Sonogashira cross-couplings of ynamides. Syntheses of urethane- and sulfonamide-terminated conjugated phenylacetylenic systems

Article abstract of DOI:10.1021/ol0493251

The first successful Sonogashira coupling of ynamides with aryl and vinyl iodides is described here. This study resolves the problem of the competing pathway involving homocoupling of ynamides and provides a practical entry to novel urethane- or sulfonami

Full text of DOI:10.1021/ol0493251

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2209-2212
Sonogashira Cross-Couplings of
Ynamides. Syntheses of Urethane- and
Sulfonamide-Terminated Conjugated
Phenylacetylenic Systems
Michael R. Tracey, Yanshi Zhang, Michael O. Frederick, Jason A. Mulder, and
Richard P. Hsung*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received April 13, 2004
ABSTRACT
The first successful Sonogashira coupling of ynamides with aryl and vinyl iodides is described here. This study resolves the problem of the
competing pathway involving homocoupling of ynamides and provides a practical entry to novel urethane- or sulfonamide-terminated conjugated
acetylenic systems. An interesting tandem hydrohalogenation and Sonogashira coupling was also observed to give an en-ynamide.
Ynamides have become useful synthons in organic synthe-
sis.1,2 Our efforts3 have led to the development of a
Cu-catalyzed N-alkynylation as a practical synthesis of
ynamides 3.4 These endeavors5 have provided access to
terminally unsubstituted ynamides 4, thereby allowing vari-
ous explorations of functionalization of this unique terminal
acetylenic carbon. Thus far, the only uncovered reactivities
have involved additions of electrophiles such as MeI to the
lithiated ynamide 4 reported by our group4b and addition of
BuBr reported by Witulski2i and, recently, a Glaser-type
coupling reported by Saa´.2a We recognized that a potentially
more important reaction would be the utility of ynamides 4
in transition metal-mediated cross-coupling reactions such
as Sonogashira coupling,6,7 which has not been reported,
(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. Engl. 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. (f) Wei, L.-L.;
Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P.
Tetrahedron 2001, 57, 459.
(4) For our syntheses of ynamides using copper-catalyzed amidations
of alkynyl bromides, see: (a) Zhang, Y.; Hsung R. P.; Tracey, M. R.; Kurtz,
K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151. (b) 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.
(2) For recent efforts in synthesis and applications of ynamides, see: (a)
Rodr´ıguez, D.; Castedo, L.; Saa´, C. Synlett 2004, 377. (b) Hirano, S.; Tanaka,
R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727. (c) Klein, M.; Ko¨nig, B.
Tetrahedron 2004, 60, 1087. (d) Marion, F.; Courillon, C.; Malacria, M.
Org. Lett. 2003, 5, 5095. (e) Witulski, B.; Alayrac, C.; Tevzaadze-Saeftel,
L. Angew. Chem., Int. Ed. 2003, 43, 4392. (f) Tanaka, R.; Hirano, S.; Urabe,
H.; Sato, F. Org. Lett. 2003, 5, 67. (g) Witulski, B.; Lumtscher, J.;
Bergstra¨sser, U. Synlett 2003, 708. (h) Naud, S.; Cintrat, J.-C. Synthesis
2003, 1391. (i) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41,
3281. (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 citations appearing before 2001, see ref 1a,b.
(5) For two related accounts involving synthesis of ynamides using copper
metal, see: (a) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
(b) Also see ref 2b for CuI-catalyzed N-alkynylations reported by Urabe
and Sato.
10.1021/ol0493251 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004

Scheme 1
Scheme 2
differ only in the C-terminal substituents. We report here
findings using ynamides 4 in Sonogashira couplings as an
approach to conjugated phenylacetylenic systems.
The feasibility of Sonogashira coupling was readily
established as shown in Scheme 2. We did not observe here
homocoupling of ynamide 9, which is an urethane-based
ynamide, as reported in the literature for sulfonyl-substituted
ynamides.2c,8 The coupling reaction of ynamide 9 with
iodobenzene using 10 mol % of Pd(Ph3P)4 and 7 mol % of
CuI in i-Pr2NH/toluene (2:1) at room temperature led to the
formation of the desired phenyl-substituted ynamide 1014 in
93% yield (Scheme 2). Although both CuCN and CuI appear
to be feasible for the Sonogashira coupling, as expected,
iodobenzene coupled much faster than bromobenzene.15
The generality of this Sonogashira coupling with various
aryl iodides is displayed in Table 1. The main features are
except two independent documentations of unsuccessful
attempts.2c,8 As an alternative, Saa´8 did report recently the
use of zinc sulfonamido-acetylides, generated in situ from
â,â′-dichloro-enamides, in Negishi-type couplings. However,
the Sonogashira protocol still represents the most efficient
and straightforward cross-couplings of any terminal alkynes.6,7
These cross-coupling reactions should lead to the preparation
of conjugated systems9 such as 7 and 8 that can be useful in
developing new materials given the significance of conju-
gated rigid rods molecular electronics9,10 and self-assembly.11-13
In addition, although the copper-catalyzed amidation of
alkynyl iodides4,5 is a viable approach for constructing these
ynamides, a successful Sonogashira coupling would provide
not only a complimentary protocol but also, more impor-
tantly, an entry that is more versatile and practical when one
intends to design and synthesize a library of ynamides that
Table 1.
(6) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. For reviews on Heck couplings, see: (b) Hegedus, L. S.
Tetrahedron 1984, 40, 2415.
(7) For reviews, see: (a) Collman, J. P.; Hegedus, L. S.; Norton, J. R.;
Finke, R. G. In Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, CA, 1987. (b) Negishi,
E. Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley-
Interscience: New York, 2002; Vol I, p 7. (c) Sonogashira, K. Cross-
coupling reactions to sp carbon atoms. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCh: New York, 1998;
pp 203-229.
(8) During our pursuit of Sonogashira couplings, Saa´ reported an
alternative Negishi coupling of sulfonyl ynamides and also documented
the lack of feasibility in related Sonogashira coupling. See: Rodr´ıguez,
D.; Castedo, L.; Saa´, C. Synlett 2004, 783.
(9) For reviews, see: (a) Ahmed, H. J. Vac. Sci. Technol., B 1997, 15,
2101. (b) Petty, M. C.; Bryce, M. R.; Bloor, D. Introduction to Molecular
Electronics; Oxford University Press: New York, 1995. (c) Molecular
Electronics and Molecular Electronic DeVices; Sienicki, K., Ed.; CRC
Press: Boca Raton, 1992; Vols. I-III. (d) Mirkin, C. A.; Ratner, M. A.
Molecular electronics. Annu. ReV. Phys. Chem. 1992, 43, 719.
(10) Also see: (a) Wada, Y. Surf. Sci. 1997,386. 265. (b) Reimers, J.
R.; Lu, T. X.; Crossley, M. J.; Hush, N. S. Nanotechnology 1996, 7, 424.
(c) Conjugated Conducting Polymers; Springer Series in Solid-State
Sciences, no. 102; Kiess H., Ed.; Springer-Verlag: Berlin, 1992.
(11) (a) Dubois, L. H.; Nuzzo, R. G. Annu. ReV. Phys. Chem. 1992, 43,
437. (b) Ulman, A. Chem. ReV. 1996, 96, 1533.
a Reactions were carried out using 10 mol % Pd(Ph3P)4 and 7 mol %
copper salt in i-Pr2NH/toluene (2:1) except for entries 1 and 7. b Isolated
yields. c In entries 1 and 7, 10 mol % PdCl2(Ph3P)2 was used. d The same
result as in Scheme 2. e 1-Bromo-1-hexyne was used.
(12) For some recent examples, see: (a) Zhang, J.: Pesak, D. J.; Ludwick,
J. L.; Moore, J. S. J. Am. Chem. Soc. 1994, 116, 4227. (b) Scherf, U.;
Mu¨llen, K. Synthesis 1992, 23. (c) Tour, J. M.; Jones, L., II; Pearson, D.
L.; Lamba, J. J. S.; Burgin, T. P.; Whitesides, G. V.; Allara, D. L.; Parikh,
A. N.; Atre, S. V. J. Am. Chem. Soc. 1995, 117, 9529.
(13) (a) Dhirani, A.-A.; Zehner, W. R.; Hsung, R. P.; Guyot-Sionnest,
P.; Sita, L. R. J. Am. Chem. Soc. 1996, 118, 3319. (b) Sandra, S. B.; Dudek,
S. P.; Hsung, R. P.; Sita, L. R.; Smalley, J. F.; Newton, M. D.; Feldberg,
S. W.; Chidsey, C. E. D. J. Am. Chem. Soc. 1997, 119, 10563. (c) Zehner,
R. W.; Parsons, B. F.; Hsung, R. P.; Sita, L. R. Langmuir 1999, 15, 1121.
as follows: (1) PdCl2(Ph3P)2 was less effective in catalyzing
these couplings than Pd(Ph3P)4 (respectively, entry 1 versus
entries 2 and 3 (or see Scheme 2), and entries 7 versus 8),
and thus only Pd(Ph3P)4 was used throughout this study. (2)
(14) Relevant procedures for new compounds and their characterizations
are in Supporting Information.
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Org. Lett., Vol. 6, No. 13, 2004

Scheme 3
Scheme 4
We suspected that en-ynamide 17 was derived from the
Sonogashira coupling of ynamide 9 with R-iodo-enamide 18,
which was likely a result of addition of HI to 9 on the basis
of what we had previously observed in the formation of
R-iodo-enamides via hydrohalogenation of ynamides using
metal halides.3c,4a Because CuI was shown not to give any
hydrohalogenation products,3c we further suspected that it
could be the presence of untrapped HI, produced in the
coupling reaction.
However, when measures were taken to reduce HI by
using Et3N as solvent, en-ynamide 17 was found as the sole
product, or when Hu¨nig’s base was used as solvent or as a
cosolvent with THF (1:1), 16 and 17 were isolated with a
1:1 ratio. Further experiments also suggest that alkylammo-
nium iodide salts do not hydrohalogenate ynamides to the
corresponding R-iodo-enamide. These preliminary findings
imply that palladium associated intermediates might be
involved in the process of either yielding 18 or going directly
to 17. We are currently further examining this issue.
Having established this Sonogashira coupling protocol, we
turned our attention to sulfonyl-substituted ynamides, and
consequently, we encountered similar difficulties as those
reported in the literature2c,8 using sulfonyl-substituted yna-
mide 19 as shown in Scheme 4. The same protocol (see
Method A), used in coupling of ynamide 9, was not useful
for 19, leading to phenyl-substituted ynamide 20 in only 20%
yield with the major product being the homocoupling (or a
Glaser-type coupling) of 19.2a,c,8
CuCN and CuI did not always provide comparable outcome
(entries 2 versus 3, entries 5 versus 6, and entries 9 versus
10), and we are not exactly sure as to the reason for this
inconsistency. In addition, a cross-Glaser-type coupling16
could be readily achieved using 1-bromo-1-hexyne (entry
11).
More interestingly, when using an ortho-substituted aryl
iodide such as o-iodo-anisole, the rate of coupling was
slowed, requiring the reaction temperature to be raised to
afford the desired product 16 (Scheme 3). We obtained an
X-ray structure of ynamide 16 (Figure 1), which represents
Fortuitously, only a minor tweaking to the conditions was
necessary (see Method B). The addition of the copper catalyst
was carried out after premixing ynamide 19 and iodobenzene
with the palladium catalyst, although at a much reduced
amount at 1.5 mol % (the range was 0.3-1.5 mol %) instead
of the original 7 mol %, and the temperature was also raised
to 65 °C.15 These minor changes in the reaction conditions
led to 20 in 60% yield with the homocoupling pathway being
mostly suppressed.
Figure 1.
the first crystal structure obtained for an ynamide.17 Although
the desired coupling product 16 was isolated in 46% yield
using CuI, we also found 20% of en-ynamide 17, which was
found to be the major product when using CuCN.
(15) Typical Procedure, Method A. See the Supporting Information.
Typical Procedure, Method B. To a reaction flask were added 428.0 mg
of ynamide 19 (1.5 mmol), 497.0 mg of ethyl 4-iodobenzoate (1.8 mmol),
86.0 mg of Pd(PPh3)4 (0.075 mmol, 5 mol %), 8 mL of TEA, and 4 mL of
toluene. The solution was stirred at room temperature for 10 min, and 4.3
mg of CuI (1.5 mol %) was then added. After heating the reaction mixture
at 60 °C for 2 h, the mixture was diluted with EtOAc, filtered through
Celite, and concentrated in vacuo. The resulting crude residue was purified
by silica gel flash column chromatography (gradient 10% to 20% EtOAc
in hexanes) to afford 473.0 mg (73% yield) of aryl ynamide 22.
(16) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. (b) For a review
see: Cadiot, P.; Chodkiewicz, W. Coupling of acetylenes. In Chemistry of
Acetylenes; Viehe, H. G., Ed.; Marcel Dekker: New York, 1969; pp 597-
647. (c) For a recent review, see: Siemsen, P.; Livingston, R. C.; Diederich,
F. Angew Chem., Int. Ed. 2000, 39, 2632.
(17) The X-ray structure reveals that there is a slight bend along the
acetylenic axis (N1-C10-C11-C12). More interestingly, the two planes
of the o-methoxyphenyl ring and the oxazolidinone ring have an approximate
dihedral angle of ∼79.9°, which is almost orthogonal as shown in the
ChemDraw reproduction.
Org. Lett., Vol. 6, No. 13, 2004
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Scheme 5
Table 2.
moderate yields, albeit 15 mol % of CuI was needed. Vinyl
bromide again was very slow and did not couple well.
Finally, to take measures toward establishing the concept
of constructing an extended conjugated phenylacetylenic
system that terminates with an amide group, we prepared
aryl iodide 32 (Scheme 5),19 and its coupling with ynamide
19 led to the isolation of TMS-capped acetylene 33 in 44%
yield with about 80% conversion. Subsequent desilylation
using K2CO3 and MeOH and a second Sonogashira coupling
of the resulting ynamide 34 with p-nitro-iodobenzene gave
the conjugated phenylacetylene 35 in 80% yield.
We have described here the first successful Sonogashira
coupling of ynamides with aryl and vinyl iodides. Our
coupling protocol circumvents the problem of competing
homocoupling of ynamides and provides a practical entry
to novel urethane- and sulfonamide-terminated conjugated
acetylenic systems. Applications of this method in prepara-
tion of new materials and other synthetic applications are
currently underway.
a All reactions employed Method B. b Isolated yields. c The reaction was
run at room temperature. d 15 mol % CuI was used, and reaction was run
at room temperature.
The minor tweaking of the reaction conditions to render
the Sonogashira coupling feasible is noteworthy. Although
Ko¨nig2c did not comment on specific conditions in their
Sonogashira attempts, Saa´8 reported that under similar
conditions (PdCl2(Ph3P)2 was used), the Sonogashira coupling
of the sulfonyl ynamide (they used Ts(Ph)NCtCH) led to
complex mixture with homocoupling as the major pathway.
We used ynamide 19 with a Bn substituent on the nitrogen
atom because we had speculated that it could be a substituent
effect, and in addition, we avoided PdCl2(Ph3P)2 since Pd-
(Ph3P)4 was better a catalyst in our study. However, the fact
that we encountered the same outcome suggests that it was
likely not due to the difference in substituents or the nature
of Pd catalysts.
Therefore, a successful Sonogashira coupling of sulfonyl
ynamide 19 was achieved by effectively delaying the addition
of the copper catalyst, which implies that there is an order
of the event. It can be suggested that this delay avoids a
quick buildup of the copper-acetylide species, which can be
funneled toward the homocoupling pathway. Concomitantly,
having a sufficient amount of presence of the oxidative-
addition intermediate derived from iodobenzene and Pd-
(Ph3P)4 prior to the addition of the copper catalyst allows
the transmetalation to compete more effectively with the
homocoupling for the available copper-acetylide species.18
This new protocol (Method B) proved to be general for
preparations of various aryl-substituted sulfonyl ynamides
(Table 2). Most notably in Table 2, we were able to construct
a series of heteroaryl-substituted ynamides 23-26 (entries
3-6) and succeeded in coupling 19 with vinyl iodides,
providing en-ynamides 27 and 28 (entries 7 and 8) in
Acknowledgment. The authors thank the NSF (CHE-
0094005) for support. We are grateful to Dr. Victor G. Young
for providing single-crystal X-ray structural analysis.
Supporting Information Available: Experimental details
and 1H NMR spectral, characterizations, and X-ray data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0493251
(18) We are not certain as to why urethane-substituted ynamide 9 does
not suffer to the same extent from the problem of homocoupling, with no
need in controlling the addition order. However, from our available
experiences now working with both urethane- and sulfonyl-substituted
ynamides, the latter appears to be much more reactive than the former.
Method B is also suitable for preparing these urethane-substituted ynamides
(19) (a) Hsung, R. P.; Babcock, J. R.; Chidsey, C. E. D.; Sita, L. R.
Tetrahedron Lett. 1995, 36, 4525. (b) Hsung, R. P.; Chidsey, C. E. D.;
Sita, L. R. Organometallics 1995, 14, 4808. (c) Lavastre, O.; Ollivier, L.;
Dixneuf, P. H.; Sibandhis, S. Tetrahedron 1996, 52, 5495.
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Org. Lett., Vol. 6, No. 13, 2004