Novel α,α-difluorohomophthalimides via copper-catalyzed tandom cross-coupling-cyclization of 2-halobenzamides with α,α-difluoro reformatskii reagent

Article abstract of DOI:10.1021/jo050599r

Novel α,α-difluorohomophthalimides 2 were prepared by reacting N-substituted 2-halobenzamides with the α,α-difluoro Reformatskii reagent BrZnCF₂CO₂Et (3) in the presence of CuBr at room temperature. The synthesis involves a CuBr-medi

Full text of DOI:10.1021/jo050599r

Novel r,r-Difluorohomophthalimides via
Copper-Catalyzed Tandom
Cross-Coupling-Cyclization of
2-Halobenzamides with r,r-Difluoro
Reformatskii Reagent
Yijun Pan, Christopher P. Holmes,* and David Tumelty
highly charged nature,4 we were interested in expanding
our PTP program5 by developing general methods to
prepare R,R-difluorohomophthalimides 2 (i.e., 4,4-di-
fluoro-2H-isoquinoline-1,3-dione), where both the fluorine
atoms and the weaker charge may together impart
favorable biological properties. To the best of our knowl-
edge, the preparation of R,R-difluorohomophthalimides
2 containing the acidic imide hydrogen has not been
reported in the literature.
Affymax, Inc., 4001 Miranda Ave.,
Palo Alto, California 94304
chris_holmes@affymax.com
Received March 24, 2005
Direct approaches to prepare aryl R,R-difluorophos-
phonates 1 and aryl R,R-difluoroacetates are based on the
copper-catalyzed coupling of aryl iodides with bromo-R,R-
difluorophosphonate and bromo-R,R-difluoroacetate, re-
spectively.6 The preparation of lactams containing R,R-
difluoromethylene carbonyl moiety has been reported by
a reaction of R-keto lactams with (diethylamino)sulfur
trifluoride (DAST) or related reagents.7 A single N-aryl
R,R-difluorohomophthalimide derivative has been re-
ported by Komoda,8 by treating a R-keto homophthalim-
ide with DAST. The cyclization of N-allylhalo-difluoro-
acetamides catalyzed by CuBr provides an alternative
strategy for the introduction of the R,R-difluoromethylene
carbonyl unit.9 We envisioned that a tandem Cu(I)-
mediated cross-coupling of 2-halobenzamides with the
R,R-difluoro Reformatskii reagent BrZnCF2CO2Et (3) and
subsequent ring-closure of the coupling product would
afford the desired R,R-difluorohomophthalimide, while
simultaneously being mild enough to tolerate a wider
variety of substituents than the highly reactive DAST
conditions (Scheme 1).
Novel R,R-difluorohomophthalimides 2 were prepared by
reacting N-substituted 2-halobenzamides with the R,R-
difluoro Reformatskii reagent BrZnCF2CO2Et (3) in the
presence of CuBr at room temperature. The synthesis
involves a CuBr-mediated cross-coupling of 3 with aryl
iodides or activated aryl bromides, followed by a spontaneous
cyclization of the ethyl 2-benzamido-R,R-difluoroacetate
intermediates at room temperature. N-unsubstituted R,R-
difluorohomophthalimides 2 (R′ ) H), bearing an acidic
imide proton capable of acting as a carboxylic acid bioisos-
tere, were also prepared by reacting 3 equiv of 3 with the
parent 2-iodobenzamides. Other aryl iodides such as 3-iodo-
imidazo[1,2-R]pyridine were also used for the tandem cou-
pling-cyclization reaction.
We initially employed a series of N-substituted 2-io-
dobenzamides as substrates for the difluoroacetate ad-
(3) (a) Asante-Appiah, E.; Patel, S.; Dufresne, C.; Roy, P.; Wang,
Q.; Patel, V.; Friesen, R. W.; Ramachandran, C.; Becker, J. W.; Leblanc,
Y.; Kennedy, B. P.; Scapin, G. Biochemistry 2002, 41, 9043-9051. (b)
Chen, L.; Wu, L.; Otaka, A.; Smyth, M. S.; Roller, P. P.; Burke, T. R.;
den Hertog, J.; Zhang, Z.-Y. Biochem. Biophys. Res. Commun. 1995,
216, 976. (c) Kotoris, C. C.; Chen, M.; Taylor, S. D. J. Org. Chem. 1998,
63, 8052-8057.
(4) (a) Xie, L.; Lee, S.-Y.; Andersen, J. N.; Waters, S.; Shen, K.; Guo,
X.-L.; Moller, N. P. H.; Olefsky, J. M.; Lawrence, D. S.; Zhang, Z.-Y.
Biochemistry 2003, 42, 12792-12804. (b) Kole, H. K.; Smyth, M. S.;
Russ, P. L.; Burke, T. R. Biochem. J. 1995, 311, 1025-1031.
(5) Li, X.; Bhandari, A.; Holmes, C. P.; Szardenings, A. K. Bioorg.
Med. Chem. Lett. 2004, 14, 4301.
(6) (a) Jia, Z.; Ye, Q.; Dinaut, A. N.; Wang, Q.; Waddleton, D.;
Payette, P.; Ramachandran, C.; Kennedy, B.; Hum, G.; Taylor, S. D.
J. Med. Chem. 2001, 44, 4584-4594. (b) Cockerill, G. S.; Easterfield,
H. J.; Percy, J. M.; Pintat, S. Perkin 1 2000, 16, 2591-2599. (c) Sato,
K.; Nishimoto, T.; Tamoto, K.; Omote, M.; Ando, A.; Kumadaki, I.
Heterocycles 2002, 56, 403-412. (d) Taguchi, T.; Kitagawa, O.;
Morikawa, T.; Nishiwaki, T.; Uehara, H.; Endo, H.; Kobayashi, Y.
Tetrahedron Lett. 1986, 27, 6103-6106.
(7) (a) Torres, J. C.; Garden, S. J.; Pinto, A. C.; Da Silva, F. S. Q.;
Boechat, N. Tetrahedron 1999, 55, 1881-1892. (b) Singh, R. P.;
Majumder, U.; Shreeve, J. M. J. Org. Chem. 2001, 66, 6263-6267.
(8) Komoda, M.; Katuta, H.; Takahashi, H.; Fujimoto, Y.; Kadoya,
S.; Kato, F.; Hashimoto, Y. Bioorg. Med. Chem. 2001, 9, 121.
(9) Nagashima, H.; Isono, Y.; Iwamatsu, S. J. Org. Chem. 2001, 66,
315-319.
The introduction of fluorine atoms into compounds is
an important topic in organic chemistry,1 and molecules
containing a CF2 group adjacent to carbonyl and carboxyl
moieties have widespread interest in medicinal and
bioorganic chemistry.2 In addition to the dramatic lower-
ing of the pKa of a carboxylic or phosphonic acid adjacent
to a CF2 group, it has been postulated that the fluorine
atoms can participate in favorable H-bonding or electro-
static interactions, particularly in protein tyrosine phos-
phatase (PTP) inhibitors such as 1.3 Because phospho-
nates 1 poorly penetrate cell membranes due to their
(1) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical Frontiers
of Fluorine Chemistry; ACS Symp. Ser. 639; American Chemical
Society: Washington, DC, 1996. (b) Fluorine in Bioorganic Chemistry;
Welch, J. T., Eswarakrishnan, S., Eds.; John Wiley and Sons: New
York, 1991.
(2) (a) Tozer, M. J.; Herpin, T. Tetrahedron 1996, 52, 8619-8683.
(b) Schirlin, D.; Baltzer, S.; Van Dorsselaer, V.; Weber, F.; Weill, C.;
Altenburger, J. M.; Neises, B.; Flynn, G.; Remy, J. M.; Tarnus, C.
Bioorg. Med. Chem. Lett. 1993, 3, 253-258. (c) Yao, Z.; Gao, Y.; Voigt,
J. H.; Ford, H.; Burke, T. R. Tetrahedron 1999, 55, 2865-2874.
10.1021/jo050599r CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/17/2005
J. Org. Chem. 2005, 70, 4897-4900
4897

SCHEME 1
SCHEME 2
TABLE 1. Formation of N-Substituted
Difluorohomophthalimidesa
°C.12 Derivative 6a bearing a dimethoxybenzyl (DMB)
protecting group was intended to serve as precursor to
the unsubstituted parent ring system. DMF appears to
be superior to THF as the reaction solvent, since CuBr
is completely soluble in DMF while only partially soluble
in THF. It was found that 0.7-0.8 equiv of CuBr gave
the best results in most cases, while considerable amounts
of the corresponding 2-bromobenzamides were generated
as byproduct when >1 equiv of CuBr was used, presum-
ably via iodide exchange. Through a series of model
reactions not shown here, we have observed 2-bromoben-
zamides to be poor substrates for the copper-mediated
coupling reaction with 3. Although we have made to date
only a modest number of examples of N-substituted R,R-
difluoro homophthalimides, the reaction scheme appears
quite general and tolerant of a variety of substituents.
Having demonstrated the feasibility of the synthetic
route, we next turned to the preparation of R,R-difluo-
rohomophthalimides 2 (R′ ) H) containing an acidic N-H
proton on the imide nitrogen. Initial attempts to remove
the DMB protecting group of 6a with TFA were unsuc-
cessful under a variety of conditions. Homophthalimide
8, chosen as a more stringent deprotection model and as
a typical intermediate of a planned library of homophal-
thimides, was prepared from 2-bromo-5-nitrobenzoic
acid.13 Unfortunately, compound 8 remained unchanged
after standard DMB removal procedures, even upon
treatment with neat CF3CO2H at 60 °C for 48 h (Scheme
2). The unusual stability of the fluorinated imide 8 to
CF3CO2H may be explained by the high electron defi-
ciency at the imide nitrogen due to the strong electron-
withdrawing effects of the fluorine atoms, and is in
agreement with the general difficulties associated with
removal of a DMB group from the related phthalimides
and maleimide rings.14 Fortunately, the desired R,R-
difluorohomophthalimide 10 could be readily prepared
in 88% isolated yield by the reaction of aryl bromide 9
with 3 equiv of bromozinc-R,R-difluoroacetate 3 and 0.8
equiv of CuBr at room temperature. This result suggests
that the primary benzamide 9 can be used in the same
way as the secondary benzamides 4 and 7 in the
a All reactions were carried out with 2-iodobenzamides 4 (0.15
mmol), CuBr (0.12 mmol), and bromozinc-R,R-difluoroacetate 3 in
DMF (0.36 mmol) at room temperature for 18 h. b Yields of isolated
products.
dition to assess whether there were steric or electronic
aspects precluding ring closure. Thus, several 2-iodoben-
zamides 4a-f were prepared from 2-iodobenzoic acid (for
4a-d) or 2-iodohippuric acid (for 4e,f) and the corre-
sponding amines with diphenylphosphoryl azide (DPPA)
as the coupling agent.10 R,R-Difluoro Reformatskii re-
agent 3 was prepared from activated zinc dust and ethyl
bromodifluoroacetate in DMF.11 When the cross-coupling
of 4a-f and 3 was carried out in the presence of CuBr,
the expected ethyl 2-benzamido-R,R-difluoroacetates 5
were not observed. Instead, we were pleased to observe
that the N-substituted R,R-difluorohomophthalimides
6a-f were formed as the sole products after a normal
reaction workup (Table 1). This transformation may be
interpreted as a spontaneous cyclization of the o-R,R-
difluoroacetate intermediate 5 formed after the initial
iodine displacement. Clearly, the facile formation of 6
results from the electron-withdrawing o-R,R-difluoroac-
etate group of 5, since the preparation of homophthal-
imides without the two R-fluorine atoms generally re-
quires fairly drastic conditions, such as heating to 140
(12) (a) Semple, J. E.; Rydzewski, R. M.; Gardner, G. J. Org. Chem.
1996, 61, 7967-7972. (b) Deady, L. W.; Quazi, N. H. J. Heterocycl.
Chem. 1994, 31, 793-796. (c) Bakthavachalam, V.; d’Alarcao, M.;
Leonard, N. J. J. Org. Chem. 1984, 49, 289-295.
(13) In contrast to model studies with 2-bromobenzamides lacking
any additional electron withdrawing group on the ring, copper-
mediated nucleophilic addition of 3 to 2-bromo-5-nitrobenzamide was
found to afford high yields of the expected cross-coupling reaction
products.
(14) Watson, D. J.; Dowdy, E. D.; Li, W.-S.; Wang, J.; Polniaszek,
R. Tetrahedron Lett. 2001, 42, 1827.
(10) Qian, L.; Sun, Z.; Deffo, T.; Mertes, K. B. Tetrahedron Lett.
1990, 31, 6469.
(11) The yield of zinc reagent 3 in DMF was estimated to be ca.
75% according to the deuteriolysis of the zinc reagent 3, and less than
10% of homocoupling product was obtained (GC-MS analysis).
4898 J. Org. Chem., Vol. 70, No. 12, 2005

TABLE 2. Formation of r,r-Difluorohomophthalimidesa
SCHEME 3
coupling-cyclization process when an excess of 3 is used,
and the requirement for excess amounts of 3 is likely due
to the acidic imide proton of the product quenching 3.
1
The structure of 10 was confirmed by MS and H, 13C,
and 19F NMR analysis. The 13C-19F coupling constant
(J ) 236 Hz) of the R-carbon atom with the R,R-gem-
fluorine atoms was measured in the 13C NMR of 10. The
chemical shift of the imide proton (δ 12.6 ppm) was also
observed in the 1H NMR of 10, and the downfield
chemical shift reflects the increased acidity of the imide
proton. The pKa of the imide proton of 10 was determined
to be 4.11 by a potentiometric titration in DMSO/H2O
(1:4) according to the methods developed by Bates and
Benet,15 which was in close agreement with the calcu-
lated pKa of 4.23 for 10.16 Both the experimental and
calculated pKa values indicate that the fluorinated 10 is
greatly more acidic than the nonfluorinated analogue
(calculated pKa 8.90), and thus the increased acidity of
the imide proton makes the R,R-difluorohomophthalim-
ides 2 a potential carboxylic acid bioisotere.
A series of N-unsubstituted R,R-difluorohomophthal-
imides with a free imide proton were prepared in an
analogous manner with 2-iodobenzamides as precursor
(Scheme 3). Due to a scarcity of available 2-iodobenza-
mides, we prepared a key 2-iodobenzamide containing a
distal carboxylic acid. Thus, methyl 4-carboxyl-2-iodo-
benzoate 1217 was prepared from methyl 4-carboxyl-2-
aminobenzoate 11 by a diazotization with tert-butyl
nitrite in CH3CN/DMSO (1:1) followed by an iodide
displacement with NaI in the same reaction medium. The
conversion of ester 12 to 13 was effected by amidation
with aqueous ammonium hydroxide. Acid 13 was coupled
with a variety of amines by using DPPA as the coupling
agent to afford the 2,4-disubstituted aryl iodides 14a-
g.
a All reactions were carried out with 2-iodobenzamides 4 (0.12-
0.15 mmol), CuBr (0.10-0.12 mmol), and bromozinc-R,R-difluo-
roacetate 3 in DMF (0.36-0.45 mmol) at room temperature for
24 h. b Yields of isolated products.
SCHEME 4
The reaction was then extended to other aryl iodides
such as 3-iodoimidazo[1,2-R]pyridine (Scheme 4). Under
the same conditions, 3-iodoimidazo[1,2-R]pyridine 18
exhibited a reactivity similar to that of 4 and 14; the
desired product 19, however, was obtained along with ca.
20% of 17 when 3 was added to a mixture of 18 and CuBr
as before. It was envisioned that a zinc-iodide exchange
between 3 and 18 generated an aryl anion intermediate,
which was protonated during the workup to give 17 as a
byproduct. To circumvent this problem, a homogeneous
solution of 3 with CuBr in DMF was prepared in situ at
-30 °C and reacted with the aryl iodide 18. The product
19 was obtained in 80% yield from 18, and only a small
amount of 17 (usually less than 2%) was detected by
HPLC.
Iodides 14a-g were reacted as before with 3 equiv of
3 and 0.8 equiv of CuBr to give the N-unsubstituted R,R-
difluorohomophthalimides 15a-g. The yields of 15a-g
after purification were 70-93%, as summarized in Table
2. The reaction proceeds with good to excellent yields for
substrates bearing a variety of functionalities such as an
ester, amide, sulfonamide, and nitro group. It is interest-
ing to note that neither the formation of the acidic imide
proton in the products nor the presence of an acidic
sulfonamide proton in the substrate (entry 3) interferes
with the overall transformation.
(15) (a) Ong, K. C.; Robinson, R. A.; Bates, R. G. Anal. Chem. 1964,
36, 1971. (b) Benet, L. Z.; Goyan, J. E. J. Pharm. Sci. 1967, 56, 665.
(c) Cookson, R. F. Chem. Rev. 1974, 74, 5. See Supporting Information
for details.
(16) The pKa of 10 and other compounds were calculated with
Daylight software from Daylight Chemical Information Systems, Inc.
(17) Kiick, K. L.; Saxon, E.; Tirrell, D. A.; Bertozzi, C. R. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 19.
In summary, we have discovered a mild and efficient
method for the preparation of novel R,R-difluorohomoph-
thalimides utilizing available 2-halobenzamides as start-
ing materials. Both the N-substituted and parent un-
J. Org. Chem, Vol. 70, No. 12, 2005 4899

under reduced pressure and diluted with CHCl3. The organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The crude ester 12 (6.12 g, 20
mmol) was dissolved in 28% ammonium hydroxide (80 mL) and
the mixture was stirred at room temperature for 12 h. The
reaction mixture was concentrated under reduced pressure and
acidified with 3 N aqueous HCl to pH 3. The resulting precipi-
tates were collected and washed with cold water and ether to
give acid 13 (3.78 g, 90%) as a light yellow powder. 1H NMR
(CD3SOCD3) δ 7.44 (d, J ) 8.0 Hz, 1H), 7.96 (dd, J ) 8.0, 1.8
Hz, 1H), 8.34 (m, 1H); 13C NMR δ 93.16, 128.15, 129.12, 132.82,
140.03, 147.35, 165.79, 170.48; MS (ESI, negative) calcd for C8H6-
INO3 209.94, found 290.0 (M - H)+.
General Procedure for the Preparation of r,r-difluo-
rohomophthalimides (15). Iodobenzamides 14 (0.12-0.15
mmol) and CuBr (0.10-0.12 mmol) were reacted with bromozinc-
R,R-difluoroacetate 3 in DMF (0.36-0.45 mmol) under the same
conditions. The crude products were purified by preparative
HPLC on a C18 column to give 15 with >99% purity as
determined by HPLC analysis.
substituted R,R-difluorohomophthalimides 2 have been
synthesized by the tandem cross-coupling-cyclization
process. The reaction proceeds in good to excellent yields
for a variety of 2-iodoarylamides bearing diverse func-
tionalities, and represents a novel method for the syn-
thesis of fluorinated heterocyclic compounds. The unsub-
stituted R,R-difluorohomophthalimide 10 shows moderate
acidity (pKa 4.11) in aqueous solution, and we anticipate
that this new acid mimetic will find broad application in
medicinal chemistry. Efforts at conducting the described
chemistry on the solid phase and the evaluation of
biological activity of compounds from this class will be
reported in due course.
Experimental Section
Preparation of Bromozinc-r,r-difluoroacetate 3. To a
mixture of zinc dust (1.1 g, 17 mmol) and anhydrous DMF (2.0
mL) in an oven-dried vial was added trifluoroacetic acid (20 µL)
under N2. The mixture was stirred at room temperature for 5
min, and DMF (12 mL) was added. A solution of ethyl bromo-
R,R-difluoroacetate (566 mg, 2.8 mmol) in DMF (3 mL) was
added to the reaction mixture at room temperature, and the vial
was shaken until it warmed (ca. 5-10 min). The mixture was
then shaken for another 2 h and was centrifuged to give a clear
solution of bromozinc-R,R-difluoroacetate 3 in DMF. The actual
concentration of 3 in DMF was estimated to be ca. 0.12 M.11
General Procedure for the Preparation of r,r-difluo-
rohomophthalimide (6). To a mixture of o-iodoarylamide (4)
(0.15 mmol) and CuBr (0.12 mmol) in an oven-dried vial was
added a solution of bromozinc-R,R-difluoroacetate 3 in DMF (3
mL, 0.36 mmol) under N2. After the mixture was stirred at room
temperature for 18 h, a solution of 2 N aqueous ammonium
chloride (5 mL) and CH2Cl2 (5 mL) were added. The aqueous
layer was washed with CH2Cl2, and the combined organic layers
were washed with brine, eluted through a short pad of SiO2 to
removed inorganic residues, and concentrated under reduced
pressure. The residue was dissolved in CH3CN and purified by
preparative HPLC on a C18 column to give 6 with >99% purity
as determined by HPLC analysis.
2-(2,4-Dimethoxybenzyl)-4,4-difluoro-7-methylisoquino-
line-1,3(2H,4H)-dione (6a). Colorless powder (47 mg, 88%). 1H
NMR (CDCl3) δ 2.48 (s, 3H), 3.76 (s, 3H), 3.79 (s, 3H), 5.18 (s,
2H), 6.41 (m, 2H), 7.13 (d, J ) 8.8 Hz, 1H), 7.60 (d, J ) 8.0 Hz,
1H), 7.76 (d, J ) 8.0 Hz, 1H), 8.03 (s, 1H); 13C NMR δ 21.64,
39.99, 55.52, 98.79, 104.38, 106.27, 116.40, 125.72, 128.21,
128.45, 128.69, 129.72, 129.95, 135.42, 143.28, 158.63, 160.76,
162.05, 162.67; MS (ESI, positive) calcd for C19H17F2NO4 361.11,
found 362.1 (M + H)+, 384.0 (M + Na)+. Anal. Calcd for C19H17F2-
NO4 (361.11): C, 63.15; H, 4.74; N, 3.88. Found: C, 62.81; H,
4.70; N, 3.85.
N-[2-(2-Chlorophenyl)ethyl]-4,4-difluoro-1,3-dioxo-1,2,3,4-
tetrahydroisoquinoline-6-carboxamide (15a). Colorless pow-
1
der (51 mg, 90%). H NMR (CDCl3) δ 3.12 (t, J ) 7.2 Hz, 2H),
4.68 (t, J ) 7.2 Hz, 2H), 7.22 (m, 2H), 7.30-7.39 (m, 2H), 8.18
(m, 1H), 8.27 (m, 2H); 13C NMR δ 32.87, 39.84, 124.53, 127.02,
128.13, 128.75, 129.42, 130.80, 131.21, 134.04, 136.83, 140.34,
153.02, 153.30, 166.48; MS (ESI, negative and positive) calcd
for C18H13ClF2N2O3 378.06, found 377.0 (M - H)+, 379.2 (M +
H)+, 401.1 (M + Na)+. Anal. Calcd for C18H13ClF2N2O3 (378.06):
C, 57.08; H, 3.46; N, 7.40. Found: C, 56.98; H, 3.52; N, 7.38.
3-Iodo-N-propylimidazo[2,1-r]isoquinoline-2-carboxam-
ide (18). Iodine (570 mg, 2.25 mmol) was added to a solution of
17 (283 mg, 1.12 mmol) in pyridine (2.5 mL), the mixture was
stirred at 60 °C for 6 h, and pyridine was evaporated under
reduced pressure. The mixture was dissolved in CH2Cl2 and
washed with 2 N aqueous Na2S2O3 solution and water. The
organic layer was concentrated, and the crude product was
dissolved in CH3CN and purified by preparative HPLC on a C18
column to give 18 as light yellow powder (386 mg, 91%). 1H NMR
(CDCl3) δ 1.00 (t, J ) 7.3 Hz, 3H), 1.68 (m, 2H), 3.44 (m, 2H),
7.20 (d, J ) 7.5 Hz, 1H), 7.62-7.69 (m, 2H), 7.72-7.76 (m, 1H),
7.76-7.82 (b, 1H), 8.03 (d, J ) 7.5 Hz, 1H), 8.60 (m, 1H); 13C
NMR δ 11.66, 23.14, 41.31, 11533, 123.42, 123.61, 127.48, 129.05,
129.75, 130.55, 137.72, 145.33, 162.08; MS (ESI, positive) calcd
for C15H14IN3O 379.02, found 380.0 (M + H)+. Anal. Calcd for
C
15H14IN3O (379.02): C, 47.51; H, 3.72; N, 11.08. Found: C,
47.21; H, 3.78; N, 10.93.
7,7-Difluoro-9-propyl-7H-6r,9,11-triazabenzo[r]fluorene-
8,10-dione (19). A solution of bromozinc-R,R-difluoroacetate 3
(4.1 mL, 0.5 mmol) was added to a slurry of CuBr (35 mg, 0.25
mmol) in anhydrous DMF (1 mL) at -30 °C under N2. After the
mixture was stirred at -30 °C for 30 min, a solution of 18 (95
mg, 0.25 mmol) in DMF (1.5 mL) was slowly added. After this
solution was stirred at room temperature for 18 h, a solution of
2 N aqueous ammonium chloride (12 mL) and CH2Cl2 (10 mL)
were added. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were washed with brine and
concentrated under reduced pressure. The residue was dissolved
in CH3CN and purified by preparative HPLC on C18 column to
give 19 as colorless powder (66 mg, 80%). 1H NMR (CDCl3) δ
0.99 (t, J ) 7.3 Hz, 3H), 1.68 (m, 2H), 3.99 (m, 2H), 7.38 (d, J )
7.5 Hz, 1H), 7.71-7.82 (m, 3H), 8.08 (d, J ) 7.1 Hz, 1H), 8.82
(m, 1H); 13C NMR δ 11.30, 21.39, 42.61, 117.37, 121.71, 123.61,
125.14, 127.64, 129.75, 130.56, 131.01, 147.47, 158.45, 162.52;
MS (ESI, positive) calcd for C17H13F2N3O2 329.10, found 330.1
(M + H)+. Anal. Calcd for C17H13F2N3O2 (329.10): C, 62.00; H,
3.98; N, 12.76. Found: C, 61.43; H, 4.03; N, 12.61.
4,4-Difluoro-7-nitroisoquinoline-1,3(2H,4H)-dione (10).
The 2-bromobenzamide 9 (612 mg, 2.5 mmol) and CuBr (258.2,
1.8 mmol) were reacted with bromozinc-R,R-difluoroacetate 3 in
DMF (62 mL, 7.5 mmol) under the same conditions, and the
crude product was purified on a SiO2 column (MeOH/CHCl3,
2:98) to give 10 (480 mg, 80%) as light yellow powder. 1H NMR
(CD3SOCD3) δ 8.20 (d, J ) 8.4 Hz, 1H), 8.60-8.65 (m, 2H); 13
C
NMR δ 105.23 (t, JCF ) 236 Hz), 122.83, 127.91, 127.96, 128.05,
128.08, 129.20, 136.35, 136.60, 136.84, 150.21, 161.10, 161.87,
162.16, 162.45; 19F NMR δ -18.65; MS (ESI, negative) calcd for
C9H4F2N2O4 242.01, found 240.9 (M - H)+. Anal. Calcd for
C9H4F2N2O4 (242.01): C, 44.64; H, 1.67; N, 11.57. Found: C,
44.97; H, 1.78; N, 11.45.
4-(Aminocarbonyl)-3-iodobenzoic Acid (13). To a solution
of NaI (18.0 g, 120 mmol) in CH3CN (100 mL) were added a
solution of methyl 4-carboxyl-2-aminobenzoate (11) (8.98 g, 46
mmol) in CH3CN/DMSO (1:1, 16 mL) and tert-butyl nitrite (6.8
g, 66 mmol). To the above solution was slowly added trifluoro-
acetic acid (0.6 mL) under stirring at room temperature. The
mixture was slowly heated to 65 °C over 45 min and stirred at
65 °C for another 1 h. The reaction mixture was concentrated
Supporting Information Available: Experimental pro-
cedures and compound characterization (1H and 13C NMR,
HPLC, and MS) for all the compounds described. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO050599R
4900 J. Org. Chem., Vol. 70, No. 12, 2005