Synthesis of disubstituted ynamides from β,β-dichloroenamides and electrophiles

Article abstract of DOI:10.1055/s-2007-984529

Treatment of β,β-dichloroenamides with n-butyllithium, followed by addition of an electrophile, provides disubstituted ynamides in far greater yield than direct functionalization of terminal ynamides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984529

LETTER
1963
Synthesis of Disubstituted Ynamides from b,b-Dichloroenamides and
Electrophiles
D
isubstitutedYnam
a
ides from
v
D
ichloroena
i
mides
a
d
nd Electrophiles Rodríguez, M. Fernanda Martínez-Esperón, Luis Castedo, Carlos Saá*
Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax +34(98)1595012; E-mail: qocsaa@usc.es
Received 27 April 2007
was obtained in only 45%, 51% and 53% yield, respec-
Abstract: Treatment of b,b-dichloroenamides with n-butyllithium,
tively (entries 1, 2, and 3). The best yield, 70%, was
achieved with LDA as deprotonating agent (entry 4),
followed by addition of an electrophile, provides disubstituted yn-
amides in far greater yield than direct functionalization of terminal
somehow indicating that the metalation of terminal
ynamides is incomplete.8 Attempts to apply this procedure
to other electrophiles, e.g. benzaldehyde, were discourag-
ing, ynamide 5b being isolated in only 36% yield in the
most favorable conditions (entry 5).
ynamides.
Key words: alkynes, dihaloenamides, disubstituted ynamides
Ynamides have emerged as potentially more useful than
ynamines1 for organic synthesis because of their superior
thermal stability, and their preparation has accordingly
attracted renewed interest.2–4 The most recent methods,
which involve the copper-promoted or copper-catalyzed
coupling of amides with alkynyl bromides 12 require the
preparation of a different alkynyl bromide for each de-
1. base, THF
Ts
Ts
–78 °C
N
N
E
2. electrophile
r.t.
Ph
Ph
5a E = TMS
5b E = CH(OH)Ph
4
sired ynamide (path A in Scheme 1). For the synthesis of Scheme 2
(hetero)aryl ynamides, palladium-catalyzed cross-cou-
pling strategies have been applied (path B in Scheme 1),
the Negishi procedure by our group5 and the Sonogashira
procedure by Hsung.6 However, the synthesis of nonaryl-
substituted derivatives starting from terminal ynamides 3
has not been explored thoroughly. To our knowledge,
there have been a few isolated reports of the introduction
of alkyl chains using metalated ynamides, with reaction
yields ranging from 30% to 60%.7 Considering that termi-
nal ynamides can easily be prepared at gram scale,3b,c we
envisaged that the development of a reliable path-B pro-
cedure for the introduction of nonaromatic substituents
would be a desirable complement to path A for the prepa-
ration of novel families of ynamides.
Table 1 Preparation of Ynamides 5a and 5b Starting from
Ynamide 4a
Entry
Base
Electrophile
TMSCl
Yield (%)b
1
2
3
4
5
n-BuLi
KHMDS
EtMgBr
LDA
45
51
53
70
36
TMSCl
TMSCl
TMSCl
LDA
PhCHO
a Reactions were carried out using THF as solvent, 1.1 equiv of base
and 2 equiv of electrophile.
b Isolated yield after column chromatography.
R1
EWG
R1
EWG
R1
EWG
Br
N
N
N
M = Pd(II)
H
At this point we reconsidered our objectives and decided
to explore the versatility of b,b-dichloroenamide 6, which
in previous work5d had been transformed into 5a in 78%
yield by treatment with n-Buli and entrapment of the re-
sulting acetylide with TMSCl (Scheme 3).9,10 Probably,
the mechanism involves halogen–metal exchange as had
been suggested by Brückner.3b,c
R2I
Cu(I) or Cu(II)
path A
R2
R2
H (ZnBr)
3
path B
1
2
Scheme 1
We began by studying the silylation of model ynamide 4,
treating it with a strong base followed by TMSCl
(Scheme 2). Surprisingly, the reaction proceeded smooth-
ly but the yields were only moderate (Table 1): when n-
BuLi, KHMDS, or EtMgBr was used as base, ynamide 5a
Ts
1. n-BuLi, THF
Ts
–78 °C
N
N
E
Ph
Cl
2. electrophile
r.t.
Ph
Cl
6
Scheme 3
SYNLETT 2007, No. 12, pp 1963–1965
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4
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-984529; Art ID: G10107ST
© Georg Thieme Verlag Stuttgart · New York

1964
D. Rodríguez et al.
LETTER
Ts
With benzaldehyde as electrophile, the reaction of
Scheme 3 afforded 5b in much better yield (88%) than
starting from ynamide 4 (Table 2, entry 2). Similarly,
methyl ynamide 5c was obtained in 74% yield by trapping
the acetylide intermediate with dimethyl sulfate (entry
3),11 and trapping with acetic anhydride, ethyl chloro-
formate, or carbon dioxide afforded the corresponding
push–pull ynamides 5d–f in excellent yields (entries 4, 5.
and 6). tert-Butyl isocyanate and diethyl chlorophosphate
(entries 7 and 8) gave ynamides with previously un-
reported substitution patterns.12
N
Si
Ts
Ph
1. n-BuLi
N
Ph
Cl
2. Cl2SiMe2
63%
Ts
N
Cl
Ph
6
9
Scheme 5
Finally, to exemplify the utility of the products of this new
methodology, the novel ynamides 5c and 8c were smooth-
ly transformed into their corresponding bromoenamides,
10a and 10b, under the reaction conditions recently re-
ported by Hsung17 (Scheme 6).
Table 2 Preparation of Ynamides 5 Starting from Dichloro-
enamide 6a
Entry
Electrophile
TMSCl
Ynamide 5
Yield (%)b
Ts
Ts
Br
MgBr2
N
R2
N
CH2Cl2
1
2
3
4
5
6
7
8
a E = TMS
78
88
74
90
96
90
53
73
R1
R1
R2
PhCHO
Me2SO4
Ac2O
b E = CH(OH)Ph
c E = Me
5c R1 = Ph, R2 = Me
8c R1 = Pr, R2 = COMe
10a R1 = Ph, R2 = Me (97%)
10b R1 = Pr, R2 = COMe (86%)
Scheme 6
d E = COMe
e E = CO2Et
ClCO2Et
CO2
In conclusion, we have developed a new protocol for the
synthesis of disubstituted ynamides starting from easily
accessible b,b-dichloroenamides. Treatment of the latter
with n-butyllithium, followed by the desired electrophile,
has allowed the construction of new ynamide substitution
patterns, and the preparation of silyl bisynamides.
f E = CO2H
t-BuNCO
ClP(O)(OEt)2
g E = C(O)NHt-Bu
h E = P(O)(OEt)2
a Reactions were carried out using THF as solvent, 2.2 equiv of n-
BuLi and 1.3 equiv of electrophile.
b Isolated yield after column chromatography.
Acknowledgment
We thank the Ministerio de Educación y Ciencia (Spain), the
European Regional Development Fund and the Xunta de Galicia
(XUGA) for financial support under projects CTQ2005-08613 and
PGIDIT06PXIC209041PN. M. F. Martínez-Esperón also thanks
XUGA for a predoctoral grant.
When dichloroenamides 7a–d13 were employed, in which
the Ph of 6 had been replaced by other substituents,
treatment with n-butyllithium, and acetic anhydride
(Scheme 4) afforded acetyl ynamides 8a–d in yields
slightly inferior to that obtained for 5d.14
References and Notes
Ts
1. n-BuLi, THF
Ts
O
(1) For recent reviews of ynamides, see: (a) Katritzky, A. R.;
Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455.
(b) Zhang, Y.; Hsung, R. P. Chemtracts 2004, 17, 442.
(c) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
–78 °C
N
N
R1
Cl
2. Ac2O, r.t.
R1
Cl
8a R1 = p-MeC6H4 (86%)
8b R1 = Bn (84%)
8c R1 = Pr (84%)
8d R1 = allyl (77%)
7a R1 = p-MeC6H4
7b R1 = Bn
7c R1 = Pr
7d R1 = allyl
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
See also: (d) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.
Synlett 2003, 1379. (e) Viehe, H. G. Chemistry of
Acetylenes; Marcel Dekker: New York, 1969, Chap. 12,
861–912. (f) Viehe, H. G. Angew. Chem., Int. Ed. Engl.
1967, 6, 767. (g) Himbert, G. In Methoden der Organischen
Chemie (Houben–Weyl); Kropf, H.; Schaumann, E., Eds.;
Georg Thieme Verlag: Stuttgart, 1993, 3267–3443.
(2) (a) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K.
C. M.; Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.;
Shen, L.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170.
(b) Hirano, S.; Fukudome, Y.; Tanaka, R.; Sato, F.; Urabe,
H. Tetrahedron 2006, 62, 3896. (c) Villeneuve, K.; Riddell,
N.; Tam, W. Tetrahedron 2006, 62, 3823. (d) Dunetz, J. R.;
Danheiser, R. L. Org. Lett. 2003, 5, 4011.
Scheme 4
Difunctionalized compounds can be prepared using
biselectrophiles as trapping agents. Gratifyingly, when
dichlorodimethylsilane was used (Scheme 5), silyl bisyn-
amide 9 was isolated in 63% yield as a white solid.15 This
compound is stable to air and moisture, and was amenable
to purification by silica gel column chromatography.16
(3) (a) Stang, P. J. J. Org. Chem. 2003, 68, 2997. (b) Brückner,
D. Synlett 2000, 1402. (c) Brückner, D. Tetrahedron 2006,
62, 3809. (d) Witulski, B.; Stengel, T. Angew. Chem. Int. Ed.
1998, 37, 489.
Synlett 2007, No. 12, 1963–1965 © Thieme Stuttgart · New York

LETTER
Disubstituted Ynamides from Dichloroenamides and Electrophiles
1965
(4) (a) For a special issue devoted to the chemistry of ynamides,
see: Tetrahedron 2006, 62, issue 16. For recent references,
see: (b) Zhang, X.; Li, H.; You, L.; Tang, Y.; Hsung, R. P.
Adv. Synth. Catal. 2006, 348, 2437. (c) Tracey, M. R.;
Oppenheimer, J.; Hsung, R. P. J. Org. Chem. 2006, 71,
8629. (d) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem. Int.
Ed. 2006, 45, 6726. (e) Couty, S.; Meyer, C.; Cossy, J.
Tetrahedron Lett. 2006, 47, 767. (f) Tanaka, K.; Takeishi,
K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586.
(g) Buissonneaud, D.; Cintrat, J.-C. Tetrahedron Lett. 2006,
47, 3139. (h) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem.
Soc. 2005, 127, 5776. (i) Tanaka, R.; Yuza, A.; Watai, Y.;
Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem.
Soc. 2005, 127, 7774. (j) Couty, S.; Barbazanges, M.;
Meyer, C.; Cossy, J. Synlett 2005, 905. (k) Riddell, N.;
Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681.
Katritzky, A. R.; Singh, S. K.; Jiang, R. Tetrahedron 2006,
62, 3794. (c) During our research, the same methodology
has been reported for the synthesis of a single push–pull
ynamide, see: Mori, M.; Wakamatsu, H.; Saito, N.; Sato, Y.;
Narita, R.; Sato, Y.; Fujita, R. Tetrahedron 2006, 62, 3872.
(10) Disubstituted ynamides have previously been synthesized
from dichloroenamides by a Suzuki–Miyaura cross-
coupling reaction followed by HCl elimination. See ref. 4j.
(11) Other electrophiles such as MeI and EtI also work but with
lower yields (30–35%), ynamide 4 was also obtained as
secondary product.
(12) Typical Procedure for N-(3-Oxobut-1-ynyl)-N-phenyl
Tosylamide (5d)
n-Butyllithium (0.64 mL, 1.6 M in hexane) was slowly
added to a solution of 6 (0.16 g, 0.47 mmol) in dry THF (7
mL) at –78 °C. After 5 min, Ac2O (57 mL, 0.61 mmol) was
added and the mixture was allowed to reach r.t. (TLC
showed clean conversion). The volatiles were removed and
the residue was dissolved in EtOAc (20 mL) and washed
with brine (2 × 30 mL). The organic layer was dried over
anhyd Na2SO4 and evaporated to dryness. The crude residue
was purified by column chromatography on silica gel using
5:1 hexane–EtOAc as eluent, yielding 5d (0.13 g, 90%) as
colorless prisms; mp 110–112 °C. 1H NMR (250 MHz,
CDCl3): d = 7.61 (d, J = 8.4 Hz, 2 H), 7.38–7.28 (m, 5 H),
7.21–7.15 (m, 2 H), 2.44 (s, 3 H), 2.32 (s, 3 H). 13C NMR +
DEPT (62.83 MHz, CDCl3): d = 183.0 (CO), 145.9 (C),
137.1 (C), 132.7 (C), 129.9 (2 × CH), 129.4 (2 × CH), 129.2
(CH), 128.1 (2 × CH), 126.4 (2 × CH), 88.3 (C), 75.7 (C),
31.8 (CH3), 21.7 (CH3). HRMS: m/z calcd for C17H15NO3S:
313.0772; found: 313.0770.
(l) Zhang, Y. Tetrahedron Lett. 2005, 46, 6483.
(5) (a) Rodríguez, D.; Castedo, L.; Saá, C. Synlett 2004, 783.
For our contributions, see: (b) Martínez-Esperón, M. F.;
Rodríguez, D.; Castedo, L.; Saá, C. Tetrahedron 2006, 62,
3843. (c) Martínez-Esperón, M. F.; Rodríguez, D.; Castedo,
L.; Saá, C. Org. Lett. 2005, 7, 2213. (d) Rodríguez, D.;
Castedo, L.; Saá, C. Synlett 2004, 377.
(6) Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.;
Hsung, R. P. Org. Lett. 2004, 6, 2209.
(7) In most of these articles, the authors have reported the
preparation of a single compound using this procedure. See:
(a) Marion, F.; Coulomb, J.; Servais, A.; Courillon, C.;
Fensterbank, L.; Malacria, M. Tetrahedron 2006, 62, 3856.
(b) See ref. 4i. (c) Witulski, B.; Alayrac, C.; Tevzadze-
Saeftel, L. Angew. Chem. Int. Ed. 2003, 42, 4257.
(d) Witulski, B.; Lumtscher, J.; Bergsträßer, U. Synlett 2003,
708. (e) 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. (f) Two push–pull
ynamides have been reported using the same procedure and
ClCO2Et as electrophile, with very different efficiency: Ref.
7a, 90% yield. (g) Ref. 2c, 11% yield.
(13) Prepared as described in ref. 3b.
(14) Methylation of 7a–d was also accomplished in satisfactory
yields following the same procedure as for 5c.
(15) Bisynamide 9: white solid. 1H NMR (250 MHz, CDCl3): d =
7.57 (d, J = 8.3 Hz, 4 H), 7.32–7.22 (m, 14 H), 2.41 (s, 6 H),
0.33 (s, 6 H). 13C NMR + DEPT (62.83 MHz, CDCl3): d =
145.1 (2 × C), 138.2 (2 × C), 132.5 (2 × C), 129.4 (4 × CH),
129.1 (4 × CH), 128.3 (2 × CH), 128.3 (4 × CH), 126.1 (4 ×
CH), 96.0 (2 × C), 70.3 (2 × C), 21.7 (2 × CH3), 0.5 (2 ×
CH3). HRMS: m/z calcd for C32H30N2O4S2Si: 598,1416;
found: 598.1414.
(8) Deuteration studies of 4 using EtMgBr and LDA as bases
and MeOD as deuterium source showed 50% and 66%
deuterium incorporation, respectively (by 1H NMR
integration). These results showed the incomplete efficiency
of metalation of terminal ynamides.
(9) This strategy has been widely used for the synthesis of
substituted ynamines, see: (a) Löffler, A.; Himbert, G.
Synthesis 1994, 383; and references therein. (b) For a recent
report on the synthesis of N-(ethynyl)benzotriazoles, see:
(16) Other members of the silyl bisynamide series exemplified by
9 have also been prepared. Optimization of this procedure
for the synthesis of nonsymmetrical derivatives is in
progress.
(17) 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.
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