An efficient synthetic process for scale-up production of 4,5-diamino-2- (trifluoromethyl)benzonitrile and 5-bromo-3-(trifluoromethyl)benzene-1,2-diamine

Article abstract of DOI:10.1021/op9000498

Starting from 4-amino-2-(trifluoromethyl)benzonitrile (6), an efficient and nonchromatographic process was developed for multihundred gram production of 4,5-diamino-2-(trifluoromethyl)- benzonitrile (1) in 73% yield and 98 HPLC area% purity over four synthetic steps. The same synthetic strategy was applied to 4-bromo-2-(trifluoromethyl)aniline (7) that afforded 5-bromo-3- (trifluoromethyl)benzene-1,2-diamine (5) in 81% overall yield and 99% HPLC area% purity.

Full text of DOI:10.1021/op9000498

Organic Process Research & Development 2009, 13, 652–655
An Efficient Synthetic Process for Scale-Up Production of 4,5-Diamino-2-
(trifluoromethyl)benzonitrile and 5-Bromo-3-(trifluoromethyl)benzene-1,2-diamine
Xun Li,* Raymond A. Ng, Yongzheng Zhang, Ronald K. Russell, and Zhihua Sui
Johnson & Johnson Pharmaceutical Research & DeVelopment, L.L.C., East Coast Research & Early DeVelopment,
1000 Route 202, Raritan, New Jersey 08869 U.S.A.
Scheme 1a
Abstract:
Starting from 4-amino-2-(trifluoromethyl)benzonitrile (6), an ef-
ficient and nonchromatographic process was developed for mul-
tihundred gram production of 4,5-diamino-2-(trifluoromethyl)-
benzonitrile (1) in 73% yield and 98 HPLC area% purity over
four synthetic steps. The same synthetic strategy was applied to
4-bromo-2-(trifluoromethyl)aniline (7) that afforded 5-bromo-3-
(trifluoromethyl)benzene-1,2-diamine (5) in 81% overall yield and
99% HPLC area% purity.
Introduction
Substituted benzene-1,2-diamines are functional building
blocks for the construction of biologically active heterocyclic
molecules. For instance, compounds 1-4 (Figure 1) were used
in the syntheses of 2,5,6-trisubstitued benzimidazole derivatives
as selective androgen receptor modulators (SARMs),1,2 and
compound 5 was used to prepare 5,7-disubstitued 1,4-dihyd-
roquinoxaline-2,3-dione analogues as glycine receptor antago-
nists.3 Because 4,5-diamino-2-(trifluoromethyl)benzonitrile (1)
a Reagents and conditions: Step 1. (CF3CO)2O, K2CO3, CH2Cl2, 20 °C, 2 h.
8 ) 100%; 9 ) 100%. Step 2. HNO3, CF3SO3H, CH2Cl2, 20 °C, 20 h. 10 )
85%; 12 ) 88%. Step 3. K2CO3, CH3OH, H2O, 20 °C, 4 h. 13 ) 94%. HCl,
EtOH, 76 °C, 120 h. 15 ) 95%. Step 4. SnCl2 ·H2O, HCl, THF, 20 °C, 20 h. 1
) 91%; 5 ) 97%.
contained a number of scale-up issues; for example, the
protection of the amino group of 6 in step 1 was conducted in
trifluoroacetic anhydride (13 equiv) as the solvent (Scheme 1),
which caused the aqueous work up to be a highly exothermic
process. An excess amount of fuming HNO3 (3 equiv)/CF3SO3H
(6 equiv) was used in step 2 for the nitration of compound 8,
which resulted in a moderate chromatographic isolated yield
(67%) of the desired 2-nitro 10 together with more than 20%
of the 2,6-dinitro byproduct 11. A large excess of indium (24
equiv) was used in step 4 for the reduction of nitroamino
intermediate 13 that required an additional column chromato-
graphic purification of the final compound 1. Herein, we report
an improved nonchromatographic synthetic process that is
suitable for large-scale production of 1.
Figure 1
was commercially unavailable when a multihundred gram
quantity of 1 was requested to support the advanced research
activities, there was a need for developing a safe and scalable
synthetic process for large-scale production of 1. The Discovery
route started with 4-amino-2-(trifluoromehthyl)benzonitrile (6)
to afford compound 1 on a small scale (∼1.0 g) in 47% yield
over four synthetic steps (Scheme 1). This route however,
* Author for correspondence. Telephone: (908)707-3321. Fax: (908)526-6469.
E-mail: xli6@its.jnj.com.
(1) (a) Ng, R. A.; Guan, J.; Alford, V. C.; Lanter, J. C.; Allan, G. F.;
Sbriscia, T.; Linton, O.; Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem.
Lett. 2007, 17, 784. (b) Ng, R.; Sui, Z.; Guan, J.; Lanter, J. C.; Alford,
V. C. Novel benzimidazole derivatives useful as selective androgen
receptor modulators (SARMS). WO 2006039243 A1, 2006; Chem.
Abstr. 2006, 144, 390918.
(2) Zhang, X.; Ng, R.; Lanter, J.; Sui, Z. Synth. Commun. 2007, 37, 1437.
(3) Weber, E.; Keana, J. F. W. Glycine receptor antagonists and the use
thereof. U.S. Patent 5,514,680 A, 1996. Chem. Abstr. 1996, 125,
114696.
Results and Discussions
During scale-up of step 1, the large excess of (CF3CO)2O
(13 equiv) was reduced to an almost stoichiometric amount
(1.05 equiv), and the reaction was performed in CH2Cl2 with
the presence of a base (K2CO3, 1.13 equiv). This modified
reaction provided a quantitative yield of trifluoroacetamide 8
in 99 HPLC area% purity.4 With only a slight excess of
652
•
Vol. 13, No. 3, 2009 / Organic Process Research & Development
10.1021/op9000498 CCC: $40.75  2009 American Chemical Society
Published on Web 04/27/2009

(CF3CO)2O in the reaction mixture, the aqueous work up was
only mildly exothermic and was easily feed controlled by
adjusting the addition rate of water.
and meta-directed 2-CF3 group, which produced the mononitro
compound 12 as the only product.
The same alkaline hydrolysis conditions that worked well
for the preparation of compound 13 only produced a moderate
isolated yield (43%) of nitroamine 15 due to the incomplete
hydrolysis of compound 12. Increasing the amount of K2CO3
to 4.4 equiv with extended reaction times (72-120 h) and
elevated temperatures (60 °C) did not push the reaction to
completion. In contrast to the alkaline conditions, treatment of
12 with a solution of HCl (10 equiv, 1.0 M in EtOH) at 76 °C
for 5 days afforded a quantitatively isolated yield of 15 (as its
HCl salt) in 95 HPLC area% purity, which could be used for
the next step without further purification. The incomplete
hydrolysis of compound 12 to 15 could be attributed to the steric
hindrance of the 2-nitro and 6-trifluoromethyl substituents of
compound 12,9 which are positioned adjacent to the -HNCOCF3
group, resulting in OH- anion attack at the carbonyl carbon of
12 being much more difficult than that for 10 (which lacks the
2,6-disubstitution). On the other hand, the EtOH2+ ion has an
easier approach to the oxygen atom of the same carbonyl of
12 to initiate and further complete the hydrolysis reaction,
although the long reaction time was a drawback of this acid-
catalyzed ethanolysis of 12. Finally, nitroamine 15 was reduced
to benzene-1,2-diamine 5 in a quantitative isolated yield using
the same SnCl2/HCl conditions, which verified that SnCl2/HCl
reduction of substituted 2-nitroaniline to benzene-1,2-diamine
is a robust alternative method for metal (Ni, Pt, or Pd)-catalyzed
hydrogenation.10 The above-described efficient process was
successfully scaled up to 456 g of benzene-1,2-diamine 1 in
our lab, and no further development is planned.
The nitro intermediate 10 was prepared by nitration of
compound 8 with nitronium trifluoromethylsulfonate salt
(NO2+CF3SO3-, a stable white crystalline solid when stored at
0 °C under nitrogen atmosphere), which was readily prepared
in high yield following a published method.5 In practice, the
reaction selectivity was an additive result of the activating ortho/
para-directing -HNCOCF3 group to the deactivating meta-
directing 4-CN group of compound 8. After the amount of
NO2+CF3SO3- salt was reduced from 3.0 to 1.35 equiv,
compound 10 was obtained in an improved isolated yield (85%)
as well as a better chemical purity (96% of 10 plus 3% of dinitro
11; HPLC area%) without the need for chromatographic
purification (step 2 of Scheme 1).
The trifluoroacetyl protecting group of 10 was cleaved using
an aqueous solution of K2CO3 (1.06 equiv) in CH3OH (step 3
of Scheme 1), and after workup, mononitroamine 13 was
collected by simple filtration as a solid in a 94% isolated yield
and 99 HPLC area% purity. Meantime, the undesired dini-
troamine 14 was completely removed in the filtrate.6
The original reduction conditions for the last step (24 equiv
of expensive indium) was replaced with SnCl2 (3.2 equiv)/
concentrated HCl (7.5 equiv) in THF.8 Under these reaction
conditions, 13 was reduced to benzene-1,2-diamine 1 in 91%
isolated yield and 98.2 HPLC area% purity without the need
for chromatographic purification. Residual tin was found at 34
ppm, the only time we measured the metal content in compound
1. This was an acceptable level because 1 was an early
intermediate used for the synthesis of target molecules.
Furthermore, the synthetic strategy described above was
applied to 4-bromo-2-(trifluoromethyl)aniline (7) that afforded
81% overall yield of the corresponding 5; of which a 38% yield
was reported in the same number of synthetic steps under
different reaction conditions.3 As with the syntheses of 1, the
protection of the amino group of compound 7 was carried out
using (CF3CO)2O (1.05 equiv), which resulted in quantitative
formation of trifluoroacetamide 9 on multihundred gram scale.
Of interest, the nitronium (NO2+) preference for the electrophilic
substitution on compound 9 was completely controlled by the
additive effects of the ortho/para-directing -HNCOCF3 group
Conclusions
An efficient and nonchromatographic synthetic process was
developed for safe scale-up production of 4,5-diamino-2-
(trifluoromethyl)benzonitrile (1) in an improved overall yield
(73% for four steps) with 98.2 HPLC area% purity. In addition,
5-bromo-3-(trifluoromethyl)benzene-1,2-diamine (5) was also
prepared in 81% isolated yield and 99.0 HPLC area% purity
using the same synthetic method without the need of chro-
matographic purification.
Experimental Section
Special cautions should be taken when handling substituted
trifluoromethylaniline deriVatiVes, due to the instability of
4-trifluoromethylaniline that has been reported.11 All reactions
were conducted in a four-neck, round-bottom flask (RBF)
(1-22 L), equipped with a thermocouple controller, an overhead
mechanical stirrer, a condenser, and a pressure-equalization
addition funnel and nitrogen inlet/outlet whenever they were
required. HPLC: Agilent Series 1100 system at 254 nm, using
a Phenomenex Luna C18 (2) column (4.6 mm ID × 50 mm,
5.0 µm) at 35 °C with flow rate of 1.0 mL/min and run time of
(4) (a) Darvesh, S.; McDonald, R. S.; Darvesh, K. V.; Mataija, D.;
Mothana, S.; Cook, H.; Carneiro, K. M.; Richard, N.; Walsh, R.;
Martin, E. Bioorg. Med. Chem. 2006, 14, 4586. (b) Takeuchi, H.;
Taniguchi, T.; Masuzawa, M.; Isoda, K. J. Chem. Soc., Perkin Trans.
2 1998, 1743.
(5) Coon, C. L.; Blucher, W. G.; Hill, M. E. J. Org. Chem. 1973, 38,
4243.
(6) 4-Amino-3,5-dinitro-2-(trifluoromethyl)benzonitrile (14) (2.4 g, 0.9%
isolated yield, 94 HPLC area%) was isolated as a yellowish solid by
filtration of the aqueous filtrate after sitting overnight. HPLC retention
1
time ) 3.52 min. The structure of 14 was confirmed by its H NMR
1
and LC-MS spectra. H NMR (300 MHz, DMSO-d6) δ 8.48 (brs, 2
H, NH2), 8.91 (s, 1 H, H6). LC-MS m/z 276 (M+), 275 ([M-H]+).
(7) (a) Banik, B. K.; Banik, I.; Samajdar, S.; Wilson, M. Heterocycles
2004, 63, 283. (b) Han, R.; Son, K. I.; Ahn, G. H.; Jun, Y. M.; Lee,
B. M.; Park, Y.; Kim, B. H. Tetrahedron Lett. 2006, 47, 7295. (c)
Unpublished internal communication.
(9) March, J. AdVanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 4th ed.; John Wiley & Sons: New York, 1992; p 275.
(10) (a) Telkar, M. M.; Nadgeri, C. V.; Chaudhari, R. V. Appl. Catal., A
2005, 295, 23. (b) Zhao, F.; Ikushima, Y.; Arai, M. J. Catal. 2004,
224, 479.
(8) (a) Velaparthi, U.; Liu, P.; Balasubramanian, B.; Carboni, J.; Attar,
R.; Gottardis, M.; Li, A.; Greer, A.; Zoeckler, M.; Wittman, M. D.;
Vyas, D. Bioorg. Med. Chem. Lett. 2007, 17, 3072. (b) Starcevic, K.;
Caleta, I.; Cincic, D.; Kaitner, B.; Kralj, M.; Ester, K.; Karminski-
Zamola, G. Heterocycles 2006, 68, 2285.
(11) Tickner, D.; Kasthurikrishnan, N. Org. Process Res. DeV. 2001, 5,
270.
Vol. 13, No. 3, 2009 / Organic Process Research & Development
•
653

10.0 min. Solvents: A - H2O + 0.05% TFA, B - CH3CN;
Gradient: B 30%/0.0 min, B 40%/1.0 min, B 90%/4.0 min, B
90%/8.0 min, B 30%/10.0 min.
13C NMR (DMSO-d6, 100.61 MHz) δ 155.29 (q, 2JCF ) 33.4
Hz), 147.65, 144.60, 134.80 (q, 3JCF ) 5.6 Hz), 134.53 (q, 2JCF
) 33.2 Hz), 132.83 (q, 3JCF ) 5.6 Hz), 125.84, 121.29 (q, 1JCF
) 273.0 Hz), 115.25 (q, 1JCF ) 289.8 Hz), 113.59, 107.11 (q,
3JCF ) 5.6 Hz). LC--MS m/z 327 (M+), 326 (M - 1)+.
N-(4-Bromo-2-nitro-6-(trifluoromethyl)phenyl)-2,2,2-tri-
fluoroacetamide (12). Prepared in the same manner as 10.
Starting from N-(4-bromo-2-(trifluoromethyl)phenyl)-2,2,2-tri-
fluoroacetamide (9, 40.0 g, 0.118 mol), compound 12 (39.8 g)
was obtained in 88% isolated yield with 98.8 HPLC area%
N-(4-Cyano-3-(trifluoromethyl)phenyl)-2,2,2-trifluoroac-
etamide (8). 4-Amino-2-(trifluoromethyl)benzonitrile (6) (450.0
g, 2.418 mol) and CH2Cl2 (8.0 L) under nitrogen were treated
with potassium carbonate (K2CO3, 377.6 g, 2.732 mol), and
the suspension was cooled to 14 °C. Trifluoroacetic anhydride
(TFAA, 358.5 mL, 2.538 mol) was added over 30 min. The
mixture was stirred at 20 °C for 1 h; the progress of the reaction
was determined by HPLC and 1H NMR. After the reaction was
cooled to 10 °C, it was quenched with H2O (3.0 L) at e20 °C
and stirred at 20 °C for 10 min. The off-pink solid was filtered,
washed with H2O (250 mL × 2), and dried by air-suction for
3 h. The filtrate was washed with brine (1.0 L × 2) and
concentrated to give a pink solid (98.0 g), which was combined
with the filtration cake. The solid was dried at ∼ 260 mmHg
at 60 °C for 18 h to afford 678.9 g (99.5% isolated yield, 99
HPLC area%) of trifluoroacetamide 8 as an off-white solid.
HPLC retention time ) 3.89 min. 1H NMR (400 MHz, DMSO-
d6) δ 8.15 (dd, J ) 1.8, 8.6 Hz, 1 H, H6), 8.18 (d, J ) 8.6 Hz,
1
purity as a beige solid. HPLC retention time ) 4.0 min. H
NMR (300 MHz, CDCl3) δ 8.04 (br s, 1 H, NH), 8.15 (d, J )
1.5 Hz, 1 H, H5), 8.41 (d, J ) 1.6 Hz, 1 H, H3). LC-MS m/z
382 (MH+), 381 (M+), 379 (M - 2)+.
4-Amino-5-nitro-2-(trifluoromethyl)benzonitrile (13). A
solution of compound 10 (489.0 g, 1.495 mol) in CH3OH (2.2
L) was treated with a solution of K2CO3 (218.8 g, 1.06 mol) in
H2O (2.2 L), and the reaction mixture was stirred at 20 °C for
4 h; the progress of the reaction was determined by HPLC and
1H NMR. H2O (12.0 L) was added with fast agitation, and the
resulting solid was stirred for 20 min and then filtered. The
filtration cake was washed with cold H2O (500 mL × 2), dried
by air-suction for 3 h and further dried at ∼260 mmHg at 50
°C for 18 h to afford 323.8 g (93.7% isolated yield; 99.0 HPLC
area%) of nitroaniline 13 as a yellow-light greenish solid. HPLC
retention time ) 3.26 min. 1H NMR (400 MHz, DMSO-d6) δ
1 H, H5) 8.28 (d, J ) 1.8 Hz, 1 H, H2), 11.9 (s, 1 H, NH). 13
C
NMR (DMSO-d6, 100.61 MHz) δ 155.17 (q, 2JCF ) 37.2 Hz),
141.10, 136.56, 131.65 (q, 2JCF ) 31.9 Hz), 123.92, 122.14 (q,
1 JCF ) 276.5 Hz), 118.36 (q, 3JCF ) 6.4 Hz), 115.21 (q, 1JCF
) 287.1 Hz), 115.20, 104.25 (q, 3JCF ) 6.4 Hz). LC-MS m/z
283 (MH+), 282 (M+), 281 (M - 1)+.
7.54 (s, 1 H, H3), 8.62 (s, 1 H, H6), 8.44 (br s, 2 H, NH2). 13
C
N-(4-Bromo-2-(trifluoromethyl)phenyl)-2,2,2-trifluoroac-
etamide (9). Prepared in the same manner as 8. Starting from
4-bromo-2-(trifluoromethyl)aniline (7, 300.0 g, 1.24 mol),
compound 9 (421.3 g) was obtained as an off-white solid in
100% crude yield with 98.8 HPLC area% purity (HPLC
retention time ) 4.07 min. 1H NMR (300 MHz, CDCl3) δ 7.76
(dd, J ) 1.7, 8.8 Hz, 1 H, H5), 7.82 (d, J ) 1.6 Hz, 1 H, H3),
8.07 (d, J ) 8.8 Hz, 1 H, H6), 8.20 (br s, 1 H, NH). LC-MS
m/z, 334 (M - 2)+, 336 (M+).
N-(4-Cyano-2-nitro-5-(trifluoromethyl)phenyl)-2,2,2-tri-
fluoroacetamide (10). Triflic acid (CF3SO3H, 336.4 mL, 3.829
mol) was cooled to 4 °C, and fuming HNO3 (80.9 mL, 1.914
mol) was added over 20 min (Caution: this was a high
exothermic process; the internal reaction temperature was
maintained below 24 °C by adjusting the addition rate of fuming
HNO3!) and stirred at 10 °C for 20 min. Methylene chloride
(CH2Cl2, 6.4 L) and trifluoroacetamide 8 (400.0 g, 1.418 mol)
were sequentially added to this white nitronium salt, and the
reaction was stirred at 20 °C for 20 h; the progress of
the reaction was determined by HPLC and 1H NMR. After the
reaction was cooled to 0 °C, it was quenched with saturated
NaHCO3 solution (3.0 L), followed by the addition of solid
Na2CO3 (180 g) in small portions over 20 min and stirred at
20 °C for another 20 min. After phase separation, the aqueous
phase was extracted with CH2Cl2 (1.0 L × 2); the combined
organic phases were washed with brine (2.0 L × 2); and
concentrated at ∼260 mmHg at 40 °C to afford 396.0 g of
mononitroamide 10 (85% isolated yield; 96% of 3 plus <3%
of dinitro byproduct 11, HPLC area%) as an orange solid.
HPLC retention time ) 4.1 min. 1H NMR (400 MHz, DMSO-
d6) δ 8.31 (s, 1 H, H6), 8.95 (s, 1 H, H3), 12.3 (br s, 1 H, NH).
NMR (DMSO-d6, 100.61 MHz) δ 147.65, 134.77, 134.19 (q,
2JCF ) 34.0 Hz), 130.62, 121.70 (q, 1JCF ) 276.5 Hz), 118.99
(q, 3JCF ) 4.8 Hz), 115.14, 91.70 (q, 3JCF ) 4.8 Hz). LC-MS
m/z 231 (M+), 230 (M - H)+, 254 ([M + Na]+).
4-Bromo-2-nitro-6-(trifluoromethyl)aniline (15) Prepared
under Alkaline Cleavage Conditions. Prepared in the same
manner as 13. Starting from 12 (30.0 g, 0.079 mol), compound
15 (9.6 g) was obtained in 43% isolated yield with 99.1 HPLC
area% purity as a yellow-brownish solid (this reaction was
conducted with an excess of K2CO3 (4.4 equiv) at 60 °C for
120 h). HPLC retention time ) 4.32 min. 1H NMR (300 MHz,
CDCl3) δ 6.68 (br s, 2 H, NH2), 7.83 (d, J ) 1.6 Hz, 1 H, H5),
8.50 (d, J ) 1.6 Hz, 1 H, H3). LC-MS m/z (no MH+ ) 286),
268 (M - NH2)+, 267 ([M - NH2] - 1)+.
4-Bromo-2-nitro-6-(trifluoromethyl)aniline (15) Prepared
under Acidic Cleavage Conditions. Compound 12 (10.0 g,
26.2 mmol) was treated with a solution of HCl (262.4 mL, 262.4
mmol) in EtOH. The reaction mixture was refluxed at 76 °C
for 120 h; the progress of the reaction was monitored by HPLC
and LC/MS. After the reaction was cooled to 20 °C, the solvent
was concentrated at ∼20 mmHg that afforded 8.7 g (100%
isolated yield, 95.0 HPLC area%) of nitroaniline 15 HCl salt
as a bright yellow-greenish solid. The 1H NMR and HPLC data
of compound 15 prepared under this acidic condition were
identical to that was prepared from alkaline hydrolysis.
4,5-Diamino-2-(trifluoromethyl)benzonitrile (1). A solu-
tion of compound 13 (578.0 g, 2.50 mol) in THF (3.0 L) was
cooled to 0 °C under nitrogen with stirring. A solution of
SnCl2 ·2H2O (1805.6 g, 8.0 mol) in conc. HCl (37.5%, 1.85 L)
was added dropwise over a 3-h period (Caution: this was an
exothermic process; the internal reaction temperature was
654
•
Vol. 13, No. 3, 2009 / Organic Process Research & Development

maintained below 13 °C by adjusting the addition rate!). After
the addition, the reaction was stirred at 20 °C for 20 h; the
progress of the reaction was determined by HPLC and 1H NMR.
The reaction mixture was diluted with THF (4.0 L) and H2O
(4.0 L) and then cooled to 0 °C. The pH of the mixture was
adjusted with 5 N NaOH solution (∼7.6 L) to pH ) 9-10.
After phase separation, the aqueous phase was extracted with
EtOAc (3.0 L × 1; 2.0 L × 2), and the combined organic phases
were washed with brine (2.0 L × 2). The solvent was
concentrated at ∼260 mmHg at 60 °C to afford 456.0 g of
compound 1 (91% isolated yield; 98.2 HPLC area%) as a light-
Na]+). Calcd for C8H6F3N3: C, 44.77; H, 3.01; N, 20.89; F,
28.33. Found: C, 44.53; H, 2.96; N, 20.63; F, 28.12. Sn ) 34
ppm.
5-Bromo-3-(trifluoromethyl)benzene-1,2-diamine (5). Pre-
pared in the same manner as for 1. Starting from 4-bromo-2-
nitro-6-(trifluoromethyl)aniline (15, 10.0 g, 3.44 mmol), com-
pound 5 (7.95 g) was obtained in 97% isolated yield with 99.0
HPLC area% purity as an orange solid. HPLC retention time
1
) 4.75 min. H NMR (300 MHz, CDCl3) δ 3.51 (br s, 2 H,
NH2), 3.92 (br s, 2 H, NH2), 6.98 (d, J ) 1.8 Hz, 1 H, H6),
7.14 (d, J ) 1.8 Hz, 1 H, H4). LC-MS m/z 255 (M+), 257 (M
+ 2)+. Calcd for C7H6BrF3N2: C, 32.97; H, 2.37; Br, 31.33; F,
22.35; N, 10.98. Found: C, 32.61; H, 2.11; Br, 31.46; F, 22.0;
N, 10.73.
1
rose solid. HPLC retention time ) 2.26 min. H NMR (400
MHz, DMSO-d6) δ 5.53 (br s, 2 H, NH2), 5.88 (br s, 2 H, NH2),
6.92 (s, 1 H, H3), 6.93 (s, 1 H, H6) 13C NMR (DMSO-d6, 100.61
MHz) δ 138.87, 137.36, 123.69 (q, 1JCF ) 273.7 Hz), 119.99
(q, 2JCF ) 31.7 Hz), 117.66, 116.90, 110.09 (q, 3JCF ) 4.0 Hz),
94.13 (d, 3JCF ) 4.0 Hz). LC-MS m/z 202 (MH+), 224 ([M +
Received for review March 6, 2009.
OP9000498
Vol. 13, No. 3, 2009 / Organic Process Research & Development
•
655