Practical preparation of ethyl 2-methylthiophene-3-carboxylate

Article abstract of DOI:10.1248/cpb.59.797

A safe and efficient process for the preparation of ethyl 2-methylthiophene-3-carboxylate (5) was devised. This process provides several advantages over the precedents, involving operational simplicity, avoidance of the use of strong bases such as n-butyllithium and application of noncryogenic conditions, and enabled to prepare 5 in 52% overall yield from commercially available 2-methylthiophene on a multikilogram scale.

Full text of DOI:10.1248/cpb.59.797

June 2011
Note
Chem. Pharm. Bull. 59(6) 797—798 (2011)
797
Practical Preparation of Ethyl 2-Methylthiophene-3-carboxylate
Masakazu KOGAMI and Nobuhide WATANABE*
Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd.; 363 Shiosaki, Hokusei-cho, Inabe, Mie 511–0406,
Japan. Received February 14, 2011; accepted March 17, 2011
A safe and efficient process for the preparation of ethyl 2-methylthiophene-3-carboxylate (5) was devised.
This process provides several advantages over the precedents, involving operational simplicity, avoidance of the
use of strong bases such as n-butyllithium and application of noncryogenic conditions, and enabled to prepare 5
in 52% overall yield from commercially available 2-methylthiophene on a multikilogram scale.
Key words 2-methylthiophene-3-carboxylic acid ester; TurboGrignard; practical preparation
Thiophenes serve as the central pharmacophore in drug
With the successful conversion of 3 into the corresponding
discovery and their bioisosteric replacement of a benzene Grignard reagent 4 in hand, several electrophiles were exam-
ring is widely accepted as a powerful strategy to improve bio- ined for installation of an ethyl ester group, and ethyl chloro-
logical activities and pharmacodynamic and pharmacokinetic formate was found to be the choice of electrophile in terms
properties.1) Therefore, use of thiophenes as building blocks of cost and efficacy. It should be noted that the use of inex-
undoubtedly continues to receive much attention in the phar- pensive diethyl carbonate gave a decreased yield (70%) ac-
maceutical industry.
companied by formation of symmetrical ketone 6 (3%).
In connection with an ongoing program, we needed kilo-
The initial scale-up runs indicated that arbitrary, rapid
gram quantities of 2-methylthiophene-3-carboxylic acid (1) temperature rise in this step would cause safety concerns
and its esters as starting raw materials. A medicinal research- about larger scale reactions. After further investigation, ther-
based route was based on C-2 methylation2—4) of dianion of mal events could be controlled by adjusting the rate of addi-
commercially available 3-thiophenecarboxylic acid (2). How- tion of ethyl chloroformate, maintaining the internal temper-
ever, because of both the expense of the reagent 2 and the use ature below 0 °C. A demonstration batch was performed with
of more than 2 eq of n-butyllithium at low temperature, this 4.6 kg of 3. Isopropylmagnesium chloride solution was added
route is far from ideal for large-scale preparation of these to 3 in the presence of LiCl for 1.5 h at ambient temperature,
raw materials. Among several precedent methods for prepa- and then the mixture was gradually warmed to 60 °C for
ration of the corresponding acid or esters, the Grignard ap- 1.5 h and the temperature was kept for 3 h, at which time
proach is thought to be a straightforward solution. In this HPLC analysis indicated that 7.9% of starting material 3 was
note, we describe a practical synthesis of 2-methylthiophene- left in the reaction mixture. Ethyl chloroformate in THF so-
3-carboxylic acid ethyl ester, capitalizing on the LiCl-medi- lution was added to the mixture in a linear manner for 4 h at
ated halogen–magnesium exchange reactions.
ꢀ4 °C. Isolation by vacuum distillation gave 1 in 63% yield
This synthesis began with 2-methylthiophene, which was with 91% HPLC purity.
converted into 3-bromo-2-methylthiophene (3) according to
We devised a safe and efficient process for the preparation
literature methods.5) As for preparation of the Grignard of ethyl 2-methylthiophene-3-carboxylate. Our work pro-
reagent from 3, the original work of Steinkopf and Jacob6—8) vides several advantages over the precedents, involving oper-
involved treatment of 3 with magnesium by an entrained ational simplicity, avoidance of the use of strong bases such
method, followed by coupling with carbon dioxide. However, as n-butyllithium and application of noncryogenic condi-
all our attempts failed when using an array of the usual acti- tions, and the process enabled us to prepare 5 in 52% overall
vators such as iodine and 1,2-dibromoethane, which was con- yield from commercially available 2-methylthiophene on a
sistent with the findings of Rieke.9,10) In recent years, there multikilogram scale.
have been several publications regarding the LiCl-mediated
halogen–magnesium exchange reactions (TurboGrignard
Experimental
General All reagents and solvents were commercially available and
reagents) of 3-bromothiophenes, and therefore we turned our
attention to this technology.11) Exchange reaction of 3 with
1.5 eq of i-PrMgCl/LiCl in tetrahydrofuran (THF) reached a
maximum conversion of 94% after 3 h at reflux, while reach-
ing plateaus of 81% and 50% of the conversions after 5 h at
40 °C and room temperature, respectively. The ratios were
determined by quantitative HPLC analysis of reaction
aliquots after quenching with an excess of aqueous ammo-
nium chloride. Extensive survey of other inexpensive Grig-
nard reagents including EtMgBr and i-PrMgBr provided poor
conversions (20—45%), illustrating the superiority of Turbo-
Grignard. Conveniently, similar acceleration was observed
when addition of LiCl to a THF solution of 3 was followed
by treatment with i-PrMgCl.12)
were used without further purifications. The 1H- and 13C-NMR spectra were
recorded by a Varian-400MR spectrometer operating at 400 MHz in CDCl3
at 25 °C with tetramethylsilane as an internal standard. The data are reported
as follows: chemical shift in ppm (d), integration, multiplicity (sꢁsinglet,
dꢁdoublet, tꢁtriplet, qꢁquartet, brꢁbroad singlet, mꢁmultiplet), and cou-
pling constant (Hz). The mass spectra were obtained using a Waters AC-
QUITY® SQD instrument. The following systems were used for quantitative
HPLC analysis: HPLC detector, Waters 2489 UV/Visible Detector, HPLC
Reagents and conditions: (a) LDA, MeI, THF, ꢀ78 °C.
Chart 1
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: no_watanabe@skk-net.com

798
Vol. 59, No. 6
the internal temperature was maintained below ꢀ2 °C during the addition.
The mixture was stirred for an additional 2 h at ꢀ3 to 5 °C and then
quenched with 2 M hydrochloric acid (18 l). The resulting mixture was
stirred for 1 h and extracted with n-heptane (18 l). The organic layers were
washed with brine (18 l) and dried over anhydrous sodium sulfate (300 g).
After evaporation of the solvents, the residue was purified by distillation
under reduced pressure to afford compound 5 (3.11 kg, yield 63%, purity
1
91% by HPLC) as a pale yellow oil. bp 90—111 °C (6 mmHg). H-NMR
(CDCl3) d: 1.36 (3H, t, Jꢁ7.1 Hz), 2.74 (3H, s), 4.31 (2H, q, Jꢁ7.1 Hz),
6.97 (1H, d, Jꢁ5.4 Hz), 7.39 (1H, d, Jꢁ5.4 Hz). 13C-NMR (101 MHz,
CDCl3) d: 14.4, 15.4, 60.2, 120.8, 128.4, 129.2, 149.1, 163.7. MS m/z: 171
(MꢃH)ꢃ, 142, 99.
Reagents and conditions: (a) i-PrMgCl, LiCl, THF, reflux; (b) ClCO2Et, THF, ꢀ5 °C.
Chart 2
References and Notes
1) For a recent review, see; Matsuoka H., Ohta M., Farumashia, 46,
215—222 (2010).
2) The method has been most often applied in recent years, see this and
the following two references; Knight D. W., Nott A. P., Tetrahedron
Lett., 21, 5051—5054 (1980).
3) Oi S., Nagaya H., Inatomi N., Nakao M., Yukimasa H., U.S. Patent
5840917 (1997) [Chem. Abstr., 126, 317493 (1997)].
4) Ueno K., Sasaki A., Kawano K., Okabe T., Kitazawa N., Takahashi K.,
Yamamoto N., Suzuki Y., Matsunaga M., Kubota A., U.S. Patent
6340759 (2002) [Chem. Abstr., 130, 311813 (2002)].
5) Steinkopf W., Jusust. Liebigs. Ann. Chem., 513, 281—294 (1934).
6) Gaertner reported another Grignard reaction approach, whereby 5 was
given in 72% yield from 2-chloromethylthiophene, see Gaertner R., J.
Am. Chem. Soc., 73, 3934—3937 (1951).
7) However, the reaction required delicate operations, including use of a
cyclic reactor, to maintain highly diluted conditions and volatile ether
as solvent, which seemed to be unsuitable for large-scale preparation
of 5, see Campaigne E., Yokley O. E., J. Org. Chem., 28, 914—917
(1963).
8) Steinkopf W., Jacob H., Jusust. Liebigs. Ann. Chem., 515, 273—283
(1935).
9) Rieke R. D., Kim S.-H., Wu X., J. Org. Chem., 62, 6921—6927
(1997).
10) Very recently, an AstraZeneca group also reported difficulty in prepa-
ration of 3-thienyl Grignard reagents by an entrained method and
found that the Grignard exchange reaction with i-PrMgCl worked well,
see Alcaraz M.-L., Atkinson S., Cornwall P., Foster A. C., Gill D. M.,
Humphries L. A., Keegan P. S., Kemp R., Merifield E., Nixon R. A.,
Noble A. J., O’Beirne D., Patel Z. M., Perkins J., Rowan P., Sadler P.,
Singleton J. T., Tornos J., Watts A. J., Woodland I. A., Org. Process
Res. Dev., 9, 555—569 (2005).
column, CAPCELLPAK C18 MGII column (3.0 mM, 20ꢂ2.0 mm, Shiseido)
at 40 °C. The flow rate of the mobile phase was 0.4 ml/min, and the detec-
tion was performed at 254 nm.
3-Bromo-2-methylthiophene (3)13) A three-necked 3 l round-bottom
flask was charged with N-bromosuccinimide (355.8 g, 2.0 mol) and AcOH
(500 ml). A solution of 2-methylthiophene (98.2 g, 1.0 mol) in AcOH
(100 ml) was added dropwise to the suspension at room temperature for
55 min, and the mixture was stirred for an additional 5 h. The resulting mix-
ture was poured into a mixture of n-heptane (500 ml) and water (500 ml) and
the layers were separated. The organic layer was washed with 1 M sodium
hydroxide (500 ml) and brine (500 ml) successively, and dried over anhy-
drous sodium sulfate. Filtration and evaporation gave 3,5-dibromo-2-
methylthiophene with 92% HPLC purity (260.6 g, yield 92%) as a pale yel-
low oil. 1H-NMR (CDCl3) d: 2.33 (3H s), 6.85 (1H, s). 13C-NMR (101 MHz,
CDCl3) d: 14.8, 108.5, 108.7, 131.9, 136.0. MS m/z: 255 (MꢃH)ꢃ, 99. The
crude product was used in the next reaction without further purification.
A four-necked 2 l round-bottomed flask was charged with magnesium
turnings (27.2 g, 1.12 mol) and tetrahydrofuran (200 ml). To the suspension,
a tenth part of a solution of 3,5-dibromo-2-methylthiophene (249.5 g, ca.
0.899 mol) in tetrahydrofuran (550 ml) was added over 10 min at room tem-
perature. After an exothermic reaction subsided, the remainder of the solu-
tion was added dropwise at such a rate that gentle reflux was maintained.
After the addition was complete, the reaction mixture was heated at reflux
for an additional 2 h. The resulting mixture was cooled to 0 °C. Water
(60 ml) was added dropwise to the mixture over 20 min and 2 M hydrochloric
acid was added until the mixture became clear. The biphase mixture was ex-
tracted with n-heptane (600 ml) and the organic layer was washed with brine
(600 ml) and dried over anhydrous sodium sulfate. After solvents were re-
moved in vacuo, the residue was purified by distillation under reduced pres-
sure to afford compound 3 (148.6 g, yield 90%, purity 97% by HPLC) as a
1
colorless oil. bp 50 °C (5 mmHg). H-NMR (CDCl3) d: 2.40 (3H, s), 6.89
(1H, d, Jꢁ5.4 Hz), 7.07 (1H, d, Jꢁ5.4 Hz). 13C-NMR (101 MHz, CDCl3) d:
14.6, 109.4, 122.7, 129.9, 134.1. MS m/z: 200 (MꢃNa)ꢃ, 177 (MꢃH)ꢃ, 99.
In practice, crude 3 is allowed to be used in the next reaction without further
purifications.
11) For a recent review, see Piller F. M., Metzger A., Schade M. A., Haag
B. A., Gavryushin A., Knochel P., Chem. Eur. J., 15, 7192—7202
(2009).
12) To our best knowledge, while many examples of LiCl-mediated direct
insertion of Mg into aromatic bromides have been reported, few exam-
ples featuring the in situ preparation of TurboGrignard reagents have
been reported, see Hauk D., Lang S., Murso A., Org. Process Res.
Dev., 10, 733—738 (2006) and references therein. The in situ prepara-
tion method described here seemed to be more convenient than the
method for pre-preparation of TurboGrignard reagent.
13) Hallberg A., Liljefors S., Pedaja P., Synth. Commun., 11, 25—28
(1981).
Ethyl 2-Methyl-thiophene-3-carboxylate (5)14) A 100 l glass-lined re-
actor was charged with 3-bromo-2-methylthiophene 3 (88% HPLC purity,
4.67 kg, ca. 23.3 mol), lithium chloride (1.66 kg, 39.2 mol, ꢄ99% purity,
Wako Pure Chemical Industries, Japan), and tetrahydrofuran (7.0 l) at room
temperature. Isopropylmagnesium chloride (19.6 l, 39.2 mol, 2 M solution in
tetrahydrofuran, Aldrich, U.S.A.) was added dropwise over 1.5 h at such a
rate that the internal temperature was maintained below 30 °C during the ad-
dition. The mixture was warmed to 60 °C over 2 h and stirred for an addi-
tional 3 h, at which time HPLC analysis indicated that 7.9% of 3 was left.
The mixture was cooled below ꢀ5 °C, and then ethyl chloroformate (4.26
kg, 39.2 mol) was added dropwise to the mixture over 4 h at such a rate that
14) Chatterjee P., Murphy P. J., Pepe R., Shaw M., J. Chem. Soc., Perkin
Trans. 1, 17, 2403—2405 (1994).