Copper-Mediated N-Alkynylation of Carbamates, Ureas, and Sulfonamides. A General Method for the Synthesis of Ynamides

Article abstract of DOI:10.1021/ol035647d

(Matrix Presented) A general amination strategy for the N-alkynylation of carbamates, sulfonamides, and chiral oxazolidinones and imidazolidinones is described. A variety of substituted ynamides are available by deprotonation of amides with KHMDS followed by reaction with CuI and an alkynyl bromide.

Full text of DOI:10.1021/ol035647d

ORGANIC
LETTERS
2003
Vol. 5, No. 21
4011-4014
Copper-Mediated N-Alkynylation of
Carbamates, Ureas, and Sulfonamides.
A General Method for the Synthesis of
Ynamides
Joshua R. Dunetz and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
danheisr@mit.edu
Received August 28, 2003
ABSTRACT
A general amination strategy for the N-alkynylation of carbamates, sulfonamides, and chiral oxazolidinones and imidazolidinones is described.
A variety of substituted ynamides are available by deprotonation of amides with KHMDS followed by reaction with CuI and an alkynyl bromide.
We report herein a convenient and general method for the
synthesis of ynamides via the copper-promoted coupling of
amides with alkynyl bromides. Interest in the application of
ynamides in organic synthesis has increased enormously in
recent years.1 Considerably more robust than simple ynamines,
ynamides are more easily stored and handled and tolerate a
variety of conditions destructive to typical ynamines. Yna-
mides have thus emerged as versatile building blocks in a
wide range of useful synthetic transformations including
Pauson-Khand reactions,2 ring-closing metatheses,3 cy-
cloadditions (and other ring-forming processes),4 and a
variety of hydrometalation and hydrohalogenation reac-
tions.5,6
efficient method for the preparation of a wide range of
ynamides, preferably via the direct alkynylation of carbam-
ates, sulfonamides, and other simple amide derivatives.
Initially we focused our attention on the reaction of metalated
amides with alkynyl(phenyl)iodonium salts (eq 1).9 Stang10
and Feldman11 have shown that this process provides an
excellent route to “push-pull”-type ynamides (4, Z ) COR,
(4) (a) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J.; Xiong,
H.; Mulder, J. A. Org. Lett. 1999, 1, 1237. (b) Witulski, B.; Stengel, T.
Angew. Chem., Int. Ed. 1999, 38, 2426. (c) Witulski, B.; Stengel, T.;
Ferna´ndez-Herna´ndez, J. M. J. Chem. Soc., Chem. Commun. 2000, 1965.
(d) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281. (e)
Witulski, B.; Lumtscher, J.; Bergstra¨sser, U. Synlett 2003, 708.
(5) (a) Witulski, B.; Buschmann, N.; Bergstra¨sser, U. Tetrahedron 2000,
56, 8473. (b) Minie`re, S.; Cintrat, J.-C. Synthesis 2001, 5, 705. (c) Minie`re,
S.; Cintrat, J.-C. J. Org. Chem. 2001, 66, 7385. (d) Timbart, L.; Cintrat,
J.-C. Chem. Eur. J. 2002, 8, 1637. (e) 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.
(6) Also see: (a) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett.
2003, 5, 67. (b) Mulder, J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M.
R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383. (c) Frederick, M. O.; Hsung,
R. P.; Lambeth, R. H.; Mulder, J. A.; Tracey, M. R. Org. Lett. 2003, 5,
2663.
In connection with our studies on [4 + 2] cycloadditions
of conjugated enynes7 and heteroenynes,8 we required an
(1) For reviews of the chemistry of ynamines and ynamides, see: (a)
Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (b) Zificsak,
C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L.
Tetrahedron 2001, 57, 7575. (c) Himbert, G. In Methoden der Organischen
Chemie (Houben-Weyl); Kropf, H., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1993; Vol. E15, Part 3, pp 3267-3443. (d) Collard-
Motte, J.; Janousek, Z. Top. Curr. Chem. 1986, 130, 89.
(2) (a) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489.
(b) Rainier, J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037. (c) Witulski,
B.; Go¨ssmann, M. J. Chem. Soc., Chem. Commun. 1999, 1879. (d) Rainier,
J. D.; Imbriglio, J. E. J. Org. Chem. 2000, 65, 7272. (e) Witulski, B.;
Go¨ssmann, M. Synlett 2000, 12, 1793.
(7) Danheiser, R. L.; Gould, A. E.; Ferna´ndez de la Pradilla, R.; Helgason,
A. L. J. Org. Chem. 1994, 59, 5514.
(8) Wills, M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378.
(9) For reviews, see: (a) Stang, P. J. In Modern Acetylene Chemistry;
Stang, P. J., Diederich, F., Eds.; VCH: Weinheim, 1995; pp 67-98. (b)
Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96, 1123. (c) Zhdankin, V.
V.; Stang, P. J. Tetrahedron 1998, 54, 10927. (d) Zhdankin, V. V.; Stang,
P. J. Chem. ReV. 2002, 102, 2523.
(3) (a) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803. (b) Huang,
J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T. P.
Org. Lett. 2002, 4, 2417.
(10) Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis 1994, 1255.
10.1021/ol035647d CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/16/2003

CO2R, SO2Ar, etc.), and more recently Witulski and Rainier
have extended this chemistry to the preparation of ynamides
where Z ) hydrogen, TMS, and phenyl.2a-d,4b Unfortunately,
this approach is not applicable to the synthesis of ynamides
in which Z is a simple alkyl group. The addition of soft
nucleophiles to alkynyl(phenyl)iodonium salts is believed to
proceed via the rearrangement of alkylidenecarbene inter-
mediates of type 3, and the requisite 1,2-shift only is a facile
process when Z is a hydrogen atom or trialkylsilyl or aryl
group.12 In addition, whereas sulfonamide derivatives (e.g.,
1, EWG ) Ts) participate smoothly in the desired transfor-
mation, reactions of lactams,1a oxazolidinones,1a and acyclic
carbamates13 proceed at best in low yield.
with 1-bromo-2-phenylacetylene gave only trace amounts of
the desired ynamide, with the predominant product being
the 1,3-diyne generated from “homocoupling” of the alkynyl
halide. During the course of our work, an important com-
munication by Hsung and co-workers appeared reporting the
successful application of Buchwald’s catalyst system15 to the
N-alkynylation of oxazolidinones and lactams.18,19 Unfortu-
nately, Hsung found these conditions to be less effective
when applied to other amide derivatives, including acyclic
carbamates and sulfonamides. Thus, under the Buchwald
protocol ureas and sulfonamides undergo alkynylation in less
than 10% yield. Somewhat better results are obtained in the
case of carbamates; by terminating reactions at 30-50%
conversion, Hsung and co-workers were able to isolate the
desired ynamides, albeit in only 24-42% yield.
Our first success in effecting the desired alkynylation was
achieved when we turned our attention to protocols in which
complete conversion of the amide substrate to its copper
derivative (e.g., 5) was carried out prior to addition of the
alkynyl halide. Under these conditions, copper-promoted
dimerization of the alkynyl halide is greatly diminished and
the desired ynamides emerge as the major product of the
reaction. As outlined in Scheme 1, oxidative addition of 5
The aforementioned limitations of alkynyl(phenyl)iodo-
nium methodology prompted us to consider alternative and
potentially more general approaches to the synthesis of the
ynamides required for our studies. Recent developments in
the laboratories of Buchwald and Hartwig have revolution-
ized methodology for carbon-nitrogen bond formation.14
Encouraged, in particular, by Buchwald’s recent success in
achieving copper-catalyzed amidation of aryl halides,15,16 we
turned our attention to the coupling of amide derivatives with
readily available alkynyl halides.17
Scheme 1
Initial results were disappointing. Application of Buch-
wald’s catalyst system15 to the coupling of acyclic carbamates
(11) Feldman, K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt, A. C.
J. Org. Chem. 1996, 61, 5440.
(12) In the case where Z is an acyl or sulfonyl group, it is not clear if a
1,2-shift is involved or whether the mechanism proceeds via an addition-
elimination pathway.
(13) Our attempts to alkynylate acyclic carbamates (1, R ) alkyl, EWG
) CO2Me) with 2 (Z ) SiMe3) produced the desired ynamides 4 in 15-
20% yield.
(14) For recent reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131. (b) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046.
(15) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421. The Buchwald procedure for amidation of aryl bromides involves
reaction with 0.01-0.1 equiv of CuI, 2 equiv of K3PO4, and 0.1 equiv of
a diamine ligand in toluene or dioxane at 110 °C for 15-24 h.
(16) Also encouraging were recent reports on the preparation of enamides
and enamines via amidation and amination of vinyl halides and triflates.
See: (a) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991,
1443. (b) Shen, R.; Porco, J. A. Org. Lett. 2000, 2, 1333. (c) Arterburn, J.
B.; Pannala, M.; Gonzalez, A. M. Tetrahedron Lett. 2001, 42, 1475. (d)
Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. J. Chem. Soc., Chem.
Commun. 2002, 2362. (e) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002,
43, 111. (f) Lebedev, A. Y.; Izmer, V. V.; Kazyul’kin, D. N.; Beletskaya,
I. P.; Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623. (g) Willis, M. C.;
Brace, G. N. Tetrahedron Lett. 2002, 43, 9085.
to the alkynyl halide presumably generates a copper(III)
intermediate 6, which then furnishes the desired ynamide
by reductive elimination. Preforming the copper amide
intermediate 5 maximizes the rate of its reaction with the
alkynyl halide, allowing amidation to more effectively
compete with the reaction of the alkynyl halide with copper
salts in pathways leading to “homodimer” byproducts.
A systematic investigation of reaction variables using
carbamate 8a as the test substrate led to the protocol outlined
in Scheme 2. Under these conditions, 1-bromo-2-phenyl-
acetylene undergoes amidation in 48% yield. Note that this
bromo alkyne is especially prone to homocoupling, and in
(18) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang,
J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125,
2368.
(19) For two early reports of the observation of copper-promoted
formation of ynamines and ynamides from reactions of amine derivatives
with terminal alkynes, see: (a) Peterson, L. I. Tetrahedron Lett. 1968, 9,
5357. (b) Balsamo, A.; Macchia, B.; Macchia, F.; Rossello, A.; Domiano,
P. Tetrahedron Lett. 1985, 26, 4141.
(17) For reviews of the chemistry of halo acetylenes, see: (a) Hopf, H.;
Witulski, B. In Modern Acetylene Chemistry; Stang, P. J., Diederich, F.,
Eds.; VCH: Weinheim, 1995; pp 33-66. (b) Brandsma, L. PreparatiVe
Acetylenic Chemistry; Elsevier: New York, 1988.
4012
Org. Lett., Vol. 5, No. 21, 2003

Scheme 2
Table 2. Synthesis of Ynamides by Alkynylation of
Carbamates
our hands the application of Buchwald’s catalyst system (as
reported by Hsung18) afforded <3% of the desired ynamide
9a. Also notable is the observation that under our conditions
the reaction proceeds smoothly at room temperature, in
contrast to the elevated temperatures (110-150 °C) required
in the Buchwald and Hsung amidations.
As summarized in Table 1, acetylenic iodides also
participate in the alkynylation, whereas chloro alkynes are
significantly less reactive and undergo amidation only upon
heating and then in poor yield (entries 1-3). As expected,
somewhat improved yields are observed when 2 equiv of
alkynyl halides are employed to compensate for losses due
to homocoupling (compare entries 2 and 9).20 Interestingly,
Table 1. Optimization of Alkynylation Conditionsa
alkyne
yield
(%)b
entry
base
CuZ
CuI
CuI
CuI
CuI
CuI
solvent
pyr
pyr
pyrc
DMF
pyr
equiv, X
a KHMDS was added as a solution in THF and the alkynyl bromide
was added as a solution in benzene. b Isolated yields of products purified
by column chromatography.
1
2
3
4
KHMDS
KHMDS
KHMDS
KHMDS
n-BuLi
1.0, I
44
48
23
26
0
20
24
40e
67f
41
40
28h
1.0, Br
1.0, Cl
1.0, Br
1.0, Br
1.0, Br
1.0, Br
0.6, Br
2.0, Br
2.0, Br
2.0, Br
5.0, Br
5
pyridine proved to be the most effective solvent for the
alkynylation reaction, clearly superior to the toluene-diamine
ligand system (entry 11) employed by Buchwald15 and
Hsung18 in their amidation studies. Under our optimal
conditions (entry 9), the desired ynamide is obtained in 67%
yield, with the yield increasing to 76% when the reaction is
carried out on a multigram scale.21
6
7
8
9
10
11
12
n-BuLi
n-BuLi
CuI
DMSO
DMSO
pyr
p yr
pyr
tol, diamineg
pyr
CuTCd
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
CuI
Cu I
CuCN
CuI
CuI
a All reactions were carried out at rt for 20 h unless otherwise indicated.
Concentration of 8a (0.200 g scale) was 0.15 M. Alkynes were added as
benzene solutions. b Isolated yields of products purified by column chro-
matography. c Reaction at 75 °C. d Copper(I) thiophene-2-carboxylate.
e Yield based on 1-bromo-2-phenylethyne. f Yield improved to 76% when
scale increased to 2.0 g of 8a. g 4.0 equiv of diamine ligand MeN(H)CH2-
CH2N(H)Me. h Reaction for 90 h.
Table 2 details the scope of the N-alkynylation reaction
as applied to acyclic carbamates. A broad range of substituted
(20) Interestingly, Hsung found that the yields of ynamides decrease
when more than 1 equiv of alkynyl halide is employed under the Buchwald
amidation conditions (which are catalytic in copper salt); see Supporting
Information in ref 18.
Org. Lett., Vol. 5, No. 21, 2003
4013

and functionalized alkynyl bromides participate in the
reaction, including systems especially prone to homocoupling
such as the bromo derivatives of conjugated enynes and
diynes. Note also that these conditions provide access to
ynamides 9e and 9f in yields considerably better than that
reported by Hsung18 using the Buchwald catalyst system.
As summarized in Table 3, we have also found that our
alkynylation protocol can be applied with good results to
several other classes of amide derivatives. Notably, both
imidazolidinones and sulfonamides undergo N-alkynylation
in good yield. Both classes of amides are exceedingly poor
substrates in alkynylations with the Buchwald catalyst
system,18 and alkynyl sulfonamides such as 17 bearing alkyl
substituents on the acetylene cannot be prepared via alkynyl-
(phenyl)iodonium methodology (vide supra).
Table 3. N-Alkynylation of Sulfonamides and Cyclic
Carbamates and Ureasa
In summary, we have developed a general procedure for
the copper-promoted N-alkynylation of a variety of amide
derivatives that is complementary to the catalytic process
recently introduced by Hsung and co-workers. Hsung’s
protocol offers the advantage of requiring only a catalytic
amount of copper salt but requires reaction at elevated
temperatures (110-150 °C) and is not applicable to the
efficient synthesis of ynamides from certain important classes
of amides such as sulfonamides and acyclic carbamates. Our
alkynylation reaction proceeds at room temperature and can
be applied to a broad range of substrates but does require a
full equivalent of (relatively inexpensive) copper iodide. Both
methods have the advantageous feature of employing alkynyl
a Amide was treated with 1 equiv each of KHMDS and CuI in pyridine-
THF (rt, 2 h); 2 equiv of bromo alkyne in benzene was then added, and the
reaction mixture was stirred at rt for 20 h. b Isolated yields of products
purified by column chromatography.
bromides, which are easily prepared by bromination of
terminal acetylenes, and thus represent more attractive
alkynylating agents than alkynyl(phenyl)iodonium salts.
(21) Typical Experimental Procedure. A 250-mL, two-necked, round-
bottomed flask equipped with a rubber septum and addition funnel fitted
with a rubber septum and argon inlet needle was charged with carbamate
8a (1.951 g, 10.89 mmol) and 44 mL of pyridine. The solution was cooled
at 0 °C while 12.0 mL of KHMDS solution (0.91 M in THF, 11 mmol)
was added via syringe over 4 min. The reaction mixture was stirred at 0 °C
for 10 min, and then a solution of CuI (2.073 g, 10.89 mmol) in 22 mL of
pyridine was added via cannula in one portion (10-mL pyridine rinse). The
ice bath was removed, and the resulting solution was stirred at room
temperature for 2 h. A solution of bromo alkyne 10a (36 mL, 0.60 M in
benzene, 22 mmol) was then added via the addition funnel over 1 h, and
the resulting mixture was stirred at room temperature for 20 h. The reaction
mixture was diluted with 300 mL of Et2O and washed with three 100-mL
portions of a 2:1 mixture of saturated NaCl solution and concentrated NH4-
OH. The combined aqueous layers were extracted with three 75-mL portions
of Et2O, and the combined organic layers were washed with 300 mL of
saturated NaCl solution, dried over MgSO4, filtered, and concentrated to
provide 4.397 g of a dark red oil. Column chromatography on 120 g of
silica gel (gradient elution with 0-3% EtOAc-hexanes) furnished 2.309 g
(76%) of ynamide 9a as a yellow oil.
Acknowledgment. We thank the National Institutes of
Health (GM 28273), Pharmacia, and Merck Research
Laboratories for generous financial support. We thank Dr.
Artis Klapars for helpful discussions concerning copper-
mediated amidation chemistry.
Supporting Information Available: Experimental pro-
cedures and characterization data for all alkynylation reac-
tions and ynamide products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL035647D
4014
Org. Lett., Vol. 5, No. 21, 2003