Manufacturing synthesis of 5-substituted phthalides

Article abstract of DOI:10.1021/op100049t

A manufacturing synthesis of 5-chlorophthalide has been elaborated. The key step of the procedure is ortho-lithiation of 4-chloro-N,N-diisopropylbenzamide, followed by formylation with dimethyl formamide. Reduction of the formyl moiety and subsequent ring

Full text of DOI:10.1021/op100049t

Organic Process Research & Development 2010, 14, 617–622
Manufacturing Synthesis of 5-Substituted Phthalides
Ferenc Faigl,*,† Angelika Thurner,† Bala´zs Molna´r,‡ Gyula Simig,‡ and Bala´zs Volk*,‡
Research Group for Organic Chemical Technology, Hungarian Academy of Sciences at Budapest UniVersity of Technology and
Economics, P.O. Box 91, H-1521 Budapest, Hungary, and EGIS Pharmaceuticals Plc., Chemical Research DiVision, P.O. Box
100, H-1475 Budapest, Hungary
Abstract:
phthalides is based on phthalic acid derivatives (phthalic
anhydride, phthalimide) and involves substitutions on the
aromatic ring, transformations of the primarily introduced
aromatic substituents and selective reduction of one of the
carboxylic functions. Various combinations of this chemistry
have been described in the literature for the synthesis of
compound 1a. Thus, 4-nitrophthalimide, obtained by nitration
of phthalimide,12,13 was hydrogenated to give 4-aminophthal-
imide, which was further reduced with zinc dust in aqueous
sodium hydroxide solution to afford 5-aminophthalide (Scheme
1, route A).14 Alternatively, these two steps can be performed
in one-pot (route B).12,15 Then, diazotization of the amino
compound, followed by Sandmeyer reaction led to the desired
compound 1a.16 Although this is the best classical procedure
for the synthesis of compound 1a, it is not efficient enough for
manufacture. The alternative methods, such as reduction of
4-chlorophthalic anhydride17 with zinc dust in acidic medium18
or with sodium borohydride in DMF19 leading to significant
amounts of regioisomeric byproduct (route C), or the synthesis20
starting from 4-chloro-2-methylbenzoic acid21 (route D) are not
satisfactory even at laboratory scale.
A manufacturing synthesis of 5-chlorophthalide has been elabo-
rated. The key step of the procedure is ortho-lithiation of 4-chloro-
N,N-diisopropylbenzamide, followed by formylation with dimethyl
formamide. Reduction of the formyl moiety and subsequent ring
closure, which can be carried out also in one pot, led to 5-chlo-
rophthalide in high overall yield. The procedure has also been
successfully adapted for the synthesis of the 5-fluoro and 5-triflu-
oromethyl analogues. The compounds thus obtained are useful
building blocks in the synthesis of various heterocyclic ring
systems.
Introduction
Phthalide (2-benzofuran-1(3H)-one) skeleton is a common
motif in drugs and drug candidates. Besides the several hundreds
of phthalide derivatives in preclinical development worldwide,
this fact is best demonstrated by two marketed drugs: the
antiarthritic agent talniflumate1-3 and the immunosuppressant
drug mycophenolate mofetil.4,5 Furthermore, 5-substituted
phthalide intermediates are used in the manufacturing process
of the blockbuster antidepressant drug citalopram6,7 and its
optically active congener escitalopram.8
At our laboratory, we were interested in a viable manufac-
turing synthesis of 5-chlorophthalide (1a, Scheme 1). Phthalides
are useful intermediates for the synthesis of more complex
heterocyclic compounds9 and several methods have been
developed for their synthesis.10,11 The classical approach to
As an alternative approach, a variety of phthalides was
obtained by directed ortho-lithiation methodology. A proper
choice of the directing group and the electrophilic reagent results
in ortho-disubstituted compounds suitable for further transfor-
mation to the required phthalides. Thus, ortho-carboxylation via
ortho-lithiation of benzylic alcohols and subsequent cyclization
furnishes the corresponding phthalides22,23 (Scheme 2, route A).
* Authors to whom correspondence should be addressed. Telephone: +36 1
4633652. Fax: +36 1 4633649. E-mail: ffaigl@mail.bme.hu. Telephone: +36 1
2655543. Fax: +36 1 2655613. E-mail: volk.balazs@egis.hu.
† Hungarian Academy of Sciences at Budapest University of Technology and
Economics.
(11) Kawasaki, T.; Saito, Sh.; Yamamoto, Y. J. Org. Chem. 2002, 67, 2653–
2658, and references cited therein.
(12) Reduction of 4-aminophthalimide to 5-aminophthalide under similar
conditions was described earlier. Levy, L. F.; Stephen, H. J. Chem.
Soc. 1931, 867–871.
‡ EGIS Pharmaceuticals Plc., Chemical Research Division.
(1) Phthalidyl-2-(3′-trifluoromethylanilino)-pyridine-3-carboxylate and pro-
cess for its preparation. Br. Pat. GB 1553171, 1979; Chem. Abstr.
1980, 93, 8024.
(13) Young, J. G.; Onyebuagu, W. J. Org. Chem. 1990, 55, 2155–2159.
(14) Warrener, R. N.; Liu, L.; Russel, R. A. Tetrahedron 1998, 54, 7485–
7496.
(15) Kurilo, M. E.; Shemyakin, M. M. J. Gen. Chem. 1945, 15, 704–710.
Chem. Abstr. 1946, 40, 29275.
(2) Torriani, H. Drugs Future 1979, 4, 448–450.
(3) Ann. Drug Data Rep. 1982, 4, 195-196.
(16) Marzi, E.; Spitaleri, A.; Mongin, F.; Schlosser, M. Eur. J. Org. Chem.
2002, 15, 2508–2517.
(4) Nelson, P. H.; Gu, C.-L. L.; Allison, A. C.; Eugui, E. M.; Lee, W. A.
Morpholinoethylesters of mycophenolic acid and pharmaceutical
compositions. U.S. Pat. 4,753,935, 1988; Chem. Abstr. 1988, 109,
149226.
(17) For the circuitous synthesis of 4-chlorophthalic anhydride, see: (a)
Shigemitsu, M. Bull. Chem. Soc. Jpn. 1959, 32, 691–693. (b) Verbicky,
J. W., Jr.; Williams, L. J. Org. Chem. 1983, 48, 2465–2468, and
references cited therein.
(5) Robinson, C.; Castaner, J. Drugs Future 1995, 20, 356–361.
(6) Hilden, L.; Rummakko, P.; Grumann, A.; Pietika¨inen, P. Process for
the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-
dihydroisobenzofuran-5-carbonitrile. PCT Int. Pat. Appl. WO/2004/
011450, 2004; Chem. Abstr. 2004, 140, 145992.
(18) Nikulin, V. I.; Pisarenko, L. M. Bull. Acad. Sci. USSR DiV. Chem.
Sci. (Engl. Transl.) 1985, 34, 141–144; Chem. Abstr. 1985, 102,
203681.
(19) Donati, C.; Prager, R. H.; Weber, B. Aust. J. Chem. 1989, 42, 787–
795.
(7) Castaner, J.; Roberts, P. J. Drugs Future 1979, 4, 407–410.
(8) Sorbera, L. A.; Revel, L.; Martin, L.; Castaner, J. Drugs Future 2001,
26, 115–120.
(20) Cherkez, S.; Herzig, J.; Yellin, H. J. Med. Chem. 1986, 29, 947–959.
(21) For the preparation of 4-chloro-2-methylbenzoic acid from 4-chlo-
robenzoic acid, see: Gohier, F.; Castanet, A.-S.; Jacques, J. J. Org.
Chem. 2005, 70, 1501–1504.
(9) Snieckus, V. Heterocycles 1980, 14, 1649–1676.
(10) Narashimhan, N. S.; Mali, R. S. Synthesis 1983, 957–986, and
references cited therein.
(22) Uemura, M.; Tokuyama, S.; Sakan, T. Chem. Lett. 1975, 1195–1198.
10.1021/op100049t  2010 American Chemical Society
Published on Web 04/15/2010
Vol. 14, No. 3, 2010 / Organic Process Research & Development
•
617

Scheme 1. Literature procedures leading to 5-chlorophthalide
Scheme 2. Directed ortho-lithiation methodologies for the synthesis of phthalides
However, since some derivatives of benzoic acids (e.g., various
amides, dihydrooxazoles) proved to be much more powerful
directors in ortho-lithiation reactions than hydroxymethyl
groups, mostly they are used as starting materials for the
synthesis of phthalides. Ortho-lithiation of suitable benzoic acid
derivatives, followed by introduction of the optionally substi-
tuted hydroxymethyl moiety and subsequent acidic treatment
lead to phthalides (Scheme 2, route B).10,20,24-26
Hauser discovered that N-methylbenzamide underwent N-
and ortho-metalation with butyllithium, in contrast to N,N-
dimethylbenzamide, which had been known to react in an
addition reaction with lithium reagents to form ketones.27
4-Chloro-N-phenylbenzamide was lithiated with 2 equiv of
butyllithium in THF at -70 °C and the dilithio intermediate
was treated with N-alkyl-4-piperidinones to give 3,3-spiro-
disubstituted-5-chlorophthalides in low yield (Scheme 3).26
From industrial point of view, the disadvantage of the use
of secondary benzamides as starting compounds for the
synthesis of phthalide 1 lies in the requirement of 2 equiv of
butyllithium for metalation and the possible insolubility of the
intermediate dianions.28
Gschwend29 and Meyers30 reported that 2-aryl-4,4-dimethyl-
4,5-dihydro-1,3-oxazoles31 can be ortho-metalated with butyl-
lithium and treated with electrophilic reagents, leading after
hydrolysis to ortho-substituted benzoic acids. Ortho-metalation
(23) Uemura, M.; Nishikawa, N.; Hayashi, Y. Tetrahedron Lett. 1980, 21,
2069–2072.
(24) Snieckus, V. Chem. ReV. 1990, 90, 879–933.
(25) de Silva, S. O.; Reed, J. N.; Billedeau, R. J.; Wang, X.; Norris, D. J.;
Snieckus, V. Tetrahedron 1992, 48, 4863–4878.
(26) Marxer, A.; Rodriguez, H. R.; McKenna, J. M.; Tsai, H. M. J. Org.
Chem. 1975, 40, 1427–1433.
(28) Phillion, D. P.; Walker, D. M. J. Org. Chem. 1995, 60, 8417–8420.
(29) Gschwend, G. W.; Hamden, A. J. Org. Chem. 1975, 40, 2008–2009.
(30) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 3158–3159.
(31) 2-Aryloxazolines were prepared from benzoyl chloride with the
appropriate amino alcohol, followed by cyclization of the amide with
thionyl chloride.
(27) Puterbaugh, W. H.; Hauser, Ch. R. J. Org. Chem. 1964, 29, 853–
856.
618
•
Vol. 14, No. 3, 2010 / Organic Process Research & Development

Scheme 3. Lithiation of 4-chloro-N-phenylbenzamide
Scheme 4. Application of the 4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl directing group
Scheme 5. Lithiation of 4-chloro-N,N-diethylbenzamide
of 2-(4-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole was
carried out with butyllithium at -70 °C in diethyl ether29
(Scheme 4).
diethylbenzamide under these conditions occurred adjacent to
the amide group (Scheme 5).39
Using this methodology, phthalides were prepared from the
corresponding 4-fluorophenyl- and 4-(trifluoromethyl)phenyl
derivatives.32-35 The lithiations were carried out with butyl-
lithium, mostly at low temperature (-42 °C, -78 °C), presum-
ably in order to avoid the addition of the lithium reagent to the
CdN double bond. Considering this and the relatively circuitous
synthesis of 2-aryl-4,4-dimethyl-4,5-dihydro-1,3-oxazoles,36 we
decided to search for an alternative approach.
Thanks to the works of Beak37 and Snieckus,25 directed
ortho-metalation chemistry of N,N-diethylbenzamides has found
numerous synthetic applications. Comparative studies demon-
strated the superiority of the N,N-diethylcarbamoyl group to
the dihydrooxazole in its ability to direct ortho-lithiation.38 The
optimal reaction conditions for the ortho-lithiation of N,N-
diethylbenzamides require s-butyllithium/TMEDA for the meta-
lation at -78 °C in THF. Lithiation of the 4-chloro-N,N-
Results and Discussion
We intended to elaborate a safe and robust manufacturing
process of phthalide 1a. Therefore, use of highly inflammable
s-butyllithium and tert-butyllithium, as the reagents in the
manufacture, was undesirable. Furthermore, because of its better
industrial applicability, it was our fixed intention s if there is
only one opportunity s to use hexyllithium as the reagent
instead of butyllithium. For this purpose, a suitable tertiary
benzamide starting compound had to be found for a high-
yielding phthalide production via ortho-lithiation reaction using
this lithiating agent.
In a detailed study on tertiary amides in directed ortho-
lithiation, Beak demonstrated that in the case of N,N-diisopro-
pylbenzamides, ortho-lithiation could be achieved with butyl-
lithium/TMEDA at -78 °C.39 However, lithiation of our
potential starting compound 4-chloro-N,N-diisopropylbenzamide
(2a, Scheme 6) has only been described with tert-butyllithium
at -78 °C in THF.40
(32) Newman, M. S.; Kannan, R. J. Org. Chem. 1979, 44, 3388–3390.
(33) Yamaguchi, M.; Koga, T.; Kamei, K.; Akima, M.; Maruyama, N.;
Kuroki, T.; Hamana, M.; Ohi, N. Chem. Pharm. Bull. 1994, 42, 1850–
1853.
After all this, it was a revelation to find that 4-chloro-N,N-
diisopropylbenzamide (2a) could be smoothly lithiated simply
with butyllithium adjacent to the amide moiety. By benefiting
from this successful key reaction step, herein we report on the
simple manufacturing synthesis of 5-chlorophthalide (1a). It has
(34) Harvey, R. G.; Cortez, C. Tetrahedron 1997, 53, 7101–7118.
(35) Newman, M. S.; Veeraraghavan, S. J. Org. Chem. 1983, 48, 3246–
3248.
(36) For the synthesis of the 4-bromo analogue, see: Meyers, A. I.; Temple,
D. L.; Haidukewych, D.; Mihelich, E. D. J. Org. Chem. 1974, 39,
2787–2793.
(37) Beak, P.; Brown, R. A. J. Org. Chem. 1977, 42, 1823–1824.
(38) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860.
(39) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34–46.
(40) Koch, K.; Chambers, R. J.; Biggers, M. S. Synlett 1994, 347–348.
Vol. 14, No. 3, 2010 / Organic Process Research & Development
•
619

Scheme 6. Manufacturing synthesis of 5-substituted phthalides
Table 1. Yields of the reaction steps (%)
regioselectivity, the yields are either low or, in certain cases,
not reported in the literature. Moreover, considering the
environmental impact, industrial application of these processes
is to be avoided e.g. because of the use of carbon tetrachloride
or that of the large (4-5 equiv) excess of elemental zinc.
Alternative approaches in the literature, based on ortho-lithiation,
apply circuitously accessible starting materials or hazardous
lithiating agents. Using the new method described here, 1a can
be synthesised in two steps from the easily available benzamide
2a, in high overall yield (80%). The methodology is appropriate
for industrial scale-up, and it has successfully been adopted for
the analogous synthesis of 5-fluoro and 5-trifluoromethyl
congeners 1b,c. The compounds thus obtained are useful
building blocks in the synthesis of various heterocyclic ring
systems.
3 f 2
2 f 4
4 f 5
5 f 1
a
82
84
82
76
(86a)
97
95 (92b)
b
c
84
82
97
99
86
89
71
a Scaled-up reaction (starting from 239.7 g of 2a). b Scaled-up reaction (starting
from 230.0 g of 4a).
been shown that the corresponding 5-fluoro- and 5-trifluoro-
methylphthalide (1b,c) could also be obtained under the same
conditions.
4-Chloro-N,N-diisopropyl-benzamide (2a) was obtained from
the corresponding acid chloride 3a, by reacting it with diiso-
propylamine in the presence of triethylamine (TEA). Contrary
to its diethyl analogue, 2a is a solid, easy-to-handle compound.
It was lithiated with butyllithium in THF, by maintaining the
temperature in the range of -78 °C to -50 °C during the
addition of the reagent (Scheme 6). Subsequent treatment with
DMF afforded formyl derivative 4a in good yield. Sodium
borohydride reduction of the formyl group gave the corre-
sponding hydroxymethyl derivative 5a. The alternative one-
step method, lithiation of benzamide 2a followed by hydroxy-
methylation with paraformaldehyde provided compound 5a only
in poor yield when compared with the overall yield of the two-
step sequence. Acidic treatment of hydroxymethyl derivative
5a led to the desired phthalides 1a. It has been demonstrated
that the corresponding 5-fluoro- (1b) and 5-trifluoromethyl-
phthalides (1c) could be obtained analogously under the same
conditions (Scheme 6). Yields of the individual reaction steps
are summarized in Table 1.
Experimental Section
All melting points were determined on a Bu¨chi B-540
capillary melting point apparatus and are uncorrected. IR
spectra were obtained on a Bruker IFS-113v FT spec-
trometer in KBr pellets or in neat. 1H NMR and 13C NMR
spectra were recorded on a Varian Unity Inova 500 (500
and 125 MHz for 1H and 13C NMR spectra, respectively),
Bruker Avance III (400 and 100 MHz for 1H and 13C NMR
spectra, respectively) or Varian Gemini 200 (200 and 50
1
MHz for H and 13C NMR spectra, respectively) spec-
trometer. DMSO-d6 or CDCl3 was used as solvent and
tetramethylsilane (TMS) as internal standard. Chemical
shifts (δ) and coupling constants (J) are given in ppm
and in Hz, respectively. Elemental analyses were per-
formed on a Vario EL III analyzer. The reactions were
followed by analytical thin layer chromatography on silica
gel 60 F254. All reagents were purchased from commercial
sources.
4-Chloro-N,N-diisopropylbenzamide (2a). A mixture of
diisopropylamine (67 mL, 48.4 g, 480 mmol) and triethylamine
(67 mL, 48.6 g, 480 mmol) was added to a solution of
4-chlorobenzoyl chloride (3a, 40.9 mL, 55.8 g, 319 mmol) in
toluene (600 mL). After stirring for 24 h at ambient temperature,
toluene (100 mL) and water (200 mL) were added. The organic
layer was separated, washed with an aqueous solution of
hydrochloric acid (5 w/w%, 150 mL) and brine (150 mL), dried
over MgSO4, and evaporated. The residue was triturated with
hexane (100 mL), and the crystalline product was collected by
For practical reasons mentioned above, the synthesis of
phthalide 1a has been further modified. Lithiation with hexyl-
lithium instead of butyllithium under the same conditions and
subsequent formylation gave similar results. Sodium boro-
hydride reduction of the formyl derivative 4a followed by acidic
cyclization, without isolation of the hydroxymethyl intermediate,
afforded phthalide 1a in 95% yield (Table 1).
Conclusion
In conclusion, the new synthesis elaborated at our laboratory
provides a convenient access to target compound 5-chlo-
rophthalide (1a). Literature processes described for the synthesis
of 1a suffer from several disadvantages. Classical methods
usually include numerous reaction steps and, due to modest
620
•
Vol. 14, No. 3, 2010 / Organic Process Research & Development

filtration to give 2a (62.5 g, 82%) as colorless crystals. Mp
92-93 °C (hexane), lit.41 mp 85-87 °C.
the temperature of the mixture rose to -45 °C. After
warming to -15 °C, the reaction mixture was diluted with
a saturated aqueous solution of ammonium chloride (750
mL) and then water (100 mL), and extracted with ethyl
acetate (1000 and 2 × 150 mL). The organic layer was
washed with brine (1000 mL), dried over a mixture of
MgSO4 (110 g) and charcoal (10 g), and evaporated. The
residue was triturated with hexane (250 mL). The crystal-
line product was collected by filtration and washed with
hexane (100 mL) to give 230.0 g (86%) of 4a as colorless
crystals.
N,N-Diisopropyl-4-fluorobenzamide (2b).42 This com-
pound was prepared analogously to 2a, starting from 3b (28.7
g, 204 mmol) to give 2b (38.6 g, 84%) as colorless crystals.
1
Mp 95-96 °C (hexane). IR (KBr, cm-1): 1620. H NMR
(CDCl3, 200 MHz): δ 7.31 (dd, J ) 8.8, 5.5 Hz, 2H), 7.06 (t,
J ) 8.8 Hz, 2H), 3.68 (br s, 2H), 1.34 (br s, 12H) ppm. 13C
NMR (CDCl3, 50 MHz): δ 167.4 (d, J ) 242.3 Hz), 160.1,
134.9 (d, J ) 3.4 Hz), 137.6 (d, J ) 8.4 Hz), 115.2 (d, J )
21.7 Hz), 48.1 (br), 20.5 ppm. Elemental analysis for
C13H18FNO (223.29): calculated C 69.93, H, 8.13, N 6.27%;
found C 69.59, H 8.21, N 6.19%.
N,N-Diisopropyl-4-fluoro-2-formylbenzamide (4b). This
compound was prepared analogously to 4a, starting from 2b
(27.8 g, 124.5 mmol). The residue obtained after the final
evaporation was triturated with hexane (100 mL), and the
crystalline product was collected by filtration to give 30.1 g
(97%) of 4b as colorless crystals. Mp 101-102 °C (hexane/
N,N-Diisopropyl-4-(trifluoromethyl)benzamide (2c).42
This compound was prepared analogously to 2a, starting from
3c (39.6 g, 190 mmol) to give 2c (42.6 g, 82%) as colorless
1
crystals. Mp 64-65 °C (hexane). IR (KBr, cm-1): 1630. H
1
EtOAc). IR (KBr, cm-1): 1708, 1618. H NMR (DMSO-d6,
NMR (CDCl3, 400 MHz): δ 7.65 (d, J ) 8.1 Hz, 2H), 7.42 (d,
J ) 8.1 Hz, 2H), 3.64 (br s, 2H), 1.51 (br s, 6H), 1.20 (br s,
6H) ppm. 13C NMR (CDCl3, 100 MHz): δ 169.4, 142.3, 130.7
(q, J ) 32.9 Hz), 125.9, 125.54 (q, J ) 3.8 Hz), 123.9 (q, J )
272.2 Hz), 50.6 (br), 46.0 (br), 20.6 ppm. Elemental analysis
for C14H18F3NO (273.30): calculated C 61.53, H 6.64, N 5.13%;
found C 61.09, H 6.65, N 5.12%.
200 MHz): δ 9.96 (s, 1H), 7.74 (dd, J ) 9.2, 2.4 Hz, 1H), 7.59
(td, J ) 8.2, 2.8 Hz, 1H), 7.45 (dd, J ) 8.5, 5.5 Hz, 1H), 3.60
(m, 1H), 3.48 (m, 1H), 1.48 (m, 6H), 1.05 (m, 6H) ppm. 13C
NMR (DMSO-d6, 50 MHz): δ 190.3 (d, J ) 1.9 Hz), 166.7,
161.7, (d, J ) 247.3 Hz), 137.0 (d, J ) 3.8 Hz), 134.3 (d, J )
6.1 Hz), 128.7 (d, J ) 7.6 Hz), 121.5 (d, J ) 21.7), 116.6 (d,
J ) 22.1 Hz), 51.0, 45.2, 20.3, 20.1 ppm. Elemental analysis
for C14H18FNO2 (251.30): calculated C 66.91, H 7.22, N 5.57%;
found C 66.74, H 7.13, N 5.53%.
N,N-Diisopropyl-2-formyl-4-(trifluoromethyl)benza-
mide (4c). This compound was prepared analogously to 4a,
starting from 2c (38.8 g, 142 mmol). The residue obtained after
the final evaporation was triturated with hexane (100 mL), the
crystalline product was collected by filtration to give 4c (30.5
g, 71%) as colorless crystals. Mp 78-79 °C (hexane). IR (KBr,
cm-1): 1702, 1629. 1H NMR (CDCl3, 500 MHz): δ 10.12 (s,
1H), 8.20 (d, J ) 1.3 Hz, 1H), 7.87 (dd, J ) 8.1, 1.3 Hz, 1H),
7.44 (d, J ) 8.1 Hz, 1H), 3.59 (m, 1H), 3.53 (m, 1H), 1.61 (d,
J ) 7 Hz, 6H), 1.13 (d, J ) 6.4 Hz, 6H) ppm. 13C NMR
(CDCl3, 125 MHz): δ 189.0, 166.8, 144.0, 132.7, 131.3 (q, J
) 33.7 Hz), 130.6, (q, J ) 3.4 Hz), 126.6, (q, J ) 3.9 Hz),
123.2, (q, J ) 272.5 Hz), 51.4, 46.4, 20.5, 20.3 ppm. Elemental
analysis for C15H18F3NO2 (301.31): calculated C 59.79, H 6.02,
N 4.65%; found C 59.55, H 6.11, N 4.59%.
4-Chloro-N,N-diisopropyl-2-formylbenzamide (4a).
Method A. Butyllithium (75.6 mL of a 2.5 M solution in hexane,
190 mmol) was added to a solution of 2a (37.6 g, 156 mmol)
in THF (360 mL) at -78 °C. After stirring for 1 h at -78 °C,
DMF (16.1 mL, 15.3 g, 208 mmol) was added, while the
temperature of the mixture rose to -50 °C. After warming to
ambient temperature, the reaction mixture was diluted with a
saturated aqueous solution of ammonium chloride (350 mL)
and extracted with ethyl acetate (350 and 2 × 120 mL). The
organic layer was washed with brine (250 mL), dried over
MgSO4, and evaporated. The residue was triturated with a
mixture of hexane (120 mL) and ethyl acetate (15 mL). The
crystalline product was collected by filtration to give 35.1 g
(84%) of 4a as colorless crystals. Mp 116-117 °C (hexane/
1
EtOAc). IR (KBr, cm-1): 1703, 1628. H NMR (DMSO-d6,
500 MHz): δ 9.96 (s, 1H), 7.99 (d, J ) 2.2 Hz, 1H), 7.79 (dd,
J ) 8.2, 2.2 Hz, 1H), 7.41 (d, J ) 8.2 Hz, 1H), 3.60 (m, 1H),
3.46 (m, 1H), 1.48 (m, 6H), 1.05 (m, 6H) ppm. 13C NMR
(DMSO-d6, 125 MHz): δ 190.4, 166.6, 138.7, 134.2, 133.8,
133.5, 130.4, 128.2, 51.0, 45.1, 20.2, 20.1 ppm. Elemental
analysis for C14H18ClNO2 (267.76): calculated C 62.80, H 6.78,
N 5.23, Cl 13.24%; found C 62.42, H 6.73, N 5.20, Cl 13.34%.
Method B. The reaction was carried out similarly to Method
A, starting from 2a (35.3 g, 147 mmol) and using hexyllithium
(82.6 mL, 2.3 M solution in hexane, 190 mmol) as the lithiating
agent to give 4a (32.2 g, 82%). Mp 115-117 °C.
Scaled-Up Process. Butyllithium (482 mL of a 2.5 M
solution in hexane, 1.20 mol) was added to a solution of
2a (239.7 g, 1.00 mol) in THF (2290 mL) at -78 °C.
After stirring for 1.5 h at this temperature, DMF (102.6
mL, 96.8 g, 1.30 mol) was added in one portion, while
4-Chloro-N,N-diisopropyl-2-(hydroxymethyl)benza-
mide (5a). Sodium borohydride (3.4 g, 88.6 mmol) was added
to a solution of 4a (17.9 g, 66.9 mmol) in methanol (150 mL)
and cooled with ice-water bath. After stirring for 5 h, the
solvent was evaporated, water (80 mL) was added to the residue,
and the mixture was extracted with diethyl ether (3 × 80 mL).
The ethereal layer was washed with brine (80 mL), dried over
MgSO4 and evaporated. The residue was triturated with diethyl
ether and collected by filtration to give 5a (14.8 g, 82%) as
colorless crystals. Mp 81-82 °C (hexane). IR (KBr, cm-1):
1
3298, 1608. H NMR (DMSO-d6, 500 MHz): δ 7.52 (d, J )
2.2 Hz, 1H), 7.33 (dd, J ) 8.1, 2.2 Hz, 1H), 7.15 (d, J ) 8.1
Hz, 1H), 5.34 (t, J ) 5.7 Hz, 1H), 4.50 (dd, J ) 12.9, 4.7 Hz,
1H), 4.40 (dd, J ) 13.6, 5.8 Hz, 1H), 3.52 (m, 2H), 1.44 (m,
6H), 1.06 (m, 6H) ppm. 13C NMR (DMSO-d6, 125 MHz): δ
168.0, 141.0, 135.4, 132.8, 126.9, 126.8, 126.4, 59.6, 50.7, 44.9,
(41) Ulibarri, G.; Choret, N.; Bigg, D. C. H. Synthesis 1996, 11, 1286–
1288.
(42) Fong, C. W.; Grant, H. G. Aust. J. Chem. 1981, 34, 1205–1214. Only
13C NMR spectra of 2b and 2c are described.
Vol. 14, No. 3, 2010 / Organic Process Research & Development
•
621

20.5, 20.4, 20.3, 20.2 ppm. Elemental analysis for C14H20ClNO2
(269.77): calculated C 62.33, H 7.47, N 5.19, Cl 13.14%; found
C 62.04, H 7.59, N 5.10, Cl 13.66%.
mL) was added, and methanol was evaporated. Concentrated
aqueous hydrochloric acid solution (80 mL) was added, and
the mixture was refluxed for 6 h. After cooling to room
temperature, the crystalline product was collected by filtration
and then washed with water (100 mL) and ethanol (20 mL) to
give 1a (16.0 g, 95%) as colorless crystals. Mp 154-155 °C,
purity >99% (1H NMR).
Method B, Scaled-Up Process. Formyl derivative 4a (230.0
g, 0.86 mol) was dissolved in methanol (1900 mL). Sodium
borohydride (42.7 g, 1.13 mol) was added over a period of 90
min, while maintaining the temperature of the reaction mixture
between 5-10 °C. After stirring for additional 2 h at ambient
temperature, water (1020 mL) was added, and methanol was
evaporated. Concentrated aqueous hydrochloric acid solution
(685 mL) was added, and the mixture was refluxed for 6 h.
After cooling to room temperature, the crystalline product was
collected by filtration and then washed with water (3 × 400
mL) and a 2:1 mixture of ethanol and water (2 × 200 mL) to
give 1a (133.4 g, 92%) as colorless crystals. Mp 155-156 °C.
5-Fluoro-2-benzofuran-1(3H)-one (1b). This compound
was prepared analogously to 1a (Method A), starting from
5b (19.2 g, 75.7 mmol) to give 1b (9.80 g, 86%) as
colorless crystals. Mp 122-123 °C (hexane/EtOAc), lit.43
mp 120-121 °C. IR (KBr, cm-1): 1749.
5-Trifluoromethyl-2-benzofuran-1(3H)-one (1c). This com-
pound was prepared analogously to 1a (Method A), starting
from 5c (29 g, 95.7 mmol) to give 1c (17.3 g, 89%) as
colorless crystals. Mp 74-75 °C (hexane), lit. mp 70-72
°C,44 65-67 °C.45 IR (KBr, cm-1): 1758. 1H NMR (CDCl3,
500 MHz): δ 8.07 (d, J ) 8.0 Hz, 1H), 7.83 (d, J ) 8.0
Hz, 1H), 7.80 (s, 1H), 5.41 (s, 2H) ppm. 13C NMR (CDCl3,
125 MHz): δ 169.4, 146.8, 135.9 (q, J ) 33 Hz), 129.0,
126.4 (q, J ) 3.5 Hz), 123.3 (q, J ) 274 Hz), 119.6, 69.5
ppm. Elemental analysis for C9H5FO2 (202.13): calculated
C 53.48, H 2.49%; found C 53.28, H 2.48%.
N,N-Diisopropyl-4-fluoro-2-(hydroxymethyl)benzamide
(5b). This compound was prepared analogously to 5a, starting
from 4b (20.0 g, 79.7 mmol) to give 5b (19.9 g, 97%) as
colorless crystals. Mp 95-96 °C (hexane). IR (KBr, cm-1):
3425, 1617. 1H NMR (CDCl3, 500 MHz): δ 7.14 (dd, J ) 9.4,
2.6 Hz, 1H), 7.13 (dd, J ) 8.4, 5.5 Hz, 1H), 6.97 (∼td, J )
8.4, 2.7 Hz, 1H), 4.61 (m, 1H), 4.40 (m, 1H), 3.77 (t, J ) 5.4
Hz, 1H), 3.76 (m, 1H), 3.53 (m, 1H), 1.55 (m, 6H), 1.15 (m,
3H), 1.10 (m, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 170.3,
162.6 (d, J ) 249.0 Hz), 141.2 (d, J ) 6.8 Hz), 133.3 (d, J )
3.9 Hz), 126.7 (d, J ) 7.8 Hz), 116.2 (d, J ) 21.5 Hz), 114.2
(d, J ) 21.5 Hz), 63.0 (d, J ) 1.5 Hz), 51.2, 46.2, 20.9, 20.6,
20.5, 20.4 ppm. Elemental analysis for C14H20FNO2 (253.32):
calculated C 66.38, H 7.96, N 5.53%; found C 66.07, H 8.09,
N 5.45%.
N,N-Diisopropyl-2-hydroxymethyl-4-(trifluoromethyl)-
benzamide (5c). This compound was prepared analogously to
5a, starting from 4c (30.0 g, 99.7 mmol) to give 5c (30.1 g,
1
99%) as colorless oil. IR (neat, cm-1): 3299, 1611. H NMR
(DMSO-d6, 500 MHz): δ 7.85 (s, 1H), 7.64 (d, J ) 7.9 Hz,
1H), 7.37 (d, J ) 7.9 Hz, 1H), 5.46 (t, J ) 5.7 Hz, 1H), 4.59
(dd, J ) 14.1, 5.1 Hz, 1H), 4.49 (dd, J ) 14.1, 6.0 Hz, 1H),
3.58 (m, 1H), 3.47 (m, 1H), 1.47 (m, 6H), 1.08 (m, 6H) ppm.
13C NMR (DMSO-d6, 125 MHz): δ 167.7, 140.4 (q, J ) 1.0
Hz), 139.9, 128.7 (q, J ) 31.7 Hz), 125.6, 124.3 (q, J ) 272.5
Hz), 123.8 (q, J ) 3.9 Hz), 59.6, 50.8, 45.1, 20.4, 20.3, 20.3,
20.1 ppm. Elemental analysis for C15H20F3NO2 (303.33):
calculated C 59.40, H 6.65, N 4.62%; found C 59.17, H 6.73,
N 4.56%.
5-Chloro-2-benzofuran-1(3H)-one (1a). Method A. A
mixture of 5a (54.7 g, 203 mmol) and aqueous hydrochloric
acid (20 w/w%, 410 mL) was refluxed for 4 h. After cooling
to ambient temperature it was extracted with dichloromethane
(4 × 100 mL). The combined organic layer was extracted with
brine (200 mL), dried over MgSO4, and evaporated. The residue
was triturated with a mixture (1:1) of hexane and ethyl acetate
(100 mL) and collected by filtration to give 1a (26.0 g, 76%)
as colorless crystals. Mp 156-158 °C (EtOH), lit.12 mp
Supporting Information Available
1H and 13C NMR spectra of new compounds 1a-c, 2b-c,
4a-c, and 5a-c. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
153.5 °C (EtOH). IR (KBr, cm-1): 1754. H NMR (CDCl3,
400 MHz): δ 7.84 (d, J ) 8.7 Hz, 1H), 7.52 (m, 1H), 7.51 (m,
1H), 5.30 (s, 2H) ppm. 13C NMR (CDCl3, 100 MHz): δ 169.7,
148.1, 140.7, 129.8, 126.8, 124.2, 122.5, 68.9 ppm. Elemental
analysis for C8H5ClO2 (168.58): calculated C 57.00, H 2.99,
Cl 21.03%; found C 56.91, H 3.03, Cl 21.15%.
Method B. Compound 1a was also prepared in one pot,
starting from formyl derivative 4a (26.9 g, 0.100 mol) which
was dissolved in methanol (225 mL) and treated with sodium
borohydride (5.0 g, 0.133 mol) while cooling with ice-water
bath. After stirring for 2 h at ambient temperature, water (120
Received for review February 15, 2010.
OP100049T
(43) Synthesis of 1b starting from 5-amino-2-benzofuran-1(3H)-one is
described in ref 14.
(44) Compound 1c was prepared via hydrolysis of the hardly accessible
2-hydroxymethyl-4-(trifluoromethyl)benzonitrile, see: Bigler, A. J.;
Boegesoe, K. P.; Toft, A.; Hansen, V. Eur. J. Med. Chem. 1977, 12,
289–295.
(45) Compound 1c was prepared by non-regiospecific lithiation followed
by carboxylation and cyclization, starting from m-(trifluoromethyl)-
benzyl alcohol, see ref 16.
622
•
Vol. 14, No. 3, 2010 / Organic Process Research & Development