Preparation of primary amides from functionalized organozinc halides

Article abstract of DOI:10.1021/ol101469f

Organozinc halides, which are prepared either by direct zinc insertion or halogen-magnesium exchange and subsequent transmetalation with ZnCl₂, react smoothly with commercially available trichloroacetyl isocyanate to give, after hydrolysis, the corresponding primary amides. This method is compatible with a variety of functional groups such as an ester or a cyano group. Also heterocyclic-, alkenyl, and acetylenic zinc reagents are converted to the corresponding primary amides under these conditions.

Full text of DOI:10.1021/ol101469f

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3648-3650
Preparation of Primary Amides from
Functionalized Organozinc Halides
Matthias A. Schade, Georg Manolikakes, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377 Mu¨nchen, Germany
Paul.Knochel@cup.uni-muenchen.de
Received June 25, 2010
ABSTRACT
Organozinc halides, which are prepared either by direct zinc insertion or halogen-magnesium exchange and subsequent transmetalation with
ZnCl2, react smoothly with commercially available trichloroacetyl isocyanate to give, after hydrolysis, the corresponding primary amides. This
method is compatible with a variety of functional groups such as an ester or a cyano group. Also heterocyclic-, alkenyl, and acetylenic zinc
reagents are converted to the corresponding primary amides under these conditions.
A primary amide funtionality (CONH2) is found in a variety
of natural products and pharmaceutically active substances.1
The preparation of functionalized amides from readily
available precursors is therefore of great interest. Among
others, the reaction of carboxylic acid derivatives with
ammonia and the hydration of nitriles are common methods
for preparing primary amides.2,3 Alternatively, organome-
tallic routes starting from organomagnesium reagents require
very low reaction temperatures, and sensitive functional
groups or heterocycles are rarely tolerated.4 In contrast, the
use of organozinc reagents is compatible with a broad range
of functional groups and sensitive heterocycles in the starting
zinc organometallic.5
Recently, we have reported several methods for the
preparation of highly functionalized organozinc reagents from
the corresponding organic halides.6 Herein, we wish to report
that various organozinc halides of type 1 are converted into
the primary amides (2) using commercially available trichlo-
roacetyl isocyanate (Scheme 1).7,8
(1) For example: (a) The Chemistry of Amides; Zabicky, J., Ed.; Wiley-
Interscience: New York, 1970. (b) Zhuo, L.; Liu, Y.; Zhang, W.; Wie, P.;
Huang, C.; Pei, J.; Yuan, Y.; Lai, L. J. Med. Chem. 2006, 49, 3440. (c)
Bhattcharaya, A.; Scott, B. P.; Nasser, N.; Ao, H.; Mahre, M. P.; Dubin,
A. E.; Swanson, D. M.; Shankley, N. P.; Wickenden, A. D.; Chaplan, S. R.
J. Pharmcol. Exp. Ther. 2007, 323, 665. (d) Pringle, W.; Peterson, J. M.;
Xie, L.; Ge, P.; Gao, Y.; Ochterski, J. W.; Lan, J. WO 2006/089076 A2,
Aug 24, 2006.
Thus, 4-cyanophenylzinc iodide (1a) prepared by the direct
insertion of zinc into 4-iodobenzonitrile reacts with trichlo-
(4) Parker, K. A.; Gibbons, E. G. Tetrahedron Lett. 1975, 12, 981.
(5) (a) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991,
56, 1445. (b) Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes,
M. J. J. Org. Chem. 1992, 57, 3397. (c) Manolikakes, G.; Schade, M. A.;
Hernandez, C. M.; Mayr, H.; Knochel, P. Org. Lett. 2008, 10, 2765. (d)
Dong, Z.; Manolikakes, G.; Li., J.; Knochel, P. Synthesis 2009, 4, 681. (e)
Crestey, F.; Knochel, P. Synthesis 2010, 1097. (f) Mosrin, M.; Petrera, M.;
Knochel, P. Synthesis 2008, 3697. (g) Monzon, G.; Knochel, P. Synlett 2010,
304.
(2) (a) For the use of Mg3N2 as NH3 source see: (a) Veitch, G. E.;
Bridegwood, K. L.; Ley, S. V. Org. Lett. 2008, 10, 3623. For a Ru-catalyzed
hydration of nitriles, see: (b) Cadierno, V.; Francos, J.; Gimeno, J.
Chem.sEur. J. 2008, 14, 6601. (c) Kukushkin, V. Y.; Pombeiro, A. J. L.
Inorg. Chim. Acta 2005, 1, 1. For a Bi(OTf)3-catalyzed Ritter reaction see
:(d) Callens, E.; Burton, A. J.; Barrett, A. G. M. Tetrahedron Lett. 2006,
47, 8699. For a Pd-catalyzed aminocarbonylation of aryl halides see: (e)
Schnyder, A.; Beller, M.; Mehltretter, G.; Nsenda, T.; Studer, M.; Indolese,
A. F. J. Org. Chem. 2001, 66, 4311
.
(6) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040. (b) Krasovskiy, A.; Knochel, P.
Angew. Chem., Int. Ed. 2004, 43, 3333. (c) Piller, F. M.; Appukkuttan, P.;
Gavryushin, A.; Helm, M.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47,
6802. (d) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; Knochel, P. Chem.sEur. J. 2009, 15, 7192. (e) Metzger,
A.; Argyo, C.; Knochel, P. Synthesis 2010, 882. (f) Despotopoulou, C.;
Gignoux, C.; McConnell, D.; Knochel, P. Synthesis 2009, 3661.
(3) (a) For related cyanations see: (a) Anbarasan, P.; Neumann, H.;
Beller, M. Chem.sEur. J. 2010, 16, 4725. For a Grignard addition-acylation
route to enamides see: (b) Fleming, F. F.; Wei, G.; Zhang, Z.; Steward,
O. W. Org. Lett. 2006, 8, 4903. For carbonylations of zinc reagents with
CO2, see: (c) Kobayashi, K.; Kondo, Y. Org. Lett. 2009, 11, 2035. (d)
Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P. Angew. Chem.,
Int. Ed. 2010, 49, 4665
.
10.1021/ol101469f  2010 American Chemical Society
Published on Web 07/22/2010

Scheme 1
.
Reaction of Unsaturated Zinc Reagents with
Table 2. Reaction of Heterocyclic Zinc Halides with
Trichloroacetyl Isocyanate Providing Heterocylcic Amides of
Type 2
Trichloroacetyl Isocyanate Leading to Unsaturated Amides
roacetyl isocyanate (1.1 equiv) at -20 to 25 °C to the
corresponding zinc imidate. After basic hydrolysis using
K2CO3 (1.5 equiv) and MeOH, 4-cyanobenzamide (2a) was
isolated in 95% yield (Table 1, entry 1).
Table 1. Reaction of Organozinc Halides with Trichloroacetyl
Isocyanate Leading to Aromatic Amides of Type 2
a For the sake of clarity, additional complexed salts are omitted. b All
reactions were hydrolyzed at 23 °C 12 h. c Isolated yield of analytically
pure product.
Using this method, other substituted benzamides have been
prepared. Thus, 4-(ethoxycarbonyl)phenylzinc iodide (1b)
reacts smoothly with trichloroacetyl isocyanate to produce
the expected primary amide 2b in 90% yield (entry 2).
Furthermore, chloro- or trifluoromethyl-substituted arylzinc
reagents react with trichloroacetyl isocyanate furnishing the
expected primary amides in 60-98% yield (entries 3-5).
Starting from 2-ethoxyphenylzinc chloride (1f), ethenzamide9
(2f), an analgesic and anti-inflammatory drug, is obtained
in almost quantitative yield (98%, entry 6).
a For the sake of clarity, additional complexed salts are omitted. b All
reactions were hydrolyzed at 23 °C 12 h. c Isolated yield of analytically
pure product.
Org. Lett., Vol. 12, No. 16, 2010
3649

The directed zinc insertion in polybrominated protected
phenols10,6d gives regioselectively the arylzinc reagents 1g
and 1h which then react with trichloroacetyl isocyanate
affording the corresponding benzamides 2g and 2h in
66-78% yield (entries 7 and 8).
Scheme 2. Preparation of Unsaturated Primary Amides
Furthermore, heterocyclic zinc reagents, such as the
thiophenylzinc derivatives 1i-1k provide the expected
primary amides 2i-2k in 61-99% yield (Table 2, entries
1-3). Moreover, ethyl 5-carbamoylfuran-2-carboxylate (2l)
and thiazole-2-carboxamide (2m) have been prepared by this
way in 78-82% yield (entries 4 and 5). Also electron-
deficient 6-membered ring N-heterocyclic zinc reagents have
been reacted with trichloroacetyl isocyanate leading to the
corresponding primary amides. 2,6-Dichloro-4-pyridylzinc
iodide (1n) is converted to the isonicotinamide 2n in 63%
yield (entry 6). Also, the substituted quinoloylzinc iodide
1o and the protected indole 1p have been smoothly converted
to the benzamides 2o and 2p in 69-73% yield (entries 7
and 8). Also, 3,5-dimethylisoxazolylzinc chloride 1q provides
the amide 2q in almost quantitative yied (98%, entry 9).
Moreover, sensitive 5-membered heterocyclic zinc reagents,
such as pyrazolylzinc iodide 1r or the zinc reagent derived
from the benzyl protected bromo-uracil derivative 1s, react
with trichloroacetyl isocyanate to their corresponding primary
amides 2r and 2s in 70-78% yield (entries 10 and 11).
Also R,ꢀ-unsaturated amides can be prepared from the
corresponding zinc reagents. Thus, the unsaturated zinc
reagents derived from R-bromostyrene6a and 3-iodocyclohex-
2-enone11 react with trichloroacetyl isocyanate to give 2t and
2u in 63-85% yield (Scheme 2).
1w can be converted to the primary amide 2w in 57% yield
(Scheme 3).
Scheme 3
.
Reaction of Alkynylzinc Halides with
Trichloroacetyl Isocyanate
In summary, we have developed a new and efficient
method for the preparation of primary amides from the
corresponding organozinc halides. This method is suitable
for a one-pot preparation of functionalized aromatic, het-
erocyclic, alkenyl and alkynyl primary amides. Further
extensions of this method are currently underway in our
laboratories.
Finally, acetylenic amides can also be prepared by this
method. Phenylacetylenezinc chloride (1v) reacts with
trichloroacetyl isocyanate at room temperature and the
acetylenic amide 2v was isolated in 71% yield (Scheme 3).
The ester substituted phenylacetylene derived zinc reagent
(7) (a) Deng, M.-Z.; Caube`re, P.; Senet, J. P.; Lecolier, S. Tetrahedron
1988, 44, 6079. (b) Manolikakes, G.; Dong, Z.; Mayr, H.; Li, J.; Knochel,
P. Chem.sEur. J. 2009, 15, 1324. For a recent overview on the addition of
organozinc reagents to carbonyl compounds, see: (c) Salvi, L.; Kim, J. G.;
Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 12483.
Acknowledgment. We thank the DFG (SFB749) and the
European Research Council (ERC) for a financial support.
We also thank Chemetall GmbH (Frankfurt) and BASF SE
(Ludwigshafen) for the generous gift of chemicals.
(8) Zinc reagents prepared by direct C-H activation using TMPZnCl·LiCl
or TMP2Zn·2 MgCl2·2 LiCl do not give the desired products. Also, the use
of the corresponding organomagnesium reagents either do not yield in the
desired primary amides or only in low yields.
Supporting Information Available: Experimental details
and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Buschmann, H.; Christoph, T.; Friderichs, E. Analgesics: From
Chemistry and Pharmacology to Clinical Application; Wiley-VCH: Wein-
heim, 2002.
(10) Boudet, N.; Sase, S.; Sinha, P.; Liu, C.-Y.; Krasovskiy, A.; Knochel,
P. J. Am. Chem. Soc. 2007, 129, 12358.
(11) Knochel, P.; Rao, C. J. Tetrahedron 1993, 49, 29.
OL101469F
3650
Org. Lett., Vol. 12, No. 16, 2010