tetrahedron 1994, 50, 1821. (i) Sarkar, T. K.; Ghorai,
B. K.; Das, S.; Grangopadhyay, P.; Rao, S. Tetrahedron Lett. 1996, 37,
6607.
(5) Although it is known that Lewis acids catalyze the ene-type
reaction in “path c”, catalyzed reactions have not been reported in “path
d”.
(6) [Rh(OCOCF3)2]2 was capable of catalyzing the reaction but found
to be much less reactive than [Rh(OAc)2]2.
(7) The reaction of substrates having slow conversion rate provides
varying amounts of the corresponding hydrazodicarboxylate.
(4) (a) Schenck, G. O.; Formaneck, H. Angew. Chem. 1958, 70, 505.
10.1021/jo035456o CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/23/2004
J . Org. Chem. 2004, 69, 3569-3571
3569

TABLE 1. Hyd r oa cyla tion of Ald eh yd esa
F IGURE 1. Catalyst screening for coupling of hexanal with
diisopropyl azodicarboxylate (1). Reactions were performed
with 10 mol % catalyst in a 1.0 M solution of 1:1 mixture of
hexanal and 1a in THF at 25 °C. The relative conversion was
estimated at the point when the [Rh(OAc)2]2-catalyzed reaction
reached to complete consumption of 1a .
Under the adjusted conditions that balanced the yield
and the amount of required catalyst loading (1.5-2.0 mol
% of [Rh(OAc)2]2, 1.0 M, EtOAc, 25 °C), 2 was obtained
in 84% yield. A variety of aliphatic saturated and
unsaturated aldehydes (6a -o) afforded the expected
hydroacylation products (7a -o) both with 1a and 1b in
good to excellent yields (Table 1). In general, the reaction
became slower as the number of carbons in the substrate
aldehyde increased. The unsaturation either at the
terminal or internal position does not interfere with the
reaction, but in certain cases, the product undergoes ene-
type reaction to generate increased amount of bis-
azodicarboxylate adduct as the reaction progressed to-
ward completion (entries e, f, and h). An aldehyde (6c)
with terminal alkyne functionality was also a suitable
substrate for this reaction (entry c). Mono- or bis-
branched aldehydes (6e,g,h ) at either the R- or â-position
provided a similar reaction rate and comparable yields
(entries e, g, h, and j).
a
Reactions were performed with 1.5-2.0 mol % [Rh(OAc)2]2
with a 1:1 ratio of aldehyde and 1a or 1b in EtOAc (1.0 M) at 25
b
°C. The reaction times were recorded in 12 h increments, and
the yields are based on the amount of isolated product. c The
relatively low yield was caused by the formation of 2:1 adduct of
Except for crotonaldehyde (entry i), the reactions of R,â-
unsaturated and aromatic aldehydes were much slower,
giving incomplete conversion even after a long reaction
time. The reaction of aromatic aldehydes with electron-
donating substituents was slower (entries k, l), whereas
that with electron-withdrawing substituents was faster
d
1a and aldehyde. The low yield is due to the formation of 8
and 9.
(entries n, o) than that of the parent benzaldehyde (entry
m). In case of 4-dimethylamino benzaldehyde (entry l),
3570 J . Org. Chem., Vol. 69, No. 10, 2004

two additional products were isolated and identified as
the C-H activation products 8 and 9. The formation of
these compounds was not unexpected on the basis of the
related transformation of compounds with a dimethy-
lamino group as well as the efficient formation of C-H
activation products 3-5 with ethereal solvents under the
same conditions. One intriguing feature of this catalyzed
process is that the presence of an aldehyde greatly
accelerated the rate of C-H activation at the R-position
of ethers and amines.
tion of the putative acyl radical10 intermediate to azodi-
carboxylate; however, other roles for the catalyst cannot
be excluded.11
In conclusion, we developed an efficient rhodium-
catalyzed hydroacylation reaction between aldehydes and
azodicarboxylates. Under these conditions, unsaturated
aldehydes give predominantly the hydroacylation product
over the ene-type adduct. Further study on the reaction
mechanism and the application of this new amide-like
bond-forming process is underway.
Mechanistically, the addition of aldehydes to azodicar-
boxylate was proposed to be a radical-mediated process.2a,b
This radical mechanism is supported by a complete
inhibition of the reaction when it was run with as low as
1 mol % of radical scavenger (4,4′-dithiobis(2,6-di-tert-
butylphenol).8 On the other hand, the catalyzed reaction
with 10 mol % of Rh2(OAc)4 proceeded in the presence of
1.0, 2.5, and 5.0 mol % of scavenger, and a complete
inhibition was reached at the amount of 10 mol % of the
scavenger.9 On the basis of this observation, it is reason-
able to assume that the rhodium-catalyzed version of this
reaction may still proceed via radical mechanism al-
though the role of rhodium catalyst is not clear at this
point. In a radical mechanism manifold somehow the
rhodium catalyst may facilitate the generation or addi-
Ack n ow led gm en t. We thank UWsMadison and
the Dreyfus Foundation for financial support of this
work as well as the NSF and NIH for NMR and Mass
Spectrometry instrumentation. We are grateful to Prof.
Hans Reich and Prof. Charles Casey for helpful discus-
sions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 2 and 7a -o. Spectral data for 2-5 and 7-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035456O
(10) (a) Gottschalk, P.; Neckers, D. C. J . Org. Chem. 1985, 50, 3498.
(b) Dang, H.-S.; Roberts, B. P. J . Chem. Soc., Perkin Trans. 1 1998,
67. (c) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev.
1999, 99, 1991. (d) Tsujimoto, S.; Iwahama, T.; Sakaguchi, S.; Ishii,
Y. Chem. Commun. 2001, 2352. (e) Brown, C. E.; Neville, A. G.; Rayner,
D. M.; Ingold, K. U.; Lusztyk, J . Aust. J . Chem. 1995, 48, 363. (f)
Chatgilialoglu, C.; Ferreri, C.; Luarini, M.; Venturini, A.; Zavitsas, A.
A. Chem. Eur. J . 1997, 3, 376.
(11) The intramolecular trapping experiments of 5-hexenoyl radical
derived from 5-hexenal and azodicarboxylate both with and without
catalyst were also carried out. In both cases, the formation of 2-methyl
cyclopentanone derivative was not observed; instead, only the normal
coupled product (7b/7b′) was isolated in good yield.
(8) The dependency of the extent of inhibition on the amount of the
radical scavenger used in the reaction was pointed out by a reviewer.
(9) Duplicates of both the uncatalyzed and catalyzed reactions were
run at 0, 1.0, 2.5, 5.0, and 10 mol % of the scavenger, 4,4′-dithiobis-
(2,6-di-tert-butylphenol), neat and in 0.2 M solution in EtOAc. The
progression of the reaction was monitored by 1H NMR spectroscopy.
The details of this experiment are described in the Supporting
Information.
J . Org. Chem, Vol. 69, No. 10, 2004 3571