Synthesis of ketene n,n-aeetals by copper-catalyzed double-amidation of 1,1-dibromo-1-alkenes

Article abstract of DOI:10.1021/ol901831s

An efficient procedure for the preparation of ketene N,N-acetals by copper-catalyzed double amidation of 1,1-dibromo-1-alkenes Is reported. The reaction was found to be general, and ketene aminals could be obtained in good yields when potassium phosphate

Full text of DOI:10.1021/ol901831s

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4454-4457
Synthesis of Ketene N,N-Acetals by
Copper-Catalyzed Double-Amidation of
1,1-Dibromo-1-alkenes
Alexis Coste, Franc¸ois Couty, and Gwilherm Evano*
Institut LaVoisier de Versailles, UMR CNRS 8180, UniVersite´ de Versailles
Saint-Quentin en YVelines, 45, aVenue des Etats-Unis, 78035 Versailles Cedex, France
eVano@chimie.uVsq.fr
Received August 7, 2009
ABSTRACT
An efficient procedure for the preparation of ketene N,N-acetals by copper-catalyzed double amidation of 1,1-dibromo-1-alkenes is reported.
The reaction was found to be general, and ketene aminals could be obtained in good yields when potassium phosphate in toluene was used
at 80 °C. The reaction was found to proceed through a regioselective monocoupling reaction followed by dehydrobromination and hydroamidation.
Ketene N,N-acetals 1, also named ketene aminals or 1,1-
enediamines, are useful intermediates in organic synthesis. They
combine two enamines in one functional group and exhibit
significant nucleophilicity at C-2 due to the delocalization of
the lone pairs of both nitrogen atoms into the double bond.
However, their exceptional reactivity renders their synthesis,
preparation, and storage difficult, which probably accounts for
how seldom they have been used, especially compared to their
O,O-, S,S-, N,O-, or N,S counterparts.1,2
Stable derivatives of ketene aminals include their push-pull
derivatives 2 (Figure 1). While their synthesis and reactivity
Figure 1. Resonance structures and stable derivatives of ketene
N,N-acetals.
have been extensively studied over the past 20 years,3,4 their
(1) For a general reference, see: Kantlehner, W. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; de Meijere, A., Ed.;
Thieme: Stuttgart, 2005; Vol. 24, pp 571-746.
applications are still limited, mostly because of the require-
ment for an electron-withdrawing group at C-2. An interest-
ing alternative to balance the reactivity and stability of ketene
N,N-acetals relies on the substitution of the nitrogen atoms
by electron-withdrawing groups such as in 3. These groups
serve to diminish the electron-donating ability of the nitrogen
atoms, therefore offering greater stability compared to
traditional ketene aminals. In addition, it also allows
substitution at C-2 with aryl, alkyl, or vinyl groups.
(2) For examples, see: (a) Gruseck, U.; Heuschmann, M. Tetrahedron
Lett. 1987, 28, 6027. (b) Ye, G.; Henry, W. P.; Chen, C.; Zhou, A.; Pittman,
C. U., Jr. Tetrahedron Lett. 2009, 50, 2135
.
(3) For a review, see: Huang, Z. T.; Wang, M. X. In The Chemistry of
Enamines; Rappoport, Z., Ed.; John Wiley: New York, 1994; pp 1303-
1363.
(4) For selected recent examples, see: (a) Shi, Y.; Zhang, J.; Grazier,
N.; Stein, P. D.; Atwal, K. S.; Traeger, S. C.; Callahan, S. P.; Malley, M. F.;
Galella, M. A.; Gougoutas, J. Z. J. Org. Chem. 2004, 69, 188. (b) Yu,
C.-Y.; Yang, P.-H.; Zhao, M.-X.; Huang, Z.-T. Synlett 2006, 1825. (c) Naito,
H.; Hata, T.; Urabe, H. Tetrahedron Lett. 2008, 49, 2298. (d) Yaqub, M.;
Yu, C.-Y.; Jia, Y.-M.; Huang, Z.-T. Synlett 2008, 1357
.
10.1021/ol901831s CCC: $40.75
Published on Web 09/02/2009
 2009 American Chemical Society

While these stable derivatives clearly hold great potential
in organic synthesis, a careful examination of the literature
reveals a lack of general methods for their preparation.5 In
this context, we report a general and straightforward proce-
dure for the preparation of electron-deficient ketene N,N-
acetals 3 by copper-catalyzed double amidation of 1,1-
dibromo-1-alkenes.
Table 1. Scope and Limitationsa
Drawing from recent experiences in the field of copper-
catalyzed cross-coupling reactions,6,7 and in the course of
our investigations on the copper-catalyzed cross-coupling
between 1,1-dibromo-1-alkenes and N-nucleophiles,8,9 we
found that ketene N,N-acetals could be cleanly isolated as
the sole products. Indeed, while the copper-catalyzed (12%
CuI, 18% N,N′-dimethylethylenediamine) reaction between
lactam 4 and dibromide 5 cleanly gave the expected ynamide
6 when cesium carbonate in dioxane was used, we unexpect-
edly isolated ketene acetal 7 by switching to potassium
phosphate in toluene (Scheme 1).10
Scheme 1. Ketene N,N-Acetals from 1,1-Dibromo-1-alkenes
Motivated by this encouraging result and by the lack of
general synthetic methods for the preparation of electron-
deficient ketene N,N-acetals such as 7, we briefly optimized
the reaction conditions and found that it was best performed at
80 °C for 20-24 h, using a slight excess (2.5 equiv) of γ-lactam
(Scheme 2). Under these conditions, ketene aminal 7 could be
Scheme 2. Optimized Reaction Conditions for the Synthesis of
Ketene N,N-Acetals from 1,1-Dibromo-1-alkenes
a Conditions: CuI (12 mol %), N,N′-dimethylethylenediamine (18 mol
%), K3PO4 (3 equiv), toluene (0.1 mol·L-1), 80 °C, 20-24 h. b Yield of
pure, isolated product. c Reaction performed on a 2 g scale. d Decomposition
of the dibromide. e No reaction.
as thiophene (Table 1, entry 5), and the presence of electron-
withdrawing (Table 1, entry 3) or donating (Table 1, entry 2)
groups had virtually no effect on the reaction.
Cinnamaldehyde-derived dibromide was also found to be
an excellent reaction partner, providing the corresponding
styryl-substituted ketene aminal in excellent yield (Table 1,
entry 6).
obtained in 94% yield after simple filtration of the crude reaction
mixture and removal of excess pyrrolidin-2-one.
With these optimized conditions in hand, the scope of the
reaction with various 1,1-dibromo-1-alkenes was next investi-
gated. Results from these studies are shown in Table 1. A variety
of ketene N,N-acetals could be obtained in moderate to good
yields.11 The reaction was found to be compatible with a variety
of aromatic groups, including heteroaromatic compounds such
(5) Ketene N,N-acetals related to 3 have been prepared by acylation of
acetamidines. See: (a) Miescher, K.; Marxer, A.; Urech, E. HelV. Chim.
Acta 1951, 34, 16. (b) Ono, M.; Tanaka, H.; Hayakawa, K.; Tamura, S.
Chem. Pharm. Bull. 1983, 31, 3534.
Org. Lett., Vol. 11, No. 19, 2009
4455

The double amidation of alkyl-substituted dibromoalkenes
turned out to be more substrate-dependent since only the
bulky TBDSP-protected hydroxymethylene was tolerated
(Table 1, entry 7). In the case of a smaller group such as an
octyl, extensive degradation was observed (Table 1, entry
8), which could be attributed to the higher unstability of the
corresponding ketene aminal under the reaction conditions.
As expected, ꢀ-lactam was also smoothly transformed to
the corresponding aminal (Table 1, entry 9), while acyclic
secondary amides such as N-methylacetamide, which are
definitely not the best reaction partners in copper-catalyzed
cross-coupling reactions, were not suitable substrates (Table
1, entry 10).
midation of intermediate ynamides,13 a reaction that had
already been observed by Skrydstrup and co-workers,14
ynamide 10 was reacted with 1 equiv of lactam 4 and excess
potassium phosphate. As suspected, the hydroamidation
product 7 was isolated as a single regioisomer in 59% yield
(Scheme 4).
Scheme 4. Hydroamidation of Ynamide to Ketene N,N-Acetal
We finally checked that the double amidation was not
limited to the small scale used for the coupling reactions
described above. Gratifyingly, it could be conveniently
performed on a 2 g scale, and ketene N,N-acetal 7 could be
isolated in 88% yield (Table 1, entry 1).
To further evaluate the scope of the double amidation and
to gain insight into its mechanism, the reactivity of protected
1,2-diamines was next examined. Carbamate-protected di-
amines 8a (R ) Me) and 8b (R ) allyl) were selected for
solubility purposes and reacted with dibromide 5 under our
standard conditions (Scheme 3). Instead of the expected
On the basis of these results, it is reasonable to assume
that this double amidation of 1,1-dibromo-1-alkenes proceeds
in three steps (Figure 2) and that ynamides are formed as
Scheme 3. Copper-Catalyzed Coupling of Protected
1,2-Diamines with 1,1-Dibromo-1-alkenes
cyclic ketene aminals, protected tetrahydropyrazine deriva-
tives 9a and 9b were isolated in moderate yields, which is
in accordance with similar results from the Urabe group.12
The formation of tetrahydropyrazines starting from pro-
tected 1,2-diamines shows that the formation of ketene N,N-
acetals from 1,1-dibromo-1-alkenes is probably more than
just a simple result from two consecutive copper-catalyzed
C(sp2)-N bond formations. Driven by these results and by
the feeling that ketene aminals might arise from the hydroa-
Figure 2. Mechanism of the copper-catalyzed double amidation
of 1,1-dibromo-1-alkenes.
intermediates. The first steps would involve a regioselective
monocoupling at the more reactive trans C-Br bond of
dibromides 11 followed by dehydrobromination to ynamides
13.8 Then, a regioselective hydroamidation,14 with introduc-
tion of the lactam ring at the more electrophilic C(sp)
(6) (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007,
46, 572. (b) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2007, 72,
9003. (c) Toumi, M.; Couty, F.; Evano, G. Synlett 2008, 29. (d) Coste, A.;
Toumi, M.; Wright, K.; Razafimahale´o, V.; Couty, F.; Marrot, J.; Evano,
G. Org. Lett. 2008, 10, 3841. (e) Toumi, M.; Rincheval, V.; Young, A.;
Gergeres, D.; Turos, E.; Couty, F.; Mignotte, B.; Evano, G. Eur. J. Org.
Chem. 2009, 3368. (f) Evano, G.; Toumi, M.; Coste, A. Chem. Commun.
2009, 4166.
(9) For leading references on the copper-catalyzed amidation of vinyl
halides, see : (a) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333. (b)
Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667.
(c) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6, 27. (d)
Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (e) Trost, B. M.; Stiles,
D. T. Org. Lett. 2005, 7, 2117.
(7) For recent reviews, see: (a) Evano, G.; Blanchard, N.; Toumi, M.
Chem. ReV. 2008, 108, 3054. (b) Monnier, F.; Taillefer, M. Angew. Chem.,
Int. Ed. 2008, 47, 3096.
(10) For metal-catalyzed reactions of vinyl dibromides with N-nucleo-
philes, see: (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Fayol,
A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (c) Nagamochi, M.;
Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955. (d) Yuen, J.; Fang,
Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653.
(8) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem.,
Int. Ed. 2009, 48, 4381.
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Org. Lett., Vol. 11, No. 19, 2009

center,15 would account for the formation of ketene N,N-
acetals 14. In the case of protected 1,2-diamines, formation
of tetrahydropyrazines would result from a 6-endo-dig
cyclization being more favorable compared to the 5-exo-dig
one.12
In conclusion, we have developed an efficient synthesis
of ketene N,N-acetals by copper-catalyzed double amidation
of 1,1-dibromo-1-alkenes. The reaction was found to proceed
through a cross-coupling/dehydrobromination/hydroamida-
tion sequence. Further applications of this method and of
the ketene aminals obtained are underway and will be
reported in due course
Acknowledgment. We thank the CNRS and the ANR
(project ProteInh) for financial support. A.C. acknowledges
the National Cancer Institute for a graduate fellowship.
Supporting Information Available: Experimental pro-
1
cedures, characterization, and copies of H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) As pointed out by one reviewer, the yield seems to depend on the
nature of the aromatic group of the dibromide. The basis for this difference
in reactivity is, however, not well understood at this stage.
(12) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc.
2008, 130, 1820.
OL901831S
(14) Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J. Org.
Chem. 2008, 73, 9447.
(15) For introduction of a nucleophile at the R-position of ynamides,
see, for example: Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale,
H.; Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
(b) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis,
A. Org. Lett. 2005, 7, 1047. (c) Kramer, S.; Dooleweerdt, K.; Lindhardt,
A. T.; Rottla¨nder, M.; Skrydstrup, T. Org. Lett. 2009, 11, 4208.
(13) For reviews on ynamides and electron-deficient ynamines, see: (a)
Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L.
Tetrahedron 2001, 57, 7575. (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung,
R. P. Synlett 2003, 1379. (c) Katritzky, A. R.; Jiang, R.; Singh, S. K.
Heterocycles 2004, 63, 1455.
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