TABLE 1. Reactivity Profile of 1 as a Function of Alcohol
Solventa
One-Step RhCl3-Catalyzed Deprotection of
Acyclic N-Allyl Amides
Michael J. Zacuto* and Feng Xu
Department of Process Research, Merck Research Laboratory,
Rahway, New Jersey 07065
R
3:4
Me
Et
n-Pr (3)
1:0
4:1
2:1
a
Molar ratios based on HPLC analysis of crude reaction mixture
measured against known samples.
available. The most common approach is a two-step procedure
involving isomerization of the double bond to an enamide by
2
2a,3
4
2d,e
the action of Rh or Ru catalysis and subsequent acidic
or oxidative
2
c,3b
cleavage of the isolated enamide. By contrast,
one-step direct deprotection procedures are relatively rare. The
use of π-allyl chemistry for direct amide deprotection is limited
to one report involving Ni(dppp)Cl2 and AlMe3 in refluxing
5
toluene. Recently, a one-step oxidative cleavage protocol was
3
A convenient one-step RhCl -catalyzed deprotection of acyclic
N-allyl amides is described. Preliminary mechanistic studies
reveal that the key to the success of the one-step deprotection
developed that involved the use of excess oxidizing agents.6
Given considerations of functional group compatibility, a
convenient one-step deprotection process that operated under
orthogonal conditions would improve the attractiveness of the
allyl protecting group for amide synthesis.
Despite the absence of any reports using Pd π-allyl chemistry
for direct amide deprotection, we briefly investigated this
reaction by subjecting N-allyl-2-pyrrolidone (1) to conditions
that were recently successful for the deallylation of a pyrroli-
process is the dual function of RhCl
3
in alcohol solvents.
Reaction of RhCl with n-PrOH not only provides an active
3
rhodium hydride species to catalyze isomerization of N-allyl
amides to corresponding enamides but also generates a
crucial catalytic amount of HCl to convert the enamides to
deallylated amides through N,O-acetal exchange.
7
dine. In this event, the use of 1 mol % Pd2(dba)3, 2 mol %
dppb, and 1.1 equiv of thiosalicylic acid in THF failed to afford
any reaction products. Given this result, our focus shifted toward
the known Rh- and Ru-catalyzed reactions. We envisioned that
the mild conditions of these metal-catalyzed olefin isomeriza-
tions could be combined in situ with a mild acidic cleavage of
The prevalence of amides in natural products and pharma-
ceuticals underscores the need for practical methods for their
synthesis, including protecting group strategies. Among the more
versatile of protecting groups for multistep organic synthesis is
the allyl group. While allyl deprotection of alcohols and amines
is a facile process that can be carried out with a wide variety of
reagents and conditions, the deprotection of allyl amides is
8
the enamide intermediate. In this Note, we report the successful
development of this strategy into a one-step deprotection of
N-allyl amides and provide preliminary mechanistic features of
this transformation.
1
considerably more challenging, and few methods are currently
Our investigations focused on rhodium catalysts due to their
high functional group tolerance. N-Allyl-2-pyrrolidone (1) was
subjected to conditions reported for the isomerization of an
N-allyl protected lactam to an enamide. A screen of catalysts
revealed that (Ph3P)4RhH gave the expected enamide 22
in 85% yield (eq 1), whereas by comparison, Wilkinson’s
catalyst afforded 1 in only 40% yield (50% conversion). The
use of H2O or dilute HCl as a cosolvent, as a means of
hydrolyzing the enamide in situ, did not affect the product
distribution and resulted in lower yields and conversion.
The addition of anhydrous acids such as benzenesulfonic acid
*
Corresponding author. Tel.: (732) 594-0363; fax: (732) 594-5170.
(
1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 4th ed.; Wiley: New York, 2006. For example, while Pd catalysis
is well known for the deprotection of N-allyl amines, there are no reports
for the use of Pd catalysis the deprotection of N-allyl amides.
e,4e
(2) (a) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139. (b) Nemeto,
H.; Jimenez, H. N.; Yamamoto, Y. Chem. Commun. 1990, 304. (c) Kanno,
O.; Miyauchi, M.; Kawamoto, I. Heterocycles 2000, 53, 173. (d) Cainelli,
G.; Giacomini, D.; Galetti, P. Synthesis 2000, 289. (e) Cainelli, G.; DaCol,
M.; Galetti, P.; Giacomini, D. Synthesis 1997, 923. (f) Chiusoli, G. P.; Costa,
M.; Fiore, A. Chem. Commun. 1990, 303.
(3) (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Org. Lett.
2
001, 3, 3781. (b) Alcaide, B.; Almendros, P.; Alonso, J. M. Tetrahedron
Lett. 2003, 43, 8693. (c) For a report on the Ru-catalyzed isomerization
but not applied to N-allyl deprotection, see: Krompiec, S.; Pigulla, M.;
Krompiec, M.; Baj, S.; Mrowiec-Bialon, J.; Kasperczyk, J. Tetrahedron
Lett. 2004, 45, 5257.
(5) Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4679.
(6) Kitov, P. I.; Bundle, D. R. Org. Lett. 2001, 3, 2835. For an application
of this reaction, see: Clement, E. C.; Carlier, P. R. Tetrahedron Lett. 2005,
45, 3633.
(7) Xu, F.; Murry, J. A.; Simmons, B. A.; Corley, E.; Fitch, K.; Karady,
S.; Tschaen, D. Org. Lett. 2006, 8, 3885. See Experimental Section.
(8) A similar strategy has been documented for the deallylation of allyl
ethers but has not been applied to amides: Boss, R.; Scheffold, R. Angew.
Chem. Int. Ed. 1976, 88, 578.
(4) Only one report for the use of Pd in this isomerization process has
appeared: (a) Dallavalle, S.; Merlini, L. Tetrahedron Lett. 2002, 43, 1835.
For Fe, see: (b) Sergeyev, S.; Hesse, M. Synlett 2002, 1313 and (c) Hubert,
A. J., Feron, A.; Goebbels, G.; Warin, R.; Teyssie, P. J. Chem. Soc., Perkin
Trans. 2 1997, 11. For Co, see: (d) Onishi, M.; Oishi, S.; Sakaguchi, M.;
Takaki, I.; Kiraki, K. Bull. Chem. Soc. Jpn. 1986, 59, 3925. For Ir, see:
(
e) Neugnot, B.; Cintrat, J.-C.; Rousseau, B. Tetrahedron 2004, 60, 3575.
10.1021/jo070553t CCC: $37.00 © 2007 American Chemical Society
6
298
J. Org. Chem. 2007, 72, 6298-6300
Published on Web 07/11/2007