Hydrophobically assisted separation-friendly Mitsunobu reaction

Article abstract of DOI:10.1055/s-0031-1290406

A separation-friendly Mitsunobu reaction using hydrophobic-tagged acids is reported. Commercially available or simply prepared and recyclable hydrophobic-tagged acids can react with various alcohols to afford the target products in high yield with easy purification based on C-18 silica solid-phase extraction or normal silica gel filtration. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290406

1696▌
LETTER
letter
Hydrophobically Assisted Separation-Friendly Mitsunobu Reaction
Hydrophobically Assisted Separation-Friendly Mitsunobu Reaction
Jian Guo, Yu-Jiao Lu, Li Zhang, Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road 38, Beijing
100191, P. R. of China
Fax +86(10)82802724; E-mail: xinshan@bjmu.edu.cn
Received: 09.04.2012; Accepted after revision: 06.05.2012
used separation material that can be used repeatedly after
Abstract: A separation-friendly Mitsunobu reaction using hydro-
recovery. In 2002, the fluorous-pronucleophile Mitsuno-
phobic-tagged acids is reported. Commercially available or simply
bu reaction was reported by the Dembinski group.4a In-
spired by this work, we herein demonstrate that the
prepared and recyclable hydrophobic-tagged acids can react with
various alcohols to afford the target products in high yield with easy
purification based on C-18 silica solid-phase extraction or normal hydrophobic tag, possessing the additional merits of low-
silica gel filtration.
cost and environmentally friendly biodegradation com-
pared with the fluorous tag, can also be applied to the
Mitsunobu reaction (Scheme 1).
Key words: Mitsunobu reaction, esterification, hydrophobic tag,
solid-phase extraction, inversion of configuration
OH
CO2H
+ Ph3P + DEAD
hydrophobic tag
hydrophobic tag
+
The Mitsunobu reaction involves the dehydrative cou-
pling of an alcohol with an acidic pronucleophile, promot-
ed by triphenylphosphine (Ph3P) and diethyl azo-
dicarboxylate (DEAD). It is a widely used method in or-
ganic synthesis and medicinal chemistry,1 in particular for
the inversion of configuration in secondary alcohols via
an esterification/hydrolysis procedure. However, it is no-
torious for its separation headaches. This reaction produc-
es the desired coupling product, along with the reagent-
derived byproducts diethoxycarbonylhydrazine (DECH)
and triphenylphosphine oxide (TPPO), which are often
difficult to remove even through careful chromatography.
R1
R2
O
O
R2
R1
+ TPPO + DECH
purification by C-18 SPE
or silica gel filtration
Scheme 1 Hydrophobically assisted separation-friendly Mitsunobu
reaction
In order to verify the feasibility of this concept, commer-
cially available p-(dodecyloxy)benzoic acid (1) was cho-
sen to test the reaction with ethanol under Mitsunobu
conditions. As expected, this reaction occurred in a quick
and quantitative manner, and rapid purification of the
product was realized by C-18 silica SPE. Since the Rf val-
ues of the product (Rf = 0.81, petroleum ether–ethyl ace-
tate, 4:1) and byproducts showed significant difference
(ΔRf > 0.6) on TLC, the isolation procedure based on sili-
ca gel filtration, which is more appropriate for large-scale
preparation, was also investigated with the optimized elu-
ent system; gratifyingly, this separation process gave the
same satisfactory result. This encouraging result led us to
check several other representative alcohols with various
functional groups and different carbon skeletons, includ-
ing some commercially available alcohols (b–g) and syn-
thetic intermediates (h and i); the results are summarized
in Table 1. Most of the reactions were complete in three
hours and gave good yields with easier purification. How-
ever, when this protocol was extended to sterically hin-
dered alcohol substrates (g, h, and i), workup of the
reactions were complicated by the similar Rf values of the
product and byproducts. In these cases, the products had
to be purified by column chromatography due to the for-
mation of byproducts 4 and 5, which showed similar po-
larities to the target products.
In recent years, separation-friendly strategies have been
introduced into the Mitsunobu reaction to facilitate prod-
uct isolation, and the advances have been reviewed com-
prehensively.1b,2 The improvements mainly include the
use of solid support,3 various ‘phase tags’,4 ring-opening
metathesis polymerization-derived oligomeric reagents
and scavengers.5 In spite of these innovations, the devel-
opment of more separation-friendly, cost-saving, and ef-
fective Mitsunobu protocols is still needed.
Hydrophobic tags, based on long alkyl chains, have been
utilized in organic synthesis, especially for reactions that
involve inefficient purification procedures.6 In compari-
son to solid-phase synthesis, hydrophobic tagging proto-
cols allow reactions to be carried out in the solution phase,
avoiding the use of excess reagents, longer reaction times,
or harsher conditions, while preserving the advantages of
straightforward isolation procedures. Such separation
procedures could be realized in a number of flexible
ways,6 especially by C-18 silica solid-phase extraction
(SPE),6a,g which can lead to separation of the hydropho-
bic-tagged compounds and non-tagged compounds rapid-
ly and effectively. Moreover, C-18 silica is a commonly
SYNLETT 2012, 23, 1696–1700
Advanced online publication: 14.06.2012
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3
6
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5
2
1
4
1
4
3
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2
0
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DOI: 10.1055/s-0031-1290406; Art ID: ST-2012-W0312-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydrophobically Assisted Separation-Friendly Mitsunobu Reaction
1697
p-(methylsulfonyl)benzoic acid because we anticipated
that substitution of its methyl group with a long alkyl
chain may meet our demands. Therefore, acid 7 was pre-
pared from 6 by successive nucleophilic aromatic substi-
tution,9 oxidation, and hydrolysis (Scheme 3). It should be
noted that the nucleophilic aromatic substitution was ac-
celerated by ultrasonic irradiation and was completed
within five minutes. With acid 7 in hand, various alcohol
substrates, including hindered menthol, were investigated
again. All of these reactions showed only one spot on the
top part of TLC and no low polarity byproducts were de-
tected. However, the introduction of a polar sulfone group
weakened the absorption of products on C-18 silica gel
significantly, especially in the case of relatively more po-
lar alcohol i. Thus, silica gel filtration was selected as the
isolation process;10 as shown in Table 2, straightforward
purification was achieved in all examples, except for alco-
hol i, the product spot of which had an Rf value that was
too similar to the byproducts (ΔRf = 0.2).
Table 1 Mitsunobu Reaction with Hydrophobic-Tagged Acid 1
ROH
n-C12H25
O
CO2H
n-C12H25
O
CO2R
Ph3P, DEAD
1
2
ROH (a–i):
HO
HO
HO
O
OH
a
b
c
d
OH
HO
·
e
f
OBn
HO
TBDPSO
OBn
OH
g
h
O
NO2
O
O
O
O
O
Ph
O
O
N–
C
Ph
O
OH
Ph3P + DEAD
C
N
OEt
i
j
EtO
+PPh3
3 or 4
Entry
ROH
Ester product
Yield (%)a
R1CO2H
O
R1
N
1
2
3
4
5
6
7
8
9
a
2a
2b
2c
2d
2e
2f
95
O
C
O
O
HN
N
C
O
C
b
c
d
e
f
92
C
OEt
N
OEt
EtO
+PPh3
90
+PPh3
EtO
OH
O
R1CO2
path 2
–
path 1
R1CO2
–
91
R2
R3
O
89
+PPh3
R3
+PPh3
O
O
N–
C
C
O
92
N
OEt
+ 3
R1
OEt
R2
R1
g
h
i
2g
2h
2i
17b
27b
15b
O
3
R1CO2
–
R1CO2
O
–
R1
O
R1
O
O
a Reaction conditions: alcohol/acid/Ph3P/DEAD = 1:1.3:2:2.1 equiv;
products were purified by filtration on silica gel.
b Purified by column chromatography.
O
N
O
C
O
O
C
N
EtO
R1
O
R1
OEt
R2
R3
R1
4
5
R1 = p-(n-C12H25O)Ph-
An exploration of the mechanism has confirmed that the
Mitsunobu reaction is sterically sensitive, and that for suc-
cessful Mitsunobu esterification, the alcohol should react
faster (path 1) than the carboxylate (path 2) (Scheme 2).7
The strong nucleophilicity of p-(dodecyloxy)benzoate
rendered it more reactive than the hindered alcohols. Con-
sequently, compounds 4 and 5 were ultimately formed. It
was suggested that the stronger acid could afford the in-
verted products in better yields for hindered alcohols and
avoid the formation of anhydride. Furthermore, it was re-
ported that aryl acids with electron-withdrawing substitu-
ents (p- or m-NO2, p-SO2Me, and p-CN) provided good
yields for hindered alcohols.8 To increase the acidity, the
introduction of nitro groups into the hydrophobic-tagged
acid was attempted but failed. Our attention then turned to
Scheme 2 The formation of byproducts 4 and 5
Considering the fact that the proportion of methanol/water
needs to be carefully optimized for C-18 SPE of the prod-
ucts derived from acid 1, otherwise the products will elute
with the byproducts, we supposed that the single long al-
kyl chain would not be hydrophobic enough to be an ideal
tag. In fact, it has been reported that the retention of single
hydrocarbon chains on C-18 silica gel depends strongly
on the polarity and charge of the headgroup, while a suf-
ficiently long, hydrophobic double chain anchor was both
adsorbed and desorbed quantitatively, independent of the
size or polarity of the headgroup.6g Thus, acid 13, with
double hydrophobic chains, was synthesized as shown in
Scheme 4. Reduction of the commercially available ke-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1696–1700

1698
J. Guo et al.
LETTER
tone 9 with LiAlH4 followed by mesylation afforded me-
sylate 10. Nucleophilic substitution of 10 with methyl 4-
mercaptobenzoate under alkaline conditions provided
compound 11. Oxidation of 11 by m-CPBA yielded the
ester 12. After hydrolysis, acid 13 was afforded as a white
solid. Although the synthesis of 13 required five steps, the
process is convenient because it only needed one chroma-
tography separation step. Mitsunobu reaction was then in-
vestigated once again. As displayed in Table 3, the
hydrophobicity of products was clearly improved; both C-
18 SPE and silica gel filtration procedure ran very
well.13,14
n-C16H33
n-C16H33
n-C16H33
LiAlH4, THF
90%
MsCl, Et3N
98%
O
OMs
n-C16H33
10
9
n-C16H33
n-C16H33
methyl 4-mercaptobenzoate
95%
S
CO2Me
11
O
S
n-C16H33
m-CPBA, CH2Cl2
CO2Me
quan.
n-C16H33
O
12
a) LiOH, THF–H2O
b) HCl
O
S
n-C16H33
n-C16H33
CO2H
95% for 2 steps
n-C18H37SH, Cs2CO3
m-CPBA, CH2Cl2
O
13
O2N
CO2Me
quan.
DMSO, ))), 90%
6
Scheme 4 Synthesis of hydrophobic-tagged acid 13
a) LiOH, THF–H2O
b) HCl
O
n-C18H37
S
CO2H
Table 3 Mitsunobu Reactions with Hydrophobic-Tagged Acid 13
96% for 2 steps
O
O
7
n-C16H33
n-C16H33
ROH
S
O
CO2H
CO2R
Scheme 3 Synthesis of hydrophobic-tagged acid 7
Ph3P, DEAD
13
Table 2 Mitsunobu Reaction with Hydrophobic-Tagged Acid 7
O
S
n-C16H33
n-C16H33
O
S
O
S
ROH
n-C18H37
CO2H
n-C18H37
CO2R
O
Ph3P, DEAD
O
7
O
8
14
Entry
ROH
Ester product
Yield (%)a
Entry
ROH
Ester product
Yield (%)a
1
2
3
4
5
6
c
d
f
14c
14d
14f
14g
14h
14i
94
1
2
3
4
5
6
7
c
d
e
f
8c
8d
8e
8f
93
91
93
95
90
g
h
i
80
96
94 (92)b
65 (56)c
g
h
i
8g
8h
8i
88
94 (92)b
66c (56)d
a Reactions conditions: alcohol/acid/Ph3P/DEAD = 1.2:1:2:2.1 equiv;
products were purified by C-18 SPE.
b Yield reported by Jeong et al.11
a Reaction conditions: alcohol/acid/Ph3P/DEAD = 1:1.3:2:2.1 equiv;
products were purified by filtration on silica gel.
b Yield reported by Jeong et al.11
c Yield reported by Vasella et al.12
c Purified by column chromatography.
d Yield reported by Vasella et al.12
Importantly, the completion of the reaction between Ph3P
and DEAD is critical in this protocol. Although equal mo-
lar amounts of Ph3P and DEAD are needed theoretically,
it was found that a slight excess of DEAD (DEAD/Ph3P =
2.1:2 equiv) was required to drive the reaction to comple-
tion. Larger amounts of DEAD had no influence on the
purification of products by the use of C-18 SPE, but may
contaminate the products purified by silica gel filtration.
Elimination is a common side-reaction in Mitsunobu es-
terification of complex alcohols.15 According to the orig-
inal procedure,12 Mitsunobu reaction with alcohol i
resulted in a large amount of elimination product j. By us-
ing our protocol, the side-product j was easily removed
along with TPPO and DECH. In contrast, the tagged Ph3P
and DEAD variants, which were developed previously,
would require chromatographic purification in this situa-
tion.
The release of the alcohols and the recovery of the tagged
acids were also examined. As exemplified in Scheme 5,
5α-cholestan-3α-ol (15) was dissociated under alkaline
conditions in 92% yield from 14f, and the tagged acid was
recovered in 90 or 93% as the methyl ester. The reuse of
Synlett 2012, 23, 1696–1700
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydrophobically Assisted Separation-Friendly Mitsunobu Reaction
1699
L.; Hanson, P. R. Org. Lett. 2003, 5, 15. (c) Harned, A. M.;
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Basha, F. Z.; Reiser, O.; Hanson, P. R. Chem. Commun.
2011, 47, 12524.
recovered acid 13 was checked and found to produce the
same results in the Mitsunobu reaction.
THF–MeOH, NaOMe
or THF–H2O, NaOH
12 or 13
14f
+
HO
(6) (a) Pozsgay, V. Org. Lett. 1999, 1, 477. (b) Pozsgay, V.
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Tetrahedron 1997, 53, 3933.
·
15
Scheme 5 Release of the alcohol and recovery of the tagged acid
In conclusion, we have demonstrated the feasibility of uti-
lizing hydrophobic-tagged acids to promote purification
efficacy in the Mitsunobu reaction. This new protocol
combines the advantages of liquid-phase synthesis with
the simplicity of solid-phase product isolation. In order to
ensure satisfactory yield and high isolation efficiency, the
acids 1, 7, and 13 could be used selectively to meet vari-
ous demands. Acid 13 showed broader application scope
and facilitated the purification procedure, in particular for
alcohols with relatively high polarity and large steric hin-
drance. The disclosed strategy may be widely applied to
the Mitsunobu reaction.
(8) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994,
59, 234.
(9) Kondoh, A.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006,
62, 2357.
(10) Mitsunobu Reaction and Purification by Silica Gel
Filtration; Typical Procedure (8g): To a solution of acid 7
(77.0 mg, 0.17 mmol), alcohol g (21.0 mg, 0.13 mmol), and
Ph3P (67.0 mg, 0.26 mmol) in THF (6 mL) under argon, was
added DEAD (47.0 mg, 0.27 mmol) dropwise. The mixture
was stirred at 0 °C for 1 h and for 2 h at r.t. Silica gel (1.00
g) was then added to the reaction vessel and the solvents
were removed. The silica gel with the adsorbed reaction
mixture on it was transferred to a column (2.5 cm diameter)
that was previously filled to a height of 5 cm with silica gel,
and washed with EtOAc–PE (1:8, v/v). The filtrates
containing the product were collected and concentrated to
give 8g as a white solid (67.0 mg, 88% yield); mp 56–57 °C.
1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.4 Hz, 2 H),
7.99 (d, J = 8.4 Hz, 2 H), 5.50 (s, 1 H), 3.12–3.08 (m, 2 H),
2.11–2.07 (m, 1 H), 1.93–1.79 (m, 2 H), 1.77–1.65 (m, 3 H),
1.58–0.83 (m, 47 H). 13C NMR (100 MHz, CDCl3): δ =
164.29, 142.81, 135.64, 130.28, 128.20, 72.94, 56.23, 46.91,
39.09, 34.71, 31.90, 29.686, 29.62, 29.60, 29.52, 29.43,
29.40, 29.34, 29.22, 28.97, 28.26, 26.79, 25.37, 22.67,
22.59, 22.10, 20.94, 20.76, 14.10. HRMS: m/z [M + NH4]+
calcd for C35H64NO4S: 594.4556; found: 594.4553.
(11) Alexander, V.; Choi, W. J.; Chun, J.; Kim, H. O.; Jeon, J. H.;
Tosh, D. K.; Lee, H. W.; Chandra, G.; Choi, J.; Jeong, L. S.
Org. Lett. 2010, 12, 2242.
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China (21072014) and ‘973’ grant from the
Ministry of Science and Technology of China (2012CB822100).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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3130. (b) Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
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2003, 68, 9831. (b) Arnold, L. D.; Assil, H. I.; Vederas, J. C.
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M. H. Tetrahedron Lett. 1998, 39, 4947. (d) Su, S.; Giguere,
J. R.; Schaus, S. E.; Porco, J. A. Jr. Tetrahedron 2004, 60,
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(e) Curran, D. P.; Bajpai, R.; Sanger, E. Adv. Synth. Catal.
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(12) Baumberger, F.; Vasella, A.; Schauer, R. Helv. Chim. Acta
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(13) In SPE operation, double hydrophobic chain tagged products
remained quantitatively adsorbed on the C-18 silica when
rinsing the support with MeOH/water (95:5), even MeOH
for the first 10 mL, whereas the other molecules without the
tag were found to be completely rinsed out of the support,
including the hydrophobic starting materials.
(14) Mitsunobu Reaction and Purification by C-18 SPE;
Typical Procedure (14h): To a solution of acid 13 (68.0 mg,
0.1 mmol), alcohol h (67.0 mg, 0.12 mmol), and Ph3P (53.0
mg, 0.2 mmol) in THF (6 mL) under argon, was added
(5) (a) Barrett, A. G. M.; Roberts, R. S.; Schröder, J. Org. Lett.
2000, 2, 2999. (b) Harned, A. M.; Mukherjee, S.; Flynn, D.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1696–1700

1700
J. Guo et al.
LETTER
DEAD (37.0 mg, 0.21 mmol) dropwise at 0 °C. The mixture
was stirred for 1 h at 0 °C and for 2 h at r.t. C-18 silica gel
[500 mg, LiChroprep RP-18 (40–63 μm)] was added to the
reaction vessel and the solvents were removed. The dry C-18
silica gel with the adsorbed reaction mixture on it was
transferred to a column (1.8 cm diameter) that was
previously filled to a height of 1 cm with C-18 silica gel. The
C-18 silica gel was washed with MeOH–H2O (2:1, 30 mL),
MeOH (2 × 20 mL), and acetone (30 mL) under reduced
pressure. The filtrates containing the desorbed product were
collected and concentrated to give 14h (114 mg, 94% yield)
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.18 (d,
J = 8.2 Hz, 2 H), 7.93 (d, J = 8.2 Hz, 2 H), 7.60 (d, J =
6.2 Hz, 4 H), 7.49–7.18 (m, 16 H), 5.50 (dd, J = 9.4, 4.8 Hz,
1 H), 4.61 (t, J = 12.6 Hz, 1 H), 4.55 (d, J = 12.1 Hz, 1 H),
4.49 (d, J = 12.1 Hz, 1 H), 4.12 (td, J = 7.9, 4.2 Hz, 1 H),
3.78–3.73 (m, 4 H), 2.91 (br s, 1 H), 1.94–1.67 (m, 5 H),
1.58–1.53 (m, 3 H), 1.50–1.12 (m, 64 H), 1.00 (s, 9 H), 0.88
(t, J = 6.5 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ =
164.59, 142.23, 138.23, 137.85, 135.51, 134.72, 133.64,
133.54, 130.30, 129.65, 128.85, 128.38, 128.30, 127.77,
127.65, 127.59, 75.05, 74.43, 73.19, 73.12, 68.26, 64.68,
59.91, 33.54, 31.91, 29.68, 29.58, 29.51, 29.34, 29.27,
27.89, 26.84, 26.75, 22.67, 19.12, 14.08. MS (MALDI): m/z
calcd for C77H116NaO7SSi: 1235.8; found: 1235.6. Anal.
Calcd for C77H116O7SSi: C, 76.19; H, 9.63. Found: C, 76.09;
H, 9.53.
(15) (a) Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski,
E. J. J. J. Am. Chem. Soc. 1988, 110, 6487. (b) Cherney,
R. J.; Wang, L. J. Org. Chem. 1996, 61, 2544.
Synlett 2012, 23, 1696–1700
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