A convenient reagent for aldehyde to alkyne homologation

Article abstract of DOI:10.1016/j.tetlet.2008.09.114

A convenient reagent for the one-carbon homologation of an aldehyde to the corresponding alkyne is reported. This reagent allows this conversion to conveniently be carried out on a large scale under ambient conditions.

Full text of DOI:10.1016/j.tetlet.2008.09.114

Tetrahedron Letters 49 (2008) 6904–6906
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A convenient reagent for aldehyde to alkyne homologation
*
Douglass F. Taber , Sha Bai, Peng-fei Guo
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient reagent for the one-carbon homologation of an aldehyde to the corresponding alkyne is
reported. This reagent allows this conversion to conveniently be carried out on a large scale under ambi-
ent conditions.
Received 10 September 2008
Accepted 17 September 2008
Available online 23 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
transfer can be effected with the atom-economical methanesulf-
onyl azide.8
In 1989, Ohira1 reported a convenient procedure for the
homologation of an aldehyde such as 1a (Eq. 1) to the correspond-
ing alkyne 3a, by condensation with dimethyl diazomethyl phos-
phonate, generated in situ from the diazo phosphonate 2.
Subsequently, Bestmann2 described a more detailed study of this
transformation.
(CH3O)3P
CH3SO2N3
NaH
O
O
O
O
ð2Þ
O
N2
4
5
6
P
P
CH3O
CH3O
Br
OCH3
OCH3
O
O
P
H
OCH3
OCH3
We were pleased to observe (Table 1) that the crude diazo
phosphonate 6 efficiently converted a variety of aldehydes to the
corresponding alkynes. The a,b-unsaturated aldehyde (entry 7)
H
O
2
ð1Þ
N2
CH3O
CH3O
K2CO3 / CH3OH
1a
3a
gave the methoxy-substituted alkyne. If desired, the methyl benzo-
ate generated as a byproduct of the reaction could be removed by
saponification during workup.
The procedure described here for the homologation of an alde-
hyde to its corresponding alkyne is inexpensive, and can be conve-
niently carried out on a large scale. In particular, with a burgeoning
interest of ‘click chemistry’,11 there is a need of the inexpensive
preparation of terminal alkynes. We expect that the diazo
phosphonate 6 will become a useful tool in the armamentarium
of organic synthesis.
Although we3 and many others4 have found the Ohira–Best-
mann reagent to be convenient, in recent years, its use has often
been displaced by alternative protocols5 for effecting this homolo-
gation. Although the reagent 2 is convenient and easy to prepare
from its precursor dimethyl 2-oxopropylphosphonate, the latter
is sufficiently expensive (ꢀ$2/mmol)6 that alternative reagents
such as TMSCH@N2 are competitive.
It occurred to us that as the acyl group is lost before the diazo-
phosophonate reacts with the aldehyde, it might be possible to use
a bulkier acyl group that would give intermediates that were less
expensive and easier to handle. The phosphonate 5 (Eq. 2)
immediately came to mind. Easy to prepare7 from the inexpensive
2-bromoacetophenone 4 (or potentially the even less expensive
2-chloroacetophenone), 5 is also easy to purify by extraction into
aqueous base followed by distillation. We have found that the de-
rived8,9 diazophosphonate 6 can be used directly,4c without any
purification other than extraction. It is particularly noteworthy
that in contrast to the preparation of the Ohira reagent, diazo
2. Experimental
Safety note: Differential scanning calorimetry on the ethyl ester
corresponding to 6, prepared at an early stage of this project,
showed a substantial exotherm at 70 °C. The diazo phosphonate
6 should not be warmed past room temperature. The commonly
used diazo phosphonate 2 showed a similar exotherm at about
the same temperature, so it also must be handled with due caution.
2.1. Dimethyl 2-oxo-2-phenylethylphosphonate (5)
Following the published procedure,7 to a solution of 2-bromo-
acetophenone (98%, 12.2 g, 60.0 mmol) in THF (6.0 mL) was added
trimethylphosphite (97%, 8.8 mL, 72.4 mmol) dropwise over 5 min.
* Corresponding author. Tel.: +1 302 831 2433; fax: +1 302 831 6335.
E-mail address: Taberdf@udel.edu (D. F. Taber).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.114

D. F. Taber et al. / Tetrahedron Letters 49 (2008) 6904–6906
6905
Table 1
7.48 (t, J = 7.6 Hz, 2H), 3.78 (d, J = 11.0 Hz, 6H), 3.64 (d,
J = 22.6 Hz, 2H); 13C NMR12 (100 MHz, CDCl3)
52.7 (d,
Homologation of aldehydes with 6
d
d
J = 6.6 Hz), 128.3, 128.6, 133.4; u 36.4, 37.7, 136.0 (d, J = 2.5 Hz),
191.4 (d, J = 6.6 Hz).
Entry
Aldehyde
Alkyne
Yield (%)
77a
OCH3
OCH3
2.2. Dimethyl 1-diazo-2-oxo-2-phenylethylphosphonate (6)
H
H
1
O
To a solution of dimethyl-2-oxo-2-phenylphosphonate 5 (99%,
1% CH2Cl2 by 1H NMR , 4.7 g, 20.4 mmol) in MeCN (20 mL) was
added NaH (60% in mineral oil, 0.99 g, 24.8 mmol) portionwise
over 2 min at 0 °C. Mesyl azide8c (99%, 3.2 g, 26.2 mmol) was then
added in one portion. The mixture was stirred for 3 h at 0 °C, and
then partitioned between CH2Cl2 and, sequentially, 1 M aqueous
NaOH (200 mL) at 0 °C and saturated aqueous NaHCO3 at 0 °C.
The combined organic extracts were dried (Na2SO4) and concen-
trated. The crude diazo compound was received as a thick orange
oil (5.3 g). A portion of the crude diazo compound (94.6 mg) was
chromatographed to yield an analytical sample of the known9 dia-
zo phosphonate 6 (87.1 mg) as a thick yellow oil. The isolated yield
was 94% based on 5. TLC Rf = 0.41 (MTBE/CH2Cl2, 2:8); 1H NMR
(400 MHz, CDCl3) d 7.64 (d, J = 7.5 Hz, 2H), 7.53 (t, J = 7.5 Hz, 2H),
7.44 (t, J = 7.5 Hz, 2H), 3.81 (d, J = 11.8, 6H); 13C NMR (100 MHz,
CDCl3), d d 53.9 (d, J = 5.8 Hz), 127.2, 128.5, 132.4; u 29.5, 136.6
(d, J = 3.2 Hz), 187.2 (d, J = 9.0 Hz). Diazo phosphonate 6 was stable
in the freezer (ꢂ20 °C).
2a
1a
OCH3
OCH3
OCH3
OCH3
2
3
4
79b
72c
73d
O
H
H
1b
2b
CH3O
CH3O
O
H
H
1c
2c
O
O
H
O
H
1d
2d
2.3. Procedure A: (2S)-1-O-benzyl-2-methoxypent-4-yn-1-ol
(2g)
O
H
BnO
H
BnO
BnO
5
6
81
92
To a mixture of the aldehyde 1 g (116 mg, 0.7 mmol) and K2CO3
(395 mg, 2.9 mmol) in MeOH (3 mL) were added the crude diazo 6
(85.8% pure, 301 mg, 1.0 mmol) and MeOH (7 mL) in one portion at
0 °C. The resulting mixture was stirred at 0 °C–rt overnight. The
reaction mixture was chromatographed to yield the known alkyne
2g10d (101 mg, 0.5 mmol, 75% yield) as a pale yellow oil. TLC
Rf = 0.24 (MTBE/PE, 1:9); 1H NMR (400 MHz, CDCl3) d 7.25–7.34
(m, 5H), 4.57 (s, 2H), 3.51–3.57 (m, 1H), 3.60–3.64 (m, 2H), 3.44
(s, 3H), 2.48–2.51 (m, 2H), 1.98 (t, 1H, J = 2.7 Hz); 13C NMR
(100 MHz, CDCl3) d d 57.6, 78.3, 127.5, 127.6, 128.3; u 20.8, 69.9,
70.6, 73.4, 80.5, 138.0.
2e
1e
O
H
H
BnO
2f
1f
O
H
CH3O
BnO
H
BnO
7
75e
2g
1g
a
Ref. 10a.
2.4. Procedure B (saponification of methyl benzoate): (1S,2S)-
(2-ethynylcyclopropyl)methyl benzyl ether (2f)
b
c
Ref. 10b.
Ref. 10c.
Ref. 10d.
Ref. 10e.
d
e
To a mixture of the aldehyde 1f (103 mg, 0.5 mmol) and K2CO3
(312 mg, 2.3 mmol) in MeOH (2 mL) were added the crude diazo 6
(92% pure, 226 mg, 0.8 mmol) and MeOH (3.4 mL) in one portion at
0 °C. The resulting mixture was stirred at 0 °C–rt overnight. Then,
solid NaOH pellets (256 mg, 6.4 mmol) were added, and the reac-
tion mixture was heated to reflux for 2 h. The reaction mixture
was cooled to rt, concentrated, and chromatographed to yield al-
kyne 2f (92 mg, 0.5 mmol, 92% yield) as a colorless oil. TLC
Rf = 0.42 (MTBE/PE, 1:9); 1H NMR (400 MHz, CDCl3) d 7.24–7.38
(m, 5H), 4.56 (s, 2H), 3.55–3.64 (m, 2H), 1.81 (d, 1H, J = 2.0 Hz),
1.46–1.52 (m, 1H), 1.32–1.38 (m, 1H), 0.97–1.02 (m, 1H), 0.53–
0.58 (q, 1H, J = 5.5 Hz); 13C NMR (400 MHz, CDCl3) d d 4.7, 17.5,
127.4, 127.7, 128.2; u 12.4, 66.2, 70.6, 72.8, 83.8, 138.3; IR (film):
3294, 3028, 2860, 2360, 2117 cmꢂ1; MS 185 (M+ꢂ1 19), 155 (31),
141 (65), 129 (61), 105 (100); HRMS calcd for C13H13O 185.0966,
obsd 185.0966.
The resulting mixture was heated to reflux overnight, then concen-
trated. The product was
ꢀ7:3 mixture of dimethyl-2-
a
oxophenylphosphonate and dimethyl 1-phenylethenyl ester by
1H NMR. The mixture was diluted with H2O (200 mL) and
CH2Cl2/petroleum ether (PE) (1:19) (10 mL), and was then stirred
with solid NaOH pellets (9.6 g, 240.0 mmol) at 0 °C for 2 h (NaOH
dissolved). The mixture was diluted with 700 mL of H2O, and
washed with 4 ꢁ 900 mL of CH2Cl2/PE (1:19). The aqueous phase
was acidified with concentrated aqueous HCl (11 M, 22 mL) at
0 °C. The reaction mixture was partitioned between CH2Cl2 and,
sequentially, H2O and saturated aqueous NaHCO3. The combined
organic extracts were dried (Na2SO4) and concentrated. The crude
phosphonate was received as
a dark orange oil. Distillation
(0.5 torr (pot) = 180–190 °C) delivered the known7b keto phospho-
nate as a pale yellow oil (7.7 g, 33.8 mmol, 55% yield). The phos-
phonate 5 was used in the diazo transfer reaction without
further purification. TLC Rf = 0.26 (MTBE/CH2Cl2, 2:8); 1H NMR
(400 MHz, CDCl3) d 8.01 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H),
Acknowledgments
We thank John Dykins for high resolution mass spectra (sup-
ported by NSF0541775), and the National Institutes of Health
(GM060287) for financial support.

6906
D. F. Taber et al. / Tetrahedron Letters 49 (2008) 6904–6906
6. For 2-oxopropylphosponate preparation see: (a) Cotton, F. A.; Schunn, R. A.
Supplementary data
J. Am. Chem. Soc. 1963, 85, 2394; (b) Kitamura, M.; Tokunaga, M.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 2931; (c) Pietruszka, J.; Witt, A. Synthesis 2006,
4266.
Experimental procedures and 1H NMR and 13C NMR spectra
for all new compounds. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/j.tetlet.
2008.09.114.
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