A new versatile synthesis of esters from Grignard reagents and chloroformates

Article abstract of DOI:10.1055/s-2007-973861

Cross-coupling reactions of chloroformates with organocopper reagents, derived from Grignard reagents, cuprous bromide and lithium bromide, provide a rapid and straightforward method for the synthesis of esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973861

974
LETTER
A New Versatile Synthesis of Esters from Grignard Reagents and
Chloroformates
Synthesisof
E
sters
a
from
G
rig
n
nardReagent
i
s
and
C
e
hloroform
l
ates a Bottalico, Vito Fiandanese, Giuseppe Marchese, Angela Punzi*
Dipartimento di Chimica, Università di Bari, Via Orabona 4, 70126 Bari, Italy
Fax +39(080)5442075; E-mail: punzi@chimica.uniba.it
Received 11 December 2006
phonium chlorides.12 However, the reaction is limited to
PhMgBr and MeMgBr and the scope of this method has
not been fully explored.
Abstract: Cross-coupling reactions of chloroformates with organo-
copper reagents, derived from Grignard reagents, cuprous bromide
and lithium bromide, provide a rapid and straightforward method
for the synthesis of esters.
So, we first explored a wide range of aliphatic as well as
Key words: organometallic reagents, cross-coupling, chemoselec- aromatic organocopper reagents in the coupling reactions
tivity, esters
with ethyl chloroformate. In all the cases examined the
cross-coupling reaction proved to be highly chemo-
selective and only the replacement of chloride functional-
ity occurred. This result prompted us to devise a
straightforward method for synthesizing a variety of
esters in high yields and under mild reaction conditions.
Esters are usually synthesized as a two-component reac-
tion from an alcohol with the corresponding carboxylic
acid. Numerous and well-established methods for this
synthetic route are known.1
We were pleased to find that, under the conditions of our
methodology, a host of Grignard reagents reacted smooth-
ly with ethyl or phenyl chloroformate (Scheme 1) to give
the corresponding esters in good to excellent yields.13
As a part of our extensive work2 in the area of direct
acylation of organometallics,3 we have recently shown
that organocopper reagents derived from Grignard
reagents, cuprous bromide and lithium bromide are highly
chemoselective reagents.4–6 Thus, a chemoselective
cross-coupling of these reagents with monoesters of di-
carboxylic acid chlorides,4 with a-acetoxy carboxylic acid
chlorides5 and with tartaric acid dichloride,6 enabled us to
achieve a straightforward method for the synthesis of a
variety of ketoesters, enantiopure a-acetoxy ketones and
C2-symmetric 1,4-diketones, respectively.
O
O
R1MgBr·CuBr·2LiBr
Cl
OR
R1
OR
THF, r.t.
1, 2
3, 4
1, 3 R = Et
2, 4 R = Ph
Scheme 1
In connection with this type of synthetic work and with
the aim to further explore the scope and limitations of our
procedure, we considered of interest to investigate on the
reactivity of chloroformates, presenting an ester and chlo-
ride functionality on the same electrophilic site, toward
the above-mentioned organocopper reagents.
In particular, as can be seen from the results depicted in
Table 1, it should be noted that the reaction of ethyl
chloroformate with phenyl- (entry 1), functionalized aryl-
(entries 2–4), including sterically hindered species (entry
3), as well as heteroaryl Grignard reagents (entry 5) were
successful and gave desired esters 3a–e in good to excel-
lent yields. Moreover, the reaction of aliphatic and ali-
cyclic Grignard reagents (entries 6–9), leading to the
esters 3f–i, was also compatible with functional groups
such as alkene or aldehyde function, in protected form,
presents on the backbones of the Grignard reagent.
Alkoxycarbonylating reagents such as alkyl pyrazole-1-
carboxylates or alkyl 1-imidazolecarboxylates were con-
veniently used in cross-coupling reactions with Grignard
reagents to afford esters in good yields.7,8 However, to the
best of our knowledge, the literature gives few reports on
the syntheses of esters directly from the reaction of
chloroformates with alkyl and aryl Grignard reagents.9–11
The yields of desired esters are usually low, though
superior yields have been reported with the complexes
‘PhMgBr/TDA-1’ in THF at –15 °C9a or by use of di-
nuclear bridged complexes as catalysts.9b Additionally,
good yields of esters are obtained by converting in situ the
chloroformates to the corresponding acyl tributylphos-
A variation of the alcohol component on the chlorofor-
mate was next examined. As can be seen from the results
in Table 1 (entries 1, 3, 4, 6, 8) the reactions of the phenyl
chloroformate with alkyl and aryl Grignard reagents per-
formed particularly well and tend to give the esters 4 in
higher yields than those obtained with ethyl chloro-
formate. In all the reactions examined small amounts of
homocoupling product accompanied the cross-coupling
products shown in Table 1, which, however, can be easily
removed by column chromatography. Another side reac-
tion was the formation of unsymmetrical carbonate.14 This
SYNLETT 2007, No. 6, pp 0974–0976
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973861; Art ID: G34806ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Esters from Grignard Reagents and Chloroformates
975
byproduct was generally <4%, and in some cases product
purification by chromatography was complicated by its
similar polarity to compounds 3 and 4.
Table 1 Esters 3 and 4 by the Reactions of Chloroformates 1 and 2
with Grignard Reagents
Entry
1
Grignard reagents
R1
Estersa
3, 4 (yields, %)
In summary the results described in the present study
demonstrate that the cross-coupling of ethyl or phenyl
chloroformate with Grignard reagents, in the presence of
cuprous bromide and lithium bromide, provides a useful
tool for the preparation of esters in a rapid and convenient
process. It should be pointed out that this new procedure
provides esters from alkyl and aryl halides by C1-carbon-
chain extension. Therefore, esters which are otherwise
difficult to produce, especially when the acid cannot be
synthesized easily,11 may be obtained in this way. The
simplicity of the operations involved and the ready avail-
ability of the starting materials suggest that this route to
esters represents a practical alternative to currently exist-
ing methodology and will enjoy widespread application.
Phenyl
O
OR
3a (84); 4a (84)
2
3
4
p-Methoxyphenyl
2,6-Dimethylphenyl
p-Fluorophenyl
O
OR
MeO
3b (70)
O
OR
Acknowledgment
3c (84); 4c (98)
This work was financially supported in part by the Ministero
dell’Istruzione, dell’Università e della Ricerca (M.I.U.R.), Rome,
and the University of Bari (PRIN 2005).
O
OR
References and Notes
F
3d (71); 4d (88)
(1) (a) Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley-VCH: New York, 1999. (b) Smith, B. M.;
March, J. Advanced Organic Chemistry, 5th ed.; J. Wiley
and Sons: Chichester, 2001.
5
6
2-Thienyl
O
OR
(2) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron Lett. 1995, 36, 7305; and references therein.
(3) For a general review on the acylation of organometallic
reagents, see: Dieter, R. K. Tetrahedron 1999, 55, 4177.
(4) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron 1996, 52, 13513.
(5) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron 1999, 55, 2431.
(6) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. J.
Organomet. Chem. 2004, 689, 326.
(7) (a) Werner, T.; Barrett, A. G. M. J. Org. Chem. 2006, 71,
4302. (b) Kashima, C.; Tsuruoka, S.; Mizuhara, S.
Tetrahedron 1998, 54, 14679.
(8) For an analogous reaction to prepare amides by cross-
coupling of carbamoyl chloride with cyano-Gilman
cuprates, see: Lemoucheux, L.; Seitz, T.; Rouden, J.; Lasne,
M.-C. Org. Lett. 2004, 6, 3703.
(9) (a) Boudin, A.; Cerveau, G.; Chuit, C.; Corriu, R. J. P.; Reye,
C. Tetrahedron 1989, 45, 171. (b) Manfred, D.; Egon, U.;
Beate, J. East Ger. Patent DD 273249, 1989; Chem. Abstr.
1991, 114, 130219. (c) Marchelli, R.; Hutzinger, O.;
Heacock, R. A. Can. J. Chem. 1969, 47, 4375.
(d) Kasparek, S.; Heacock, R. A. Can. J. Chem. 1966, 44,
2805. (e) Kurtman, A. I. Zh. Obshch. Khim. 1952, 22, 1385.
(10) For scattered examples using others organometallic
reagents, see: (a) Zhang, X.; Qiu, W.; Burton, D. J.
Tetrahedron Lett. 1999, 40, 2681. (b) Wiedenau, P.;
Blechert, S. Synth. Commun. 1997, 27, 2033. (c) Gawley,
R. E.; Zhang, Q. J. Org. Chem. 1995, 60, 5763.
(d) Taschner, M. J.; Rosen, T.; Heathcock, C. H. Org. Synth.,
Coll. Vol. VII 1990, 226.
S
3e (60)
n-Octyl
O
OR
OR
3f (71); 4f (76)
7
8
9
9-Decenyl
O
3g (72)
Cyclohexyl
O
OR
3h (70); 4h (84)
2-(1,3-Dioxan-2-yl)ethyl
O
O
OR
O
3i (97)
a All compounds exhibited spectral data consistent with the assigned
structure; yields refer to products purified by chromatography.
Synlett 2007, No. 6, 974–976 © Thieme Stuttgart · New York

976
D. Bottalico et al.
LETTER
(11) a-Diazocarbonyl compounds have been metalated using
Grignard reagents and subsequently allowed to react with
chloroformates to produce a-diazocarbonyl-b-ketoesters,
see: Cuevas-Yanez, E.; Muchowski, J. M.; Cruz-Almanza,
R. Tetrahedron Lett. 2004, 45, 2417.
(12) Maeda, H.; Takahashi, K.; Ohmori, H. Tetrahedron 1998,
54, 12233.
(13) Typical Experimental Procedure
phenyl 2,6-dimethylbenzoate 4c (0.707 g, 98% yield). The
residual solid was crystallized from hexane giving white
crystals of 4c, mp 50–51 °C. IR (KBr): nmax = 1744, 1600,
1587, 1491, 1466, 1261, 1244, 1182, 1105, 1053, 916, 764,
731, 690 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.48–7.41
(m, 2 H), 7.32–7.22 (m, 4 H), 7.10 (d, J = 7.2 Hz, 2 H), 2.48
(s, 6 H). 13C NMR (100.6 MHz, CDCl3): d = 168.3, 150.6,
135.2, 132.9, 129.8, 129.6, 127.7, 126.1, 121.5, 19.9. MS:
m/z (%) = 226 (<1) [M+], 133 (100), 105 (27), 77 (13), 65 (6),
51 (5). The side product phenyl 2,6-dimethylphenyl
carbonate (<2%) was identified by the comparison with
mass spectral data of an authentic sample independently
synthesized: MS: m/z (%) = 242 (99) [M+], 198 (62), 197
(25), 183 (97), 165 (49), 155 (18), 148 (44), 121 (27), 120
(100), 105 (32), 103 (20), 94 (20), 92 (48), 91 (72), 79 (40),
78 (22), 77 (73), 51 (25).
A THF solution (10 mL) of anhyd LiBr (0.665 g, 7.66 mmol)
was added at r.t., under nitrogen, to CuBr (0.549 g, 3.83
mmol). A freshly prepared THF solution of 2,6-dimethyl-
phenylmagnesium bromide (4.7 mL, 3.83 mmol) and soon
afterwards phenyl chloroformate (0.4 mL, 3.19 mmol) in
THF (5 mL) were quickly added to the stirred solution of
salts. The mixture was stirred at r.t. for 15 h, quenched with
sat. aq NH4Cl and extracted with EtOAc. The organic
extracts were dried over Na2SO4 and concentrated under
vacuum. The residue was purified by column
(14) At present, the formation of this side product is not yet clear
and is subject to further investigations.
chromatography (silica gel, PE–EtOAc, 9.8:0.2) leading to
Synlett 2007, No. 6, 974–976 © Thieme Stuttgart · New York

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