A green synthetic route to imides from terminal alkynes and amides by simple solid catalysts

Article abstract of DOI:10.1246/cl.2012.866

An atom-efficient and green synthetic route to highly valuable imides (5492% yields) from terminal alkynes and amides has been developed. This new route is composed of two consecutive reactions, that is, (i) the reported Cu(OH)2-catalyzed cross-coupling o

Full text of DOI:10.1246/cl.2012.866

doi:10.1246/cl.2012.866
866
Published on the web August 11, 2012
A Green Synthetic Route to Imides from Terminal Alkynes and Amides by Simple Solid Catalysts
Xiongjie Jin, Kazuya Yamaguchi, and Noritaka Mizuno*
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656
(Received April 23, 2012; CL-120352; E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp)
An atom-efficient and green synthetic route to highly
valuable imides (54-92% yields) from terminal alkynes and
amides has been developed. This new route is composed of two
consecutive reactions, that is, (i) the reported Cu(OH)2-catalyzed
cross-coupling of terminal alkynes and amides to ynamides and
(ii) the Sn-W mixed oxide-catalyzed regioselective hydration of
ynamides.
The cross-coupling products of ynamides are very attractive
compounds. Thus, the substitution of amide functionalities to
terminal alkynes to form ynamides can strongly polarize the
triple bonds, and the carbon atom adjacent to the amide
functionality becomes more susceptible to nucleophilic attack
than another sp-hybridized carbon atom. By employing the
reactivities, highly regio- and stereoselective transformations
have been realized to date.4
From the above-mentioned unique reactivity of ynamides,
we expected that hydration of ynamides possibly regioselec-
tively proceeds to give the corresponding imides. Thus, the
Brønsted acid-catalyzed hydration of an ynamide 3aa was
initially carried out. We used the Sn-W mixed oxide catalyst
for the hydration, which is reported to be active for the
Markovnikov hydration of various terminal alkynes.5a In this
study, we found that the regioselectivity for 3aa was completely
opposite to that for a terminal alkyne 1a, and that the hydration
of 3aa regioselectively proceeded to give the corresponding
imide of 3-(2-phenylacetyl)oxazolidin-2-one (4aa) in >99%
yield (Scheme 2).
From the result of the above regioselective hydration and
our previous finding of the Cu(OH)2-catalyzed cross-coupling,3
we came up with an idea to construct a new green synthetic route
to imides, that is, the combination of the reported Cu(OH)2-
catalyzed cross-coupling of terminal alkynes and amides and the
newly found Sn-W mixed oxide-catalyzed regioselective hydra-
tion of ynamides (Figure 1).
Imides are very important synthetic intermediates in a wide
range of organic synthesis1,2 and essentially useful as pharma-
cophores in many biologically active compounds such as
immunosuppressants,2a antibiotics,2b antifeedants,2c and cyto-
toxic anticancer agents.2d To date, great progress has been made
for the development of synthetic routes to imides;1,2f for
example, (i) acylation of amides with carboxylic acid derivatives
such as chlorides, anhydrides, and esters, (ii) aminocarbonyla-
tion of aryl bromides, (iii) the reaction of isonitriles and
carboxylic acids, (iv) oxidative decarboxylation of amino acids,
and (v) oxygenation of amides. However, at present, imides have
still generally been prepared by the “nongreen” step-by-step
procedure of deprotonation of amides with strong bases such
as n-butyllithium followed by acylation with acyl halides
(Figure 1). In this antiquated procedure, several side reactions2f
such as elimination to nitriles, formation of triacylamides, and
acyl group scrambling proceed in some cases, and generation of
at least stoichiometric amounts of wastes such as butane and
lithium halides are inevitable. Hence, from the environmental
point of view, the development of atom-efficient and green
routes to these important compounds is highly desirable.
Very recently, we have reported that simple Cu(OH)2 can
efficiently catalyze cross-coupling of terminal alkynes and
amides to ynamides; for example, the cross-coupling of phenyl-
acetylene (1a) and 1,3-oxazolidin-2-one (2a) gave 3-(phenyl-
ethynyl)oxazolidin-2-one (3aa) in 91% yield (Scheme 1).3 The
substrate scope for the cross-coupling is very broad with respect
to both terminal alkynes and amides (Figures S1 and S27). The
reaction employs air as a terminal oxidant and produces only
water as a sole by-product.
O
O
Cu(OH)2
air
O
HN
O
Ph
+
+
Ph
N
H2O
3aa
1a
2a
91% yield
Scheme 1. Oxidative cross-coupling of phenylacetylene and
2-oxazolidinone (Figure S2).3,7
O
H
+ H+
+ H2O
H
− H+
H
1a
92% yield
opposite
O
O
Classical procedure
O
O
O
H
O
O
R1
R3
+ H+
+ H2O
− H+
N
LiX
n-C4H10
O
N
O
O
O
X
O
N
R1
R3
n-BuLi +
R2
N
Li
3aa
N
R3
R2
R2
N
H
4aa, >99% yield
New green procedure
Scheme 2. The Sn-W mixed oxide-catalyzed hydration of 1a
and 3aa. Yields were determined by gas chromatography using
biphenyl as an internal standard. Reaction conditions for 3aa:
3aa (0.1 mmol), Sn-W mixed oxide (50 mg), H2O (0.3 mmol),
mesitylene (1 mL), 100 °C, under air (1 atm), 1 h. Reaction
conditions for 1a: 1a (0.5 mmol), Sn-W mixed oxide (50 mg),
H2O (1 mmol), cyclooctane (2 mL), 100 °C, under air (1 atm), 1 h.
R2
R2
N
O
O
Cu(OH)2
Sn−W oxide
O
O
R1
R1
H
R1
+
H N
N
R3
R2
R3
H2O
R3
1/2O2
H2O
High atom efficiency (theoretically 100%)
Figure 1. Synthetic procedure for imides.
Chem. Lett. 2012, 41, 866-867
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

867
R2
N
O
O
corresponding N-acyloxazolidinones in high yields. In the case
of halo-substituted aromatic alkynes, the desired imides were
obtained in high yields without dehalogenation. Therefore, it
would be possible to utilize these halo-functionalities for further
modification of the imide molecules. A heteroatom-containing
alkyne, 3-ethynylthiophene, was efficiently reacted with an
amide to afford the corresponding imide in a high yield. In
addition, not only aromatic alkynes but also aliphatic ones could
act as good substrates. Oxazolidinone and sulfonamide deriv-
atives could be utilized as nitrogen nucleophiles in the present
catalyst system.
In summary, we have successfully developed an efficient
synthetic route to imides by the Cu(OH)2-catalyzed aerobic
oxidative cross-coupling of terminal alkynes and amides
followed by the Sn-W mixed oxide-catalyzed regioselective
hydration. From this new procedure, various kinds of imides
could be obtained in moderate to high yields (54-92% yields).
O
Cu(OH)2
R1
R2
R1
H
+
N
H
R3
R3
Sn−W oxide
1
2
4
O
O
O
O
O
O
O
O
O
N
N
N
4aa, 90%
4ba, 86%
4ca, 87%
O
O
O
O
O
O
O
O
O
O
O
N
N
N
F
Cl
4da, 80%
4ea, 85%
4fa, 85%a
O
O
O
O
Cl
O
O
O
N
N
N
F3C
Br
4ha, 91%b
4ia, 83%c
4ga, 90%
O
O
O
O
O
MeO
O
O
This work was supported in part by Japan Chemical
Innovation Institute (JCII) and Grants-in-Aid for Scientific
Researches from Ministry of Education, Culture, Sports, Science
and Technology.
N
O
O
N
N
S
4ka, 90%d
4ja, 82%
4la, 92%
O
O
N
O
O
O
O
N
O
N
O
O
References and Notes
Cl
1
2
J. Sperry, Synthesis 2011, 3569.
4na, 86%
4oa, 88%
4ma, 81%
a) F. E. Koehn, R. E. Longley, J. K. Reed, J. Nat. Prod. 1992, 55,
613. b) G. R. Pettit, Y. Kamano, C. Dufresne, R. L. Cerny, C. L.
Herald, J. M. Schmidt, J. Org. Chem. 1989, 54, 6005. c) H.
Nakamura, Y. Iitaka, H. Sakakibara, H. Umezawa, J. Antibiot. 1974,
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Org. Lett. 2010, 12, 4102. f) Z. Habibi, P. Salehi, M. A. Zolfigol, M.
Yousefi, Synlett 2007, 812.
O
O
N
O
O
O
S
O
N
4ab, 70%e
4ac, 54%e
3
4
X. Jin, K. Yamaguchi, N. Mizuno, Chem. Commun. 2012, 48, 4974.
a) J. R. Dunetz, R. L. Danheiser, J. Am. Chem. Soc. 2005, 127,
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Very recently, we have reported that the Sn-W mixed oxide can act
as an efficient heterogeneous Brønsted acid catalyst for alkyne
hydration,5a C-C bond-forming reactions,5b and conversion of
saccharides to furan derivatives:5c a) X. Jin, T. Oishi, K.
Yamaguchi, N. Mizuno, Chem.®Eur. J. 2011, 17, 1261. b) Y.
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A typical procedure for synthesis of imides: Into a Pyrex-glass
screw cap vial (volume: ca. 20 mL) were successively placed
Cu(OH)2 (5 mol % with respect to an alkyne), a base (5-20 mol %),
an alkyne (0.1 mmol), an amide (2-3 equivalents with respect to an
alkyne), and mesitylene (1 mL). A Teflon-coated magnetic stir bar
was added, and the reaction mixture was vigorously stirred at 100-
120 °C under 1 atm of air. After completion of the cross-coupling of
a terminal alkyne and an amide, Cu(OH)2, a base, and the remaining
amide are filtered off. Then, the filtrate was added to a Pyrex-glass
screw cap vial (volume: ca. 20 mL) containing the Sn-W oxide
catalyst (50 mg), water (0.3 mmol), and a Teflon-coated magnetic
stir bar, and the reaction mixture was vigorously stirred at 100 °C.
After the reaction was completed, the crude reaction mixture was
directly subjected to column chromatography on silica gel (n-
hexane/ethyl acetate = 9/1-2/3 (v/v)), giving the analytically pure
imide (see the Supporting Information in more detail7).
Figure 2. Sequential synthesis of imides. The isolated yields
(based on 1) are reported. See Figure S2 for the reaction
conditions for cross-coupling steps. For the hydration steps, Sn-
W mixed oxide (50 mg), H2O (0.3 mmol), 100 °C, 1 h. Other
reaction time: 3, 5, 24, and 2 h. Yields were determined by
GC using biphenyl as an internal standard.
a
b
c
d
e
5
6
This unprecedented route intrinsically produces no wastes,
and the atom efficiency is theoretically 100%. The procedure is
also very simple;6 after completion of the cross-coupling
(Figure S27), Cu(OH)2, a base, and the remaining amides are
filtered off followed by addition of the filtrate to the reactor
containing the Sn-W mixed catalyst and water. The regioselec-
tivities for the hydration steps were higher than 99% in all cases.
Through this novel synthetic route, various kinds of structurally
diverse imides could successfully be synthesized in high to
excellent yields (Figure 2). The isolated yields of the imide
products are summarized in Figure 2 (unless otherwise noted).
In the Cu(OH)2-catalyzed cross-coupling of terminal alkynes
and amides as well as the Sn-W mixed oxide-catalyzed
regioselective hydration, no further conversion of substrate
was observed upon separation of the catalysts by simple
filtration during the reaction. Thus, this can rule out any
contribution to the observed catalysis from metal species that
leached into the reaction solution, and the observed catalysis is
intrinsically heterogeneous.
Aromatic alkynes with electron-donating as well as elec-
tron-withdrawing substituents all smoothly reacted to give the
7
Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2012, 41, 866-867
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/