In situ generation of the Ohira-Bestmann reagent from stable sulfonyl azide: Scalable synthesis of alkynes from aldehydes

Article abstract of DOI:10.1021/jo501803f

We report an improved method for in situ generation of the Ohira-Bestmann reagent. Using the recently reported bench-stable imidazole-1-sulfonyl azide as diazotransfer reagent, this new method represents a scalable and convenient approach for the transformation of aldehydes into terminal alkynes. The method features an easier workup compared to the existing in situ protocol due to increased aqueous solubility of waste products.

Full text of DOI:10.1021/jo501803f

Note
pubs.acs.org/joc
In Situ Generation of the Ohira−Bestmann Reagent from Stable
Sulfonyl Azide: Scalable Synthesis of Alkynes from Aldehydes
Tue Heesgaard Jepsen and Jesper Langgaard Kristensen*
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen,
Universitetsparken 2, 2100 Copenhagen, Denmark
S
* Supporting Information
ABSTRACT: We report an improved method for in situ
generation of the Ohira−Bestmann reagent. Using the recently
reported bench-stable imidazole-1-sulfonyl azide as diazotrans-
fer reagent, this new method represents a scalable and
convenient approach for the transformation of aldehydes
into terminal alkynes. The method features an easier workup
compared to the existing in situ protocol due to increased aqueous solubility of waste products.
he Corey−Fuchs reaction represents the first synthetically
unstable and explosive diazotransfer reagent (TsN3) that
compromises the scalability of the reaction. Furthermore, the
waste products of the reaction are, contrary to the ex situ
procedure,5 no longer removable by aqueous workup due to
the formation of p-toluene-sulfonylamide, and thus further
purification of the product is necessary.
T
useful method for transforming aldehydes into alkynes by
a two-step procedure using strong base.1,2 A more convenient
alternative, the Seyferth−Gilbert homologation3,4 (Scheme 1),
Scheme 1. Homologation Reactions
Here we report an improved method for the in situ
generation of the Ohira−Bestmann reagent. In recent years
several alternative diazotransfer reagents (Figure 1) with
improved safety and handling properties have been devel-
oped.17 Although frequently used, TfN3, MsN3, and TsN3 are
considered as highly unstable reagents, whereas alternatives,
such as ABSA, are considerably safer to handle.8 The crystalline,
shelf-stable (when stored under anhydrous conditions!), and
water-soluble imidazole-1-sulfonyl azide hydrochloride (2)18−20
is one of the most convenient diazotransfer reagents available.21
Thus, application of this reagent would provide a safer and
more scalable procedure than the current in situ protocols. This
imidazole-based diazotransfer reagent, contrary to most other
alternatives, generates water-soluble waste products, which
should predominantly be removable by aqueous workup, and
thus allows easy purification, comparable to the ex situ
Bestmann protocol.5 We became interested in this trans-
formation when we needed to prepare several grams of alkyne
4f. With the aim of avoiding the scale-up using p-toluene-
sulfonylazide, we looked for alternatives. It was not obvious that
2 would be suitable for the task as imidazole-1-sulfonyl azide is
known to possess poor reactivity toward activated methylene
compounds,22 and other water-soluble azides perform poorly in
the preparation of 1.13 Various reaction conditions were
screened in order to optimize the protocol (Table 1).
Gratifyingly, the formation of the Ohira−Bestmann reagent
proceeded smoothly with full conversion (judged by HPLC and
TLC) of dimethyl-2-oxopropylphosphonate in all test reactions.
has proven to be a reliable and efficient method that has
become very popular. The Ohira−Bestmann modification5 uses
even milder reaction conditions, employing a weak base in
alcoholic solvent at ambient temperature in order to generate
the same reactive species in situ. The Ohira−Bestmann
modification has indeed evolved as an efficient procedure for
preparation of alkynes from aldehydes, and modifications to the
original procedure continue to be reported.6−12
Although the Ohira−Bestmann reagent (1) generally delivers
high-yielding reactions with short reaction times, one of the
drawbacks is the relatively high price of the commercially
available material. In 2004 Bestmann and colleagues reported
an in situ generation of the Ohira−Bestmann reagent.13 The
reagent was generated from dimethyl-2-oxopropylphosphonate
and TsN3 (Figure 1) in the presence of K2CO3 in MeCN
followed by addition of the desired aldehyde in MeOH.
Although it was a clear improvement with yields comparable to
those of the original procedure, it still requires the use of an
Received: August 5, 2014
Figure 1. Commonly used diazotransfer reagents.
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
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a
K2CO3 was crucial in order to generate the reactive anionic
species. Moreover, the Horner−Wadsworth−Emmons product
(5) was observed when DIPEA (entry 11) was used as a base
and when DMF (entry 2) or MeOH (entry 12) was used as
solvent A. MeCN was found to be superior for generating and
stabilizing 1, and interestingly we found that the ratio between
solvent A and MeOH (added along with the aldehyde) was
crucial to the conversion rate (entries 7−9). Attempts to utilize
water as a solvent (entries 4−6) worked with minor success,
although extended reaction time gave higher conversion than
those listed in entries 4−6. Attempts to develop one-pot
conditions (entries 13 and 14) proved inferior, and the
optimized conditions ended up being entry 9 with full
conversion into the desired alkyne 4 based on LC−MS. In
this optimized protocol dimethyl-2-oxopropylphosphonate and
imidazole-1-sulfonyl azide hydrochloride (2) were added to a
suspension of K2CO3 in MeCN. After stirring for 2 h at 25 °C
the desired aldehyde (dissolved in MeOH) was added, and
stirring was continued at 25 °C for 15 h. The waste products
formed were mostly removable by aqueous workup leaving a
product pure enough for subsequent manipulation without the
need for further purification.
With this new protocol in hand we set out to compare the
scope of the reaction with the previous syntheses. The
experiments were performed on 1.0 mmol scale in order to
compare directly with the previous procedures by Bestmann
and colleagues.5,13 Generally the isolated yields were com-
parable and in some cased even improved slightly, ranging from
71% to 90%, with LC/GC yields ranging from 85% to >95%
(Table 2). In analogy to the procedures by Bestmann and
colleagues the scope of this method is broad and effective with
Table 1. Optimization of Reaction Conditions
solvent ratio
(A:MeOH)
LC−MS yield
entry
solvent A
3:4:5
b
1
DMF
DMF
no MeOH
2:1
100:0:0
44:39:17
67:33:0
51:49:0
91:9:0
2
3
4
5
6
7
8
9
MeCN/DMSO (5:1)
MeCN/H2O (5:1)
H2O
2:1
2:1
2:1
THF/H2O (2:1)
MeCN
2:1
79:21:0
91:9:0
6:1
MeCN
2:1
10:90:0
0:100:0
53:47:0
52:0:48
55:36:10
100:0:0
34:66:0
MeCN
1:1
c
10
MeCN
1:1
d
11
MeCN
1:1
b
,e
12
13
14
MeOH
f
MeCN/H2O (5:1)
MeOH
no MeOH
f
a
General conditions: 2·HCl (1.3 equiv), dimethyl-2-oxopropylphosph-
onate (1.2 equiv), K2CO3 (4.5 equiv), solvent A, 25 °C, 2 h; then p-
chlorobenzaldehyde (3, 1.0 equiv), MeOH, 25 °C, 15 h. Aldehyde
was added without solvent. Temperature was 50 °C. DIPEA (4.5
equiv) was used instead of K2CO3. Reaction time was 0.5 h before
aldehyde addition. All reagents were mixed in one pot.
b
c
d
e
f
However, the homologation step was rather sensitive to the
specific reaction conditions, and the presence of MeOH and
a
Table 2. Comparison of This Method for the Synthesis of Alkynes 4a−4h with Existing Protocols
a
General conditions: 2·HCl (1.2 mmol), dimethyl-2-oxopropylphosphonate (1.2 mmol), K2CO3 (4.5 mmol), MeCN, 25 °C, 2 h; then aldehyde (3,
1.0 mmol), MeOH, 25 °C, 15 h. Isolated yields based on Bestmann and colleagues previous protocols5,13 if not noted otherwise. According to the
literature, 4h has previously been prepared by 1,3-dipolar cycloaddition chemistry.16 Our NMR data is inconsistent with those reported in the
literature, and thus the literature yield should be viewed with caution.
b
c
B
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The Journal of Organic Chemistry
Note
mg, 1.3 mmol) in MeCN (10 mL), and the colorless suspension was
stirred at 25 °C for 2 h. Then a solution of aldehyde 3a (141 mg, 1.0
mmol) in MeOH (10 mL) was added to the now pale yellow
suspension and stirred at 25 °C for 15 h. The reaction mixture was
filtered, the filter cake was washed with Et2O (3 × 3 mL), and the clear
solution was carefully evaporated onto Celite without evaporating the
volatile alkyne products. The material was loaded onto a short plug (2
cm high), flushed with pentane (4 × 10 mL), and concentrated
carefully in vacuo to afford alkyne 4a (117 mg, 86%) with spectral data
in accordance with previous characterizations.13 Rf = 0.55 (silica gel,
heptane/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.5
Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 3.11 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 134.9, 133.4, 128.7, 120.6, 82.5, 78.2; GC−MS 136 m/z
(M+)
both aliphatic (3d−3f) and aryl aldehydes (3a−3c) as well as
enolizable aldehydes (3d−3f). Even electron-rich aryl alde-
hydes (3b, 3c) work successfully. Several functional groups
have generally proven to be compatible with the methodology
including bromoether (3c23), isolated olefin (3d), amino acid
derivative (3f24), and indole and triazole derivatives (3g, 3h). It
should be noted that the highly volatile nature of a number of
terminal alkynes (4b, 4d, 4f) influenced the isolated yields. LC/
GC yields indicated full and clean conversion of starting
material into the desired alkynes in most cases.
In order to demonstrate the scalability and robustness of this
new procedure, two of the compounds were additionally
prepared on multigram scale with even higher yields compared
to the minor scale. Compound 4f was prepared on 5.2 g scale
(26.4 mmol) in 76% yield after chromatography compared to
the 71% on 1.0 mmol scale. Compound 4h was prepared on 7.9
g scale (46.5 mmol) in 89% yield after recrystallization
compared to the 81% on 1.0 mmol scale (Scheme 2).
4b. The general procedure was followed by using aldehyde 3b (136
mg, 121 μL, 1.0 mmol), and the highly volatile alkyne 4b (98 mg,
74%) was isolated with spectral data in accordance with previous
characterizations.26 Rf = 0.41 (silica gel, heptane/EtOAc, 4:1); 1H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7
Hz, 2H), 3.81 (s, 3H), 3.00 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
159.9, 133.6, 114.2, 113.9, 83.7, 75.8, 55.3; GC−MS 132 m/z (M+)
4c. The general procedure was followed by using aldehyde 3c23
(277 mg, 1.0 mmol), and the desired alkyne 4c (241 mg, 88%) was
isolated with spectral data in accordance with previous character-
izations.14,27 Rf = 0.39 (silica gel, heptane/EtOAc, 4:1); 1H NMR (400
MHz, CDCl3) δ 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.56 (dd, J = 7.7, 1.7
Hz, 1H), 7.27 (m, 2H), 7.12−7.00 (m, 2H), 6.94 (dd, J = 8.1, 1.5 Hz,
1H), 6.77 (dd, J = 8.3, 1.1 Hz, 1H), 3.25 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 157.9, 153.4, 134.4, 133.8, 130.2, 128.6, 125.2, 123.4,
120.5, 117.7, 114.8, 114.0, 82.1, 79.0; GC−MS 274 m/z (M+)
4d. The general procedure was followed by using aldehyde 3d (154
mg, 180 μL, 1.0 mmol), and the highly volatile alkyne 4d (115 mg,
77%) was isolated with spectral data in accordance with previous
characterizations.13 Rf = 0.48 (silica gel, heptane/EtOAc, 4:1); 1H
NMR (400 MHz, CDCl3) δ 5.03 (m, 1H), 2.15−1.89 (m, 4H), 1.88 (t,
J = 2.7 Hz, 1H), 1.65−1.56 (m, 4H), 1.54 (m, 3H), 1.44−1.33 (m,
1H), 1.25−1.14 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 131.5, 124.4, 83.4, 69.0, 36.0, 31.9, 25.7, 25.5, 22.3,
19.3, 17.6; GC−MS 150 m/z (M+)
Scheme 2. Scale-Up Experiments
In summary, we have developed an improved procedure for
the Bestmann modification of the Seyferth−Gilbert homo-
logation. Our methodology takes advantage of a very
convenient diazotransfer reagent, which is among the safest
available, in the one-pot Ohira−Bestmann reagent preparation
and subsequent homologation reaction in order to prepare
alkynes from aldehydes. We have demonstrated comparable or
improved yields in the synthesis of a various alkynes compared
to the previous methods, and this protocol allows for more
convenient product purification since most waste products are
removable by aqueous workup, using a safer combination of
reagents.
4e. The general procedure was followed by using aldehyde 3e (184
mg, 222 μL, 1.0 mmol), and the desired alkyne 4e (162 mg, 90%) was
isolated with spectral data in accordance with previous character-
izations.13 Rf = 0.59 (silica gel, heptane/EtOAc, 4:1); H NMR (400
1
MHz, CDCl3) δ 2.17 (m, 2H), 1.92 (t, J = 2.7 Hz, 1H), 1.56−1.22 (m,
18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 82.9,
66.2, 30.1, 27.8, 27.7, 27.5, 27.3, 26.9, 26.7, 20.8, 16.6, 12.3, 12.2; GC−
MS 180 m/z (M+)
4f. Dimethyl-2-oxopropylphosphonate (6.90 g, 5.74 mL, 41.6
mmol) was added to a suspension of K2CO3 (21.5 g, 156 mmol)
and 1H-imidazole-1-sulfonyl azide hydrochloride (9.44 g, 45.0 mmol)
in MeCN (300 mL), and the colorless suspension was stirred at 25 °C
for 2 h. Then a solution of aldehyde 3f24 (6.90 g, 34.6 mmol) in
MeOH (300 mL) was added to the pale yellow suspension and stirred
at 25 °C for 15 h. The reaction mixture was filtered, the filter cake was
washed with Et2O (3 × 50 mL), and the clear solution was carefully
evaporated onto Celite without evaporating the volatile alkyne. The
Celite-absorbed material was purified by dry column vacuum
chromatography (heptane → EtOAc, 5% gradient), and the highly
volatile alkyne 4f (5.16 g, 76%) was isolated with spectral data in
accordance with previous characterizations.6 Rf = 0.70 (silica gel,
EXPERIMENTAL SECTION
■
All reactions were carried out under a nitrogen atmosphere with
HPLC grade solvents. Yields refer to chromatographically and
spectroscopically (1H and 13C NMR) homogeneous materials.
Reagents were purchased at the highest commercial quality and used
without further purification. Reactions were monitored by LC−MS
(ESI) or GC−MS (EI) and TLC carried out on 0.25 mm silica gel
plates using UV light as visualizing agent and either ninhydrin or
potassium permanganate stain as an indicator. Silica gel (60 Å,
academic grade, particle size 15−40 μm) was used for short plugs and
for dry column vacuum chromatography.25 NMR spectra were
recorded on 400 and 600 MHz instruments and calibrated using
residual undeuterated solvent as an internal reference. Low-resolution
mass spectra were obtained by either GC−MS (EI) or LC−MS (ESI).
Abbreviations: THF, tetrahydrofuran; DMF, N,N-dimethylformamide;
MeOH, methanol; MeCN, acetonitrile; EtOAc, ethyl acetate
1
heptane/EtOAc, 1:1); H NMR (400 MHz, CDCl3) δ 4.38 (m, 1H),
3.46−3.33 (m, 1H), 3.24 (m, 1H), 2.15 (s, 1H), 1.98 (m, 3H), 1.83
(m, 1H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 154.0, 84.3,
79.7, 69.5, 47.9, 45.6, 33.6, 33.1, 29.0, 28.5, 28.5, 23.6, 22.7, 21.0; GC−
MS 195 m/z (M+)
4g. The general procedure was followed by using aldehyde 3g (159
mg, 1.0 mmol). The Celite-absorbed material was purified by dry
column vacuum chromatography (heptane → EtOAc, 2% gradient),
and the desired alkyne 4g (135 mg, 87%) was isolated with spectral
data in accordance with previous characterizations.15 Rf = 0.52 (silica
General Procedure. 4a. Dimethyl-2-oxopropylphosphonate (199
mg, 166 μL, 1.2 mmol) was added to a suspension of K2CO3 (622 mg,
4.5 mmol) and 1H-imidazole-1-sulfonyl azide hydrochloride20 (272
C
dx.doi.org/10.1021/jo501803f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
gel, heptane/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 7.59 (dt, J =
8.0, 1.0 Hz, 1H), 7.32−7.26 (m, 2H), 7.12 (ddd, J = 8.0, 4.8, 3.2 Hz,
1H), 6.83 (s, 1H), 3.82 (s, 3H), 3.47 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 137.1, 126.9, 123.3, 121.1, 120.9, 120.2, 109.5, 108.3, 83.3,
75.6, 30.6; GC−MS 155 m/z (M+)
(20) Sminia, T. J.; Pedersen, D. S. Synlett 2012, 23, 2643.
(21) Subsequent to their original publication (ref 18) Goddard-
Borger et al. published a warning about the reagent. It is crucial that
the material is kept under anhydrous conditions as detonation of a wet
sample has been observed, presumably due to the formation of
hydrazoic acid. Further details about these concerns can be found in
Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2011, 13, 2514−2514.
The hydrogen sulfate salt was recently reported as a safer alternative,
but in our hand this salt did not precipitate as described: Fischer, N.;
4h. Dimethyl-2-oxopropylphosphonate (10.4 g, 8.62 mL, 62.4
mmol) was added to a suspension of K2CO3 (32.3 g, 234 mmol) and
1H-imidazole-1-sulfonyl azide hydrochloride (14.2 g, 67.6 mmol) in
MeCN (450 mL), and the colorless suspension was stirred at 25 °C
for 2 h. Then a solution of aldehyde 3h (9.0 g, 52.0 mmol) in MeOH
(450 mL) was added to the pale yellow suspension and stirred at 25
°C for 15 h. The reaction mixture was filtered, the filter cake was
washed with Et2O (3 × 50 mL), and the clear solution was carefully
evaporated to dryness. Water was added (400 mL), the aqueous layer
was extracted with Et2O (4 × 100 mL), and the combined organic
layers were washed with brine (2 × 50 mL), dried with magnesium
sulfate, filtered, and concentrated in vacuo. The crude material was
recrystallized from EtOH/water to furnish alkyne 4h with spectral data
deviating from previous characterizations.16 (7.86 g, 89%). Rf = 0.65
Goddard-Borger, E. D.; Greiner, R.; Klapotke, T. M.; Skelton, B. W.;
̈
Stierstorfer, J. J. Org. Chem. 2012, 77, 1760.
(22) Presset, M.; Mailhol, D.; Coquerel, Y.; Rodriguez, J. Synthesis
2011, 2549.
(23) Jepsen, T. H.; Larsen, M.; Jørgensen, M.; Nielsen, M. B. Synlett
2012, 3, 418.
(24) Molander, G. A.; Romero, J. A. C. Tetrahedron 2005, 61, 2631.
(25) Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 2431.
(26) Feng, Y.-S.; Xie, C.-Q.; Qiao, W.-L.; Xu, H.-J. Org. Lett. 2013,
15, 936.
1
(silica gel, heptane/EtOAc, 1:1); H NMR (400 MHz, CD3OD) δ
(27) Tietze, L. F.; Hungerland, T.; Eichhorst, C.; Dufert, A.; Maaß,
̈
8.74 (s, 1H), 7.90−7.78 (m, 2H), 7.65−7.46 (m, 3H), 3.87 (s, 1H);
13C NMR (101 MHz, CDCl3) δ 138.0, 131.9, 131.0, 130.4, 127.1,
121.7, 83.4, 73.4; LC−MS 170 m/z (M + 1)
C.; Stalke, D. Angew. Chem., Int. Ed. 2013, 52, 3668.
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectral data for all compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jesper.kristensen@sund.ku.dk.
■
Notes
The authors declare no competing financial interest.
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