Chelation-Based Homologation by Reaction of Organometallic Reagents with O -Alkyl S -Pyridin-2-yl Thiocarbonates: Synthesis of Esters from Grignard Reagents

Article abstract of DOI:10.1055/s-0037-1611868

The one-carbon homologative esterification of Grignard reagents with O- alkyl S -pyridin-2-yl thiocarbonates has been explored. This one-step synthesis of esters from Grignard reagents is the first case to involve chelation-stabilized intermediates.

Full text of DOI:10.1055/s-0037-1611868

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
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S. Usami et al.
Letter
Synlett
Chelation-Based Homologation by Reaction of Organometallic
Reagents with O-Alkyl S-Pyridin-2-yl Thiocarbonates: Synthesis of
Esters from Grignard Reagents
Shun Usami
Br
Tomoyuki Suzuki
Koudai Mano
Mg
N
O
R2 MgBr
O
N
O
R2
OR1
OR1
S
OR1
S
Kosaku Tanaka, III
Yoshimitsu Hashimoto
Nobuyoshi Morita
Osamu Tamura*
R2
10 examples
from 50% to quant yield
R1 = Bn, tBu or Me; R2 = aryl, alkyl, alkenyl or alkynyl group
Showa Pharmaceutical University, Higashi-tamagawagakuen, Machida,
Tokyo 194-854, Japan
tamura@ac.shoyaku.ac.jp
This paper is dedicated to the memory of Professor Teruaki Mukaiyama,
a prominent scientist who made major contributions to the field.
Received: 20.04.2019
Accepted after revision: 03.06.2019
Published online: 27.06.2019
2). However, a chelation-based approach, as exemplified by
Mukaiyama’s 2-pyridyl thioesters8 or Weinreb amides9 in
ketone syntheses, has rarely been investigated.10 Here, we
show that Grignard reagents react with O-alkyl S-pyridin-
2-yl thiocarbonates to give one-carbon-homologated esters,
probably via chelated intermediates (Scheme 1, Equation 3).
DOI: 10.1055/s-0037-1611868; Art ID: st-2019-u0223-l
Abstract The one-carbon homologative esterification of Grignard re-
agents with O-alkyl S-pyridin-2-yl thiocarbonates has been explored.
This one-step synthesis of esters from Grignard reagents is the first case
to involve chelation-stabilized intermediates.
Reaction of alkoxycarbonyl donors having regulated leaving groups (X)
O
OM
O
R2
M
Key words alkyl pyridinyl thiocarbonates, Grignard reagents, esterifi-
H2O
(1)
cation, one-step synthesis, homologation
X
OR1
R2
OR1
R2
OR1
X
regulated leaving group
X = R3P+, pyrazole, imidazole
One-carbon homologative esterification of organome-
tallic compound, especially Grignard reagents, is an import-
ant transformation. This transformation is usually conduct-
ed by a two-step conversion through the reaction of a Gri-
gnard reagent with carbon dioxide to give a carboxylic acid,
followed by esterification, because the reaction of a Gri-
gnard reagent with a carbonate derivative such as ethyl
chloroformate, ethyl cyanoformate, or diethyl carbonate
usually give a tertiary alcohol (three-to-one adduct) instead
of an ester.1,2 To eliminate this complexity, two categories of
one-step method for the preparation of esters from Gri-
gnard reagents have been explored (Scheme 1). The first is
the use of an alkoxycarbonyl donor having regulated leav-
ing activity, such as an alkoxycarbonyl phosphonium salt,3 a
1-(alkoxycarbonyl)pyrazole,4 or a 1-(alkoxycarbonyl)imid-
azole,5 to form a tetrahedral intermediate (Scheme 1, Equa-
tion 1). The other is the use of an alkyl chloroformate with
an organometallic compound having a regulated nucleop-
hilicity, such as a powdered Grignard reagent chelated with
tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1)6 or an or-
ganocopper reagent derived from a Grignard reagent,7 to
avoid overreaction of the ester product (Scheme 1, Equation
Reaction of alkyl chloroformates with organometallic compounds
with regulated nucleophilicity
regulated nucleophilicity
O
O
R2
M
(2)
Cl
OR1
R2
OR1
Cl–
R2–M = R2MgX/TDA-1 complex or R2MgBr–CuBr–2LiBr
This work: Chelation-based method for the synthesis of esters
X
Mg
1) R2 MgX
OR1
N
O
2) H2O
N
O
O
(3)
S
S
OR1
R2
OR1
R2
Scheme 1 Methods for the synthesis of esters from Grignard reagents
Acylating reagents 1,11a 2, and 311a were readily pre-
pared from commercially available reagents (Scheme 2).
Thus, O-benzyl S-pyridin-2-yl thiocarbonate (1) and the
corresponding O-methyl derivative 2 were obtained by
treatment of pyridine-2-thiol with the appropriate alkyl
chloroformate in the presence of Et3N, whereas the O-tert-
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Usami et al.
Letter
Synlett
butyl derivative 3 was prepared in high yield from pyridine-
2-thiol and (Boc)2O in the presence of Et3N and a catalytic
amount of DMAP.12
Table 1 Reaction of Acylating Agent 1 with Phenyl Organometallic
Compounds
M
O
M
S
O
N
O
N
O
NH4Cl
H2O
OBn
N
O
Cl
OR
NH
S
OBn
OBn
THF
Et3N
Ph
1
S
OR
A
4a
CH2Cl2
S
1: R = Bn (92%)
2: R = Me (70%)
Entry Conditions
Yield of Recovery
4a (%) of 1 (%)
N
O
(Boc)2O, Et3N
cat. DMAP, CH3CN
NH
S
OtBu
1
2
3
4
5
6
7
PhLi (5) (1 equiv), –78 °C, 3.5 h
25
66
none
88
84
3
16
S
3 (97%)
PhMgBr (6a) (1 equiv), –78 °C, 3 h
6a (1 equiv.), CuBr (1 equiv)
6a (2 equiv), –78 °C, 2 h
15
Scheme 2 Preparation of acylating reagents 1–3
69
none
none
none
(78)a
6a (1 equiv), 50 °C, 1 h
First, we examined the benzyloxycarbonylation of phe-
nyl metal compounds by using thiocarbonate 1 (Table 1).
Reaction of phenyllithium (5, 1.0 equiv) with 1 in THF at –
78 °C gave benzyl benzoate (4a) in 25% yield, along with a
16% recovery of the acylating agent 1 (Table 1, entry 1). In-
terestingly, the use of the corresponding Grignard reagent
6a afforded a much better yield (66%), probably due to for-
mation of a more stable chelation intermediate A, although
the reaction appeared to stop despite the presence of 15% of
the remaining thiocarbonate 1 (entry 2). The reason for the
deactivation of PhMgBr (6a) is unclear, but the formation of
a 2:1 complex of adduct A with 6a is a plausible explana-
tion. The addition of Cu(I), which has a a high affinity for
sulfur, inhibited the reaction (entry 3). Complete consump-
tion of thiocarbonate 1 required two equivalents of PhMgBr
(6a) at a low temperature, and these conditions afforded 4a
in high yield (88%; entry 4). Taking into account the dissoci-
ation of the putative complex, we examined several sets of
conditions, and we finally found that mild heating (50 °C)
was effective in providing 4a in high yield (84%) without
any recovery of 1 (entry 5).13 In contrast, the use of the con-
ventional acylating reagent benzyl chloroformate (7) result-
6a (1 equiv), ClCO2Bn (7, 1 equiv), 0 °C, 5 h
6a (1 equiv), MeON(Me)CO2Bn (8,1 equiv), 50 °C, 3 h none
a Acylating agent 8 was recovered.
ed in a complex reaction that gave only a trace of 4a (entry
6). Moreover, the Weinreb amide analogue 8 failed to react
with 6a and was recovered in 78% yield (entry 7).
Next, we examined the corresponding reactions of other
Grignard reagents 6b–d (Table 2). In all cases, reaction at
room temperature was incomplete, with recovery of acylat-
ing agent 1, whereas reaction at 50 °C afforded high yields
of products 4b–d without recovery of unreacted 1 (entries
1–6). Although the order of reactivity of the Grignard re-
agents 6b–d at room temperature was 6b (sp3, 77%), 6c (sp2,
39%), and 6d (sp, 0%), Grignard reagents 6b–d all afforded
satisfactory yields of the corresponding products 4b–d at
50 °C. The use of ClCO2Bn (7) again afforded lower yields of
products 4b–d (entries 2, 3, 6: in parentheses).
Next, the reaction of Boc derivative 3 was examined (Ta-
ble 3). The results were similar to those obtained with 1, al-
though the reactivity of 3 was slightly lower than that of 1.
Table 2 Reaction of Thiocarbonate 1 with Various Grignard Reagents
O
N
O
1) R–MgBr, 1.0 equiv, THF
2) NH4Cl aq
R
OBn
S
OBn
1
4b–d
Entry
RMgBr
Temp (°C)
Time (h)
Product
Yield (%)
Recovery of 1 (%)
1
2
3
4
5
6
EtMgBr (6b)
r.t.
15.5
1
4b
4b
4c
4c
4d
4d
77
14
–
50 °C
r.t.
80 (0)a
39 (18)a
50
(E)-PhCH=CHMgBr (6c)
MeC≡CMgBr (6d)
20
1
4
50 °C
r.t.
–
24
4
–
69
–
50 °C
74 (55)a
a Yield from reaction of RMgBr (6) with 7.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D

C
S. Usami et al.
Letter
Synlett
Table 3 Reaction of Acylating Agent 3 with Grignard Reagents
O
N
O
1) R–MgBr, 1.0 equiv, THF
2) NH4Cl aq
OtBu
OtBu
R
S
3
9a,c–e
Entry
RMgBr
Temp (°C)
Time
Product
Yield (%)
Recovery of 3 (%)
1
2
3
4
5
6
7
8
PhMgBr (6a)
r.t.
20 h
19 h
27 h
4 h
9a
9a
9e
9e
9c
9c
9d
9d
21
61
78
79
18
62
–
44
–
50 °C
r.t.
Ph(CH2)2MgBr (6e)
(E)-PhCH=CHMgBr (6c)
MeC≡CMgBr (6d)
14
–
50 °C
r.t.
17 h
9 h
57
–
50 °C
r.t.
1 week
2 days
46
–
50 °C
quant
Thus, the yields of esters 9a and 9c–e at room temperature
were strongly associated with the s character of the Gri-
gnard reagent 6, and the yield of 9e (78%) was much higher
than that of 9a (21%), 9c (18%), or 9d (0%) (Table 3, entries 1,
3, 5, and 7). Gentle heating improved the yields of the ester
products 9 (entries 2, 4, 6, and 8); in particular, 9d was ob-
tained in quantitative yield (entry 8).
Finally, two more reactions were conducted to illustrate
the scope of the reaction (Scheme 3). Thus, the reaction of
thiocarbonate 1 with the bulky reagent cyclohexylmagne-
sium bromide (6f), at 50 °C gave benzyl cyclohexanecarbox-
ylate (4f) in 71% yield. A sterically less-hindered acylating
agent could also be used: acylating agent 2 reacted with ar-
omatic Grignard reagent 6g at 50 °C without any difficulty
to afford methyl 4-tert-butylbenzoate (10) in 95% yield.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611868.
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References and Notes
(1) (a) March’s Advanced Organic Chemistry: Reactions, Mechanism,
and Structure (6th ed.); Smith, M. B.; March, J., Ed.; Wiley-Inter-
science: Hoboken, 2007, Chap. 16 1445. (b) Moyer, W. W.;
Marvel, C. S. Org. Synth. Col. Vol II; Wiley: London, 1931, 602.
(2) A dry carbon dioxide equivalent of the Grignard reaction has
recently been reported; see: (a) Inagaki, F.; Matsumoto, C.;
Iwata, T.; Mukai, C. J. Am. Chem. Soc. 2017, 139, 4639. More
recently, sodium methyl carbonate was found to react with Gri-
gnard reagents to afford carboxylic acids; see: (b) Hurst, T. E.;
Deichert, J. A.; Kapeniak, L.; Lee, R.; Harris, J.; Jessop, P. G.;
Snieckus, V. Org. Lett. 2019, 21, 3882.
1) 50 °C
THF
MgBr
CO2Bn
N
O
(3) Maeda, H.; Takahashi, K.; Ohmori, H. Tetrahedron 1998, 54,
12233.
(4) Kashima, C.; Tsuruoka, S.; Mizuhara, S. Tetrahedron 1998, 54,
14679.
S
OBn
2) NH4Cl aq
4f (71%)
1
6f (1 equiv)
(5) Werner, T.; Barrett, A. G. M. J. Org. Chem. 2006, 71, 4302.
(6) For Grignard reagent complexes chelated with TDA-1, see:
Boudin, A.; Cerveau, G.; Chuit, C.; Corriu, R. J. P.; Reye, C. Tetra-
hedron 1989, 45, 171.
(7) Bottalico, D.; Fiandanese, V.; Marchese, G.; Punzi, A. Synlett
2007, 974.
1) 50 °C
THF
MgBr
CO2Me
N
O
S
OMe
2) NH4Cl aq
6g (1 equiv)
10 (95%)
2
Scheme 3 Illustrative scope of the alkoxycarbonylation of Grignard re-
(8) For Mukaiyama’s 2-pyridyl thioesters, see: Mukaiyama, T.;
Araki, M.; Takei, H. J. Am. Chem. Soc. 1973, 95, 4763.
(9) For Weinreb amides, see: (a) Nahm, S.; Weinreb, S. M. Tetrahe-
dron Lett. 1981, 22, 3815. For a review of the synthetic utility of
Weinreb amides, see: (b) Balasubramaniam, S.; Aidhen, I. S. Syn-
thesis 2008, 3707.
agents
In conclusion, we have discovered a novel one-carbon
homologation reaction of Grignard reagents via chelated in-
termediates. This method provides an alternative to con-
ventional transformations of Grignard reagents into esters.
(10) The use of dialkyl alkoxycarbonylphosphonates might be classi-
fied into this category: see ref. 3.
(11) (a) Kim, S.; Lee, J. I.; Yi, K. Y. Bull. Chem. Soc. Jpn. 1985, 58, 3570.
(b) Lee, J. I.; Jung, H. J. J. Korean Chem. Soc. 2005, 49, 609.
Funding Information
This work was supported by JSPSKAKENHI Grant Number 17K0821
(O.T.).
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© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D

D
S. Usami et al.
Letter
Synlett
(12) Compound 3 was originally prepared in two steps by the reac-
tion of phosgene with pyridine-2-thiol to give S,S-di-2-pyridyl
dithiocarbonate, followed by treatment with Cu(OtBu)2.11a The
present method provides an operationally simple one-step syn-
thesis.
cooled to 0 °C. An aqueous solution of NH4Cl was added, and the
mixture was extracted with Et2O. The organic layer was washed
with brine, dried (Na2SO4), and concentrated in vacuo. The
residue purified by chromatography [silica gel, hexane–EtOAc
1
(20:1)] to give 4a as an oil; yield: 17.5 mg (84%). H NMR (300
(13) Benzyl Benzoate (4a); Typical Procedure
MHz, CDCl3):  = 8.10–8.06 (m, 2H), 7.32–7.59 (m, 8 H), 5.37 (s,
A 1.0 M solution of PhMgBr (5a) in THF (98 mL, 98 mmol) was
added to a stirred solution of 1 (24.1 mg, 98.2 mol) in dry THF
(1.0 mL) at 0 °C and the mixture was kept at 50 °C for 1 h, then
2 H). This spectrum was identical with that reported.14
(14) Li, L.; Sheng, H.; Xu, F.; Shen, Q. Chin. J. Chem. 2009, 27, 1127.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D