Synthesis of 4,6-dichloro- and 4,6-difluorophthalides: A systematic study on the lithiation of 3,5-dihalo-N,N-diisopropylbenzamides

Article abstract of DOI:10.1002/ejoc.201001529

By taking advantage of the N,N-diisopropylcarbamoyl moiety as a versatile ortho-directing lithiation group, the preparation of 4,6-dichloro- and 4,6-difluorophthalides, starting from the corresponding 3,5-dihalo-N,N- diisopropylbenzamides, is described he

Full text of DOI:10.1002/ejoc.201001529

FULL PAPER
DOI: 10.1002/ejoc.201001529
Synthesis of 4,6-Dichloro- and 4,6-Difluorophthalides: a Systematic Study on
the Lithiation of 3,5-Dihalo-N,N-diisopropylbenzamides
Balázs Molnár,[a] Gyula Simig,[a] and Balázs Volk*[a]
Keywords: Synthetic methods / Lithiation / Regioselectivity / Oxygen heterocycles
By taking advantage of the N,N-diisopropylcarbamoyl moi-
ety as a versatile ortho-directing lithiation group, the prepa-
ration of 4,6-dichloro- and 4,6-difluorophthalides, starting
from the corresponding 3,5-dihalo-N,N-diisopropylbenz-
amides, is described here. The role of the lithiating agent,
the formation of kinetically and thermodynamically favored
products, and the marked difference between the dichloro
and difluoro derivatives are discussed in detail.
Introduction
butyllithium (BuLi) or hexyllithium (HexLi) can be applied
as the lithiating agents instead of sec-butyllithium (sBuLi),
thus opening the door to a less hazardous industrial imple-
mentation of the reaction.
As a part of our ongoing research project we aimed at
extending the route shown in Scheme 1 for the synthesis
of 4,6-dichloro- and 4,6-difluorophthalides (4, Scheme 1),
starting with ortho-directing lithiation of 3,5-dichloro- and
3,5-difluoro-N,N-diisopropylbenzamide.[13]
The phthalide [2-benzofuran-1(3H)-one] skeleton is a
common motif in biologically active substances, as demon-
strated by two marketed drugs, the immunosuppressant my-
cophenolate mofetil[1,2] and the antiarthritic agent talniflu-
mate.[3–5] Furthermore, 5-substituted phthalide intermedi-
ates are used in the manufacturing process of the antide-
pressant drug citalopram[6,7] and its optically active form
escitalopram.[8]
Recently, we reported the manufacturing synthesis of 5-
Our literature search revealed that several examples have
chlorophthalide (1, Scheme 1). The key step of the pro- been published for the lithiation of benzene derivatives ex-
cedure is the selective ortho-lithiation of 4-chloro-N,N-di- hibiting both a directing metalation group (DMG) and also
isopropylbenzamide (2) to produce lithio derivative 3, fol- the two fluorine or two chlorine atoms in the meta posi-
lowed by formylation with N,N-dimethylformamide tions. Of course, the halogen atoms can also act as DMGs.
(DMF).[9] The advantage of the N,N-diisopropylcarbamoyl Lithiation of 3,5-difluoroanisole (5a, Scheme 2) with BuLi
group as an ortho-directing lithiation group over the more (1 equiv., –78 °C, 45 min) in tetrahydrofuran (THF) oc-
widely used N,N-diethylcarbamoyl analogue[10–12] is that curred at the 4-position to give 6a, which was trapped with
Scheme 1.
carbon dioxide to give 2,6-difluoro-4-methoxybenzoic acid
[a] EGIS Pharmaceuticals Plc., Chemical Research Division,
P. O. Box 100, 1475 Budapest, Hungary
Fax: +36-1-2655613
(7a) in 81%[14,15] and 86%[16] yield.
However, lithiation of 1,3-difluoro-5-(methoxymethoxy)-
benzene (5b) with BuLi (1 equiv., –75 °C, 6 h) in diethyl
E-mail: volk.balazs@egis.hu
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Synthesis of Dihalophthalides: Lithiation Study of Dihalobenzamides
Scheme 2.
ether occurred predominantly at the site adjacent to the nating properties of the substituents, the nature of the met-
methoxymethoxy group to give 8b, as shown by the isola- alating agents, and the choice of the solvents. The role of
tion of benzoic acid 9a in 61% yield (Scheme 2). The for- kinetic and thermodynamic control in the product distribu-
mation of the isomeric product 7b was also detected (ca. tion was not studied in these papers. It is not clear whether
2%). Compound 7b was prepared in 83% yield by met- the isolated products reflect a final distribution or just a
alation of 5b with the superbasic mixture LICKOR snapshot of the lithio intermediates at the time of quench-
(1 equiv. BuLi and 1 equiv. potassium tert-butoxide) at ing.
–75 °C in THF for 2 h, followed by carboxylation and re-
Dabrowski et al. described a more detailed investigation
of the lithiation reaction of 3,5-dibromoanisole (5g) with
moval of the protecting group in the course of workup.[17]
Kauch and Hoppe elaborated an efficient method for the lithium diisopropylamide (LDA) at –85 °C in THF.[22] By
ortho-specific derivatization of N-isopropyl-N-(trimethyl- trapping in situ with chlorotrimethylsilane (TMSCl), the
silyl)carbamates 5c and 5d of phenols. Lithiation with BuLi prepared product 9e indicated the primary formation of
(2.0–2.2 equiv.) and N,N,NЈ,NЈ-tetramethylethane-1,2-di- 2,4-dibromo-6-methoxyphenyllithium (8g). However, when
amine (TMEDA, 2.0–2.2 equiv.) at –78 °C for 1 h,[18,19] fol- the lithiation was carried out prior to the quench with an
lowed by treatment with DMF and hydrolysis of the carb- electrophile (ca. –85 °C, 2 h), the formation of the isomeric
amate moiety gave salicylaldehydes 9b (81%) and 9c (86%), product 7d derived from lithio derivative 6g was also ob-
respectively.[18]
served. The amount of the latter compound 7d increased
Deprotonation of 3,5-dichloroanisole (5e) with BuLi after longer lithiation times. It was suggested that lithiation
(1.4 equiv.) and TMEDA (1.4 equiv.) at –78 °C in THF for at the 2-position was kinetically favored. However, the re-
1.5 h and subsequent carboxylation yielded a mixture of sultant aryllithium compound 8g isomerized to form the
benzoic acids, which were separated after esterification to thermodynamically more stable 2,6-dibromo-4-methoxy-
give methyl esters 7c (16%) and 9d (14%).[20] Lithiation of phenyllithium (6g).[22]
the same substrate 5e with sBuLi (1.05 equiv.) at –95 °C in
Schlosser mentioned several other examples in his review
THF for 1 h occurred regioselectively between the methoxy for lithiations of various substrates, where the initially
and chloro groups producing 8e. In contrast, the tert-butyl- formed metalated intermediate isomerized to the more
dimethylsilyl (TBDMS) ether of 3,5-dichlorophenol (5f) stable lithio species (basicity-lowering isomerization).[13c]
underwent lithiation under the same conditions (1.05 equiv.
sBuLi, –95 °C, THF, 1 h) exclusively at the position be-
tween the two chlorine atoms to produce 6f. This was due
Results and Discussion
to the steric hindrance of the TBDMS protecting group.[21]
The results of the lithiation reactions shown above do
We aimed at applying the manufacturing route leading
not give a consistent view and eventually differ from the to 5-chlorophthalide (1, Scheme 1) for the analogous prepa-
expectations based on the electron-withdrawing and coordi- ration of 4,6-dichloro- and 4,6-difluorophthalides (4a and
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B. Molnár, G. Simig, B. Volk
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Scheme 3.
4b, respectively) using the regioselective ortho-lithiation of 2-lithio species 11b under these conditions. However, in ac-
4,6-dichloro- and 4,6-difluoro-N,N-diisopropylbenzamide cordance with the formation of aldehyde 14b, quenching of
(10a and 10b, respectively, Scheme 3). Our experiments re- the lithiation reaction (BuLi, THF, –78 °C) with TMSCl
vealed that 4a could be obtained under similar conditions, after 1 h gave trimethylsilyl derivative 14d, showing that the
but the preparation of 4b necessitated the elaboration of a initially formed lithio intermediate 11b isomerized to the
modified synthetic approach. The results are described be- thermodynamically more stable (less basic) species 12b. The
low in detail.
regioselectivities observed in both cases were practically
Lithiation of 3,5-dichloro-N,N-diisopropylbenzamide perfect. The ratios of 13d/14d in the crude products were
(10a) with BuLi in THF at –78 °C for 1 h (Scheme 3) and 100:1 and 1:64, respectively, as shown by GC measure-
subsequent treatment with DMF afforded formyl derivative ments.
13a in 99% yield, demonstrating that lithiation occurred at
The isomerization of 3,5-dichloro-2-lithio derivative 11a
the 2-position to give 11a. Aldehyde 13a was transformed to the 4-lithio species 12a proceeded similarly to that of the
to hydroxymethyl derivative 15 and then to the required corresponding difluoro analogue, but much slower. In situ
phthalide 4a by conventional methods.
quenching of the metalation mixture (BuLi, THF, –78 °C)
However, when the 3,5-difluoro analogue 10b was treated with TMSCl afforded 13c in 88% yield, the 13c/14c ratio,
under the same conditions (BuLi, THF, –78 °C, 1 h), lithi- shown by GC measurements, being 65:1 in the crude prod-
ation occurred at the 4-position flanked by two fluoro sub- uct. However, when trapping was performed after 7 h of
stituents giving 12b, as indicated by the formation of alde- reaction time (BuLi, THF, –78 °C), the 13c/14c ratio, as
hyde 14b in 91% yield. This aldehyde is obviously unsuit- shown by GC measurements, was 1:100 in the crude prod-
able for the synthesis of the required 4,6-difluorophthalide uct, and isomer 14c was obtained in 83% yield. As ex-
4b. To find a solution for our synthetic problem, we decided pected,[23] LDA (THF, –78 °C) abstracted the proton from
to scrutinize the lithiation reactions of 3,5-dichloro- and the most acidic site of compounds 10a and 10b, resulting
3,5-difluoro-N,N-diisopropylbenzamides 10.
after a short reaction time (1 h) in the formation of the
On the basis of all this, we decided to investigate first thermodynamically more stable lithio isomers in both cases,
whether lithio derivative 12b was a kinetic or thermo- as demonstrated by the isolation of compounds 14.
dynamic product. In situ trapping with TMSCl of the lithio
Due to the very fast displacement of the metal atom in
species, formed when difluoro derivative 10b is treated with the initially formed lithio derivative 11b to the 4-position in
BuLi (THF, –78 °C), afforded trimethylsilyl derivative 13d, lithio derivative 12b, the required aldehyde 13b could not
demonstrating the initial preference for the formation of the be obtained without substantial amounts of isomeric impu-
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Synthesis of Dihalophthalides: Lithiation Study of Dihalobenzamides
Scheme 4.
rity 14b. Therefore, we decided to synthesize the required
The synthesis of 4,6-difluorophthalide via the 2-lithio-
phthalide 4b starting from compound 14d using the tri- benzamide intermediate has been carried out with the tem-
methylsilyl moiety as a protecting group in the 4-position porary protection of the 4-position.
(Scheme 4). Lithiation of compound 14d followed by for-
mylation afforded aldehyde 16 in high yield, which was re-
duced to hydroxymethyl derivative 17. The removal of the
Experimental Section
protecting group with CsF[24,25] could be carried out either
General: All melting points were measured with a Büchi B-540 cap-
illary melting point apparatus. Infrared (IR) spectra were recorded
before or after the cyclization of the furan ring (see 18 and
19) to produce phthalide 4b in high overall yield.
with a Bruker IFS-113v FT spectrometer in KBr pellets or neat.
1H and 13C NMR spectra were recorded with a Varian Unity Inova
500 (500 and 125 MHz for 1H and 13C NMR spectra, respectively),
with a Bruker Avance III (400 and 100 MHz for 1H and 13C NMR
spectra, respectively) or with a Varian Gemini 200 (200 and
Conclusions
Although numerous papers discuss the lithiation reac-
tions of 1,3,5-trisubstituted benzene derivatives 5 with two
identical halogen substituents and an ortho-directing met-
alation group, very few systematic studies have investigated
the role of kinetic and thermodynamic control of the lithi-
ation reactions with this family of compounds. The system-
atic lithiation study of 3,5-dihalo-N,N-diisopropylbenz-
amides described here revealed that in the case of the 3,5-
dichloro derivative, the rearrangement of the primarily
formed 2-lithio intermediate was fairly slow; thus, deriva-
tives substituted adjacent to the benzamide moiety could be
prepared. By benefiting from this highly selective key reac-
tion step, title compound 4,6-dichlorophthalide was pre-
pared in high overall yield.
On the contrary, when lithiating the 3,5-difluoro conge-
ner, very fast isomerization of the initially formed 2-lithio
intermediate to the thermodynamically more stable 4-lithio
species was observed. In general, longer reaction times with
BuLi or the use of LDA led to the 4-lithio intermediate
by starting from either 3,5-dichloro- or 3,5-difluoro-N,N-
diisopropylbenzamide.
1
50 MHz for H and 13C NMR spectra, respectively) spectrometer.
Deuterated dimethyl sulfoxide ([D6]DMSO) or CDCl3 was used as
the solvent, and tetramethylsilane was used as the internal stan-
dard. Chemical shifts (δ) and coupling constants (J) are given in
ppm and in Hz, respectively. Elemental analyses were performed
with a Vario EL III analyzer. GC measurements were recorded
with an Agilent 6890N chromatograph (column = DB-5.625,
30 mϫ0.25 mmϫ0.25 μm; temperature program
= 80 °C for
2 min, 20 °C/min to 300 °C, 300 °C for 20 min; injector temperature
= 250 °C; detector temperature = 300 °C; split = 50:1; flow rate =
1 mL/min; helium). The reactions were followed by analytical thin
layer chromatography on silica gel 60 F254. All reagents were pur-
chased from commercial sources. Analytical samples of new com-
pounds were obtained by recrystallization from the solvents given
below. Procedures where the lithiation step used BuLi are referred
to as Method A and those using LDA are referred to as Method B.
3,5-Dichloro-N,N-diisopropylbenzamide (10a): A mixture of diiso-
propylamine (40 mL, 28.9 g, 285 mmol) and triethylamine (40 mL,
29.0 g, 287 mmol) was added to a solution of 3,5-dichlorobenzoyl
chloride (45.0 g, 215 mmol) in toluene (370 mL). After stirring at
ambient temperature for 24 h, water (150 mL) was added. The or-
ganic layer was separated, washed with an aqueous solution of hy-
Eur. J. Org. Chem. 2011, 1728–1735
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B. Molnár, G. Simig, B. Volk
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drochloric acid (10%, 150 mL) and brine (100 mL), and then dried
with MgSO4. The solvents were evaporated and, the residue was
triturated with hexane (70 mL). The crystalline product was col-
lected by filtration to give 10a (48.7 g, 84%) as off-white crystals.
M.p. 132–133 °C (hexane, colorless crystals); ref.[26] m.p. 127–
(d, J = 6.9 Hz, 3 H), 1.51 (d, J = 6.9 Hz, 3 H), 1.19 (d, J = 6.7 Hz,
3 H), 1.12 (d, J = 6.2 Hz, 3 H), 0.42 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.5, 147.8, 143.0, 135.4, 133.7, 129.3,
124.3, 51.0, 46.0, 20.6, 20.2, 20.1, 20.0, 1.2 ppm. C16H25Cl2NOSi
(346.38): calcd. C 55.48, H 7.28, Cl 20.47, N 4.04; found C 55.69,
H 7.45, Cl 20.43, N 4.05.
129 °C. IR (KBr): ν = 1634 cm–1. 1H NMR (500 MHz, [D6]-
˜
DMSO): δ = 7.62 (t, J = 1.6 Hz, 1 H), 7.36 (d, J = 1.6 Hz, 2 H),
3.59 (m, 2 H), 1.45 (m, 6 H), 1.14 (m, 6 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 166.6, 142.1, 134.5, 128.3, 124.2, 50.9,
45.2, 20.3 ppm.
3,5-Difluoro-N,N-diisopropyl-2-(trimethylsilyl)benzamide (13d):
A
solution of BuLi (2.5 m in hexane, 12.35 mL, 30.9 mmol) was added
to a solution of 10b (6.15 g, 25.5 mmol) and TMSCl (9.65 mL,
8.35 g, 76 mmol) in THF (63 mL) at –78 °C. After stirring at
–78 °C for 1 h, the cooling bath was removed, and the temperature
of the mixture rose to ambient temperature over a period of 1.5 h.
After dilution with a saturated aqueous solution of ammonium
chloride (50 mL), the reaction mixture was extracted with diethyl
ether (50 mL and 2ϫ30 mL). The organic layer was washed with
brine (100 mL) and dried with MgSO4. The solvents were evapo-
rated, and the residue (8.35 g, 13d/14d = 100:1 by GC) was tritu-
rated with cold pentane (approximately –20 °C, 25 mL) to give of
3,5-Difluoro-N,N-diisopropylbenzamide (10b): A mixture of diiso-
propylamine (27.8 mL, 20.07 g, 198.3 mmol) and triethylamine
(27.8 mL 20.18 g, 199.5 mmol) was added to a solution of 3,5-di-
fluorobenzoyl chloride (25.0 g, 141.6 mmol) in toluene (208 mL).
After stirring at ambient temperature for 24 h, water (200 mL) was
added. The organic layer was separated, washed with an aqueous
solution of hydrochloric acid (10%, 200 mL) and brine (150 mL),
and then dried with charcoal and MgSO4. The solvents were evapo-
rated, and the residue was triturated with cold pentane (approxi-
mately –20 °C, 40 mL). The crystalline product was collected by
filtration to give 10b (25.6 g, 75%) as colorless crystals. M.p. 103–
13d (6.31 g, 79%) as colorless crystals. M.p. 126–127 °C (pentane).
1
IR (KBr): ν = 2970, 1626 cm–1. H NMR (500 MHz, CDCl ): δ =
˜
3
6.71 (td, J = 9.3, 2.2 Hz, 1 H), 6.65 (dd, J = 8.6, 2.4 Hz, 1 H), 3.71
104 °C (hexane). IR (KBr): ν = 1632 cm–1. 1H NMR (500 MHz, (m, 1 H), 3.50 (m, 1 H), 1.52 (≈ t, J = 8.1 Hz, 6 H), 1.16 (≈ t, J =
˜
CDCl3): δ = 6.83 (m, 2 H), 6.81 (m, 1 H), 3.65 (m, 2 H), 1.44 (m, 6.9 Hz, 6 H), 0.34 (d, J = 1.8 Hz, 9 H) ppm. 13C NMR (125 MHz,
6 H), 1.26 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 167.9 CDCl3): δ = 169.5 (t, J = 2.9 Hz), 168.4 (dd, J = 243.7, 11.2 Hz),
(t, J = 2.5 Hz), 162.9 (dd, J = 250.9, 12.4 Hz), 141.7 (t, J = 8.3 Hz),
114.0 (t, J = 25.4 Hz), 108.8 (dd, J = 20.0, 6.4 Hz), 50.9, 46.1,
20.5 ppm. C13H17F2NO (241.28): calcd. C 64.71, H 7.10, N 5.81;
found C 64.38, H 7.22, N 5.71.
163.5 (dd, J = 252.5, 13.9 Hz), 147.3 (dd, J = 12.2, 7.3 Hz), 119.3
(dd, J = 30.8, 4.0 Hz), 109.0 (dd, J = 21.0, 3.4 Hz), 103.1 (dd, J =
31.7, 23.4 Hz), 50.8, 46.0, 20.6, 20.3, 20.0, 0.4 (d, J = 2.9 Hz) ppm.
C16H25F2NOSi (313.47): calcd. C 61.31, H 8.04, N 4.47; found C
61.20, H 8.23, N 4.36.
3,5-Dichloro-2-formyl-N,N-diisopropylbenzamide (13a): A solution
of BuLi (2.5 m in hexane, 40.5 mL, 101 mmol) was added to a solu-
3,5-Dichloro-4-formyl-N,N-diisopropylbenzamide (14a). By Method
tion of 10a (23.0 g, 83.9 mmol) in THF (200 mL) at –78 °C. After A: A solution of BuLi (2.5 m in hexane, 9.6 mL, 24 mmol) was
stirring at –78 °C for 1 h, DMF (8.4 mL, 7.93 g, 108.5 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 (170 mL)
and extracted with ethyl acetate (170 mL and 2ϫ70 mL). The or-
ganic layer was washed with brine (120 mL) and dried with MgSO4.
The solvents were evaporated, and the resulting residue was tritu-
rated with hexane (70 mL). The crystalline product was collected
by filtration to give 13a (25.0 g, 99%) as colorless crystals. M.p.
added to a solution of 10a (5.48 g, 20 mmol) in THF (48 mL) at
–78 °C. After stirring at –78 °C for 7 h, DMF (3 mL, 2.85 g,
39 mmol) was added while the temperature of the mixture rose to
–50 °C. After warming to ambient temperature, the reaction mix-
ture was diluted with a saturated aqueous solution of ammonium
chloride (50 mL) and extracted with ethyl acetate (40 mL and
2ϫ20 mL). The organic layer was washed with brine (50 mL) and
dried with MgSO4. The solvents were evaporated, and the residue
was triturated with hexane (15 mL). Filtration of the crystalline
product gave 14a (4.77 g, 79%) as colorless crystals. M.p. 95–96 °C
116–117 °C (hexane/ethyl acetate). IR (KBr): ν = 1702, 1630 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 10.41 (s, 1 H), 7.45 (d, J =
(hexane/ethyl acetate). IR (KBr): ν = 1710, 1634 cm–1. 1H NMR
˜
1.8 Hz, 1 H), 7.10 (d, J = 1.8 Hz, 1 H), 3.53 (m, 1 H), 3.47 (m, 1 H), (400 MHz, [D6]DMSO): δ = 10.35 (s, 1 H), 7.55 (s, 2 H), 3.58 (m,
1.58 (m, 6 H), 1.13 (d, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ 2 H), 1.43 (m, 6 H), 1.23 (m, 6 H) ppm. 13C NMR (100 MHz, [D6]-
= 188.3, 166.5, 142.4, 140.4, 138.9, 130.0, 127.4, 125.4, 51.3, 46.0,
DMSO): δ = 189.1, 165.8, 144.21, 135.7, 130.2, 126.6, 51.0, 45.3,
20.52, 20.2 ppm. C14H17Cl2NO2 (302.20): calcd. C 55.64, H 5.67, 20.2 ppm. C14H17Cl2NO2 (302.20): calcd. C 55.64, H 5.67, Cl
Cl 23.26, N 4.63; found C 55.44, H 5.76, Cl 23.55, N 4.60.
23.26, N 4.63; found C 55.76, H 5.73, Cl 23.51, N 4.55. By Method
B: A solution of LDA (1.8 m in THF/heptane/ethylbenzene,
16.8 mL, 30 mmol) was added to a solution of 3,5-dichloro-N,N-
diisopropylbenzamide (10a, 5.48 g, 20 mmol) in THF (48 mL) at
–78 °C. After stirring at –78 °C for 1 h, DMF (3.0 mL, 2.85 g,
39 mmol) was added while the temperature of the mixture rose to
–55 °C. After warming to ambient temperature, the reaction mix-
ture was diluted with a saturated aqueous solution of ammonium
chloride (50 mL) and extracted with ethyl acetate (40 mL and
2ϫ15 mL). The organic layer was washed with brine (80 mL) and
dried with MgSO4. The solvents were evaporated, and the resulting
residue was triturated with hexane (20 mL). The crystalline product
was collected by filtration to give of 14a (4.90 g, 81%) as colorless
crystals. M.p. 95–96 °C (hexane/ethyl acetate).
3,5-Dichloro-N,N-diisopropyl-2-(trimethylsilyl)benzamide (13c): A
solution of BuLi (2.5 m in hexane, 4.8 mL, 12 mmol) was added to
a solution of 10a (2.74 g, 10 mmol) and TMSCl (3.8 mL, 3.27 g,
30 mmol) in THF (24 mL) at –78 °C. After stirring at –78 °C for
1 h, the cooling bath was removed, and the temperature of the reac-
tion mixture rose to –20 °C over a period of 1.5 h. After dilution
with a saturated aqueous solution of ammonium chloride (40 mL),
the reaction mixture was extracted with ethyl acetate (30 mL and
2ϫ15 mL). The organic layer was washed with brine (50 mL) and
dried with MgSO4. The solvents were evaporated, and the residue
(13c/14c = 65:1 by GC) was triturated with hexane (10 mL). The
crystalline product was collected by filtration to give 13c (3.06 g,
88%) as colorless crystals. M.p. 130–131 °C (hexane). IR (KBr): ν
˜
= 1637 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 2.0 Hz,
1 H), 6.96 (d, J = 2.0 Hz, 1 H), 3.67 (m, 1 H), 3.50 (m, 1 H), 1.54
3,5-Difluoro-4-formyl-N,N-diisopropylbenzamide (14b). By Method
A: A solution of BuLi (2.5 m solution in hexane, 20.9 mL, 52 mmol)
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Synthesis of Dihalophthalides: Lithiation Study of Dihalobenzamides
was added to a solution of 10b (11.0 g, 45.6 mmol) in THF
(112 mL) at –78 °C. After stirring at –78 °C for 1 h, DMF
(4.72 mL, 4.06 g, 61 mmol) was added while the temperature of the
mixture rose to –55 °C. After warming to ambient temperature, the
reaction mixture was diluted with a saturated aqueous solution of
ammonium chloride (100 mL) and extracted with ethyl acetate
(100 mL and 2ϫ50 mL). The organic layer was washed with brine
(100 mL) and dried with MgSO4. The solvents were evaporated,
and the residue was triturated with cold hexane (approximately
–20 °C, 25 mL). The crystalline product was collected by filtration
3,5-Difluoro-N,N-diisopropyl-4-(trimethylsilyl)benzamide (14d). By
Method A: A solution of BuLi (2.5 m in hexane, 24.7 mL, 61 mmol)
was added to a solution of 10b (12.3 g, 51 mmol) in THF (126 mL)
at –78 °C. After stirring at –78 °C for 1 h, TMSCl (19.3 mL, 16.7 g,
152 mmol) was added while the temperature of the mixture rose to
–60 °C. After warming to ambient temperature, the reaction mix-
ture was diluted with a saturated aqueous solution of ammonium
chloride (100 mL) and extracted with diethyl ether (70 mL and
2ϫ50 mL). The organic layer was washed with brine (100 mL) and
dried with MgSO4. The solvents were evaporated, and the resulting
to give 14b (11.2 g, 91%) as colorless crystals. M.p. 105–105.5 °C residue (15.95 g, 14d/13d = 64:1 by GC) was triturated with cold
(hexane/ethyl acetate). IR (KBr): ν = 1705, 1631 cm–1. 1H NMR
pentane (approximately –50 °C, 30 mL) to give 14d (12.45 g, 78%)
as colorless needles. M.p. 80–80.5 °C (pentane). IR (KBr): ν =
˜
(200 MHz, CDCl3): δ = 10.34 (s, 1 H), 6.93 (m, 2 H), 3.61 (m, 2
˜
H), 1.33 (m, 12 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 183.7 2975, 1632 cm–1. H NMR (200 MHz, CDCl3): δ = 6.74 (m, 2 H),
1
(t, J = 4.2 Hz), 166.6 (t, J = 1.9 Hz), 163.1 (dd, J = 266.0, 5.7 Hz),
146.5 (t, J = 9.9 Hz), 114.1 (t, J = 11.1 Hz), 109.8 (dd, J = 23.2,
3.0 Hz), 50.9, 46.5, 20.5 ppm. C14H17F2NO2 (269.29): calcd. C
62.44, H 6.36, N 5.20; found C 62.11, H 6.22, N 5.13. By Method B:
A solution of LDA (1.8 m in THF/heptane/ethylbenzene, 16.8 mL,
30 mmol) was added to a solution of 10b (4.82 g, 20 mmol) in THF
3.65 (m, 2 H), 1.34 (m, 12 H), 0.37 (s, 9 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 168.2 (t, J = 2.7 Hz), 166.9 (dd, J = 245.7,
16.5 Hz), 142.7 (t, J = 9.5 Hz), 119.2 (t, J = 5.3 Hz), 108.4 (dd, J
= 30.2, 2.3 Hz), 50.7, 47.2, 20.6, 0.1 (t, J = 2.7 Hz) ppm.
C16H25F2NOSi (313.47): calcd. C 61.31, H 8.04, N 4.47; found C
60.89, H 8.23, N 4.38. By Method B: A solution of LDA (1.8 m
(48 mL) at –78 °C. After stirring at –78 °C for 1 h, DMF (3.0 mL, solution in THF/heptane/ethylbenzene, 16.8 mL, 30 mmol) was
2.83 g, 39 mmol) was added while the temperature of the mixture
rose to –60 °C. After warming to ambient temperature, the reaction
mixture was diluted with a saturated aqueous solution of ammo-
nium chloride (40 mL) and extracted with ethyl acetate (40 mL and
2ϫ20 mL). The organic layer was washed with brine (90 mL) and
dried with MgSO4. The solvents were evaporated, and the resulting
residue was triturated with cold hexane (approximately –20 °C,
15 mL). The crystalline product was collected by filtration to give
14b (4.55 g, 81%) as an off-white solid. M.p. 105–105.5 °C (hexane/
ethyl acetate).
added to a solution of 10b (4.82 g, 20 mmol) in THF (48 mL) at
–78 °C. After stirring at –78 °C for 1 h, TMSCl (5 mL, 4.33 g,
39 mmol) was added while the temperature of the mixture rose to
–60 °C. After warming to ambient temperature, the reaction mix-
ture was diluted with a saturated aqueous solution of ammonium
chloride (40 mL) and extracted with ethyl acetate (40 mL and
2ϫ20 mL). The organic layer was washed with brine (90 mL) and
dried with MgSO4. The solvents were evaporated, and the residue
was triturated with cold pentane (approximately –50 °C, 15 mL).
The crystalline product was collected by filtration to give of 14d
(5.20 g, 83%) as an off-white solid. M.p. 80–80.5 °C (pentane).
3,5-Dichloro-N,N-diisopropyl-4-(trimethylsilyl)benzamide (14c). By
Method A: A solution of BuLi (2.5 m in hexane, 4.8 mL, 12 mmol)
was added to a solution of 10a (2.74 g, 10 mmol) in THF (24 mL)
at –78 °C. After stirring at –78 °C for 7 h, TMSCl (2.0 mL, 1.72 g,
15.8 mmol) was added while the temperature of the mixture rose
to –65 °C. After warming to ambient temperature, the reaction
mixture was diluted with a saturated aqueous solution of ammo-
nium chloride (50 mL) and extracted with ethyl acetate (25 mL and
2ϫ10 mL). The organic layer was washed with brine (40 mL) and
dried with MgSO4. The solvents were evaporated, and the resulting
residue (14c/13c = 100:1 by GC) was triturated with pentane
(12 mL). The crystalline product was collected by filtration to give
3,5-Dichloro-2-(hydroxymethyl)-N,N-diisopropylbenzamide (15): So-
dium borohydride (1.0 g, 26.4 mmol) was added to a solution of
13a (5.0 g, 16.5 mmol) in methanol (80 mL), and the reaction mix-
ture was cooled in an ice/water bath. After stirring for 5 h, the
solvent was evaporated, water (40 mL) was added to the residue,
and the mixture was extracted with diethyl ether (3ϫ30 mL). The
ethereal layer was washed with brine (40 mL) and dried with
MgSO4. The solvents were evaporated, and the residue was tritu-
rated with hexane (20 mL). The product was collected by filtration
to give 15 (4.20 g, 83%) as colorless crystals. M.p. 141–142 °C (hex-
ane). IR (KBr): ν = 3510, 3069, 1615 cm–1. 1H NMR (200 MHz,
˜
[D6]DMSO): δ = 7.58 (d, J = 2.2 Hz, 1 H), 7.24 (d, J = 2.2 Hz, 1
H), 5.10 (dd, J = 5.5, 4.0 Hz, 1 H), 4.59 (dd, J = 11.7, 4.0 Hz, 1
H), 4.45 (dd, J = 11.7, 5.9 Hz, 1 H), 3.55 (m, 1 H), 3.53 (m, 1 H),
1.45 (d, J = 6.6 Hz, 6 H), 1.10 (d, J = 6.6 Hz, 3 H), 1.08 (d, J =
6.6 Hz, 3 H) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 166.7,
142.2, 135.5, 133.9, 133.0, 128.6, 123.8, 57.8, 50.8, 45.0, 20.3, 20.1,
20.0, 19.7 ppm. C14H19Cl2NO2 (304.22): calcd. C 55.27, H 6.30, Cl
23.31, N 4.60; found C 55.35, H 6.39, Cl 23.34, N 4.54.
14c (2.87 g, 83%) as off-white crystals. M.p. 129–131 °C (hexane,
1
colorless crystals). IR (KBr): ν = 1632 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 7.16 (s, 2 H), 3.73 (m, 1 H), 3.60 (m, 1 H), 1.43 (m, 6
H), 1.23 (m, 6 H), 0.51 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 167.7, 142.0, 141.3, 137.3, 125.6, 51.1, 46.2, 20.6, 2.8 ppm.
C16H25Cl2NOSi (346.38): calcd. C 55.48, H 7.28, Cl 20.47, N 4.04;
found C 55.81, H 7.38, Cl 20.56, N 3.84. By Method B: A solution
of LDA (1.8 m solution in THF/heptane/ethylbenzene, 16.8 mL,
30 mmol) was added to a solution of 10a (5.48 g, 20 mmol) in THF
(48 mL) at –78 °C. After stirring at –78 °C for 30 min, TMSCl
(7.6 mL, 6.50 g, 60 mmol) was added while the temperature of the
mixture rose to –60 °C. After warming to ambient temperature, the
reaction mixture was diluted with a saturated aqueous solution of
ammonium chloride (80 mL) and extracted with ethyl acetate
(60 mL and 2ϫ20 mL). The organic layer was washed with brine
(80 mL) and dried with MgSO4. The solvents were evaporated, and
the resulting residue was triturated with hexane (30 mL). The crys-
talline product was collected by filtration to give 14c (6.43 g, 93%)
as pale brown crystals. M.p. 129–131 °C (hexane, colorless crys-
tals).
3,5-Difluoro-2-formyl-N,N-diisopropyl-4-(trimethylsilyl)benzamide
(16): A solution of BuLi (2.5 m in hexane, 15 mL, 37.5 mmol) was
added to a solution of 14d (10.3 g, 32.9 mmol) in THF (72 mL)
at –78 °C. After stirring at –78 °C for 1 h, DMF (3.4 mL, 3.21 g,
44 mmol) was added while the temperature of the mixture rose to
–60 °C. After warming to ambient temperature, the reaction mix-
ture was diluted with a saturated aqueous solution of ammonium
chloride (50 mL) and extracted with ethyl acetate (50 mL and
2ϫ20 mL). The organic layer was washed with brine (50 mL) and
dried with MgSO4. The solvents were evaporated, and the residue
(11.1 g) was triturated with cold pentane (approximately –50 °C,
35 mL) to give 16 (8.25 g, 74%) as colorless crystals. M.p. 87–88 °C
Eur. J. Org. Chem. 2011, 1728–1735
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1733

B. Molnár, G. Simig, B. Volk
FULL PAPER
(pentane). IR (KBr): ν = 2976, 1638 cm–1. 1H NMR (500 MHz,
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.7 (dd, J = 4.9,
˜
CDCl3): δ = 10.27 (s, 1 H), 6.67 (d, J = 7.9 Hz, 1 H), 3.52 (m, 2 2.9 Hz), 167.6 (dd, J = 246.6, 12.7 Hz), 160.4 (dd, J = 248.5,
H), 1.59 (m, 6 H), 1.12 (d, J = 6.6 Hz, 6 H), 0.41 (t, J = 1.3 Hz, 9 16.1 Hz), 130.5 (dd, J = 11.2, 6.8 Hz), 128.1 (dd, J = 24.9, 2.9 Hz),
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 185.9 (d, J = 8.3 Hz),
170.1 (dd, J = 255.7, 17.6 Hz), 169.7 (dd, J = 257.2, 17.6 Hz), 166.6
(t, J = 1.0 Hz), 143.9 (dd, J = 10.2, 1.9 Hz), 117.3 (dd, J = 12.7,
3.0 Hz), 114.7 (t, J = 34.7 Hz), 109.9 (dd, J = 28.8, 2.9 Hz), 51.2,
46.0, 20.4, 20.0, 0.0 (t, J = 2.6 Hz) ppm. C17H25F2NO2Si (341.48):
calcd. C 59.80, H 7.38, N 4.10; found C 60.37, H 7.42, N 4.11.
121.2 (dd, J = 36.6, 31.7 Hz), 107.8 (dd, J = 30.3, 4.9 Hz), 66.9 (d,
J = 1.5 Hz), –0.14 (t, J = 3.4 Hz) ppm. C11H12F2O2Si (242.30):
calcd. C 54.53, H 4.99; found C 54.48, H 4.91.
4,6-Dichloro-2-benzofuran-1(3H)-one (4a): A mixture of 15 (40.0 g,
131.5 mmol) and aqueous hydrochloric acid (10%, 215 mL) was
heated to reflux for 10 h. After cooling to ambient temperature, the
reaction mixture was extracted with dichloromethane (3ϫ100 mL).
The organic layers were combined, extracted with brine (200 mL),
and dried with MgSO4. The solvents were evaporated, and the resi-
due was triturated with a mixture of hexane/ethyl acetate (10:1,
120 mL). The product was collected by filtration to give 4a (20.9 g,
78%) as colorless crystals. M.p. 87–88 °C (hexane/ethyl actate). IR
3,5-Difluoro-2-(hydroxymethyl)-N,N-diisopropyl-4-(trimethylsilyl)-
benzamide (17): Sodium borohydride (1.0 g, 26.4 mmol) was added
to a solution of 16 (6.0 g, 17.6 mmol) in methanol (50 mL), and
the reaction mixture was cooled with an ice/water bath. After stir-
ring for 5 h, the solvent was evaporated, water (40 mL) was added
to the residue, and the mixture was extracted with diethyl ether
(3ϫ40 mL). The ethereal layer was washed with brine (50 mL) and
dried with MgSO4. The solvents were evaporated, and the residue
was triturated with hexane (20 mL). The product was collected by
filtration to give of 17 (5.54 g, 92%) as colorless crystals. M.p. 110–
(KBr): ν = 1775 cm–1. 1H NMR (200 MHz, CDCl ): δ = 7.81 (d, J
˜
3
= 1.5 Hz, 1 H), 7.66 (d, J = 1.6 Hz, 1 H), 5.28 (s, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 168.5, 142.8, 136.4, 133.8, 129.5,
129.1, 124.2, 68.4 ppm. C8H4Cl2O2 (203.03): calcd. C 47.33, H
1.99, Cl 34.92; found C 47.36, H 2.03, Cl 34.89.
111 °C (hexane). IR (KBr): ν = 3283, 1621 cm–1. 1H NMR
˜
(200 MHz, CDCl3): δ = 6.62 (dd, J = 7.9, 0.9 Hz, 1 H), 4.67 (m, 1
H), 4.45 (m, 1 H), 3.82 (m, 1 H), 3.55 (m, 1 H), 3.17 (t, J = 6.7 Hz,
1 H), 1.55 (m, 6 H), 1.15 (m, 6 H), 0.38 (t, J = 1.5 Hz, 9 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 168.6 (dd, J = 3.4, 2.7 Hz), 166.0
(dd, J = 246.5, 16.4 Hz), 165.4 (dd, J = 247.3, 16.4 Hz), 142.3 (dd,
J = 8.8, 5.3 Hz), 121.1 (dd, J = 22.1, 3.8 Hz), 114.4 (dd, J = 36.2,
33.9 Hz), 107.6 (dd, J = 28.2, 4.2 Hz), 56.2 (d, J = 5.3 Hz), 51.3,
46.3, 20.8, 20.5, 20.5, 20.3, 0.1 (t, J = 3.1 Hz) ppm. C17H27F2NO2Si
(343.49): calcd. C 59.45, H 7.92, N 4.08; found C 59.14, H 8.09, N
3.95.
4,6-Difluoro-2-benzofuran-1(3H)-one (4b). By Deprotection of 19: A
mixture of 19 (0.80 g, 3.3 mmol) and cesium fluoride (0.94 g,
6.2 mmol) in acetonitrile (12 mL) was stirred at ambient tempera-
ture for 24 h. The solvent was evaporated, water (20 mL) was added
to the residue, and the mixture was extracted with ethyl acetate
(20 mL and 2ϫ15 mL). The organic layer was washed with brine
(50 mL) and dried with MgSO4. The solvents were evaporated, the
residue was triturated with hexane (10 mL), and the product was
collected by filtration to give of 4b (0.45 g, 80%) as colorless need-
les. M.p. 88–89 °C (hexane). IR (KBr): ν = 1761 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 7.44 (dd, J = 6.6, 2.0 Hz, 1 H), 7.15 (td, J
= 8.6, 2.0 Hz, 1 H), 5.35 (s, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 168.4 (dd, J = 4.4, 2.5 Hz), 163.6 (dd, J = 252.4,
8.8 Hz), 156.7 (dd, J = 54.9, 12.2 Hz), 129.7 (dd, J = 10.3, 5.8 Hz),
128.4 (dd, J = 19.5, 2.9 Hz), 109.6 (dd, J = 27.4, 22.9 Hz), 108.5
(dd, J = 23.9, 4.4 Hz), 66.7 (d, J = 1.0 Hz) ppm. C8H4F2O2
(170.12): calcd. C 56.48, H 2.37; found C 56.31, H 2.36. By Cycliza-
tion of 18: A mixture of 18 (1.40 g, 5.16 mmol) and aqueous hydro-
chloric acid (18%, 12 mL, 60 mmol) was heated to reflux for 3 h.
After cooling to ambient temperature, the reaction mixture was
extracted with diethyl ether (3ϫ10 mL). The ethereal layers were
combined, extracted with brine (15 mL), and dried with MgSO4.
The solvents were evaporated, and the residue was triturated with
cold hexane (approximately –20 °C, 5 mL). The product was col-
lected by filtration to give of 4b (0.81 g, 92%) as colorless needles.
M.p. 88–89 °C (hexane).
3,5-Difluoro-2-(hydroxymethyl)-N,N-diisopropylbenzamide (18): A
mixture of 17 (2.0 g, 5.8 mmol) and cesium fluoride (2.0 g,
13.2 mmol) in acetonitrile (20 mL) was stirred at ambient tempera-
ture for 16 h. The solvent was evaporated, water (20 mL) was added
to the residue, and the mixture was extracted with ethyl acetate
(20 mL and 2ϫ15 mL). The organic layer was washed with brine
(50 mL) and dried with MgSO4. The solvents were evaporated, and
the residue was triturated with hexane (10 mL). The product was
collected by filtration to give 18 (1.55 g, 98%) as colorless needles.
M.p. 134–134.5 °C (hexane/ethyl acetate). IR (KBr): ν = 3346,
˜
1618 cm–1. 1H NMR (500 MHz, CDCl3): δ = 6.84 (app. td, J = 9.3,
2.0 Hz, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 4.69 (d, J = 11.5 Hz, 1 H),
4.46 (d, J = 11.5 Hz, 1 H), 3.79 (m, 1 H), 3.56 (m, 1 H), 3.15 (m,
1 H), 1.57 (d, J = 6.2 Hz, 3 H), 1.54 (d, J = 6.2 Hz, 3 H), 1.20 (d,
J = 6.0 Hz, 3 H), 1.14 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 168.4 (d, J = 3.0 Hz), 162.0 (dd, J = 251.0,
12.2 Hz), 161.6 (dd, J = 252.0, 11.7 Hz), 141.4 (dd, J = 12.2,
11.7 Hz), 121.8 (d, J = 17.5, 3.9 Hz), 108.1 (dd, J = 22.4, 3.9 Hz),
104.3 (dd, J = 26.4, 25.0 Hz), 55.8 (d, J = 4.9 Hz), 51.4, 46.3, 20.8,
20.5, 20.3 ppm. C14H19F2NO2 (271.31): calcd. C 61.98, H 7.06, N
5.16; found C 61.63, H 7.17, N 5.07.
Acknowledgments
The authors thank Dr. Márta Porcs-Makkay for a careful reading
of the manuscript.
4,6-Difluoro-5-(trimethylsilyl)-2-benzofuran-1(3H)-one (19): A mix-
ture of 17 (4.0 g, 11.6 mmol) and aqueous hydrochloric acid (12%,
40 mL, 140 mmol) was heated to reflux for 6 h. After cooling to
ambient temperature, the reaction mixture was extracted with
dichloromethane (3ϫ25 mL). The organic layers were combined,
extracted with brine (50 mL), and dried with MgSO4. The solvents
were evaporated, and the residue was triturated with cold hexane
(approximately –20 °C, 8 mL). The product was collected by fil-
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1
(hexane). IR (KBr): ν = 1766 cm–1. H NMR (500 MHz, CDCl ):
˜
3
δ = 7.33 (d, J = 6.8 Hz, 1 H), 5.32 (s, 2 H), 0.43 (t, J = 1.6 Hz, 9
1734
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: November 12, 2010
Published Online: February 9, 2011
Eur. J. Org. Chem. 2011, 1728–1735
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1735