Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed amidations of alkynyl bromides. Synthesis of heteroaromatic amine substituted ynamides

Article abstract of DOI:10.1021/ol049827e

(Equation presented) A practical cross-coupling of amides with alkynyl bromides using catalytic CuSO₄·5H₂O and 1,10-phenanthroline is described here. This catalytic protocol is more environmentally friendly than the use of CuCN or copper halides and provides a general entry for syntheses of ynamides including various new sulfonyl and heteroaromatic amine substituted ynamides. Given the interest in ynamides, this N-alkynylation of amides should be significant for the future of ynamides in organic synthesis.

Full text of DOI:10.1021/ol049827e

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1151-1154
Copper
Sulfate-Pentahydrate-1,10-Phenanthroline
Catalyzed Amidations of Alkynyl
Bromides. Synthesis of Heteroaromatic
Amine Substituted Ynamides
Yanshi Zhang, Richard P. Hsung,* Michael R. Tracey, Kimberly C. M. Kurtz, and
Eymi L. Vera
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received January 29, 2004
ABSTRACT
A practical cross-coupling of amides with alkynyl bromides using catalytic CuSO ‚5H O and 1,10-phenanthroline is described here. This
4
2
catalytic protocol is more environmentally friendly than the use of CuCN or copper halides and provides a general entry for syntheses of
ynamides including various new sulfonyl and heteroaromatic amine substituted ynamides. Given the interest in ynamides, this N-alkynylation
of amides should be significant for the future of ynamides in organic synthesis.
Ynamides have been attracting wide attention from the
synthetic community in the past 10 years.1-3 Inspired by
Buchwald’s copper-catalyzed N-arylations of amides,4 we
communicated syntheses of ynamides 3 via a Cu(I)-catalyzed
cross-coupling5-9 of alkynyl bromides 1 with amides 2
(Scheme 1).10a This study illustrates the concept of transition-
metal-catalyzed N-alkynylations of amides10b,c and provides
a practical and improved synthetic access to ynamides over
(1) For reviews on ynamides, 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. For
the first preparations of ynamides, see: (c) Janousek, Z.; Collard, J.; Viehe,
H. G. Angew. Chem., Int. Ed. 1972, 11, 917.
(3) For our recent applications of ynamides, see: (a) Shen, L.; Hsung,
R. P. Tetrahedron Lett. 2003, 44, 9353. (b) Frederick, M. O.; Hsung, R.
P.; Lambeth, R. H.; Mulder, J. A. Tracey, M. R. Org. Lett. 2003, 5, 2663.
(c) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H. A.; Frederick,
M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547. (d) Huang, J.;
Xiong, H.; Hsung, R. P.; Rameshkumar. C.; Mulder, J. A.; Grebe, T. P.
Org. Lett. 2002, 4, 2417. (e) Mulder, J. A.; Hsung, R. P.; Frederick, M. O.;
Tracey, M. R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383.
(4) For recent key papers on copper-catalyzed N-arylations of amides
from the Buchwald group, see: (a) Jiang, L.; Job, G. E.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2003, 5, 3667. (b) Klapars, A.; Huang, X.;
Buchwald S. L. J. Am. Chem. Soc. 2002, 124, 7421. (c) Klapars, A.; Antilla,
J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (d)
Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
(5) For recent contributions on copper-catalyzed N-arylations of amides
from the Porco group, see: (a) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr.
Org. Lett. 2004, 6, 27. (b) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman,
B. J.; Porco, J. A. Jr. J. Am. Chem. Soc. 2003, 125, 7889. (c) Shen, R.;
Porco, J. A., Jr. Org. Lett. 2000, 2, 1333.
(2) For recent efforts in synthesis and applications of ynamides, see: (a)
Rodriguez, D.; Castedo, L.; Saa´, C. Synlett 2004, ASAP. (b) Klein, M.;
Ko¨nig, B. Tetrahedron 2004, 60, 1087. (c) Marion, F.; Courillon, C.;
Malacria, M. Org. Lett. 2003, 5, 5095. (d) Witulski, B.; Alayrac, C.;
Tevzadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257. (e) Witulski,
B.; Lumtscher, J.; Bergstra¨sser, U. Synlett 2003, 708. (f) Witulski, B.;
Alayrac, C. Angew. Chem. Int. Ed. 2002, 41, 3281. (g) Tanaka, R.; Hirano,
S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67. (h) Gravestock, D.; Dovey,
M. C. Synthesis 2003, 523. (i) Naud, S.; Cintrat, J.-C. Synthesis 2003, 1391.
(j) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803. (k) Timbart, J.-C.;
Cintrat. J.-C. Chem. Eur. J. 2002, 8, 1637. (l) Minie`re, S.; Cintrat. J.-C.
Synthesis 2001, 705. (m) Minie`re, S.; Cintrat. J.-C. J. Org. Chem. 2001,
66, 7385. (n) Hoffmann, R. W.; Bru¨ckner, D. New. J. Chem. 2001, 25,
369. (o) For papers before 2000, please refer to ref 1a and b.
10.1021/ol049827e CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/02/2004

since sulfonyl ynamides are the substrates employed most
in an array of elegant methodologies that has been devel-
oped.2,13,14
Scheme 1
In addressing this limitation, Danheiser15 recently reported
a useful solution using a stoichiometric amount of copper
along with a strong base, KHMDS. Danhesier’s protocol
should capture much interest, for it allows reactions to
proceed at room temperature, which is much lower than ours
at 110 °C, thereby rendering potential preparations of
thermally sensitive ynamides feasible. We elected to re-
examine this coupling reaction and overcome this limitation
by developing a catalytic protocol16 based on Buchwald’s4,17
and Porco’s5 meticulous studies on copper-catalyzed N-
arylations of amides and enamides. We report here copper
sulfate-pentahydrate-1,10-phenanthroline catalyzed amida-
tions of alkynyl bromides using sulfonamides and hetero-
aromatic amines in addition to lactams and urethanes.
To successfully develop a general catalytic protocol for
preparation of ynamides, variables such as Cu(I) or Cu(II)
salts,18a ligands, solvents,18b concentrations,18c bases,18d and
temperatures18e were carefully screened using acyclic car-
bamate 6 and alkynyl bromide 7 as model substrates as
summarized in Scheme 2. The best Cu(I) salt, CuCN, could
existing protocols.1b,2h-i,11,12 It also allows subsequent access
to ynamides such as 5 via deprotonation of parent ynamides
3 (R1 ) H) and methylation of lithium acetylides 4. However,
despite such development, there remain severe limitations.
Although oxazolidinones 2a were useful in the coupling with
1, amides 2b-d were mostly poor and sulfonamides 2e were
not suitable at all. This latter limitation is the least desirable
(6) For some earlier accounts, see: (a) Yamamoto, T.; Kurata, Y. Can.
J. Chem. 1983, 61, 86 and references therein. (b) Yamamoto, T.; Ehara,
Y.; Kubota, M.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1980, 53, 1299. (c)
Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. For recent references
of copper catalyzed N-arylations of amides and enamides, see: (d) Lam,
P. Y. S.; Vinvent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44,
4927. (e) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002,
231. (f) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600. (g) Collman,
J. P.; Zhong, M. Org. Lett. 2000, 2, 1233. (h) Mederski, W. W. K. R.;
Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757. (i)
Murakami, Y.; Watanabe, T.; Hagiwara, T.; Akiyama, Y.; Ishii, H. Chem.
Pharm. Bull. 1995, 43, 1281. (j) Kato, Y.; Conn, M. M.; Rebek, J., Jr. J.
Am. Chem. Soc. 1994, 116, 3279. (k) Ogawa, T.; Kiji, T.; Hayami, K.;
Suzuki, H. Chem. Lett.1991, 1443. For recent references of copper-catalyzed
N-arylations of amides alcohols, see: (l) Wolter, M.; Nordmann, G.; Job,
G. E.; Buchwald, S. L. Org Lett. 2002, 4, 973. (m) Fagan, P. J.; Hauptman,
E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043.
(7) For a recent review on copper-mediated C-N and C-O bond
formation, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400. Also see: (b) Lindley, J. Tetrahedron 1984, 40, 1433.
(8) For reviews on the related palladium-catalyzed N-arylations of amines
and amides, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. For an earlier account, see: (c) Kosugi, M.; Kameyama,
M, Migita, T. Chem. Lett. 1983, 927.
(9) For recent examples on palladium-catalyzed N-arylations of amines
and amides, see: (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
K. H.; Alcazar- Roman, L. M. J. Org. Chem. 1999, 64, 5575. (c) Cacchi,
S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539. (d)
Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett. 2001,
42, 4381. (e) Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett.
2000, 2, 1109. (h) Bolm, C.; Hildebrand, J. J. Org. Chem. 2000, 65, 169.
(10) (a) 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. (b) For an earlier documentation of copper-promoted
coupling of amide with alkyne, see: Balsamo, A.; Macchia, B.; Macchia,
F.; Rossello, A. Tetrahedron Lett. 1985, 26, 4141. (c) For a much earlier
account of such copper(II) acetate/O2 catalyzed Csp-N bond formation in
synthesis of ynamines, see: Petersen, L. I. Tetrahedron Lett. 1968, 9, 5357.
(11) (a) Bru¨ckner, D. Synlett 2000, 1402. (b) Fromont, C.; Masson, S.
Tetrahedron 1999, 55, 5405. (c) Feldman, K. S.; Bruendl, M. M.;
Schildknegt, K.; Bohnstedt, A. C. J. Org. Chem. 1996, 61, 5440. (d)
Novikov, M. S.; Khlebnikov, A. F.; Kostikov, R. R. J. Org. Chem. USSR
1991, 27, 1576. (e) Tikhomirov, D. A.; Eremeev, A. V. Chem. Heterocycl.
Compd. (N. Y.) 1987, 23, 1141.
Scheme 2
give 819 in an optimal 36% isolated yield at 0.2 equiv, similar
to what we had reported.10 A stoichiometric amount of CuCN
led to 8 in only 7% yield with the major product being the
homocoupled product from 7 when K3PO4 was the base of
(13) For Witulski’s earlier work, see: (a) Witulski, B.; Stengel, T. Angew.
Chem., Int. Ed. 1998, 37, 489. (b) Witulski, B.; Stengel, T. Angew. Chem.,
Int. Ed. 1998, 38, 2426. (c) Witulski, B.; Go¨ssmann, M. Chem. Commun.
1999, 1879. (d) Witulski, B.; Go¨ssmann, M. Synlett 2000, 1793. (e) Witulski,
B.; Stengel, T.; Ferna`ndez-Herna`ndez, J. M. Chem. Commun. 2000, 1965.
(f) Witulski, B.; Buschmann, N.; Bergstra¨sser, U. Tetrahedron 2000, 56,
8473.
(14) (a) Rainier, J. D.; Imbriglio, J. E. J. Org. Chem. 2000, 65, 7272.
(b) Rainier, J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037.
(15) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
(16) During the submission of our work, we became aware of the success
in the synthesis of sulfonyl-substituted ynamides using catalytic CuI, see:
Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, ASAP.
(17) For key references in using 1,10-phenanthroline as a ligand in copper
catalyzed N-arylations of amides from the Buchwald group, see: (a)
Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999,
40, 2657. (b) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002,
4, 581. (c) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3,
3803.
(12) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C.
J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
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Org. Lett., Vol. 6, No. 7, 2004

choice. The outcome improved incrementally when we
switched to Cu(II) salts and, specifically, CuSO4‚5H2O. It
was not until 1,10-phenanthroline4,5,17,20,21 was used as the
ligand that ynamide 8 was isolated in 73% yield with 80%
conversion of 6 and complete suppression of homocouplings.
The use of CuSO4‚5H2O represents a catalytic protocol
that is much cheaper and more environmentally friendly than
the CuCN method, and it compares quite favorably with the
CuCN catalyst, as shown in entries 1 and 2 in Table 1. In
More significantly, the CuSO4‚5H2O/1,10-phenanthroline
catalytic system was very useful in the preparation of sulfonyl
ynamides (Table 2).22 An array of sulfonyl ynamides were
Table 2.
Table 1.
a Reactions were carried out using 5-10 mol % CuSO4‚5H2O, 1,10-
phenanthroline (2 equiv to copper), 2.0 equiv of K2CO3 in toluene (0.5-
1.0 M based on the amide) at 60-65 °C for 18-36 h. b Isolated yields.
c Run in DMF.
prepared to illustrate (1) the range of different alkynyl
bromides employed (entries 1-8), (2) the ability to synthe-
size chiral sulfonyl ynamides (entries 9 and 12), (3) tolerance
of various substituted sulfonamides (entries 10 and 17),
including those containing functional groups such as shown
in ynamides 38 and 39 (entries 16 and 17), and (4)
permutations in substitution patterns one can achieve in these
ynamides. In these reactions, K2CO3 appears to be a better
base than K3PO4. Given the current synthetic interest, these
new sulfonyl ynamides should find further utility in organic
synthesis.
a Reactions were carried out using 5-20 mol % CuSO4‚5H2O, 1,10-
phenanthroline (2 equiv to copper), 2.0 equiv of K3PO4 in toluene (0.5-
1.0 M based on the amide) at 60-65 °C for 18-36 h. b Isolated yields.
c Yields from using 5 mol % CuCN and DMED. d Run at 80-85 °C. e Run
at 90-95 °C. f Base was Cs2CO3. g 2 equiv of 1,10-phenanthroline and 1.6
equiv of alkynyl bromide were used.
Finally, given the pharmaceutical significance of hetero-
addition, we found that formerly poor substrates such as aza-
camphor (entries 3-6), imidazolidinone (entries 7-10), and
acyclic-urethanes (11-13) are now quite suitable for cou-
pling with their respective alkynyl bromides using the new
protocol. Even simple lactams underwent coupling to give
ynamides 21 and 22 (entries 14 and 15). It is noteworthy
that the loading is mostly in the range of 5-10 mol % of
CuSO4‚5H2O and that temperature is now at 60-65 °C
instead of 110 °C,10a which is much lower than what had
been used in the CuCN protocol.
aromatic amine substituted alkynes,23 we applied this catalytic
(22) Preparative Procedure Illustrating the Preparation of Ynamide
30. (Entry 8 in Table 2) To a solution of 1-bromo-2-triisopropylsilylacetylene
(575.0 mg, 2.20 mmol) in 2 mL of freshly anhydrous toluene in a reaction
vial were added N-benzyltoluenesulfonamide (522.0 mg, 2.00 mmol), K2CO3
(560.0 mg, 4.00 mmol), CuSO4‚5H2O (50.0 mg, 0.20 mmol), and 1,10-
phenanthroline (74.0 mg, 0.40 mmol). The reaction mixture was capped
under a blanket of nitrogen and heated in an oil bath at 60-65 °C for 32
h. The progress of the reaction was monitored using TLC analysis. Upon
completion, the reaction mixture was cooled to room temperature and diluted
with 12 mL of chloroform. The resulting mixture was filtered through a
pipet-size Celite column, and the filtrate was concentrated in vacuo. The
crude residue was purified using silica gel column flash chromatography
(gradient eluent 0-10% EtOAc in hexane) to give ynamide 30 (852.0 mg,
97%) as clear oil. Note: This amidation procedure is also suitable for larger
scale preparations. Specifically, we were able to prepare the relatively less
stable ynamide 12 at a 6.69-mmol scale and obtained 2.52 g of 12 in 70%
yield (entry 4 in Table 1).
(23) (a) Majumdar, K. C.; Ghosh, S. K. Synth. Commun. 1994, 24, 217.
(b) Joshi, R. V.; Xu, Z.-Q.; Ksebati, M. B.; Kessel, D.; Corbett, T. H.;
Drach, J. C.; Zemlicka, J. J. Chem. Soc., Perkin Trans 1 1994, 1089. (c)
Galy, J. P.; Elguero, J.; Vincent, E. J.; Galy, A. M.; Barbe, J. Synthesis
1979, 944. (d) Mahamoud, A.; Galy, J. P.; Vincent, E. J.; Barbe, J. Synthesis
1981, 917. (e) Radl, S.; Kovarova, L.; Holubeck, J. Coll. Czech. Chem.
Commun. 1991, 56, 439. (f) Radl, S.; Kovarova, L. Collect. Czech. Chem.
Commun. 1991, 56, 2413. (g) Katritzky, A. R.; Ramer, W. H. J. Org. Chem.
1985, 50, 852.
(18) (a) Cu(I) salts screened: CuCl, CuI, Cu2O, CuTc [Tc ) thiophene-
carboxylate], and CuCN. Cu(II) salts screened: Cu(OAc)2 and CuO. Cu(0)
metal was also examined. (b) Solvents screened: Dioxane, NMP, CH3-
CH2OCH2CH2OH, DMSO, and DMF. (c) Concentration points: 0.1, 0.2,
0.25, 0.4, 0.5, and 1.0 M. (d) Bases screened: KOt-Bu, K2CO3, and
n-Bu4NOH. (e) Temperature points: 110 versus 60 °C.
(19) All new compounds were characterized by 1H NMR, 13C NMR,
FTIR, mass spectroscopy, and [R]23
.
D
(20) For the usage of 1,10-phenanthroline in ligand accelerated couplings
of N-arylations of diarylamines, see: Goodbrand, H. B.; Hu, N.-X. J. Org.
Chem. 1999, 64, 670.
(21) For the usage of 1,10-phenanthroline as ligand in intramolecular
N-arylations of guanidines, see: Evindar, G.; Batey, R. A. Org. Lett. 2003,
5, 133.
Org. Lett., Vol. 6, No. 7, 2004
1153

medicinal applications. Temperatures for these reactions were
higher at 70-80 °C, and both K2CO3 and K3PO4 appeared
to be suitable bases.
Table 3.
Interestingly, R-bromoenamide 51 was isolated as a result
of formal addition of “HBr” to the vinylogous ynamide
product formed initially.3c The assignment of E-stereochem-
istry is based on our previous work on formation of
R-haloenamides from treatment of ynamides with hydrated
magnesium halides.3c However, we would note that in this
reaction, the only metal halide species would likely be CuBr,
but CuI was found not to be effective in giving R-iodo-
enamide in our earlier studies.3c In addition, this appears to
be the sole case in all of the Cu-coupling reactions. We are
looking into the possible cause of this unexpected hydro-
bromonation.
We have described here a useful copper(II) salt catalyzed
amidation of acetylenic carbons. This route provides a
general entry to a diverse array of ynamides including
sulfonyl and heteroaromatic amine substituted ynamides.
Given the surging interest in ynamides, this catalytic protocol
should have a significant impact on the future utility of
ynamides in organic synthesis.
a Reactions were carried out in toluene (0.5-1.0 M based on the amide)
using 10 mol % CuSO4‚5H2O, 20 mol % 1,10-phenanthroline, 2.0 equiv of
K3PO4 at 70-80 °C for 18-36 h. For entries 2, 4, 5, and 10-12, 2.0 equiv
of K2CO3 was used. b Except for entries 5 and 7-9, 1.1 equiv of alkynyl
bromide was used; for entries 5 and 7-9, it was 1.3-1.4 equiv. c Isolated
yields. d Run at 85 °C.
Acknowledgment. This work is supported by the NSF
[CHE-0094005].
protocol to the synthesis of various novel vinylogous
ynamides.2h As shown in Table 3, indoles (entries 1-6),
pyrroles (entries 7-9), benzo-2-imidazolidinone (entries 10
and 11), and pyridones (entry 12) could all be successfully
coupled to give respective vinylogous ynamides 40-51 that
can be very attractive for further synthetic as well as
Supporting Information Available: Experimental details
and H NMR spectral and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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