A stable reagent for synthesis of conjugated enynes from enals

Article abstract of DOI:10.1055/s-0029-1218010

Several conjugated enynes, which were not accessible if using the Ohira-Bestmann reagent, were synthesized from the corresponding enals using a newly developed reagent that has a longer shelf lifetime and can be activated under mild conditions. Georg Thie

Full text of DOI:10.1055/s-0029-1218010

LETTER
3037
A Stable Reagent for Synthesis of Conjugated Enynes from Enals
C
onjugated Enyne
a
s
n Zhang, Yun Li, Yikang Wu*
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86 (0)2164166128; E-mail: yikangwu@mail.sioc.ac.cn
Received 3 August 2009
One of the feasible routes to the new reagent 3 is shown in
Scheme 1. Deprotonation of the known 43 with n-BuLi
followed by treatment with g-butyrolactone introduced
the desired acyl chain. The hydroxyl group was then
masked4 as a Et3Si (TES) ether to suppress the possible in-
tramolecular attack of the hydroxyl group on the acyl
group leading to formation of g-butyrolactone (the same
process as desired in later reaction with aldehydes to yield
alkynes) during introduction of the diazo group. The TES
protecting group was then cleaved with AcOH–H2O in
THF at 0 °C to give the new reagent 3, a compound that
can be stored at room temperature for months without any
discernible decomposition.5,6
Abstract: Several conjugated enynes, which were not accessible if
using the Ohira–Bestmann reagent, were synthesized from the cor-
responding enals using a newly developed reagent that has a longer
shelf lifetime and can be activated under mild conditions.
Key words: alkynes, Wittig reactions, elimination, carbenes, phos-
phates
Dimethyldiazomethylphosphonate (1, Figure 1) is a mild
and useful reagent for the conversion of aldehydes into
corresponding alkynes.1 However, it is not very stable and
thus has to be prepared prior to use.1f To overcome this
shortcomings, Ohira2a and Bestmann2b introduced a mod-
ified reagent 2, which can be readily prepared and is much
easier to handle. On treatment with K2CO3 in MeOH, 2
undergoes facile reaction with the in situ formed methox-
ide anion to generate MeOAc and the anion of 1. The lat-
ter then reacts further with the aldehyde present in the
reaction mixture, yielding corresponding terminal alkyne.
O
O
P
O
O
P
O
P
OEt
OEt
OEt
OEt
a (ii)
a (i)
OEt
OEt
a (iii)
OTES
4
OH
4a
4b
O
O
OEt
b
a (iv)
TESO
P
3
While the Ohira–Bestmann reagent 2 is much more con-
venient to use than 1 and indeed works very well in many
cases, it is not applicable to substrates sensitive to MeOH/
methoxide (e.g., conjugated enals).2b,c In another project,
we needed to gain access to certain conjugated enynes
from the corresponding enals. Repeated failure with 2
prompted us to design a new reagent 3 (Figure 1), which
carries a hydroxyl group at the terminal of a three-carbon
chain and allows for generation of the desired diazo-
methane anion by cleavage of the acyl functionality via
lactonization instead of the intermolecular attack by a
methoxide ion as required for 2. Those side reactions
caused by methoxide hence can be avoided altogether.
OEt
5
N2
Scheme 1 Reagents and conditions: a) (i) n-BuLi, THF, g-butyro-
lactone, –78 °C; (ii) LDA; (iii) TESCl, 87% from 4; (iv) TsN3,
K2CO3, 68%; b) AcOH, H2O, THF, 0 °C, 70% from 5.
Conversion of aldehydes into alkynes with 3 was then
tested on conjugated enals (Scheme 2), the most difficult
subtype to which the Ohira–Bestmann reagent 2 is entire-
ly inapplicable. As cleavage of the acyl group in 3 to re-
lease the diazomethane anion 3a does not rely on the
intermolecular attack of methoxide ion and the relative
high temperature required in experiments with 2 is no
longer necessary, the reactions were performed at –78 °C
to minimize potential complications.
O
P
base
H
O
P
O
P
O
O
base
OMe
OMe
OEt
OEt
OMe
OMe
O
P
O
base
O
P
R1
R2
CHO
R3
N2
N2
O
OEt
OEt
N2
1
2
H
MeO
3
OEt
OEt
N2
O
H
N2
3
O
P
O
P
O
6
a
OEt
OEt
OMe
O
OEt
P
OMe
AcOMe
N2
••
N2
3a
O
OEt
1a
R1
R1
R2
C
O
N2
R1
R2
H
Figure 1 The structures of 1, 2, 3, and the anions generated
H
R2
R3
7
R3
R3
SYNLETT 2009, No. 18, pp 3037–3039
x
x
.x
x
.2
0
0
9
Advanced online publication: 08.10.2009
DOI: 10.1055/s-0029-1218010; Art ID: W12209ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Reagents and conditions: a) NaHMDS, THF, 18-crown-
5, –78 °C.

3038
Y. Zhang et al.
LETTER
Table 1 Results of Reaction of 3 with 6 Leading to 7a (continued)
Preliminary results with 3 are outlined in Table 1. Com-
pared with the broadly employed 2, which is entirely in-
applicable to these enals, the newly developed reagent 3
showed unambiguous advantages. In most cases the de-
sired conjugated enynes were formed in moderate to good
yields. Except 6a, which reacted well without any added
crown ether, all other substrates required addition of sub-
stantial amounts of 15-crown-5 ether to facilitate the reac-
tion.7,8
Entry Substrate
Product
Yield (%)
CHO
8
78
O2N
O2N
6h
7h
Table 1 Results of Reaction of 3 with 6 Leading to 7a
a Confer the general procedure given in ref. 8.
b No 15-crown-5 was used in this run.
c Along with 20% of recovered 6b.
d Along with 25% of recovered 6c.
e Along with 28% of recovered 6d.
f Along with 15% of recovered 6e.
g Along with 50% of recovered 6f.
h Along with 17% of recovered 6g.
Entry Substrate
Product
Yield (%)
83b
CHO
OTBS
I
I
OTBS
1
TESO
TESO
3
3
6a
7a
It was noted that in most runs where significant amounts
of starting aldehydes were recovered at the end of the
reaction, some unidentified intermediates (most likely,
the adducts before elimination of the phosphate and N2)
were also obtained in substantial quantities.
O
O
O
O
2
68c
H
H
CHO
In conclusion, a new reagent for conversion of aldehydes
into alkynes was developed, which contains a self-activa-
tion mechanism and thus may generate reactive diazo-
methane anion at low temperature on treatment with
NaHMDS in the presence of 15-crown-5. Compared with
the classic reagent 1, the newly developed 3 is remarkably
more stable, without any difficulty to store at ambient
temperature for months. Fresh preparation of the reagent
every time in need as with 1 is thus avoided. On the other
hand, because activation of this reagent (i.e., the cleavage
of the acyl group to generate the diazomethane anion)
does not rely on intermolecular attack of methoxide ion as
with the Ohira–Bestmann reagent 2, all the side reactions
stemming from the presence of MeOH/methoxide are
hence eliminated. As a consequence, the additional limi-
tations on the types of substrates associated with 2, which
appear to be the price one has to pay for its facile prepara-
tion, storage, and use compared with 1, are circumvented.
Conjugated enynes as those shown in Table 1, which are
not attainable with 2, can now be smoothly obtained from
the corresponding enals.
6b
7b
CHO
3
4
42d
t-Bu
t-Bu
6c
7c
CHO
OBn
22e
OBn
6d
6e
7d
CHO
OBn
5
6
7
38f
63g
35h
OBn
7e
7f
OTBS
CHO
OTBS
O
O
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
6f
CHO
Acknowledgment
Financial support from the National Natural Science Foundation of
China (20672129, 20621062, 20772143) and the Chinese Academy
of Sciences (‘Knowledge Innovation’, KJCX2.YW.H08) is grate-
fully acknowledged.
6g
7g
Synlett 2009, No. 18, 3037–3039 © Thieme Stuttgart · New York

LETTER
Conjugated Enynes
3039
sat. NH4Cl, and dried over anhyd Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography
(PE–EtOAc = 3:1) on silica gel gave 5 as a colorless oil
(5.53 g, 68% from the intermediate acyl phosphate).
1H NMR (300 MHz, CDCl3): d = 4.25–4.08 (m, 4 H), 3.65
(t, J = 6.0 Hz, 2 H), 2.66 (t, J = 7.3 Hz, 2 H), 1.86 (quin,
J = 6.6 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 6 H), 0.96 (t, J = 7.9 Hz,
9 H), 0.59 (q, J = 7.9 Hz, 6 H). FT-IR (film): 3412, 2955,
2123, 1659, 1253, 1019, 977, 742, 589 cm–1. ESI-MS: m/z =
401.1 [M + Na]+. ESI-HRMS: m/z calcd for
References and Notes
(1) (a) Seyferth, D.; Marmor, R. S. Tetrahedron Lett. 1970,
2493. (b) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org.
Chem. 1971, 36, 1379. (c) Brown, D. G.; Velthuisen, E. J.;
Commerford, J. R.; Brisbois, R. G.; Hoye, T. R. J. Org.
Chem. 1996, 61, 2540. (d) Colvin, E. W.; Hamill, B. J.
J. Chem. Soc., Chem. Commun. 1973, 151. (e) Gilbert,
J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.
(f) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 74,
1837. (g) A referee informed us that Maehr et al. recently
reported that 1 is more stable than previously believed and
could be stored in refrigerators for years, see: Maehr, H.;
Uskokovic, M. R.; Schaffner, C. P. Synth. Commun. 2009,
39, 299.
C15H31N2O5PSiNa: 401.1632 [M + Na]+; found: 401.1634.
AcOH (11 mL) was added slowly to a solution of 5 (2.5 g,
6.76 mmol) in THF–H2O (20 mL, 1:1 v/v) stirred in an ice-
water bath. After completion of the addition, the mixture was
stirred at the same temperature for another 10 min. Na2CO3
was carefully added to neutralize the acid. The mixture was
extracted with EtOAc. The combined organic layers were
concentrated on a rotary evaporator. The residue was
chromatographed (PE–EtOAc = 1:2) on silica gel to give 3
as yellowish oil (1.25 g, 4.73 mmol, 70%).
(2) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Roth, G. J.;
Liepold, B.; Müller, S.; Bestmann, H. J. Synthesis 2004, 59.
(c) Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J.
Synlett 1996, 521.
(3) Teulade, M.-P.; Savignac, P.; Aboujaoude, E. E.; Collignon,
1H NMR (300 MHz, CDCl3): d = 4.30–4.10 (m, 4 H), 3.66
(t, J = 6.1 Hz, 2 H), 2.72 (t, J = 6.9 Hz, 2 H), 2.10–1.90 (br
s, 1 H), 1.92 (quin, J = 6.5 Hz, 2 H), 1.39 (t, J = 7.0 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 193.2 (d, JC–P = 14 Hz),
63.5 (d, JC–P = 6 Hz), 61.3, 35.9, 27.1, 15.9 (d, JC–P = 7 Hz).
FT-IR (film): 3443, 2986, 2118, 1656, 1369, 1251, 1032,
977, 593 cm–1. ESI-MS: m/z = 287.0 [M + Na]+. ESI-HRMS:
m/z calcd for C9H17N2O5PNa: 287.0767 [M + Na]+; found:
287.0769.
N. J. Organomet. Chem. 1986, 312, 283.
(4) Ditrich, K.; Hoffmann, R. W. Tetrahedron Lett. 1985, 26,
6325.
(5) Synthesis of Compound 3
n-BuLi (2.5 M in hexanes, 15.76 mL, 39.4 mmol) was added
to a solution of 4 (6.0 g, 39.4 mmol) in dry THF (40 mL)
stirred at –78 °C under argon. The mixture was stirred at the
same temperature for 1 h before a solution of g-butyro-
lactone (2.15 mL, 28 mmol) in dry THF (5 mL) was
introduced. The originally slightly cloudy mixture now
became clear. The bath temperature was allowed to rise
slowly to ambient temperature. The stirring was then
continued for another 2 h. After that, the bath was re-cooled
to –78 °C before a solution of LDA (28 mmol, freshly
prepared from 4.0 mL of i-Pr2NH and 11.2 mL of 2.5 M n-
BuLi) in dry THF (20 mL) was introduced. The mixture was
stirred for 30 min. TESCl (9.4 mL, 56 mmol) was then
added. The mixture was stirred at ambient temperature
overnight. Aq sat. NH4Cl was added, followed by EtOAc.
The phases were separated. The organic layer was washed
with H2O and brine before being dried over anhyd Na2SO4.
Removal of the solvent by rotary evaporation and column
chromatography (PE–EtOAc = 1:1 to 1:2) on silica gel gave
the intermediate acyl phosphate 4b as a colorless oil (8.57 g,
87% from 4).
(6) For the reaction of diakyl methylphosphate with g-
butyrolactone, see: Ditrich, K.; Hoffmann, R. W.
Tetrahedron Lett. 1985, 26, 6325.
(7) In the absence of the crown ether, the reaction was very
slow; most of the starting enal (except 6a) remained
unchanged after 4–5 h at –78 °C along with some
uncharacterized intermediates and small amounts of the
desired enyne.
(8) General Procedure for the Conversion of 6 into 7
NaHMDS (2.0 M in THF, 55 mL, 0.11 mmol) was added to
a solution of 3 (29 mg, 0.11 mmol) in dry THF (1.0 mL)
stirred at –78 °C under argon. The mixture was stirred at the
same temperature for 30 min, when a solution of enal 6
(0.073 mmol) in dry THF (0.5 mL) was added slowly (the
mixture darkened soon). 15-Crown-5 ether (22 mL, 0.11
mmol) was then added in one portion. The mixture was
stirred at the same temperature for 1 h. Aq sat. NH4Cl was
added, followed by Et2O. The phases were separated. The
organic layer was dried over anhyd Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography
on silica gel gave the corresponding 7.
A portion of this oil (4b, 7.596 g, 21.5 mmol) was dissolved
in THF (30 mL). With cooling (ice-water bath) and stirring,
powdered K2CO3 (3.3 g, 23.9 mmol) was added, followed by
TsN3 (4.7 g, 23.9 mmol). The mixture was stirred at the bath
temperature for 2 h and then at ambient temperature
overnight before being diluted with Et2O, washed with aq
Synlett 2009, No. 18, 3037–3039 © Thieme Stuttgart · New York

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