Copper(II)-catalyzed amidations of alkynyl bromides as a general synthesis of ynamides and Z-enamides. An intramolecular amidation for the synthesis of macrocydic ynamides

Article abstract of DOI:10.1021/jo060230h

A general and efficient method for the coupling of a wide range of amides with alkynyl bromides is described here. This novel amidation reaction involves a catalytic protocol using copper(II) sulfate-pentahydrate and 1,10-phenanthroline to direct the sp-C-N bond formation, leading to a structurally diverse array of ynamides including macrocyclic ynamides via an intramolecular amidation. Given the surging interest in ynamide chemistry, this atom economical synthesis of ynamides should invoke further attention from the synthetic organic community.

Full text of DOI:10.1021/jo060230h

Copper(II)-Catalyzed Amidations of Alkynyl Bromides as a General
Synthesis of Ynamides and Z-Enamides. An Intramolecular
Amidation for the Synthesis of Macrocyclic Ynamides
Xuejun Zhang, Yanshi Zhang, Jian Huang, Richard P. Hsung,* Kimberly C. M. Kurtz,
Jossian Oppenheimer, Matthew E. Petersen, Irina K. Sagamanova, Lichun Shen, and
Michael R. Tracey
DiVision of Pharmaceutical Sciences and Department of Chemistry, 777 Highland AVenue,
UniVersity of Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
ReceiVed February 3, 2006
A general and efficient method for the coupling of a wide range of amides with alkynyl bromides is
described here. This novel amidation reaction involves a catalytic protocol using copper(II) sulfate-
pentahydrate and 1,10-phenanthroline to direct the sp-C-N bond formation, leading to a structurally
diverse array of ynamides including macrocyclic ynamides via an intramolecular amidation. Given the
surging interest in ynamide chemistry, this atom economical synthesis of ynamides should invoke further
attention from the synthetic organic community.
Introduction
intermediates such as sigmatropic rearrangements, Pictet-
Spengler reactions, and enyne cyclizations.
Ynamides have attracted much attention from the synthetic
community in recent years.1-4 A large number of new meth-
odologies have been developed employing ynamides as a
versatile organic building block, leading to the synthesis of a
structurally diverse array of useful functional groups and
carbocycles as well as heterocycles.3,4 Depending on the
reactivities involved, these transformations can be classified into
two major categories: (1) those ynamides with reactivities
similar to simple alkynes, such as metal-catalyzed cycloaddi-
tions, RCM, addition reactions, cross-coupling reactions, radical
cyclizations, and other tandem reactions, and (2) those with
reactivities based on the in situ generated ketene iminium
At the very same time, the synthesis of ynamides2,5-7 had
largely suffered from harsh reaction conditions, laborious
(3) For recent efforts in synthesis and applications of ynamides, see: (a)
Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776. (b)
Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681. (c) Zhang,
Y. Tetrahedron Lett. 2005, 46, 6483. (d) Martinez-Esperon, M. F.;
Rodriguez, D.; Castedo, L.; Saa´, C. Org. Lett. 2005, 7, 2213. (e) Bendikov,
M.; Duong, H. M.; Bolanos, E.; Wudl, F. Org. Lett. 2005, 7, 783. (f) Marion,
F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria, M. Org. Lett.
2004, 6, 1509. (g) Rosillo, M.; Dom´ınguez, G.; Casarrubios, L.; Amador,
U.; Pe´rez-Castells, J. J. Org. Chem. 2004, 69, 2084. (h) Couty, S.; Lie´gault,
B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511. (i) Rodr´ıguez, D.; Castedo,
L.; Saa´, C. Synlett 2004, 783. (j) Rodr´ıguez, D.; Castedo, L.; Saa´, C. Synlett
2004, 377. (k) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004,
6, 727. (l) Klein, M.; Ko¨nig, B. Tetrahedron 2004, 60, 1087. (m) Marion,
F.; Courillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095. (n) Witulski, B.;
Alayrac, C.; Tevzaadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257.
(o) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67. (p)
Witulski, B.; Lumtscher, J.; Bergstra¨sser, U. Synlett 2003, 708. (q) Naud,
S.; Cintrat, J.-C. Synthesis 2003, 1391. (r) Denonne, F.; Paul Seiler, P.;
Diederich, F. HelV. Chim. Acta 2003, 86, 3096. (s) Witulski, B.; Alayrac,
C. Angew. Chem. Int. Ed. 2002, 41, 3281. (t) Saito, N.; Sato, Y.; Mori, M.
Org. Lett. 2002, 4, 803. (u) Timbart, J.-C.; Cintrat. J.-C. Chem. Eur. J.
2002, 8, 1637. (v) For many other contributions before 2001, see ref 1.
(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) Zhang, Y.; Hsung, R. P. ChemTracts 2004, 17, 442. (c) Katritzky, A.
R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455.
(2) For reviews on syntheses of ynamides, see: (a) Mulder, J. A.; Kurtz,
K. C. M.; Hsung, R. P. Synlett 2003, 1379. (b) Tracey, M. R.; Hsung, R.
P.; Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y. In
Science of Synthesis, Houben-Weyl Methods of Molecular Transformations;
Weinreb, S. M., Ed.; Georg Thieme Verlag KG: Stuttgart, Germany, 2005;
Chapter 21.4.
10.1021/jo060230h CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/04/2006
4170
J. Org. Chem. 2006, 71, 4170-4177

Cu(II)-Catalyzed Amidations of Alkynyl Bromides
SCHEME 1. Ynamides and Amidations of Alkynyl
Bromides
reaction sequence, and narrow substrate scope. This deficiency
had seriously hindered the development of this field. Inspired
by the seminal work from Buchwald’s group on copper-
catalyzed amidation of aryl halides,8-13 known as the Goldberg
reaction,9 we communicated a methodology14 for the ynamide
synthesis that involved a direct cross-coupling of alkynyl
bromides and amides catalyzed by Cu(I) salts (Scheme 1). This
methodology represents the first practical C-N bond formation
process involving sp-hybridized carbons15 and offered an atom
economical entry toward a more ideal synthesis of ynamides
over the previously existing protocols.5-7
However, there had remained an unacceptable limitation
within this new protocol, with oxazolidinones being the most
useful amide substrates for the transformation. Other important
classes of amides such as lactams, imidazolidinones, acyclic
carbamates, and sulfonamides were all poor coupling partners.
(4) For our recent applications of ynamides, see: (a) Kurtz, K. C. M.;
Hsung R. P.; Zhang, Y. Org. Lett. 2006, 8, 231. (b) Kurtz, K. C. M.;
Frederick, M. O.; Lambeth, R. H.; Mulder, J. A.; Tracey, M. R.; Hsung, R.
P. Tetrahedron 2006, 62, 3928. (c) Zhang, Y.; Hsung, R. P.; Zhang, X.;
Huang, J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7, 1047. (d) Tracey,
M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.; Hsung, R. P. Org. Lett.
2004, 6, 2209. (e) Shen, L.; Hsung, R. P. Tetrahedron Lett. 2003, 44, 9353.
(f) Frederick, M. O.; Hsung, R. P.; Lambeth, R. H.; Mulder, J. A.; Tracey,
M. R. Org. Lett. 2003, 5, 2663. (g) 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. (h) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar.
C.; Mulder, J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417. (i) Mulder, J. A.;
Hsung, R. P.; Frederick, M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett.
2002, 4, 1383.
SCHEME 2. An Intramolecular Amidation
(5) For a pioneering preparation of ynamides, see: Janousek, Z.; Collard,
J.; Viehe, H. G. Angew. Chem., Int. Ed. 1972, 11, 917.
(6) For some examples of alkynyl iodonium triflate salts, see: (a)
Feldman, K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt, A. C. J. Org.
Chem. 1996, 61, 5440. (b) Witulski, B.; Stengel, T. Angew. Chem. Int. Ed.
1998, 37, 489. (c) Witulski, B.; Stengel, T.; Ferna`ndez-Herna`ndez, J. M.
Chem. Commun. 2000, 1965. (d) Witulski, B.; Buschmann, N.; Bergstra¨âer,
U. Tetrahedron 2000, 56, 8473. (e) Rainier, J. D.; Imbriglio, J. E. J. Org.
Chem. 2000, 65, 7272. (f) Bru¨ckner, D. Synlett 2000, 1402. (g) Fromont,
C.; Masson, S. Tetrahedron 1999, 55, 5405.
(7) (a) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas,
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459. Also see: (b) Couty, S.;
Barbazanges, M.; Meyer, C.; Cossy, J. Synlett 2005, 906. (c) See ref 4h.
(8) For a recent review on copper mediated C-N and C-O bond
formation, see: (a) Dehli, J. R.; Legros. J.; Bolm, C. Chem. Commun. 2005,
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
Also see: (c) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (d)
Lindley, J. Tetrahedron 1984, 40, 1433.
Shortly after, Danheiser addressed this limitation by developing
a stoichiometric copper(I)-mediated amidation protocol.16 In
their work, a stronger base, KHMDS, was employed to generate
the desired copper amide species. A distinctly attractive feature
of this coupling reaction is that it can proceed at room
temperature, thereby allowing the preparation of thermally
sensitive ynamides. Subsequently, Urabe and Sato3k documented
their success examples of using sulfonamides in CuI-catalyzed
amidation of alkynyl halides exactly where we had failed.
Despite these practical modifications, we decided to reinves-
tigate the effect of different combinations of copper salts and
ligands on the efficiency of this C-N bond formation method.
Consequently, we communicated a more efficient and general
method for the synthesis of ynamides and heterocycle-substituted
ynamines, featuring a copper sulfate-pentahydrate-1,10-
phenanthroline driven catalytic system.17 This success further
allowed us to explore the possibility of achieving an intramo-
lecular amidation for the synthesis of unique macrocyclic
ynamides that can lead to macrocyclic enamides (Scheme 2).
The inspiration came from macrocyclic enamide-containing
natural products such as securine B and securamine B.18 We
report here the entire synthetic scope of this amidation of alkynyl
halide, an interesting competing N-alkynylation, and develop-
ment of an intramolecular amidation of alkynyl halides.
(9) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
(10) 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) Kwong, F. Y.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2002, 4, 581.
(11) For an earlier accounts, see: Yamamoto, T.; Kurata, Y. Can. J.
Chem. 1983, 61, 86, and references therein.
(12) For some recent references of copper-catalyzed N-arylations of
amides and enamides: (a) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman,
B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889. (b) Shen, R.;
Porco, J. A., Jr. Org. Lett. 2002, 2, 1333. (c) Yamada, K.; Kubo, T.;
Tokuyama, H.; Fukuyama, T. Synlett 2002, 231. (d) 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.
(13) 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.
(14) 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.
(15) 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.
(16) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
(17) Zhang, Y.; Hsung R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E.
L. Org. Lett. 2004, 6, 1151.
(18) Rahbaek, L.; Anthoni, U.; Christophersen, C.; Nielsen, P. H.;
Petersen, B. O. J. Org. Chem. 1996, 61, 887.
J. Org. Chem, Vol. 71, No. 11, 2006 4171

Zhang et al.
TABLE 1. Screening of Copper Salts, Ligands, and Bases
n-Bu4NOH, and K3PO4 proves to be the base that led to the
most consistent results, especially when amidations involve
acyclic urethanes (or amides). Although our previous disclosures
have suggested that the choice of the base is critical and that
K3PO4 works the best for most amidations,14,17 we would state
here more explicitly that K2CO3 has failed in most amidations
using acyclic urethanes (or acyclic amides) (see entry 2), as
attested by Tam’s recent report (entry 1).3b Even when employ-
ing the new catalytic system with CuSO4‚5H2O and 1,10-
phenanthroline, K3PO4 remains a better choice than K2CO3
(entries 6 and 8 versus 7).
copper salta
[mol %]
entry
R
amide
ligandb
basec ynamide % yieldd
1
2
3
4
5
6
7
8
9
Bn
1a CuCN [6.0] DMEDAe K2CO3
1a CuCN [50.0] DMEDA K2CO3
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
0f
Bn
Bn
Bn
Bn
Bn
Bn
Bn
5-9g,h
1a CuCN [5.0] DMEDA
1a CuCN [20.0] DMEDA
1b CuSO4 [20.0] DMEDA
K3PO4
K3PO4
K3PO4
7
17
20
1a CuSO4 [10.0] 1,10-phen K3PO4
1a CuSO4 [10.0] 1,10-phen K2CO3
1a CuSO4 [20.0] 1,10-phen K3PO4
32i
To further support the significance of using K3PO4 as the
base in these amidations, we re-examined one of Tam’s
substrates (amidation using 1b) that they had some real
difficulties with3b (entry 9 in Table 1) even when employing
CuSO4‚5H2O and 1,10-phenanthroline but with K2CO3 as the
base.3b We repeated this reaction and found that, in our hands,
we could only manage isolating the desired ynamides 3b in 15%
yield using K2CO3, even when we used 20 mol % of copper
salt (entry 10). Interestingly, while Cs2CO3 gave 0% (entry 11),
we isolated 3b in 46-60% yield with several trials when K3-
PO4 was the base (entry 12). This difference is likely due to
the pKa’s of amides, although we are not certain at this time of
the exact rationale.
5
73-79h,j
0k
c-Hex 1b CuSO4 [10.0] 1,10-phen K2CO3
10 c-Hex 1b CuSO4 [20.0] 1,10-phen K2CO3
11 c-Hex 1b CuSO4 [20.0] 1,10-phen Cs2CO3
12 c-Hex 1b CuSO4 [20.0] 1,10-phen K3PO4
15
0
46-60l
a CuSO4 ) CuSO4‚5H2O. b DMEDA ) N,N′-dimethylethylenediamine;
1,10-phen ) 1,10-phenanthroline. The ratio of copper salt:ligand ) 1:2 in
all cases, unless otherwise indicated. c 2.0 equiv was used in all cases.
d Isolated yields. e 10 mol % of DMEDA was used. f Reported in entry 9
of Table 1 in ref 3b, and the temperature was 110 °C. g The temperature
was 110 °C. h The range obtained from several trials. i Concentration )
0.5 M. The yield was only 19% when concentration ) 1.0 M. j The yield
was only 18% when the solvent and CuSO4 were scrupulously dried.
k Reported in entry 1 of Table 1 of ref 3b. l T ) 80 °C and yields were
lower at 50 and 110 °C.
Finally, it is noteworthy that (1) the reaction was equally
efficient in most cases using a sealed reaction flask without
flushing and blanketing with an inert atmosphere and (2) the
use of CuSO4‚5H2O represents a catalytic protocol that is much
cheaper and environmentally more acceptable than the original
CuCN method. With a temperature range of 60-80 °C instead
of 110 °C, this new protocol represents a much milder condition
than the original one.
Results and Discussion
1. Screening of Cu Salts, Ligands, and Bases. To develop
a more general protocol for the preparation of ynamides,
variables such as Cu salts, ligands, solvents, concentrations, and
bases were carefully screened using acyclic carbamate 1a and
bromoalkyne 2 as the model substrates (see Table 1). Under
original reaction conditions using 20 mol % of CuCN as the
catalyst (entries 2-4) and 40 mol % N,N′-dimethylethylenedi-
amine (DMEDA) as the ligand with K3PO4 as the base, the
desired ynamide 3a19 was obtained in a best yield of 17% (entry
4) with the major reaction pathway being homocoupling of
bromoalkyne 2. Given this poor starting point, it was clear that
a much better and more general amidation protocol was needed.
Without getting inundated by details of our screening efforts,
which had been documented in our previous communica-
tions,14,17 we re-examined the entire catalytic system. A brief
screening of solvents confirmed that a nonpolar solvent such
as toluene was the most effective in favor of the ynamide
formation. Polar solvents such as DMF, NMP, and 2-ethoxy-
ethanol favored homocoupling of bromoalkynes such as 2.
Subsequently, a series of readily available copper salts were
carefully studied. While most of the copper species showed poor
to moderate activities, an enhanced selectivity toward the
ynamide formation was observed when using CuSO4‚5H2O
(entries 5-8). Further optimizations of ligands demonstrated
that 1,10-phenanthroline is a more superior ligand than DMEDA
while employing CuSO4‚5H2O (entry 6 versus 5). When using
20 mol % of CuSO4‚5H2O and 1,10-phenanthroline as the ligand
(entry 8), the desired ynamide 3a was isolated in 73-79% yield.
It is noteworthy that the yield dropped to 18% when CuSO4‚
5H2O was scrupulously dried.
2. Carbamate, Urea, and Lactam-Substituted Ynamides.
The scope of this new protocol was explored using a diverse
array of bromoalkynes and amides (Table 2). We note that
examples presented in this paper are new substrates that have
not appeared in our previous communications.14,17 These new
coupling conditions employing CuSO4‚5H2O and 1,10-phenan-
throline appeared to tolerate a wide range of substitutions on
the bromoalkyne (Table 2). In addition to alkyl, aryl, and silyl
groups, other relatively sensitive functional groups such as silyl
ethers, imides, and ketones all survived the coupling conditions
to afford the desired ynamides in good yields. Even sterically
demanding alkynyl bromides coupled very efficiently to give
the desired ynamides in very good yields (see 4-7).
Oxazolidinones bearing different substitutions, including
phenyl, benzyl, diene, and furyl substitutions, all participated
in the coupling reaction with the desired oxazolidinone-
substituted ynamides being isolated mostly in 60-98% yields
(see 4-14). Both K2CO3 and K3PO4 proved to be comparably
efficient here for the cyclic oxazolidinone series. A six-
membered ring carbamate was also reasonably effective for this
amidation when Cs2CO3 or K3PO4 was used.
More importantly, formally poor substrates such as acyclic
carbamates are now suitable for the coupling if K3PO4 was
employed as the base (see 16-18). As expected, the N-
alkynylation of the Boc-protected carbamate proceeded at a
much slower rate, which can be attributed to the steric effect of
the bulky Boc group (see 17 isolated at <40% conversion).
Finally, urea (see 19) and lactam (see 20) are also suitable for
amidations, and we can effectively construct push-pull yna-
However, another key difference is the base. Among the bases
that we screened were K3PO4, K2CO3, Cs2CO3, KOt-Bu, and
(19) See Supporting Information for details.
4172 J. Org. Chem., Vol. 71, No. 11, 2006

Cu(II)-Catalyzed Amidations of Alkynyl Bromides
TABLE 2. Syntheses of Carbamate, Urea, and Lactam Substituted
Ynamidesa
SCHEME 4. Rh(I)-Catalyzed Stereoselective Diels-Alder
Cycloaddition
For example, as shown in Scheme 4, we were able to quickly
demonstrate that Witulski’s elegant intramolecular ynamide-
Diels-Alder cycloaddition method20,21 could be rendered ste-
reoselective using chiral ynamides. While chiral ynamide 25
was feasible for intermolecular reactions, leading to interesting
cycloadducts such as chiral anilide 27 and bicyclic chiral
enamide 29a/b (∼2:1 ratio, but unassigned), the stereoselectivity
was not good. However, we could prepare tetrahydroindole 30
in 75% yield as a single diastereomer from chiral ynamide 29
via a Rh(I)/AgSbF6-catalyzed20 Diels-Alder cycloaddition.
3. Sulfonyl-Substituted and Simple Ynamides. Most sig-
nificantly, this new amidation protocol proves to be extremely
efficient for the preparation of sulfonyl-substituted ynamides.
Sulfonyl-substituted ynamides are important because they have
been most prominently displayed in an array of elegant
methodologies.1-3 A diverse array of sulfonyl-substituted yna-
mides has been prepared to illustrate the range of functionalities
on the amide nitrogen (Table 3).
a Reactions were carried out using 10 mol % CuSO4‚5H2O, 1,10-phen
(2 equiv to copper), and 2.0 equiv of K3PO4, K2CO3, or Cs2CO3 in toluene
(0.5-1.0 M based on amide) at 65-75 °C for 18-36 h. b Isolated yields.
c 5 mol % CuCN and 10 mol % of DMEDA. d The reaction only proceeded
well with the base being 2.0 equiv of K3PO4.
SCHEME 3. Large-Scale Preparations
In addition to simple alkyl and aryl, other functionalities such
as vinyl bromide, propargyl, allyl, silyl ether, and Boc-protected
indole can tolerate the coupling conditions to give the corre-
sponding ynamides in good to excellent yields (see 31-35).
Successful formation of the ynamide 32, bearing a terminal
alkyne, is quite encouraging, since a copper-catalyzed Glaser-
type coupling of the terminal alkyne with bromoalkyne was
originally expected to be a major competing pathway. Substitu-
tions on the sulfonyl groups were also studied, indicating that
Bs, Ns, and Ms are also viable sulfonamides for the amidation
(see 36-39). No noticeable rate or efficiency difference was
observed, with all the ynamides being obtained in excellent
yields
mides such as 21 by employing the CuSO4‚5H2O/1,10-phenan-
throline catalytic system.
To demonstrate that this catalytic protocol is not limited in
scale, we undertook a scale-up of our work. As shown in
Scheme 3, ynamides such as 24a and 24b could be prepared in
gram quantities. This realization is significant, because it allows
one to envision ynamides being part of a linearly sequenced
synthetic plan toward natural product syntheses.4c
The success in the preparation of diverse ynamides in a large
quantity allows the flexibility to develop stereoselective meth-
odologies employing chiral ynamides, which still represents a
major directive that has not been undertaken at this point.3b,k
We believe our amidation protocol should help advocate efforts
toward this goal.
The effect of various functionalized bromoalkynes on the
efficiency of the coupling reactions was investigated (see 40-
(20) Witulski, B.; Lumtscher, J.; Bergstra¨sser, U. Synlett 2003, 708.
(21) For reviews, see: (a) Varela, J A.; Saa´, C. Chem. ReV. 2003, 103,
3787. (b) Rubin, M.; Sromek, A. W.; Gervorgyan, V. Sylett 2003, 2265.
(c) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813. (d)
Saito, S. Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (e) Ojima, I.;
Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635. (f)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (g) Fru¨hauf,
H.-W. Chem. ReV. 1997, 97, 523. (h) Hegedus, L. S. Coord. Chem. ReV.
1997, 161, 129. (d) Wender, P. A.; Love, J. A. In AdVances in Cycloaddition;
JAI Press: Greenwich, 1999; Vol. 5, pp 1-45.
J. Org. Chem, Vol. 71, No. 11, 2006 4173

Zhang et al.
TABLE 3. Syntheses of Sulfonyl Substituted Ynamidesa
TABLE 5. Hydrogenations of Ynamides
a Reactions were carried out using 10 mol % CuSO4‚5H2O, 1,10-phen
(2 equiv to copper), and 2.0 equiv of K2CO3 in toluene (0.5-1.0 M based
on amides) at 65-75 °C for 18-36 h. b Isolated yields. c Ns ) 4-nitroben-
zene sulfonyl; Ms ) methane sulfonyl; Bs ) benzene sulfonyl.
TABLE 4. Syntheses of Simple Ynamidesa
a Lindlar catalyst: 5% w/w Pd on CaCO3 support poisoned with Pb.
The mol % here represents the actual amount of Pd present. b All are isolated
yields. All Z:E ratios were determined by 1H NMR. c Quinoline was added.
d Pd on BaSO4.
enamides.2b,8,10,12,22,23 However, given that a diverse array of
ynamides can be prepared via this catalytic amidation, prepara-
tion of enamides via hydrogenations of ynamides, especially
those Z-enamides, which remains challenging kinetically, can
represent a quite attractive option. More significantly, we
pursued this endeavor because enamides represent another
unique functional group that has not been widely studied,22,24,25
and they are frequently found in natural products.26
As shown in Table 5, the concept of preparing a wide range
of Z-enamides via Lindlar hydrogenations of ynamides can be
established. While the yields of these hydrogenations are
generally high as expected, the Z: E ratio is not great in some
special instances (entries 3, 4, 10, and 11). Specifically, we
found that bulky substituents such as TIPS (52b) and Ph (52c)
tend to retard the rate of hydrogenation (entries 3-5), and while
the rate may not play a role in the selectivity, it appears that
the TIPS group presents a problem in attaining high Z-selectivity
(entries 3 and 4), even when the hydrogenation was carried out
at 0 °C. The other instance involved the synthesis enamide 56
(entry 10-12), but we were able to improve its ratio by
a Reactions were carried out using 10 mol % CuSO4‚5H2O, 20 mol %
1,10-phen, and 2.0 equiv of K3PO4 in toluene at 80 °C for 18-36 h.
b Isolated yields.
45). To our delight, a wide range of ynamides with novel
structural features on the alkynes, including propargyl pyrone,
propargyl anilide, propargyl phenol, pyrrolidine, imide, and aryl
were obtained efficiently using the new protocol. A relatively
lower yield was observed on ynamide 40 due to the instability
of the corresponding bromoalkyne. We should note that the
nature of the base is not critical in these amidations.
Finally, the synthesis of simple ynamides such as 46-49 in
which the nitrogen atom is substituted with a simple acetyl or
benzyol group could be achieved in good yields employing
CuSO4‚5H2O and 1,10-phenanthroline with K3PO4 as the base
(Table 4). Although for reasons we are not certain of at this
time, we were unable to prepare ynamides 50-51, ynamides
46-49 should be more versatile given the removable TIPS
group, and we have in part addressed a frequently asked question
whether one can access these simple ynamides in lieu of other
useful ongoing methodological development.
(22) Rappoport, Z. The Chemistry of Enamides in the Chemistry of
Functional Groups; John Wiley and Sons: New York, 1994.
(23) For a recent elegant report on the synthesis of enamides, see: Brice,
J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6, 1845.
(24) For recent applications of the chemistry of enamides, see: (a)
Sivaguru, J.; Saito, H.; Poon, T.; Omonuwa, T.; Franz, R.; Jockusch, S.;
Hooper, C.; Inoue, Y.; Adam, W.; Turro, N. J. Org. Lett. 2005, 7, 2089.
(b) Robiette, R.; Cheboub-Benchaba, K.; Peeters, D.; Marchand-Brynaert,
J.; J. Org. Chem. 2003, 68, 9809. (c) Poon, T.; Turro, N. J.; Chapman, J.;
Lakshminarasimhan, P.; Lei, X.; Jockusch, S.; Franz, B.; Washington, I.;
Adam, W.; Bosio, S. G. Org. Lett. 2003, 4, 4951. (d) Padwa, A.; Danca,
M. D. Org. Lett. 2002, 4, 715. (e) Fuch, J. R.; Funk, R. L. Org. Lett. 2001,
3, 3349. (f) Maeng, J.-H.; Funk, R. L. Org. Lett. 2000, 2, 1125.
(25) For our own work on the chemistry of enamides: see: Xiong, H.;
Hsung, R. P.; Shen, L.; Hahn, J. M. Tetrahedron Lett. 2002, 43, 4449.
(26) Yet, L. Chem. ReV. 2003, 103, 4283.
4. Stereoselective Synthesis of Z-Enamides. One of the
simplest applications of ynamides would be to prepare enamides
via Lindlar-type hydrogenations, which has not been ac-
complished. There had been no real reason to prepare enamides
through this method when ynamides were not readily available,
especially given the existing methods for the synthesis of
4174 J. Org. Chem., Vol. 71, No. 11, 2006

Cu(II)-Catalyzed Amidations of Alkynyl Bromides
SCHEME 5. Z- and E-Enamides
bromides when the tryptamine nitrogen atom was substituted
with a Ts group (tryptamide 60 for entries a-h in Table 6), the
indolyl N-alkynylation products 65a-h, which are inseparable
from ynamides 64a-h, were produced consistently throughout
as minor products with the ratio ranging from 7:1 to 18:1. Only
when employing a stronger electron-withdrawing Ns group, as
shown in tryptamide 61 (entry i), was production of the minor
product 65i completely eliminated. The bis-N-alkynylated
products 66a-i, however, were observed in all cases.
TABLE 6. Competing Amidation in the Indole Seriesa
Intriguingly, our attempt to construct ynamide 64j using the
carbamate-protected tryptamide 62 led to the indolyl N-
alkynylation product 65j exclusively in 62% yield (entry j).
Please note that K2CO3 was chosen as the base to be consistent
with the other entries, and it turned out to be suitable in this
particular amidation. Furthermore, substitutions on the indole
also had a significant effect on the selectivity. The indolyl
N-alkynylation product 65k became the sole dominant product
when N-p-toluenesulfonyl 2-bromotryptamide 63 was employed.
The desired ynamide 64k was not observed at all (entry k).
These selectivities are likely associated with their respective
pKa’s, and the amidation favors the more acidic nitrogen site.
For example, the pKa of aryl sulfonamido-NH is ∼16.1 (in
DMSO),30 while the indolyl-NH is less acidic with a pKa of
21.0 (DMSO),31 Thus, the N-alkynylation favored the aryl
sulfonamide nitrogen atom (entry a-h), and when using the
Ns group, the N-alkynylation of sulfonamide was the only
observed product, presumably because the acidity of Ns-NH is
even higher (entry i). On the other hand, the pKa of a urethane-
NH is approximately 24.8 (in DMSO).30 In this comparison,
the indolyl-NH is now relatively more acidic with a pKa of
∼21.0 (in DMSO),31 the N-alkynylation in this case was
observed to favor the indolyl nitrogen atom (entry j).
%
% yieldsb/ yield
entry indole
X
E
R
products
ratiosc
66a-k
a
b
c
d
e
f
g
h
i
60
60
60
60
60
60
60
60
61
62
63
H
H
H
H
H
H
H
H
H
H
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ns
(CH2)3Cl
(CH2)3OBn
n-Hex
64a, 65a 55/7:1
64b, 65b 69/9:1
64c, 65c 64/12:1
64d, 65d 66/10:1
64e, 65e 63/11:1
64f, 65f 64/18:1
64g, 65g 60/10:1
15
20
NDd
ND
ND
ND
ND
ND
ND
ND
15
n-Bu
Ph
CH2OTBDPS
(CH2)4OTBS
(CH2)2CH(OEt)2 64h, 65h 63/15:1
n-Hex
64i, 65i 55/g25:1
64j, 65j 62/e1:25
64k, 65k 65/e1:25
j
k
CO2Me n-Hex
n-Hex
Br Ts
a Reactions were carried out using 10 mol % CuSO4‚5H2O, 1,10-phen
(2 equiv to copper), and 2.0 equiv of K2CO3 in toluene (0.5-1.0 M based
on amide) at 65-75 °C for 18-36 h. b Isolated yields. c Ratios were
determined using H NMR. d ND ) Yields not determined, for they were
1
generally <5%.
employing quinoline-poisoned Pd-BaSO4 (entry 12). We
believe that the E-isomer is a result of isomerization during the
reaction and/or purification thereafter.
Unfortunately, we could not find the exact pKa of 2-bro-
moindolyl-NH in the literature, but 5-bromo-indolyl-NH is more
than a magnitude more acidic than indolyl-NH,32 and thus,
2-bromo indolyl-NH should approach the pKa of aryl sulfona-
mide-NH or could actually be more acidic, leading to a favored
N-alkynylation of the indolyl nitrogen atom. While mechanisti-
cally we have thus far followed those proposed by Buchwald8,10
in amidation of vinyl halides given the similarity between these
amidations, this selectivity has not been observed before. Thus,
this could provide future mechanistic insights to this copper-
catalyzed N-alkynylation and other related amidation reactions.
6. Intramolecular Amidations. To develop an intramolecular
variant of this amidation,33 we prepared amides 67a and 67b
tethered to the alkynyl bromide motif (Scheme 6). Without much
fanfare, the proposed intramolecular amidation proceeded
smoothly to give 13-membered ring macrocyclic ynamides 68a
and 68b in 80% and 96% yield, respectively, even with the
base being K2CO3. Subsequent hydrogenation of 68a gave
macrocyclic enamide 69a in 95% yield with exclusively
Z-selectivity, thereby establishing in principle that we could
pursue the synthesis of macrocyclic Z-enamide natural products
such as securine B and securamine B18 via this intramolecular
amidation-Lindlar hydrogenation sequence. We were able to
Finally, we were able to employ the push-pull ynamide 57
to demonstrate that both Z- and E-enamide (58 and 59) could
be accessed, respectively, in high selectivity depending upon
the reductive conditions used (Scheme 5).
5. Observation of a Competing N-Alkynylation. It is very
intriguing that a competing N-alkynylation was observed in the
preparation of tryptamide-substituted ynamides. During our
studies toward utilizing ynamides in the natural product
synthesis,4c we needed to prepare a series of tryptamide-
substituted ynamides 64a-k (Table 6), a key precursor for the
subsequent ketene iminium Pictet-Spengler cyclization reaction
en route to total syntheses of indole alkaloids desbromoarbores-
cidine A and C,4c,27-29 However, in our attempts, we found
unexpected competing N-alkynylation from the indolyl nitrogen
atom, leading to ynamides 65 as well as bis-coupled product
66.
Our studies revealed that the relative acidities of the indolyl
NH and amide proton had likely played a significant role in
the amidation reaction. While the desired ynamides 64a-h were
obtained as major products with a range of different alkynyl
(27) (a) For isolation of 10-desbromoarborescidine A, see: Johns, S. R.;
Lamberton, J. A.; Occolowitz, J. L. Aust. J. Chem. 1966, 19, 1951. (b) For
isolation of arborescidine A-D, see: Chbani, M.; Pa¨ıs, M. J. Nat. Prod.
1993, 56 99.
(28) For total syntheses of arborescidine A, see: (a) Hua, D. H.; Bharathi,
S. N.; Panangadan, J. A. K.; Tsujimoto, A. J. Org. Chem. 1991, 56, 6998.
(b) Meyers, A. I.; Sohda, T.; Loewe, M. F. J. Org. Chem. 1986, 51, 3108.
(29) For total syntheses of arborescidine C, see: (a) Burm, B. E. A.;
Meijler, M. M.; Korver, J.; Wanner, M. J. Koomen, G.-J. Tetrahedron 1998,
54, 6135. (b) Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem. 2004,
69, 1283.
(30) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(31) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981,
46, 632.
(32) Mun˜oz, M. A.; Guardado, P.; Hidalgo, J.; Carmona, G.; Balo´n, M.
Tetrahedron 1992, 48, 5901.
(33) For some recent examples of Cu(I)-catalyzed intramolecular ami-
dations, see: (a) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035. (b) Yang, T.; Lin,
C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7, 4781.
J. Org. Chem, Vol. 71, No. 11, 2006 4175

Zhang et al.
SCHEME 6. Intramolecular Amidations
have a significant impact on the future applications of ynamides
in organic synthesis.
Experimental Section
A. For Ynamides from Tables 1-4. To a mixture of an amide
(1.0 equiv), K3PO4 or K2CO3 (2.0 equiv), CuSO4‚5H2O (0.10 equiv),
and 1,10-phenanthroline (0.20 equiv) in a reaction vial was added
a solution of a respective 1-bromoalkyne (1.1 equiv, 1.0 M) in
toluene. The reaction mixture was capped and heated in an oil bath
at 65-75 °C for 32 h while being monitored with TLC analysis.
Upon completion, the reaction mixture was cooled to room
temperature and diluted with EtOAc and filtered through Celite,
and the filtrate was concentrated in vacuo. The crude products were
purified by silica gel flash column chromatography (gradient eluent,
EtOAc in hexane) to afford the desired ynamide.
SCHEME 7. A Chiral Macrocyclic Ynamide
B. For Ynamides of the Indole Series in Table 6. To a mixture
of an amide (1.0 equiv), K3PO4 (1.2 equiv), CuSO4‚5H2O (0.1
equiv), and 1,10-phenanthroline (0.2 equiv) in a reaction vial was
added a solution of respective 1-bromoalkyne (1.2 equiv, 0.66 M)
in DMF/toluene (1/10). The reaction mixture was capped and heated
in an oil bath at 75 °C for 32 h while being monitored with TLC
analysis. Upon completion, the reaction mixture was cooled to room
temperature, diluted with EtOAc, and filtered through Celite, and
the filtrate was concentrated in vacuo. The crude products were
purified by silica gel flash column chromatography (gradient eluent,
EtOAc in hexane) to afford the desired ynamide.
Ynamide 4: [R]20 ) -205.9 (c 2.75, CH2Cl2); IR (thin film)
D
3070 (w), 2966 (w), 2254 (w), 1774 (s), 1596 (m), 1497 (m), 1460
(m), 1403 (s), 1250 (s), 1197 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 3.73 (s, 3 H), 4.32 (dd, 1 H, J ) 7.0, 8.5 Hz), 4.78 (dd, 1 H, J
) 8.5, 8.5 Hz), 5.17 (dd, 1 H, J ) 7.0, 8.5 Hz), 6.81 (t, 1 H, J )
7.5 Hz), 6.82 (t, 1 H, J ) 7.5), 7.18-7.25 (m, 2 H), 7.40-7.48
(m, 5 H); 13C NMR (75 MHz, CDCl3) δ 55.5, 62.1, 69.0, 70.6,
81.5, 110.5, 111.2, 120.1, 126.8, 129.0, 129.2, 129.4, 133.2, 136.0,
155.3, 159.7; mass spectrum (APCI) m/e (% relative intensity) 294
(14) (M + H)+, 268 (100), 250 (5), 120 (4); HRMS (ESI) calcd
for C18H15NO3Na 316.0944, found 316.0946.
Ynamide 34: IR (film) 2955 (s), 2930 (s), 2859 (s), 2048 (s),
1686 (w), 1471 (w), 1090 (m) cm-1; 1H NMR (300 MHz, CD2Cl2)
δ 0.04 (s, 6 H), 0.89 (s, 9 H), 1.20-1.57 (m, 8 H), 1.73-1.86
(quint, 2 H, J ) 6.6 Hz), 2.25 (t, 2 H, J ) 6.9 Hz), 2.43 (s, 3 H),
3.36 (t, 2 H, J ) 6.6 Hz), 3.63 (t, 2 H, J ) 6.3 Hz), 7.32 (d, 2 H,
J ) 8.1 Hz), 7.78 (d, 2 H, J ) 8.1 Hz); 13C NMR (75 MHz, CD2-
Cl2) δ -5.7, 14.1, 18.3, 18.5, 21.6, 22.6, 25.9, 28.5, 28.9, 31.0,
31.4, 48.6, 59.8, 70.2, 73.2, 127.7, 129.6, 134.6, 144.3; mass
spectrum (ESI) m/e (% relative intensity) 474.3 (100) (M + Na)+,
452.3 (18) (M + H)+; HRMS (ESI) calcd for C24H41NO3SSiNa
474.2469, found 474.2473.
explore the scope of this intramolecular amidation by preparing
a nine-membered ring (70) all the way up to a 19-membered
ring system (74), although yields began to diminish with
increasing entropy.
While this intramolecular amidation should find applications
in natural products syntheses, we prepared a chiral macrocyclic
ynamide 79 and its corresponding macrocyclic enamide 80 from
S-binol in good overall yields, employing a general sequence
for the preparations of most of aforementioned amidation
precursors (Scheme 7). These 16-membered chiral macrocyclic
amides possess high optical rotations, and these rotations
progressively increased from the acyclic compound (see 78) to
the Z-enamide 80. This exercise suggests that the intramolecular
amidation may find utilities in synthesizing structurally interest-
ing macrocyclic materials for non-natural product oriented
endeavors.
Ynamide 46: Rf ) 0.50 (20% EtOAc in hexane); 1H NMR (300
MHz, CDCl3) δ 1.09 (s, 21H), 2.35 (s, 3H), 3.15 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 11.1, 18.4, 22.0, 35.8, 69.7, 99.6, 172.3; IR
(thin film) 2944 (s), 2866 (s), 2171 (s), 1707 (s), 1463 (m) cm-1
;
HRMS (EI) calcd for C14H28NOSi (M + H+) 254.1935, found
254.1932.
Ynamide 64a: IR (thin film) 3414 (s), 3056 (w), 2924 (m), 2254
(m), 1597 (m), 1493 (w), 1457 (m), 1428 (w), 1354 (s), 1186 (w),
1
1166 (s), 1092 (m) cm-1; H NMR (300 MHz, CDCl3) δ 1.96 (q,
J ) 6.6 Hz, 2 H), 2.46 (s, 3 H), 2.53 (t, J ) 6.6 Hz, 2 H), 3.13 (t,
J ) 7.5 Hz, 2 H), 3.64 (m, 4 H), 7.12-7.42 (m, 6 H), 7.59 (d, J )
7.8 Hz, 1 H), 7.76 (d, J ) 8.4 Hz, 2H), 8.04 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 15.8, 21.5, 24.0, 31.3, 43.5, 51.6, 68.4, 74.0, 111.1,
111.6, 118.4, 119.4, 122.0, 122.2, 127.1, 127.4, 128.9, 134.5, 136.1,
144.3; mass spectrum (APCI) m/e (% relative intensity) 413(100)
(M+H)+; HRMS (ESI) calcd for C22H23ClN2O2SNa 437.1061,
found 437.1070.
Conclusion
We have developed highly useful copper(II) salt catalyzed
inter- and intramolecular amidations of alkynyl bromides that
provide a general entry to a diverse array of ynamides. Given
the emerging interest in ynamides, this synthetic protocol should
Ynamide 65j: IR (film) 3338 (brs), 2931 (s), 2858 (m), 2264
(m), 1723 (s), 1704 (s), 1530 (m), 1461 (m), 1256 (m), 1233 (m)
1
cm-1; H NMR (300 MHz, CD2Cl2) δ 1.01 (t, 3 H, J ) 6.9 Hz),
4176 J. Org. Chem., Vol. 71, No. 11, 2006

Cu(II)-Catalyzed Amidations of Alkynyl Bromides
1.38-1.78 (m, 8 H), 2.54 (t, 2 H, J ) 6.9 Hz), 2.97 (t, 2 H, J )
6.6 Hz), 3.53 (q, 2 H, J ) 6.6 Hz), 3.68 (s, 3 H), 5.05 (s, 1 H),
7.09 (s, 1 H), 7.26 (ddd, 1 H, J ) 0.9, 7.2, 8.1 Hz), 7.38 (ddd, 1
H, J ) 0.9, 7.2, 8.1 Hz), 7.58 (dt, 1 H, J ) 8.1, 0.9 Hz), 7.64 (d,
1 H, J ) 8.1 Hz); 13C NMR (75 MHz, CD2Cl2) δ 13.7, 18.2, 22.4,
25.3, 28.4, 28.9, 31.2, 40.7, 51.6, 70.0, 71.5, 110.9, 114.9, 118.9,
121.0, 123.2, 126.4, 127.2, 138.6, 156.8; mass spectrum (ESI) m/e
(% relative intensity) 349.3 (100) (M + Na)+, 327.3 (4) (M + H)+;
HRMS (ESI) calcd for C20H26N2O2Na 349.1886, found 349.1877.
Ynamide 66a: IR (thin film) 3060 (w), 2960 (m), 2925 (m),
2872 (w), 2264 (m), 1597 (m), 1464 (m), 1363 (m), 1168 (m),
for another day or two. Then the reaction mixture was cooled to
room temperature and filtered. The filtrate was concentrated under
reduce pressure. The crude residue was purified via silica gel
column chromatography (using EtOAc/hexane as eluent) to give
the desired product 68a in 80% yield.
Ynamide 70: Rf ) 0.46 (33% EtOAc in hexanes); IR (film)
3032 (w), 2959 (s), 2926 (m), 2854 (w), 2237 (m), 1710 (s), 1498
(w), 1400 (m), 1295 (m), 1261 (w), 1236 (m), 1130 (m), 1038 (m),
1
1020 (w) cm-1; H NMR (500 MHz, CD2Cl2) δ 2.53 (t, 2 H, J )
7.0 Hz), 2.60-2.63 (m, 2 H), 3.80-3.94 (m, 2 H), 4.40-4.80 (br,
2 H), 5.18 (s, 2 H), 7.36-7.43 (m, 5 H); 13C NMR (125 MHz,
CD2Cl2) δ 18.9, 33.2, 48.9, 64.8, 68.7, 77.0, 78.5, 128.2, 128.4,
128.6, 135.6, 153.5, 174.0; mass spectrum (ESI) m/e (% relative
intensity) 296.1 (100) (M + Na)+; HRMS (ESI) calcd for C15H15-
NO4Na 296.0893, found 296.0889.
1
1119 (m), 1092 (m) cm-1; H NMR (500 MHz, CDCl3) δ 1.89-
1.96 (m, 2 H), 2.07-2.13 (m, 2 H), 2.43 (s, 3 H), 2.49 (t, 2 H, J
) 7.2 Hz), 2.70 (t, 2 H, J ) 7.2 Hz), 3.04 (t, 2 H, J ) 7.2 Hz),
3.58-3.63 (m, 4 H), 3.76 (t, 2 H, J ) 6.5 Hz), 6.94 (s, 1 H), 7.20
(t, 1 H, J ) 8.0 Hz), 7.25 (d, 2 H, J ) 8.0 Hz), 7.31 (t, 1 H, J )
8.0 Hz), 7.47 (d, 1 H, J ) 8.0 Hz), 7.51 (d, 1H, J ) 8.0 Hz), 7.66
(d, 2 H, J ) 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 16.0, 16.1,
21.7, 23.9, 31.5, 43.6, 43.7, 51.2, 68.2, 68.9, 72.7, 74.0, 111.2,
113.7, 118.9, 121.4, 123.5, 126.8, 127.1, 127.4, 129.6, 134.6, 138.4,
144.4; mass spectrum (ESI) m/e (% relative intensity) 537 (100)
(M + Na)+, 539 (80), 515 (15) (M + H)+; HRMS (ESI) calcd for
C27H28Cl2N2O2SNa 537.1141, found 537.1153.
Ynamide 68a: Rf ) 0.41 (33% EtOAc in hexanes); IR (thin
film) 2943 (m), 2259 (w), 1724 (s), 1450 (w), 1285 (m) cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.53-1.64 (m, 2 H), 1.64-1.79 (m, 4
H), 1.87-1.98 (m, 2 H), 2.48-2.67 (m, 4 H), 3.52 (t, 2 H, J ) 6.0
Hz), 4.25 (t, 2 H, J ) 5.1 Hz), 5.24 (s, 2 H), 7.30-7.48 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 17.4, 21.5, 21.7, 25.5, 26.7, 32.6,
48.6, 63.2, 67.9, 68.4, 74.8, 127.4, 127.9, 128.4, 136.0, 155.7, 173.4;
mass spectrum (APCI) m/e (% relative intensity) 330 (18) (M+1)+,
304 (21), 286 (100), 214 (38), 196 (12); HRMS (EI) calcd for
C19H23NO4Na (M + Na+) 352.1519, found 352.1523.
Diels-Alder Cycloadditions. AgSbF6 (7.6 mg, 0.022 mmol)
was added to a solution of RhCl(PPh3)3 (20.5 mg, 0.022 mmol) in
dry toluene (4.6 mL) under nitrogen. After stirring for 30 min at
room temperature, ynamide 13 (29.0 mg, 0.11 mol in 1 mL dry
toluene solution) was added and the reaction mixture was stirred
at room temperature. After TLC showed all ynamide 13 was
consumed, the reaction mixture was filtered through a small plug
of Celite, the solvent was evaporated, and the resulting crude
product was purified by column chromatography (Al2O3, III/N,
Ynamide 79: Rf ) 0.44 (33% ethyl acetate in hexanes); [R]20
D
) -136.8 (c 0.67, CHCl3); IR (film) 2941 (m), 1755 (s), 1733 (s),
1652 (m), 1558 (m), 1243 (m), 1213 (m) cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.03-1.12 (m, 1 H), 1.48-1.58 (m, 2 H), 1.76-1.98
(m, 2 H), 2.07-2.16 (m, 1 H), 2.22-2.39 (m, 1 H), 2.45-2.55
(m, 1 H), 3.27-3.37 (m, 1 H), 3.68-3.79 (m, 1 H), 3.95-4.03
(m, 1 H), 4.36-4.46 (m, 1 H), 5.21 (s, 2 H), 7.06 (d, 1 H, J ) 8.0
Hz), 7.15 (d, 1 H, J ) 8.0 Hz), 7.14-7.48 (m, 10 H), 7.83 (d, 2 H,
J ) 8.0 Hz), 7.92-8.00 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ
17.5, 21.2, 22.9, 28.0, 32.6, 46.5, 64.4, 68.2, 80.8, 111.7, 113.6,
117.3, 121.7, 123.6, 125.1, 125.4, 125.5, 126.2, 126.5, 126.6, 127.0,
127.6, 128.1, 128.2, 128.6, 128.7, 129.0, 129.9, 131.7, 133.8, 133.9,
146.8, 154.0, 171.6; mass spectrum (ESI) m/e (% relative intensity)
592.2 (100) (M + Na)+; HRMS (ESI) calcd for C37H31NO5Na
592.2094, found 592.2108.
gradient eluent). 30: Rf ) 0.40 (33% EtOAc in hexanes); [R]20
D
) -17.8 (c 0.61, CHCl3); IR (film) 3033 (w), 2959 (m), 2924 (m),
2856 (m), 2814 (w), 1762 (s), 1704 (m), 1454 (m), 1382 (m), 1258
1
(m), 1119 (m), 1017 (m) cm-1; H NMR (500 MHz, CDCl3) δ
0.88 (t, 3 H, J ) 7.0 Hz), 1.23-1.54 (m, 9 H), 2.18-2.32 (m, 3
H), 2.56-2.63 (m, 1 H), 2.69-2.73 (m, 1 H), 3.12-3.22 (m, 1 H),
4.17-4.25 (m, 2 H), 4.50 (t, 1 H, J ) 8.0 Hz), 5.80 (d, 1 H, J )
9.0 Hz), 5.83-5.88 (m, 1 H); 13C NMR (125 MHz, CDC3) δ 14.2,
22.7, 27.9, 29.4, 31.4, 31.9, 33.9, 35.7, 41.8, 60.6, 66.1, 118.7,
126.3, 128.3, 131.4, 156.9; mass spectrum (ESI) m/e (% relative
intensity) 284.2 (100) (M + Na)+; HRMS (ESI) calcd for C16H23-
NO2Na 284.1621, found 284.1630.
Intramolecular Amidations. To a solution of bromide 67a (41
mg, 0.1 mmol) obtained above in 20 mL of dry toluene were added
K3PO4 (43 mg, 0.2 mmol) or K2CO3 (28 mg, 0.2 mmol),
CuSO4‚5H2O (2.5 mg, 0.01 mmol), and 1,10-phenanthroline (3.7
mg, 0.02 mmol). After the reaction mixture was refluxed for 24 h,
1.2 mg of CuSO4‚5H2O and 1.8 mg of 1,10-phenanthroline were
added. After reflux for another 24 h, 1.2 mg of CuSO4‚5H2O and
1.8 mg of 1,10-phenanthroline were added and reflux continued
Acknowledgment. TheauthorsthankNIH-NIGMS(GM066055)
and NSF (CHE-0094005) for generous support. This work was
in most part carried out at the University of Minnesota. We
thank Profs. Richard Larock and Paul Wender for invaluable
discussions on the utility of simple ynamides.
Supporting Information Available: Experimental procedures,
NMR spectra, and characterizations for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO060230H
J. Org. Chem, Vol. 71, No. 11, 2006 4177