Mild and catalytic transesterification reaction using K2HPO 4 for the synthesis of methyl esters

Article abstract of DOI:10.1055/s-0030-1258491

K₂HPO₄ is an efficient catalyst for the transesterification reaction to produce methyl esters. Various functional groups are compatible under the mild reaction conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258491

LETTER
2141
Mild and Catalytic Transesterification Reaction Using K2HPO4 for the
Synthesis of Methyl Esters
Transesterificat
e
ionReactiotnUsings2 4
K
H
PO
u
for the Synt
r
hesisof
oMethyl Esters Shinada,* Makoto Hamada, Kota Miyoshi, Masato Higashino, Taiki Umezawa, Yasufumi Ohfune*
Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Fax +81(6)66053153; E-mail: ohfune@sci.osaka-cu.ac.jp; E-mail: shinada@sci.osaka-cu.ac.jp
Received 5 May 2010
a stoichiometric amount of each inorganic salt (Table 1).
Among them, K2HPO4 was found to be the inorganic salt
of choice to give the methyl ester 8 without any significant
side reactions. The methyl ester 8 was simply isolated by
the removal of MeOH and filtration of the insoluble
K2HPO4 through a thin silica gel pad in 92% yield.8 The
epimerized (2R,3R)-threonine methyl ester and a dehy-
droxylated product were not detected at all during this
process, suggesting no deprotonation was encountered
during the reaction process. Na2CO3 exhibited the same
potency as that of K2HPO4 (entry 6). However, a small
amount of BnOH derived from the formation of the car-
bamate 9 was detected within one hour. Other inorganic
salts, such as Na2HPO4, KHCO3, and NaHCO3, afforded
8 in lower yields along with recovery of the starting mate-
rial 7 (entries 2–4). The exclusive formation of the car-
bamate 9 was observed in the case of K2CO3 (entry 5).
Abstract: K2HPO4 is an efficient catalyst for the transesterification
reaction to produce methyl esters. Various functional groups are
compatible under the mild reaction conditions.
Key words: transesterification, K2HPO4, methyl ester, catalyst
Transesterification is one of the important methods for the
synthesis of esters. Extensive efforts have been made for
developing catalytic, operationally simple, and highly
functional group compatible protocols.1,2 During the
course of our recent study on the total synthesis of (–)-kai-
tocephalin (1),3 the conversion of the highly functional-
ized 4-methyl-2,6,7-trioxabicyclo [2.2.2]ortho (OBO)
ester4–6 2 into the corresponding methyl ester 4 posed a
challenging task in order to achieve the total synthesis
(Scheme 1). The OBO ester 2 possesses a variety of func-
tional groups in a close structural proximity. Several un-
desired side reactions, e.g., removal of protecting groups,
b-hydroxy group elimination, epimerization, and the g-
lactam- and carbamate-forming reactions were predict-
able under the transesterification process. We sought a
mild stepwise method involving the initial acidic hydrol-
ysis of 2 to ester 3, followed by a mild transesterification
reaction to give the methyl ester 4.
Cl
HO
H
CO2H
N
Cl
NH2
N
H
CO2H
O
H
HO
CO2H
kaitocephalin (1)
An initial model study using compound 5, the C3 epimer
of 3, under the known conditions (K2CO3 in MeOH)7
failed to produce a trace amount of the corresponding
methyl ester 6 and the undesired cyclic carbamate. We
attempted various conditions and found that K2HPO4 ef-
fectively promoted the desired transesterification to give
6 in 68% yield from 5. This process was successfully ap-
plied to the total synthesis of kaitocephalin via the conver-
sion of 3 into 4.3 To the best of our knowledge, the use of
K2HPO4 for the transesterification reactions of highly
functional substrates has not been reported. We now re-
port the scope of the K2HPO4-mediated transesterification
reactions that is characterized by a mild and catalytic
transformation to produce various methyl esters.
NHCbz
AcOH
CO2Me
NHCbz
H2O
TBSO
O
OH
OH
N
THF
(3:1:1)
Boc
HO
O
O
3
O
O
2
NHCbz
K2HPO4
MeOH
CO2Me
4
CO2Me
NHCbz
CO2Me
NHCbz
TBSO
N
Boc
HO
O
OH
OH
6
O
5
K2CO3, MeOH: trace
K2HPO4, MeOH: 68%
We initially compared the synthetic potency of K2HPO4
with those of other commercially available inorganic
salts, such as K2CO3, Na2CO3, KHCO3, NaHCO3, and
Na2HPO4, using Cbz-threonine ethyl ester 7 as the sub-
strate. These reactions were carried out in the presence of
Scheme 1 Key transesterification step in the total synthesis of kai-
tocephalin (1)
Next, the extension to a catalytic process using isopropyl
dihydrocinnamate (10) as a model compound was investi-
gated (Table 2). The ester 10 was inert to transesterifica-
tion using one equivalent of K2HPO4 in MeOH at room
temperature for 24 hours resulting in recovering of the
SYNLETT 2010, No. 14, pp 2141–2145
x
x
.x
x
.2
0
1
0
Advanced online publication: 09.07.2010
DOI: 10.1055/s-0030-1258491; Art ID: U03510ST
© Georg Thieme Verlag Stuttgart · New York

2142
T. Shinada et al.
LETTER
converted into 11 after a prolonged reaction period in
good yields (entries 3 and 4). The ethyl benzoates 15 and
17 were converted into the methyl esters 16 and 18, re-
spectively, in good yields (entries 5 and 6). Adipic acid di-
ethyl ester (19) underwent transesterification to give 20
without the Dieckmann cyclization (entry 7). It is note-
worthy that various functional groups, such as amide,
Cbz, diol, azo, epoxide, and phosphonate, were tolerated
under the standard conditions (entries 8–13). Removal of
the acyloxy group of 31 with 1 M NaOH gave a complex
mixture due to the instability of the resulting a-silylprop-
argyl alcohol moiety. This decomposition was avoided by
the K2HPO4-mediated transesterification condition to
give 32 in 81% yield without loss of the chirality (entry
14). Chemoselective transesterification was observed
when 33 was treated with K2HPO4 in MeOH at room tem-
perature to give a mixture of regioisomeric monoben-
zoates 34 (entry 15). On the other hand, the use of K2CO3
exclusively gave dihydroxy methyl ester 35 (entry 16).
Table 1 Transesterification of 7 with Inorganic Salts
O
H
H
H
BnO
N
OMe
O
O
OH
H
H
BnO
N
base (1.0 equiv)
Cbz-Thr-OMe
(8)
OEt
2S
MeOH (0.1 M)
r.t.
3R
O
OH
CO2Me
NH
H
Cbz-Thr-OEt (7)
O
9
O
Product ratioa
Entry
Base
Time (h)
7
8
9
1
2
3
4
5
6
K2HPO4
3
3
3
3
1
1
0
88
34
34
0
100b
12
66
66
0
0
0
0
0
Na2HPO4
KHCO3
NaHCO3
K2CO3
The OBO ester is a useful protecting group of carboxylic
acids4–6 and widely utilized in the synthesis of biological-
ly active natural products and their derivatives.7 The re-
moval and transformation to carboxylic acid has been
achieved by the treatment with HCl–H2O to give the cor-
responding carboxylic acid in one step. The substrates that
are labile to the acidic conditions were transformed into
carboxylic acids by the following stepwise method: initial
hydrolysis of the OBO ester using AcOH, PPTS, or
KHSO4 in the presence of H2O to give a 2,2-dihydroxy-
methyl-1-propyl ester, followed by saponification (1 M
NaOH). In this way, the use of K2CO3–MeOH instead of
1 M NaOH allowed the conversion into the methyl esters.
We considered that K2HPO4–MeOH would be a milder al-
ternative to K2CO3–MeOH for the stepwise method.9 In
fact, the 2,2-dihydroxymethyl-1-propyl ester 37 derived
from 36 was subjected to K2HPO4–MeOH to produce the
methyl ester 11 in a quantitative yield (entry 17). Under
the standard conditions, the glycine OBO ester 38 bearing
a base-sensitive Fmoc group was converted into Fmoc-
Gly-OMe 4010 via the diol 39 in 94% yield without re-
moval of the Fmoc group (entry 18).
100c
4c
Na2CO3
0
96
a Estimated by 1H NMR.
b 92% yield after workup.
c Estimated from the amount of BnOH.
starting material (entry 1). In order to accelerate this con-
version, the reaction mixture was heated to reflux to pro-
duce the methyl ester 11 in good yield (entry 2). Similarly,
the catalytic use of K2HPO4 also mediated this conversion
(entries 3–5). Among them, the condition in entry 4 [10
mol% K2HPO4 in MeOH (0.1 M), reflux] was chosen as
the standard condition to investigate the substrate scope.
Various substrates were subjected to the optimized condi-
tion (Table 3). Dihydrocinnamic acid esters 12 and 13 un-
derwent transesterification to give 11 in high yields under
the standard condition (entries 1 and 2). The sterically
bulkier neopentyl and isopropyl esters 14 and 10 were
Table 2 Catalytic Transesterification of 10 Using K2HPO4
O
The sterically bulky tert-butyl benzoate 41 and p-nitro
benzoate 42 did not react under the standard conditions
(entries 19 and 20). The a,a-disubstituted malonate deriv-
ative 33 was inert and the starting material was recovered
(entry 21). The transesterification reactions of the methyl
ester 11 with ethyl, allyl, propargyl, and isopropyl alco-
hols were much slower to give the corresponding esters in
poor to moderate yields (Scheme 2). The ethyl ester 12
did not react with propargyl, allyl, and isopropyl, and
isobutyl alcohols at all under the conditions. These results
indicated that the present method was influenced by the
steric congestions of the substrates and alcohols. Al-
though these are obstacles to be overcome, the character-
istic reactivity offers an opportunity to develop a selective
transesterification method, e.g., chemoselective deacyla-
tion reactions for the synthesis of highly functionalized
molecules.
Ph
OR
10 R = i-Pr
11 R = Me
K2HPO4
MeOH (0.1 M)
reflux, 24 h
Entry
K2HPO4 (equiv)
Ratioa 10/11
100:0b
15:85
1
2
3
4
5
1
1
0.5
0.1
0.05
15:85
25:75
50:50
a Estimated by 1H NMR.
b Room temperature.
Synlett 2010, No. 14, 2141–2145 © Thieme Stuttgart · New York

LETTER
Transesterification Reaction Using K2HPO4 for the Synthesis of Methyl Esters
2143
Table 3 K2HPO4-Mediated Catalytic Transesterification with Various Substrates
Entry
Substrate
Product
Time (h)
Yield (%)a
CO2R
CO2Me
Ph
Ph
88b
98b
1
2
12 R = Et
11
5
13 R = Bn
11
11
24
62
3
4
5
14 R = neopentyl
24
24
24
(14, 32%)c
75
10 R = i-Pr
11
(10, 25%)c
PhCO2Et
15
PhCO2Me
16
82b
98b
93b
CO2Et
CO2Me
6
7
5
O2N
O2N
17
18
CO2Et
CO2Me
24
EtO2C
MeO2C
19
20
OH
OH
CO2Me
CO2Et
8
9
6
93b
80b
MeO2C
EtO2C
OH
OH
21
22
CO2Et
CO2Me
Ph
O
Ph
O
24
23
24
H
H
H
N
H
BnO
CO2Et
BnO
O
N
CO2Me
10
1
93b
O
OH
OH
H
H
7
8
NHAc
CO2Et
NHAc
11
12
1
1
84b
98b
CO2Me
EtO2C
MeO2C
26
MeO2C
25
EtO2C
N
N
N
CO2Et
N
CO2Me
27
28
O
O
CO2Et
CO2Me
P
P
13
14
6
2
80c
EtO
EtO
OEt
OEt
29
30
TBS
O
O2N
TBS
84b,d
O
OH
32 (92% ee)e
31 (92% ee)
HO
CO2Me
OR2
O
HO
R1 = H, R2 = Bz, 14%b,g
R1 = Bz, R2 = H, 76%b,g
15
2f
O
OR1
OBz
34 (r.t., 2 h)
33
34
Synlett 2010, No. 14, 2141–2145 © Thieme Stuttgart · New York

2144
T. Shinada et al.
LETTER
Table 3 K2HPO4-Mediated Catalytic Transesterification with Various Substrates (continued)
Entry
16
Substrate
Product
Time (h)
Yield (%)a
HO
CO2Me
OH
33
1h
96b
OH
35
O
Ph
O
O
36
98%b
(2 steps)
AcOH
H2O
CO2Me
17
1
Ph
OH
OH
11
O
O
37
O
O
Fmoc
N
H
O
38
94%b
(2 steps)
Fmoc
AcOH
H2O
CO2Me
N
18
1
H
OH
OH
40
O
O
39
O
Ot-Bu
X
19
20
41 X = H
42 X = NO2
24
24
no reaction
no reaction
EtO2C
CO2Et
21
24
no reaction
43
a K2HPO4 (0.1 equiv), MeOH (0.1 M), reflux.
b Isolated yield.
c Estimated by 1H NMR.
d 1 M NaOH, r.t., 3 h: decomposition.
e Determined by the Mosher method.
f Carried out at room temperature.
g Inseparable mixture on silica gel chromatography.
h K2CO3, MeOH.
K2HPO4 (0.1 equiv)
In summary, we have developed a new catalytic transes-
terification method to produce various methyl esters. The
present method exhibits an excellent functional group
compatibility. Further study to develop chemo- and ste-
reoselective transesterifications using K2HPO4 is current-
ly underway.11–13
Ph
Ph
Ph
CO2R
ROH (0.1 M)
reflux, 24 h
CO2Me
CO2Et
R = Et, propargyl, allyl,
i-Pr (5–52%)
11
12
K2HPO4 (0.1 equiv)
Ph
CO2R
ROH (0.1 M)
reflux, 24 h
R = Me (5 h, 88%)
R = propargyl, allyl,
i-Pr (no reaction)
Scheme 2 Scope and limitation of K2HPO4-mediated transesterifi-
cation
Synlett 2010, No. 14, 2141–2145 © Thieme Stuttgart · New York

LETTER
Transesterification Reaction Using K2HPO4 for the Synthesis of Methyl Esters
2145
E. M.; Shchepinov, M. S. Chem. Commun. 2005, 3466.
(m) Paek, S.-M.; Seo, S.-Y.; Kim, S.-H.; Jung, J.-W.; Lee,
Y.-S.; Jung, J.-K.; Suh, Y.-G. Org. Lett. 2005, 7, 3159.
(n) Hansen, D. B.; Wan, X.; Carroll, P. J.; Joullie, M. M.
J. Org. Chem. 2005, 70, 3120. (o) Kai, T.; Sun, X.-L.;
Faucher, K. M.; Apkarian, R. P.; Chaikof, E. L. J. Org.
Chem. 2005, 70, 2606. (p) Ichige, T.; Kamimura, S.;
Mayumi, K.; Sakamoto, Y.; Terashita, S.; Ohteki, E.;
Kanoh, N.; Nakata, M. Tetrahedron Lett. 2005, 46, 1263.
(q) Giner, J. Org. Lett. 2005, 7, 499.
Acknowledgment
This work was supported by the Japan Society for the Promotion of
Science (JSPS), and the Grants-in-Aid for Scientific Research (Nos.
19201045 and 21310145).
References and Notes
(1) For reviews, see: (a) Chenevert, R.; Pelchat, N.; Jacques, F.
Curr. Org. Chem. 2006, 10, 1067. (b) Grasa, G. A.; Singh,
R.; Nolan, S. P. Synthesis 2004, 971. (c) Hoydonckx, H. E.;
De Vos, D. E.; Chavan, S. A.; Jacobs, P. A. Top. Catal.
2004, 27, 83. (d) Otera, J. In Esterification; Wiley-VCH:
Weinheim, 2003. (e) Larock, R. In Comprehensive Organic
Transformations, 2nd ed.; Wiley: New York, 1996.
(f) Otera, J. Chem. Rev. 1993, 93, 1449. (g) Mulzer, J. In
Comprehensive Organic Synthesis, Vol. 6; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: New York, 1992.
(2) For recent progress on the catalytic transesterification, see:
(a) Iwasaki, T.; Maegawa, Y.; Hayashi, Y.; Ohshima, T.;
Mashima, K. J. Org. Chem. 2008, 73, 5147. (b) Ishihara,
K.; Niwa, M.; Kosugi, Y. Org. Lett. 2008, 10, 2187.
(c) Kondaiah, G. C. M.; Reddy, L. A.; Babu, K. S.; Gurav,
V. M.; Huge, K. G.; Bandichhor, R.; Reddy, P. P.;
Bhattacharya, A.; Anand, R. V. Tetrahedron Lett. 2008, 49,
106. (d) Inahashi, N.; Fujiwara, T.; Sato, T. Synlett 2008,
605. (e) Ohshima, T.; Iwasaki, T.; Maegawa, Y.;
(8) Typical Synthetic Procedure: To a solution of the N-Cbz-
threonine ethyl ester (7; 1 mmol) in MeOH (10 mL) was
added K2HPO4 (0.1 equiv). The mixture was heated at reflux
for 1 h and concentrated under reduced pressure. The crude
material was then dissolved in EtOAc–hexane (1:1, 10 mL).
The mixture was filtered through a thin silica gel pad. The
filtrate was concentrated under reduced pressure to give the
N-Cbz-threonine methyl ester(8) in 92% yield.
(9) (a) Transesterification of the Ortho Ester 38 to 40: In a
similar manner to the reported method,6 38 was synthesized
from Fmoc-Gly-OH in 45% yield (two steps). Analytical
data of 38: IR (ATR): 3347, 3066, 2944, 2881, 1722, 1525,
1450, 1402, 1245, 1049, 1004, 910 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.75 (d, J = 7.3 Hz, 2 H), 7.60 (d, J = 7.3
Hz, 2 H), 7.38 (t, J = 7.3 Hz, 2 H), 7.27 (t, J = 7.3 Hz, 1 H),
5.09 (br s, 1 H), 4.38 (d, J = 6.9 Hz, 2 H), 4.23 (t, J = 6.9, 2
H), 3.92 (s, 6 H), 3.43 (br d, J = 6.0 Hz, 2 H), 0.82 (s, 3 H).
HRMS (FAB): m/z [M + H]+ calcd for C22H24NO5:
382.1655; found: 382.1654. (b) A mixture of 38 (130 mg,
0.33 mmol) in AcOH–THF–H2O (5:1:1, 0.7 mL) was stirred
for 12 h and concentrated under reduced pressure. The
remaining AcOH and H2O were removed as an azeotropic
mixture of toluene. The crude 39 was subjected to the next
step without purification. Analytical data of 39: 1H NMR
(400 MHz, CDCl3): d = 7.76 (d, J = 7.3 Hz, 2 H), 7.60 (d,
J = 7.3 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.39 (t, J = 7.3 Hz,
2 H), 5.45 (br s, 1 H), 4.41 (d, J = 7.1 Hz, 2 H), 4.21–4.25
(m, 3 H), 4.01 (br s, 1 H), 3.55 (br s, 4 H), 0.85 (s, 3 H).
(c) To a solution of 39 in MeOH (3.5 mL) was added
K2HPO4 (0.11 mmol). The mixture was heated to reflux for
1 h and concentrated under reduced pressure. The crude
mixture was diluted with EtOAc–hexane (1:1, 10 mL) and
filtered through a thin silica gel pad. The filtrate was
concentrated under reduced pressure to give 40 in 94% yield.
The analytical data were identical to the authentic data.10
(10) Mineno, T.; Kansui, H. Chem. Pharm. Bull. 2006, 54, 918.
(11) The role of K2HPO4 in the mild transesterification reaction
has been unclear. In our experiments using various inorganic
salts, the reaction rate and product yield were varied and not
necessarily dependent on the cationic or anionic nature of
inorganic salts.
Yoshiyama, A.; Mashima, K. J. Am. Chem. Soc. 2008, 130,
2944. (f) Remme, N.; Koschek, K.; Schneider, C. Synlett
2007, 491. (g) Jiang, P.; Zhang, D.; Li, Q.; Lu, Y. Catal.
Lett. 2006, 110, 101. (h) de Sairre, M. I.; Bronze-Uhle,
E. S.; Donate, P. M. Tetrahedron Lett. 2005, 46, 2705.
(i) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S. P.
J. Org. Chem. 2004, 69, 209.
(3) Hamada, M.; Shinada, T.; Ohfune, Y. Org. Lett. 2009, 11,
4664.
(4) Green, T. W.; Wuts, P. G. In Protecting Groups in Organic
Synthesis, 4th ed.; John Wiley & Sons, Inc.: New York,
2007.
(5) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
(6) Rose, N. G. W.; Blaskovich, M. A.; Evindar, G.; Wilkinson,
S.; Luo, Y.; Fishlock, D.; Reid, C.; Lajoie, G. A. Org. Synth.,
Coll. Vol. X; Wiley: New York, 2004, 73.
(7) For recent examples, see: (a) Winkler, J. D.; Fitzgerald,
M. E. Synlett 2009, 562. (b) Jahn, U.; Dinca, E. Chem. Eur.
J. 2009, 15, 58. (c) Zhdanko, A. G.; Nenajdenko, V. G.
J. Org. Chem. 2009, 74, 884. (d) Ichige, T.; Okano, Y.;
Kanoh, N.; Nakata, M. J. Org. Chem. 2009, 74, 230.
(e) Tange, S.; Fukuhara, T.; Hara, S. Synthesis 2008, 3219.
(f) Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R.
J. Am. Chem. Soc. 2008, 130, 11486. (g) Nicolaou, K. C.;
Dethe, D. H.; Leung, G. Y. C.; Zou, B.; Chen, D. Y.-K.
Chem. Asian J. 2008, 3, 413. (h) Martynow, J. G.; Jozwik,
J.; Szelejewski, W.; Achmatowicz, O.; Kutner, A.;
Wisniewski, K.; Winiarski, J.; Zegrocka-Stendel, O.;
Golebiewski, P. Eur. J. Org. Chem. 2007, 689. (i) Bowen,
M. E.; Monguchi, Y.; Sankaranarayanan, R.; Vagner, J.;
Begay, L. J.; Xu, L.; Jagadish, B.; Hruby, V. J.; Gillies,
R. J.; Mash, E. A. J. Org. Chem. 2007, 72, 1675.
(12) The transesterification reaction of methyl esters to other
esters using K2CO3 has been reported, see: Barry, J.; Bram,
G.; Petit, A. Tetrahedron Lett. 1988, 29, 4567.
(13) Catalytic activity and selectivity of various inorganic salts
except for K2HPO4 have been evaluated for the
transesterification reactions of sunflower oil to produce
long-chain fatty acid methyl esters (biodiesel), see:
Arzamendi, G.; Arguinarena, E.; Campo, I.; Zabala, S.;
Gandia, L. M. Catal. Today 2008, 133-135, 305.
(j) Raghavan, B.; Johnson, R. L. J. Org. Chem. 2006, 71,
2151. (k) Snider, B. B.; Gao, X. Org. Lett. 2005, 7, 4419.
(l) Bernad, P. L. Jr.; Khan, S.; Korshun, V. A.; Southern,
Synlett 2010, No. 14, 2141–2145 © Thieme Stuttgart · New York