A convenient scalable one-pot conversion of esters and Weinreb amides to terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2004.05.139

Esters and amides undergo reduction to the corresponding aldehydes using DIBAL-H followed by same pot conversion to terminal alkynes utilizing the Bestmann-Ohira reagent in good to excellent yields. Additionally chiral nonracemic substrates undergo this transformation with complete preservation of stereochemical integrity.

Full text of DOI:10.1016/j.tetlet.2004.05.139

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5597–5599
A convenient scalable one-pot conversion of esters and Weinreb
amides to terminal alkynes
q
Hamilton D. Dickson, Stephon C. Smith and Kevin W. Hinkle*
Microbial, Musculoskeletal, and Proliferative Diseases Medicinal Chemistry, GlaxoSmithKline, RTP, NC 27709, USA
Received 18 May 2004; revised 24 May 2004; accepted 26 May 2004
Abstract—Esters and amides undergo reduction to the corresponding aldehydes using DIBAL-H followed by same pot conversion
to terminal alkynes utilizing the Bestmann–Ohira reagent in good to excellent yields. Additionally chiral nonracemic substrates
undergo this transformation with complete preservation of stereochemical integrity.
Ó 2004Elsevier Ltd. All rights reserved.
Recent advances in synthetic chemistry, like the Sono-
1
and the Bestmann–Ohira reagent affording smooth
conversion to the homologated alkynes (Eq. 1).
gashira cross-coupling reaction,
Grubbs olefin
2
3
metathesis, and the Ru catalyzed Alder-ene reaction
have greatly enhanced the synthetic utility of terminal
alkynes. A variety of synthetic procedures have been
developed to access terminal alkynes including the
1) DIBAL-H
O
O
CH Cl , -78 C
2
2
4
5
R2
R3
Corey–Fuchs, Seyferth–Gilbert, Colvin rearrange-
or
R
O
R
N
R
H
6
7
ment, and alkyne zipper reactions. These procedures
generally utilize strictly anhydrous conditions and can
require multiple steps, often using strong base, making
them of limited use with delicate substrates. The intro-
2)
O
O
P
R4
O
O
N2
MeOH, K CO , rt
8
2
3
duction of the Bestmann–Ohira modification of the
Seyferth–Gilbert reagent represents a significant ad-
vance in this technology, allowing for terminal alkynes
to be synthesized directly from aldehydes at room tem-
perature under mild conditions with a readily prepared
reagent. Herein we report a convenient one-pot syn-
thesis of terminal alkynes from esters and Weinreb
amides that takes advantage of the mild nature of the
Bestmann–Ohira reaction. In situ reduction of the
starting esters and amides is accomplished by treatment
with DIBAL-H at low temperature followed by a
methanol quench. The resulting solution of aldehyde is
ð1Þ
The reaction works with a variety of alkyl esters, entries
a–c (Table 1). The scope of the reaction extends to cover
a broad range of functional groups, such as nonconju-
gated double bonds (entry b), ethers and carbamates
(
entries d and e). Entry f is noteworthy as the reductive
alkynylation takes place in the presence of an unpro-
tected alcohol. The procedure requires an extra equiv-
alent of DIBAL-H, presumably to first form an
aluminum alkoxide of the free hydroxyl before reducing
the ester. Additionally, entry f has been carried out on 1,
2 3
further diluted with methanol and treated with K CO
1
7
0, and 27 g of starting ester affording 74%, 75%, and
9
2% yield of the desired alkyne, respectively. Impor-
tantly, the conversion of this substrate and other chiral
substrates leads to terminal alkynes with complete
preservation of stereochemical integrity. This transfor-
mation also works with Weinreb amides to afford the
terminal alkynes in yields equivalent to the ester sub-
strates (entries g–j).
Keywords: Bestmann–Ohira; Seyferth–Gilbert; Alkynes; Weinreb
amides.
q
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.05.139
*
Corresponding author. Tel.: +1-9194831453; fax: +1-9194836053;
e-mail: kevin.w.hinkle@gsk.com
0
040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.139

5598
H. D. Dickson et al. / Tetrahedron Letters 45 (2004) 5597–5599
Table 1
a;b
Entry
Substrate
Product
% Yield
88
O
a
5
5
O
O
b
76
84
7
5
7
5
O
O
c
O
OBn
OBn
O
d
72
71
O
Boc
N
Boc
N
O
e
f
O
O
O
HO
HO
75
O
N
N
Boc
Boc
O
N
g
h
i
O
85
78
83
77
1
4
14
O
Boc
N
N
Boc
N
N
H
O
H
O
N
O
N
Boc
Boc
O
Boc
N
Boc
N
j
N
H
O
H
O
a
1
10–14
Satisfactory H NMR, HRMS, and optical rotations were obtained.
Reaction yields have not been optimized.
b
Typical procedure: Ester a (1.0 g, 5.37 mmol) was dis-
solved in 10 mL anhydrous dichloromethane, and the
solution cooled to )78 °C. DIBAL-H (6.44 mL,
amides to the corresponding homologated alkynes that
tolerates a wide range of functionality and is accom-
plished under mild conditions.
6
1
.44 mmol, 1 M solution in heptane) was added over
0 min, and the mixture stirred at )78 °C. The reaction
was monitored by TLC and judged to be complete after
the starting ester was consumed. The excess DIBAL-H
was quenched with 5 mL anhydrous methanol, and the
reaction mixture allowed to warm to 0 °C. Potassium
carbonate (1.48 g, 10.7 mmol), the Bestmann–Ohira re-
agent (1.25 g, 6.44 mmol), and 5 mL anhydrous methanol
were added and the reaction stirred overnight at rt. Ro-
chelle’s salt (20 mL) and diethyl ether (40 mL) was added
and the mixture stirred vigorously for 1 h. The organic
layer was separated, washed with brine, dried over mag-
nesium sulfate, and the solvent was removed under re-
duced pressure. The crude mixture was purified via silica
gel chromatography with5% ethyl acetate/hexane, eluting
the terminal alkyne as a colorless oil (720 mg, 88% yield).
References and notes
1
. Elangovan, A.; Wang, Y.; Ho, T. Org. Lett. 2003, 5, 1841–
844.
1
. Kim, S.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H.
2
J. Org. Chem. 1996, 61, 1073–1081.
3. Trost, B. M.; Indolese, A. F.; Mueller, T. J. J.; Treptow, B.
J. Am. Chem. Soc. 1995, 117, 615–623.
. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36,
769–3772.
. Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.;
4
5
3
Brisbois, R. G.; Hoye, T. R. J. Org. Chem. 1996, 61, 2540–
2
541.
. Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 2, 107–
08.
. Macaulay, S. R. J. Org. Chem. 1980, 45, 734–735.
6
1
7
In summary, we have developed a convenient scalable
two step one-pot conversion of esters and Weinreb
8. Mueller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J.
Synlett 1996, 6, 521–522.

H. D. Dickson et al. / Tetrahedron Letters 45 (2004) 5597–5599
5599
9
. Typical large scale experimental procedure: ester f (27.0 g,
10 mmol) was dissolved in dichloromethane (100 mL),
reduced pressure. The crude was purified with 50% ethyl
acetate/hexane eluting the alkyne as a white solid (16.9 g,
72% yield).
1
anhydrous toluene (300 mL) was added, and the solution
cooled to )78 °C. DIBAL-H (242 mL, 242 mmol, 1 M
solution in toluene) was added via syringe over 45 min,
and the mixture stirred for 4h at )78 °C. The reaction was
monitored by TLC and judged to be complete after the
starting ester was consumed. The mixture was quenched
with anhydrous methanol (100 mL) at )78 °C and allowed
to warm to 0 °C. The solvent volume was then reduced by
approximately 50% under reduced pressure at 0 °C. More
MeOH (300 mL) was added followed by potassium
carbonate (61.0 g, 220 mmol) and dropwise addition of
the Bestmann–Ohira reagent (27.7 g, 143 mmol). The
reaction was stirred to completion overnight at room
temperature. Most of the solvent was removed, then ethyl
acetate (800 mL) and Rochelle’s salt (800 mL) was added.
The mixture was stirred for 2 h and the organic layer was
separated from the aqueous, washed with brine, dried over
magnesium sulfate, and the solvent was removed under
2
0
10. Optical rotation for d ½aꢀ +106.1 (c 0.015, CHCl
3
),
D
2
0
compared to ½aꢀ +110.5 (c 0.96, CHCl
3
) Ortiz, J.; Ariza,
D
X.; Garcia, J. Tetrahedron: Asymmetry 2003, 14, 1127–
1131.
2
0
11. Optical rotation for e ½aꢀ +93 (c 0.018, CHCl
3
),
D
2
D
0
13
compared to ½aꢀ +90 (c 0.007, CHCl Dondoni, A.;
Mariotti, G.; Marra, A.; Massi, A. Synthesis 2001, 14,
3
)
2129–2137.
2
D
0
12. No diastereomers/epimerization observed for f ½aꢀ )121
2 2
(c 1.7, CH Cl ).
2
D
0
13. Optical rotation for i ½aꢀ )99 (c 0.015, MeOH), compared
2
0
to ½aꢀ )99 (c 0.010, MeOH) Cossy, J.; Cases, M.; Pardo,
D
D. G. Bull. Soc. Chim. Fr. 1997, 134, 141–144.
2
D
0
14. Optical rotation for j ½aꢀ )59.4( c 0.014, CHCl
3
),
2
0
compared to ½aꢀ )61.5 (c 0.010, CHCl
3
) Reginato, G.;
D
Mordini, A.; Messina, F.; Degl’Innocenti, A.; Poli Giov-
anni Tetrahedron 1996, 5, 10985–10996.