Concise synthesis of dimethyl (2-oxopropyl)phosphonate and homologation of aldehydes to alkynes in a tandem process

Article abstract of DOI:10.1080/00397910802372566

The synthesis of dimethyl (diazomethyl)phosphonate, a useful reagent for the homologation of aldehydes to alkynes, is described as a one-pot process and comprises the generation of the azide transfer agent, diazotransfer to dimethyl (2-oxopropyl)phosphonate, and methanolysis, followed by a simple extraction protocol. Previously described syntheses for this bulk product are much more elaborate. The homologation of aldehydes to alkynes can also be extended to a single-step process by adding the aldehyde directly to the reaction mixture prior to isolation of the reagent. The homologation process using dimethyl (diazomethyl)phosphonate was shown to proceed also in nonprotic solvents with mild bases, emphasizing the importance of a facile access to the reagent. The oxidation of alcohols to the required aldehydes was performed by a TEMPO-mediated process using chloramine-T as electron acceptor. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802372566

This article was downloaded by: [University of Saskatchewan Library]
On: 22 September 2012, At: 04:07
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Concise Synthesis of Dimethyl
(2-Oxopropyl)phosphonate and
Homologation of Aldehydes to
Alkynes in a Tandem Process
Hubert Maehr a , Milan R. Uskokovic a & Carl P.
Schaffner b
a Bioxell Inc., Nutley, New Jersey, USA
b Waksman Institute, Rutgers The State University,
Piscataway, New Jersey, USA
Version of record first published: 22 Dec 2008.
To cite this article: Hubert Maehr, Milan R. Uskokovic & Carl P. Schaffner (2008):
Concise Synthesis of Dimethyl (2-Oxopropyl)phosphonate and Homologation
of Aldehydes to Alkynes in a Tandem Process, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:2,
299-310
To link to this article: http://dx.doi.org/10.1080/00397910802372566
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions

This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communications1, 39: 299–310, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802372566
Concise Synthesis of Dimethyl
(2-Oxopropyl)phosphonate and Homologation
of Aldehydes to Alkynes in a Tandem Process
Hubert Maehr,1 Milan R. Uskokovic,1 and Carl P. Schaffner2
1Bioxell Inc., Nutley, New Jersey, USA
2Waksman Institute, Rutgers The State University, Piscataway,
New Jersey, USA
Abstract: The synthesis of dimethyl (diazomethyl)phosphonate, a useful reagent
for the homologation of aldehydes to alkynes, is described as a one-pot process
and comprises the generation of the azide transfer agent, diazotransfer to
dimethyl (2-oxopropyl)phosphonate, and methanolysis, followed by a simple
extraction protocol. Previously described syntheses for this bulk product are
much more elaborate. The homologation of aldehydes to alkynes can also be
extended to a single-step process by adding the aldehyde directly to the reaction
mixture prior to isolation of the reagent. The homologation process using
dimethyl (diazomethyl)phosphonate was shown to proceed also in nonprotic sol-
vents with mild bases, emphasizing the importance of a facile access to the
reagent. The oxidation of alcohols to the required aldehydes was performed by
a TEMPO-mediated process using chloramine-T as electron acceptor.
Keywords: Alcohols, aldehydes, alkynes, homologation, oxidation
INTRODUCTION
The elaboration of aldehydes to terminal alkynes[1] with one additional
carbon is a significant chemical transformation that has recently gained
in importance with the increasing popularity of chemical reactions requir-
ing this functional group.[2,3] Further to the traditional uses, many new
Received May 9, 2008.
Address correspondence to Hubert Maehr, Bioxell, Inc., 340 Kingsland Street,
Nutley, NJ 07110. E-mail: Hubert.Maehr@bioxell.com
299

300
H. Maehr, M. R. Uskokovic, and C. P. Schaffner
examples, such as three- and four-component reactions, a myriad
of metathetic transformations, insertion reactions, click chemistry,
cycloadditions, and numerous uses in natural product syntheses, under-
score the pivotal role of terminally positioned acetylenes. We were
primarily interested in the homologation of aldehydes to alkynes for
the side-chain modification of vitamin D analogs because introduction
of a C23-C24-alkyne moiety imparts metabolic resistance to the degrada-
tive sequence initiated by 24-hydroxylation.[4]
A number of protocols are available to achieve this homologation.
The method of Corey and Fuchs[5] extends an aldehyde to a 1,1-dibro-
moalkene,[6] which is converted to the lithium acetylide by dehydrohalo-
genation and halogen exchange. Hydrolysis affords the terminal olefins,
or, alternatively, reactions with electrophiles generate substituted
alkynes. This reaction sequence was adapted to a solid-phase version
within a ‘‘safety-catch’’ strategy,[7] while selective dehydrobrominations
gave bromoacetylenes.[8] The analogous 1,1-dichloroalkene, prepared
by the reaction of the aldehyde with the trichloromethyl anion followed
by tosylation of the resulting alcohol and elimination, was similarly con-
verted to the acetylene.[9] Alternatively, Wittig chloromethylenation of an
aldehyde using chloromethyltriphenylphosphonium chloride and subse-
quent dehydrochlorination of the resulting 1-chloroalkene also leads to
the terminal acetylene.[10] The conversion was also performed with
dibromomethyltriphenylphosphonium bromide,[11] with diethyl dichloro-
methylphosphonate,[12] and by other methods. In a significant variation,
Colvin and Hamill devised base-induced reactions with (diazomethyl)-
trimethylsilane or (diazomethyl)phosphonic acid dimethyl ester 1a[13] to
produce acetylenes in one step. More recently, [diazo(trimethylsilyl)-
methyl]phosphonous diamides served for this homologation without
the addition of a base.[14] The required reagent is not readily available,
however, and (1-hydroxyalkyl)phosphonic diamide, derived from the
reactant aldehyde, is formed in an equimolar amount.
(Diazomethyl)trimethylsilane applications were emulated by
others,[15] but the use of 1a was fortunate because it stimulated general
interest in aldehyde homologation to alkynes in view of the reaction sim-
plicity. Procedures for the syntheses of 1a and 1b are available[13a,16,17]
and were developed further.[18] Gilbert and Weerasooriya[19] studied the
alkynylation reaction in detail and supported the originally proposed
mechanism of Colvin and Hamill as shown in Scheme 1.
Homologations of aldehydes with 1a were traditionally carried out
with strong bases such as BuLi and t-BuOK, the available synthetic pro-
cedures for 1a and 1b are lengthy, and the products are afflicted with the
stigma of instability.[20–22] Ohira[23] had shown that 2a, the acetylated
form of 1a, was easier to prepare than 1a itself by diazo transfer from

Homologation of Aldehydes to Alkynes
301
Scheme 1. Sequence of alkynylation reaction.
tosyl azide to dimethyl 2-(oxopropyl)phosphonate (5a) and that 2a could
serve directly for the homologation of aldehydes to acetylenes with potas-
sium carbonate in methanol, hence avoiding previously employed strong
bases. Accordingly, the use of 1a was shunned in favor of 2a and used
either in accordance with the Ohira protocol, prepared in situ,[21,22] or
incorporated into a solid-phase system in the form of the ROMPgel-
supported reagent.[24] In actuality, however, 2a is merely a precursor of
1a,[23] and it is 1a that homologates aldehydes to acetylenes under
mild conditions; in other words, the notion that 1 requires strong bases
for the homologation reaction is unfounded, and the need for a short
synthesis of 1a is apparent.
RESULTS AND DISCUSSION
We have found that 1a, contradicting previous beliefs, is stable for years
when kept in the refrigerator; but more important, 1a mediates, equally
efficiently in crude or in pure form, the conversion of aldehydes to acet-
ylenes with methanol and potassium carbonate or cesium carbonate.
Because the required solvolytic de-acetylation process of 2 is already
accomplished, the homologation step with 1a also proceeds in nonprotic
solvents. Using cesium carbonate as base, the reaction rates were fastest
in methanol, but toluene, DMF, acetonitrile, THF, and 2-propanol also
give acetylenes, although requiring extended reaction times without
reaching the yields attained with methanol. Accordingly, these solvents
are used more advantageously in combination with methanol. We have
also tested a few solvent pairs for the conversion of 6 to 7 with cesium
carbonate as base and found the fastest reaction rate in 1:1 methanol–
dichloromethane and 4:1 methanol–THF, both comparable to neat
methanol; the rate was only slightly slower in 1:1 methanol–toluene
but lagged significantly behind the reaction in 1:1 methanol–acetonitrile
or neat 2-propanol. When methanol was used as solvent for the conver-
sion of 6 to 7, we observed little difference between potassium carbonate
and cesium carbonate, but the latter is preferred when solvent mixtures
are employed. Triethylamine in THF was ineffective, but 1 equivalent

302
H. Maehr, M. R. Uskokovic, and C. P. Schaffner
of DBU per equivalent of 1a, when added as a 2 M solution in toluene to
a solution of 1a (1.5 eq) and 6 (1 eq) in THF at ꢀ10 ꢁC, afforded crystal-
line 7, in 50% yield, after allowing the reaction mixture to warm to 0 ꢁC
overnight and the workup described later for 7. The unreacted starting
material was quantitatively recovered, suggesting the possibility for
further process optimization.
In view of these observations, 1a became the focal point of an improved
synthesis, which we describe herein as a one-pot process. It comprises the
generation of the azide transfer agent, actual diazotransfer to dimethyl 2-
(oxopropyl)phosphonate, and methanolysis of the resulting 2a. A very sim-
ple filtration and evaporation protocol furnishes 1a, which can be used
directly in homologation experiments or may be further purified either by
flash chromatography or distillation. Similar to distilled 1a and 1b, we
found no detectable deterioration of the crude and chromatographed 1a
when stored in the freezer for more than 2 years, and there was no difference
between the crude and further purified 1a in terms of efficacy. To reduce
exposure and handling of this potentially toxic and explosive substance,
we recommend using the undistilled material as described here.
Further, we proffer a reaction sequence, illustrated in Scheme 2,
which converts the aldehyde to the homologated acetylene in a tandem
reaction comprising the generation of the azide transfer agent, diazo-
transfer, methanolysis, and homologation, all in one reaction vessel.
We selected mesyl azide in acetonitrile[25] and cesium carbonate[26] to
effect the diazo transfer reaction and preferred TEMPO-based oxidations
of the alcohols to obtain the required aldehydes for homologations.
A number of electron acceptors have been employed for this trans-
formation, but we found chloramine-T particularly propitious as it is
Scheme 2. One-pot homologation of aldehydes to alkynes in a tandem process.

Homologation of Aldehydes to Alkynes
303
inexpensive, stable, soluble in water, and has a built-in buffer capacity.
TEMPO-based oxidations in a two-phase system of dichloromethane
and aqueous buffers have been shown to be selective for primary
alcohols[27] and with chloramine-T using a buffer such as 0.5 M dipotas-
sium hydrogen phosphate as the aqueous component, this selectivity
appears to be unaltered. The reaction time is longer in less basic solutions
such as 0.5 M potassium hydrogen carbonate and thus requires larger
quantities of chloramine-T. In the presence of a secondary hydroxyl
group as in 8, selectivity can be enhanced by lower reaction temperatures,
limited quantities of the oxidant, and monitoring the consumption of the
alcohol without enforcing the complete disappearance thereof. The gen-
erated benzenesulfonamide is removable either by filtration, extraction,
or flash chromatography.
Representative examples are illustrated in Scheme 3. The homologa-
tion of 6 to 7 was compared using the one-pot method with a procedure
employing preformed 1a. First, generation of 1a and subsequent homo-
logation of 6 were conducted in acetonitrile and methanol using cesium
carbonate (70% yield). In the second process, preformed and undistilled
1a was employed with methanol and potassium carbonate (84% yield).
The syntheses of alkyne 10 from the alcohol 8 were also compared
by the two processes wherein the one-step method afforded 10 in 63%
Scheme 3. Examples of alkynylations.

304
H. Maehr, M. R. Uskokovic, and C. P. Schaffner
overall yield from the alcohol, while the two-step alternate gave 10 in 80%
yield. The equivalent conversion of 11 to 13 via 12 proceeded in 93%
overall yield.
EXPERIMENTAL
(Diazomethyl)phosphonic Acid Dimethyl Ester (1a)
A mixture of powdered sodium azide (4.0 g, 61.5 mmol), acetonitrile
(50 mL), and mesyl chloride (6.99 g, 61.0 mmol) was stirred overnight
then cooled in an ice bath, and dimethyl 2-oxopropylphosphonate
(9.14 g, 7.60 mL, 55 mmol)[28] was added. Cesium carbonate (19.55 g,
60 mmol) was added after 10 min, and the mixture was stirred for 1 h in
the ice bath, for 2 h at ambient temperature, and again cooled in an ice
bath. Then methanol (25 mL) was added within 5 min. The ice bath
was removed after 4.5 h, and the mixture was diluted with toluene
(75 mL), stirred for 5 min, and then filtered through a bed of Celite.
The filter cake was washed with several portions of toluene, and the fil-
trate and washings were concentrated to a residue of ca. 38 g in the form
of two liquid layers. The upper layer was decanted from the oily bottom
layer, which was washed repeatedly with toluene. All toluene-containing
liquids were evaporated and coevaporated from hexane to afford 1a of
1
sufficient purity for homologation experiments (for H NMR, see addi-
tional data file 1). Alternatively, the toluene-containing liquids were
charged to a silica-gel plug (65 ꢂ 30 mm), and the product was eluted with
1:1 ethyl acetate–hexane and ethyl acetate to yield 1a as a straw-colored
1
oil, 6.21 g, 75%; TLC (EtOAc) Rf 0.33, UV and I2 detection; H NMR
2
3
(400 MHz, CDCl3) d 3.76 (1H, JHP ¼ 11 Hz), 3.77 (6H, JHP ¼ 11.7 Hz);
13C NMR (CDCl3) d 52.9 (2JC,P ¼ 5.3 Hz), 28.4 (1JC,P ¼ 233 Hz); 31P
NMR (162 MHz, CDCl3) d 20.0. HR-MS calcd. for C3H7N2O3P
150.0194; found 150.0194.[17]
1-Ethynyl-4-(phenylmethoxy)benzene (7)
One-Pot Reaction Commencing with 3
A mixture of sodium azide (111 mg, 1.70 mmol), acetonitrile (1.5 mL),
and mesyl chloride (0.189 g, 1.65 mmol, 128 mL) was stirred overnight,
then cooled in an ice bath. Dimethyl 2-(oxopropyl)phosphonate
(0.240 g, 1.45 mmol, 200 mL) was added, followed by cesium carbonate
(0.521 g, 1.6 mmol). The cooling bath was removed after 30 min, and

Homologation of Aldehydes to Alkynes
305
stirring at ambient temperature continued for 2.5 h. The suspension was
again cooled in an ice bath, stirred for 10 min, diluted with MeOH
(0.75 mL), and stirred in the ice bath for 1 h. To this suspension, 4-benzy-
loxybenzaldehyde (154 mg, 0.725 mmol) was added, followed by cesium
carbonate (0.43 g, 1.3 mmol). The ice bath was removed after 25 min;
the mixture was stirred overnight and then evaporated. The residue
was distributed between dichloromethane and water. The aqueous layer
was extracted once with dichloromethane; the combined extracts were
dried (MgSO4) and evaporated. TLC (1:4 ethyl acetate–hexane, detection
with phosphomolybdic acid) showed the complete disappearance of the
starting material (Rf 0.42). The residue was flash chromatographed
(1:19 ethyl acetate–hexane) to furnish 7 as a crystalline residue that was
recrystallized from aqueous methanol, 0.1062 g, 70%; TLC (1:4 ethyl
acetate–hexane) Rf 0.68; mp 66 ꢁC. Anal. calcd. for C15H12O: C, 86.51;
H, 5.81. Found: C, 86.66; H, 5.87.[29]
Reaction Using 1a=MeOH=K2CO3
A mixture of undistilled 1a (0.150 mL, 0.183 mg, 1.22 mmol), 4-benzyloxy-
benzaldehyde (149 mg, 0.70 mmol), and methanol (2.5 mL) was stirred in
an ice bath for 10 min, and powdered potassium carbonate (0.202 g,
1.46 mmol) was added. The ice bath was removed after 2 h; the mixture
was stirred overnight, then concentrated and distributed between ethyl
acetate (20 mL) and water (10 mL). The organic phase was washed with
water (3 mL) and brine (2 mL), dried, and evaporated to a crystalline resi-
due of 7, which was recrystallized from aqueous methanol (0.123 g, 84%).
(1R,3aR,4S,7aR)-7a-Methyl-1-((1S)-1-methyl-prop-2-ynyl)-
octahydro-inden-4-ol (10)
A solution of the Inhoffen-Lythgoe diol 8[30] (212 mg, 1 mmol) and
TEMPO (32 mg, 0.2 mmol) in dichloromethane (8 mL) was vigorously
stirred, and a solution of 0.5 M dipotassium phosphate (8 mL) containing
tetrabutylammonium chloride hydrate (56 mg, 0.2 mmol) was added,
followed by chloramine-T (0.423 g, 1.5 mmol). The mixture was stirred
vigorously until only a trace of starting material remained (TLC, 1:1 ethyl
acetate–hexane, Rf 0.45; ca. 4 h). The mixture was diluted with ethyl acet-
ate (20 mL), and the organic layer washed with water (10 mL) and brine
(5 mL), dried (sodium sulfate), and evaporated. The residue was tritu-
rated with 1:1 dichloromethane–hexane, and the resulting solution was
purified by flash chromatography using 1:19 and 1:4 ethyl acetate–hexane

306
H. Maehr, M. R. Uskokovic, and C. P. Schaffner
to furnish (S)-2-((1R,3aR,4S,7aR)-4-hydroxy-7a-methyl-octahydro-
inden-1-yl)-propionaldehyde (9) as a colorless syrup, 0.20 g, 95%; TLC
(1:1 ethyl acetate–hexane) Rf 0.72. This material was used directly in
the next step. For analysis it was rechromatographed on silica gel using
1
1:19 methanol–dichloromethane to furnish pure 9; H NMR (400 MHz,
CDCl3) d 0.89 (s, 3H), 1.0 (d, 3H, J ¼ 6.8 Hz), 1.06–1.18 (m, 1H), 1.22–
1.48 (m, 5H), 1.5–1.6 (m, 1H), 1.66–1.8 (m, 4H), 1.8–1.87 (m, 1H),
1.88–2.0 (m, 1H), 2.27 (m, 1H), 4.00 (br, 1H), 9.47 (d, 1H, J ¼ 3.2 Hz);
13C NMR (100 MHz, CDCl3) d 13.4, 13.7, 17.4, 22.9, 26.2, 33.6, 40.2,
42.9, 49.2, 51.5, 51.9, 68.9, 205.0); IR (CHCl3): 1720 cmꢀ1 (CO); LR-
MS-APCI (þ) m=z 193 (100%, M þ H-H2O).[31]
One-Step Process from 9
To a stirred suspension of sodium azide (130 mg, 2 mmol) and acetonitrile
(2.1 mL), methanesulfonyl chloride (0.140 mL, 1.82 mmol) was added,
and the mixture was stirred overnight. This suspension was added, via
syringe, to a mixture of dimethyl 2-(oxopropyl)phosphonate (232 mg,
1.4 mmol), acetonitrile (1.5 mL), and cesium carbonate (0.50 g,
1.54 mmol) that had been previously stirred for 10 min. The resulting
mixture was stirred for 4 h, and a solution of 9 (0.205 g, 0.965 mmol),
as obtained previously and dissolved in methanol (2 mL), was added.
After a few minutes of stirring, cesium carbonate (0.51 g) was added.
The reaction was ca. 90% complete after 2 h but was stirred for an addi-
tional 14 h and then distributed between water (5 mL) and ethyl acetate
(35 mL). The organic layer was dried and evaporated, and the residue
was flash chromatographed using 1:19 ethyl acetate–hexane as mobile
phase to yield 10 as a colorless syrup (0.13 g, 63%) from alcohol 8;
TLC (1:4 ethyl acetate–hexane) Rf 0.49; [a]30D þ 50.1 (c 0.52, methanol);
1H NMR (400 MHz, CDCl3) d 0.93 (s, 3H), 1.05–1.15 (m, 1), 1.18 (d, 3H,
J ¼ 6.8 Hz), 1.28–1.36 (m, 2H), 1.36–1.62 (m, 7H), 1.72–1.90 (m, 2H),
1.90–2.03 (m, 2H), 2.42 (m, 1H), 4.06 (br 1H); 13C NMR (100 MHz,
CDCl3) d 13.9, 17.4, 21.1, 22.5, 26.6, 27.3, 33.6, 39.8, 41.8, 52.4, 55.8,
68.4, 69.1, 89.2 ppm; LR-MS-EI(+) m=z 206 (M þ).[32]
Two-Step Process from 8
The oxidation of the diol 8 was repeated as described previously, the
resulting aldehyde was dissolved in methanol (2.5 mL), 1a (238 mg,
1.58 mmol, undistilled material) was added, and the solution was cooled
in an ice bath. To the stirred solution, powdered potassium carbonate

Homologation of Aldehydes to Alkynes
307
(0.25 g, 1.8 mmol) was added. The ice was allowed to melt, and stirring
continued overnight. The mixture was distributed between water (5 mL)
and ethyl acetate (35 mL). The upper layer was washed with water
(5 mL) and brine (3 mL), dried, and evaporated. The residue was flash
chromatographed (1:19 ethyl acetate–hexane) to afford 10 as a colorless
oil (173 mg, 80% from alcohol 8).
tert-Butyl-dimethyl-[(1R,3aR,4S,7aR)-7a-methyl-1-(1-prop-2-ynyl-
cyclopropyl)-octahydro-inden-4-yloxy]silane (13)
A mixture of 2-{1-[(1R,4S,7aR)-4-(tert-buty-dimethyl-silanyloxy)-7a-
methyl-octahydro-inden-1-yl]-cyclopropyl}-ethanol (11) (860 mg, 2.44
mmol), dichloromethane (18 mL), and 0.5 M potassium hydrogen carbo-
nate solution (18 mL) containing TBAC hydrate (112 mg, 0.4 mmol) was
stirred vigorously, and TEMPO (63 mg, 0.4 mmol) was added, followed
by chloramine-T (1.37 g, 4.86 mmol). TLC (1:4, ethyl acetate–hexane)
monitored the conversion of 11 (Rf 0.40) to 12 (Rf 0.84). After 45 min,
11 was no longer detectable. The mixture was diluted with ethyl acetate
(20 mL), and the organic layer was washed with water (10 mL), dried,
and evaporated. The resulting crude {1-[(1R,4S,7aR)-4-(tert-butyl-
dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-cyclopropyl}-
acetaldehyde (12) was redissolved in hexane and flash chromatographed
using 1:79 ethyl acetate–hexane as mobile phase to afford 12, an oil that
crystallized upon standing (0.83 g, mp 75–76 ꢁC, 97%). 1H NMR
(300 MHz, CDCl3) dꢀ0.02 (s, 3H), 0.0 (s, 3H), 0.3 (m, 2H), 0.5 (m,
1H), 0.8 (m, 1H), 0.88 (9H, s), 0.97 (s, 3H), 1.1 (m, 1H), 1.2–1.6 (m,
7H), 1.6–1.8 (m, 4H), 1.95 (m, 1H), 2.93 (ddd, 1H, Jgem ¼ 16.5, J ¼ 3.8,
J ¼ 1.7 Hz), 3.96 (br, 1H), 9.82 (m, 1H). Anal. calcd. for C21H38O2Si:
C, 71.94; H, 10.92. Found: C, 71.81; H, 11.02. The aldehyde 12, obtained
previously, was dissolved in 1:4 THF–methanol (10 mL), and undistilled
1a (0.45 g, 3 mmol) was added. The solution was cooled in an ice bath,
and powdered potassium carbonate (0.55 g, 4 mmol) was added to the
stirred solution. The ice bath was removed after 15 min, then stirred at
room temperature overnight. The disappearance of the starting material
(Rf 0.64) and the generation of the product (Rf 0.94) was followed by
TLC (1:9 ethyl acetate–hexane). The suspension was equilibrated with
water (5 mL) and hexane (30 mL); the aqueous phase was re-extracted
once with hexane (10 mL). The combined organic layers were washed
with brine (5 mL), dried (sodium sulfate), and evaporated. The residue
was flash chromatographed to elute 13 (hexane), which crystallized upon
standing (0.79 g, 96%, mp 48 ꢁC). 13C NMR (100 MHz, CDCl3) dꢀ4.86,
ꢀ4.54, 8.05, 9.06, 15.61, 17.71, 17.92, 18.27, 22.78, 22.97, 26.09, 28.28,

308
H. Maehr, M. R. Uskokovic, and C. P. Schaffner
34.64, 40.54, 43.98, 52.32, 53.28, 69.45, 69.70, 82.99. Anal. calcd. for
C22 H38OSi: C, 76.23; H, 11.05. Found: C, 76.08; H, 11.12.[33]
REFERENCES
1. Patai, S. (Ed.). The Chemistry of the Carbon-Carbon Triple Bond; Wiley:
New York, 1978.
2. Diederich, F.; Stang, P. J.; Tykwinski, R. R. (Eds.). Acetylene Chemistry;
Wiley: New York, 2004.
3. Grubbs, R. H. (Ed.). Handbook of Metathesis; Wiley: New York, 2003.
4. (a) Reddy, G. S.; Tserng, K. Y. Calcitroic acid, end product of renal
metabolism of 1,25-dihydroxyvitamin D3 through the C-24 oxidation
pathway. Biochem. 1989, 28, 1763–1769; (b) Horst, R. L.; Reinhardt, T. A.;
Reddy, G. S. Vitamin D metabolism. In Vitamin D, 2nd ed.; D. Feldman,
F. H. Glorieux, and J. W. Pike (Eds.); Academic Press: Amsterdam, 2005;
vol. 1, pp. 15–35.
5. Corey, E. J.; Fuchs, P. L. A synthetic method for formyl ! ethynyl
conversion (RCHO ! RCꢃCH or RCꢃCR0). Tetrahedron Lett. 1972, 13,
3769–3772.
6. Ramirez, F.; Desai, N. B.; McKelvie, N. A new synthesis of 1,1-dibromoo¨le-
fins via phosphine-dibromomethylenes: The reaction of triphenylphosphine
with carbon tetrabromide. J. Amer. Chem. Soc. 1962, 84, 1745–1747.
7. Furst, M.; Ruck-Braun, K. Safety-catch propargyl-based linker strategy for
¨
¨
the immobilization of amines and carboxylic acids in SPOS. Synlett. 2002,
12, 1991–1994.
8. Bestmann, H. J.; Frey, H. Reactions with phosphinealkylenes, 39: New
methods for the preparation of 1-bromoacetylenes and aromatic and
conjugated enynes. Liebigs Ann. Chem. 1980, 2061–2071.
9. Wang, Z.; Campagna, S.; Yang, K.; Xu, G.; Pierce, M. E.; Fortunak, J. M.;
Confalone, P. N. A practical preparation of terminal alkynes from aldehydes.
J. Org. Chem. 2000, 65, 1889–1891.
10. (a) Corey, E. J.; Achiwa, K.; Katzenellenbogen, J. A. Total synthesis of
dl-sirenin. J. Am. Chem. Soc. 1969, 91, 4318–4320; (b) Corey, E. J.; Ruden,
R. A. Stereoselective methods for the synthesis of terminal cis and trans
enyne units. Tetrahedron Lett. 1973, 14, 1495–1499; (c) Hengartner, U.;
Bernhard, K.; Meyer, K.; Englert, G.; Glinz, E. Synthesis, isolation, and
NMR-spectroscopic characterization of fourteen (Z)-isomers of lycopene
and of some acetylenic didehydro- and tetradehydrolycopenes. Helv. Chim.
Acta 1992, 75, 1848–1865; (d) Charoenying, P.; Davies, D. H.; McKerrecher,
D.; Taylor, R. J. K. A new stereocontrolled, pyrylium-based route to conju-
gated dienynes: The first synthesis of carduusyne A. Tetrahedron Lett. 1996,
37, 1913–1916.
11. Michel, P.; Gennet, D.; Rassat, A. A one-pot procedure for the synthesis
of alkynes and bromoalkynes from aldehydes. Tetrahedron Lett. 1996, 40,
8575–8578.

Homologation of Aldehydes to Alkynes
309
12. Carran, J.; Waschbusch, R.; Marinetti, A.; Savignac, P. An improved
¨
synthesis of dichloroalkylphosphonates, chloroalkynes, and terminal alkynes
via diethyl dichloromethylphosphonate. Synthesis 1996, 12, 1494–1498.
13. (a) Colvin, E. W.; Hamill, B. J. A simple procedure for the elaboration of car-
bonyl compounds into homologous alkynes. J. Chem. Soc. Perkin Trans. 1
1977, 869–874; (b) Colvin, E. W.; Hamill, B. J. One-step conversion of carbo-
nyl compounds into acetylenes. J. Chem. Soc., Chem. Commun. 1973, 151–152.
14. Illa, O.; Bagan, X.; Cazorla, A. M.; Lyon, C.; Baceiredo, A.; Branchadell, V.;
Ortuno, R. M. Reaction of C-silylated a-diazophosphines as nucleophiles
toward carbonyl compounds: A mechanistic study and application to the
synthesis of alkynes and a-hydroxyphosphonamides. J. Org. Chem. 2006,
71, 5320–5327.
15. (a) Miwa, K.; Shioiri, T.; Aoyama, T. Extension of the Colvin rearrangement
using trimethylsilyldiazomethane: A new synthesis of alkynes. Synlett 1994,
107–108; (b) Ito, Y.; Aoyama, T.; Shioiri, T. A new preparation of benzofur-
ans utilizing trimethylsilyldiazomethane. Synlett 1997, 10, 1163–1164.
16. Regitz, M.; Liedhegener, A.; Eckstein, U.; Martin, M.; Anschuetz, W. Diazo
compounds and azides, XIII: Mercuric and silver derivatives from diphenyl-
phosphinyl- and diethylphosphonodiazomethane. Liebigs Ann. Chem. 1971,
748, 207–210.
17. Seyferth, D.; Marmor, R. S.; Hilbert, P. Reactions of dimethylphosphono-
substituted diazoalkanes: (MeO)2P(O)CR transfer to olefins and 1,3-dipolar
additions of (MeO)2P(O)C(N2)R. J. Org. Chem. 1971, 36, 1379–1386.
18. Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois, R. G.; Hoye,
T. R.
A convenient synthesis of dimethyl (diazomethyl)phosphonate
(Seyferth=Gilbert reagent). J. Org. Chem. 1996, 61, 2540–2541.
19. Gilbert, J. C.; Weerasooriya, U. Diazoethenes: Their attempted synthesis
from aldehydes and aromatic ketones by way of the Horner–Emmons
modification of the Wittig reaction: A facile synthesis of alkynes. J. Org.
Chem. 1982, 47, 1837–1845.
20. Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. An improved one-pot
¨
procedure for the synthesis of alkynes from aldehydes. Synlett 1996, 521–522.
21. Meffre, P.; Hermann, S.; Durand, P.; Reginato, G.; Riu, A. Practical one-step
synthesis of ethynylglycine synthon from Garner’s aldehyde. Tetrahedron
2002, 58, 5159–5162.
22. Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Further improve-
¨
ments of the synthesis of alkynes from aldehydes. Synthesis 2004, 59–61.
23. Ohira, S. Methanolysis of dimethyl (1-diazo-2-oxopropyl)phosphonate:
Generation of dimethyl (diazomethyl)phosphonate and reaction with
carbonyl compounds. Synth. Commun. 1989, 19, 561–564.
24. (a) Barrett, A. G. M.; Hopkins, B. T.; Love, A. C.; Tedeschi, L. Parallel
synthesis of terminal alkynes using a ROMPgel-supported ethyl 1-diazo-2-
oxopropylphosphonate. Org. Lett. 2004, 6, 835–837; (b) For a review of
ROMP polymerization, see Harned, A. M.; Zhang, M.; Vedantham, P.;
Mukherjee, S.; Herpel, R. H.; Flynn, D. L.; Hanson, P. R. Aldrichimica Acta
2005, 38, 3–16.

310
H. Maehr, M. R. Uskokovic, and C. P. Schaffner
25. Taber, D. F.; Ruckle, Jr., R. E.; Hennessy, M. J. Mesyl azide: A superior
reagent for diazo transfer. J. Org. Chem. 1986, 51, 4077–4078.
26. Lee, J. C.; Yuk, J. Y. An improved and efficient method for diazo
transfer reaction of active methylene compounds. Synth. Commun. 1995,
25, 1511–1515.
27. (a) Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. A selective and
efficient method for alcohol oxidations mediated by N-oxoammonium salts
in combination with sodium bromite. J. Org. Chem. 1990, 55, 462–466;
(b) Siedlecka, R.; Skarzewski, J.; Mlochowski, J. Selective oxidation of pri-
mary hydroxy groups in prinary-secondary diols. Tetrahedron Lett. 1990,
31, 2177–2180; (c) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L.
Efficient and highly selective oxidation of primary alcohols to aldehydes by
N-chlorosuccinimide mediated by oxoammonium salts. J. Org. Chem. 1996,
61, 7452–7454.
28. Corbel, B.; L’Hostis-Kervella, I.; Haelters, J.-P. On a safe and practical
method fort he preparation of b-keto phosphonates. Synth. Commun. 1996,
26, 2561–2568.
´
29. Khabnadideh, S.; Didier Pez, D.; Musso, A.; Brun, R.; Ruiz Perez, L. M.;
Gonzalez-Pacanowska, D.; Gilbert, I. H. Design, synthesis, and evaluation
ꢀ
of 2,4-diaminoquinazolines as inhibitors of trypanosomal and leishmanial
dihydrofolate reductase. Bioorg. Med. Chem. 2005, 13, 2637–2649.
30. Lythgoe, B.; Roberts, D. A.; Waterhouse, I. Calciferol and its relatives,
part 20: A synthesis of Windaus and Grundmann’s C19 ketone. J. Chem.
Soc. Perkin Trans. 1 1977, 2608–2612.
31. Bouillon, R.; De Clerq, P. J.; Pirson, P.; Vandewalle, M.; Baudrihaye, M.
Preparation of epoxidized vitamin D derivatives as drugs. WO Patent,
9221695, 1992.
32. Barbier, P.; Bauer, F.; Mohr, P.; Muller, M.; Pirson, W. Preparation of
arylsecocholadiene derivatives with vitamin
9847866, 1998.
D activity. WO Patent,
33. Manchand, P. S.; Uskokovic, M. Preparation of 1,3-dihydroxy-20,20-dialkyl-
vitamin D3 analogs for pharmaceutical use. WO Patent, 9912894, 1999.