Practical synthesis of 4-fluoro-2-(methylthio)benzylamine and the corresponding sulfone and sulfonamide

Article abstract of DOI:10.1080/00397910701319221

Practical syntheses of 4-fluoro-2-(methylthio)benzylamine 1 and the corresponding 2-methylsulfonyl analog 2 are reported. The methylthio moiety was introduced regioselectively by two methods. In the first method, metallation of 4-fluoro-2-bromobenzoic acid, followed by treatment with dimethyl disulfide resulted in an easily isolated intermediate, which was suitable for further elaboration to the benzylamine 1. In the second method, selective nucleophilic aromatic substitution of 2,4-difluorobenzonitrile with methanethiolate was explored, and a mechanistic rationale was offered for solvent effects on regioselectivity. Optimized conditions furnished the key 4-fluoro-2-(methylthio) benzonitrile for further functionalization to the 2-methylsulfonyl-4- fluorobenzylamine 2. In addition, the analogous sulfonamide 3 was prepared in a straightforward manner from 5-fluoro-2-methylbenzenesulfonyl chloride. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701319221

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Practical Synthesis of
4‐Fluoro‐2‐(methylthio)benzylamine and the
Corresponding Sulfone and Sulfonamide
Debra S. Perlow a , Michelle S. Kuo a , H. Marie Moritz a , John S. Wai a
Melissa S. Egbertson a
&
a Merck Research Laboratories, Department of Medicinal Chemistry , West
Point, Pennsylvania, USA
Published online: 30 Jun 2007.
To cite this article: Debra S. Perlow , Michelle S. Kuo , H. Marie Moritz , John S. Wai & Melissa S. Egbertson
(2007) Practical Synthesis of 4‐Fluoro‐2‐(methylthio)benzylamine and the Corresponding Sulfone and
Sulfonamide, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:11, 1887-1897, DOI: 10.1080/00397910701319221
To link to this article: http://dx.doi.org/10.1080/00397910701319221
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Synthetic Communicationsw, 37: 1887–1897, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701319221
Practical Synthesis of 4-Fluoro-2-
(methylthio)benzylamine and the
Corresponding Sulfone and Sulfonamide
Debra S. Perlow, Michelle S. Kuo, H. Marie Moritz,
John S. Wai, and Melissa S. Egbertson
Merck Research Laboratories, Department of Medicinal Chemistry,West
Point, Pennsylvania, USA
Abstract: Practical syntheses of 4-fluoro-2-(methylthio)benzylamine 1 and the
corresponding 2-methylsulfonyl analog 2 are reported. The methylthio moiety was
introduced regioselectively by two methods. In the first method, metallation of
4-fluoro-2-bromobenzoic acid, followed by treatment with dimethyl disulfide resulted
in an easily isolated intermediate, which was suitable for further elaboration to the
benzylamine 1. In the second method, selective nucleophilic aromatic substitution of
2,4-difluorobenzonitrile with methanethiolate was explored, and a mechanistic rationale
was offered for solvent effects on regioselectivity. Optimized conditions furnished
the key 4-fluoro-2-(methylthio)benzonitrile for further functionalization to the
2-methylsulfonyl-4-fluorobenzylamine 2. In addition, the analogous sulfonamide 3 was
prepared in a straightforward manner from 5-fluoro-2-methylbenzenesulfonyl chloride.
Keywords: lithiation, nucleophilic aromatic substitution, sulfonamide, sulfone, thiol
INTRODUCTION
In the course of our research on HIV-1 integrase inhibitors, we became inter-
ested in preparing 4-fluoro-2-(methylthio)benzylamine 1, the corresponding
sulfone 2, and dimethylsulfonamide 3.[1] Although 2-(methylthio)benzyla-
mine and 2-methylsulfonylbenzylamine are commercially available, prep-
arations of the 4-fluoro derivatives have not been reported in the literature.
Received in the USA October 19, 2006
Address correspondence to Debra S. Perlow, Merck and Co Inc., WP 14-3;
P.O. Box 004, West Point, PA 19486, USA. E-mail: debbie_perlow@merck.com
1887

1888
D. S. Perlow et al.
We report here two complementary approaches for preparation of 1 and 2 and
an efficient synthesis of 3.
RESULTS AND DISCUSSION
We proposed that reaction of the dianion 5 derived from commercially available
2-bromo-4-fluorobenzoic acid 4 with a CH3Sþ synthon would provide the key
4-fluoro-2-(methylthio)benzoic acid intermediate 6, which would be suitable
for further elaboration to the corresponding benzylamine 1 (Scheme 1).[2]
Indeed, successive treatment of 2-bromo-4-fluorobenzoic acid 4 with methyl-
magnesium chloride at 08C in THF[3] followed by lithiation with n-butyllithium
and addition of dimethyl disulfide at 2788C provided 4-fluoro-2-(methylthio)-
benzoic acid 6 in 80% isolated yield (Scheme 1). Treatment of the acid 6 with
ammonium chloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) in the presence of 1-hydroxy-7-azabenzotriazole (HOAt)
in DMF produced quantitatively the corresponding 4-fluoro-2-(methylthio)ben-
zamide 7. Lithium aluminum hydride reduction of the amide 7 in ether afforded
the benzylamine 1 as a crystalline solid in an overall isolated yield of 63% from
commercially available starting material 4 without the need for chromatography.
It appeared that we could prepare the sulfone 2 from the sulfide inter-
mediate 7. As such, amide 7 was oxidized to the corresponding 4-fluoro-2-
(methylsulfonyl)benzamide with m-CPBA in methylene chloride. Although
Scheme 1. Reagents and conditions: a) MeMgCl (1.1 equiv), THF, 08C; n-BuLi
(2.2 equiv) 2788C; below 2658C, 1 h; b) CH3SSCH3 (6 equiv), 2788C, 10 min;
08C 2 h; c) NH4Cl (2 equiv), EDC (2 equiv), HOAt (2 equiv), Hunig’s base
(4 equiv), DMF, rt. 4 h; d) 6 suspended in ether, LAH, 08C to rt.

4-Fluoro-2-(methylthio)benzylamine
1889
it is well established that under appropriate conditions an amide could be
selectively reduced to the corresponding amine in the presence of a sulfone
functional group,[4] the crystalline 4-fluoro-2-(methylsulfonyl)-benzamide
was found to be too insoluble in solvents amenable for reduction. To circum-
vent this problem, an alternative route was investigated. It was anticipated that
regioselective nucleophilic displacement of the 2-fluoro group from the com-
mercially available 2,4-difluorobenzonitrile 8 with methanethiolate would
furnish the key 4-fluoro-2-(methylthio)benzonitrile 9 for further functionaliza-
tion.[5] Reactions of 2-4-difluoro-benzonitrile (0.7 mmol) and sodium metha-
nethiolate (1.0 equiv) in various solvents (0.35 M) under nitrogen in sealed
tubes were set up in parallel. The reaction mixtures were stirred at room temp-
erature for 16 h. The effects of different solvents on rate and regioselectivity of
this substitution reaction are summarized in Table 1 as percentages of starting
material remaining and products generated in the reaction mixtures.
In acetone, the product distribution between the 2-, 4-, and disubstituted
products 9, 10, and 11 was in the ratio of ꢀ2:1:0.1, respectively (Table 1, entry
1). In DMF, the selectivity between 2- and 4-substitution improved to a ratio
of ꢀ3:1, but the amount of disubstituted product 11 formed was more than that
of the desired regioisomer 9 (entry 2). A slight exotherm was noted in the
DMF and DMSO reactions. A similar distribution was seen with DMSO
Table 1. Effect of solvent and temperature on product distributiona
Entry Solvent
Temp.
8
9
10
11
1
2
3
4
5
6
Acetone
DMF
rt
10 + 1.5%ꢀ 61 + 0.6% 26 + 0.6%
3 + 1.1%
rt
34 + 3.2%
30 + 2.3%
12 + 1.0%
24 + 3.5%
9 + 3.5%
26 + 4.2%
33 + 4.0%
77 + 0.0% 10 + 0.6%
74 + 3.0%
89 + 3.5%
8 + 1.0% 32 + 1.7%
7 + 0.6% 30 + 2.3%
DMSO
THF
rt
rt
1 + 0.0%
0 + 0.0%
0 + 0.0%
Toluene
Toluene
rt
2 + 0.6%
2 + 0.6%
608C
aProduct distribution was determined by integration of a reverse-phase HPLC chro-
matogram (UV absorbance at 215 uM) of filtered reaction mixtures. Toluene co-elutes
with the di-substituted product and because the 2,4-difluorobenzonitrile 8 is volatile,
analysis of reaction mixtures in Table 1, entries 5 and 6, was performed in two
parts. HPLC of the filtered reaction gave the ratio of remaining starting material to
desired product 9. The toluene was then removed on a rotovap without heating and
pumped on in vacuo, which also removed starting material 8. HPLC of this residue
showed the ratio of 9 to 10 and 11. Normalizing each component to compound 9
gave the reported percentages. Identity of each component was confirmed by purifi-
cation and 1H NMR characterization. The ratios reported are averages of three indepen-
1
dent experiments under the same conditions. These are further substantiated with H
NMR spectra of the crude product mixture from DMF.

1890
D. S. Perlow et al.
(entry 3). With THF, a less polar solvent, selection for 9 versus 10 was about
8:1 but with no significant quantity of disubstituted product 11 generated
(entry 4). With toluene, the least polar solvent in the study, selection for 9
versus 10 improved to 37:1, and no disubstituted product 11 was observed
(entry 5). However, the rate of consumption of starting material was slower
in toluene than in THF.
We reasoned that there is an intrinsic difference in energy associated with
the transition states 12 and 13 that favors formation of the 2- versus the 4-
substitution products, 9 and 10, respectively, in polar, nonprotic solvents such
as acetone, DMF, and DMSO (Fig. 1).[5] Nonpolar solvents such as THF and
toluene may further bias against transition state 13 with charge separation.
For the same reason, formation of disubstituted product 11 from 2-substituted
9 may be slower than that from 4-substituted 10 under these conditions. This
could reinforce selectivity against formation of the disubstituted product 11
as observed when THF or toluene was used in the reaction. The reaction was
further optimized using toluene as the solvent. Heating the reaction at 608C
resulted in most of the starting material being consumed after 16 h and
further improvement in the product distribution for 9, 10, and 11 of 45:1:0.
This reaction scaled well from 0.1 g to 5 g in a sealed flask.
Figure 1. Mechanistic rationale for observed regioselectivity.
Oxidation of the 4-fluoro-2-(methylthio)benzonitrile 9 with m-chloroperox-
ybenzoic acid in methylene chloride at room temperature followed by
purification via recrystallization from methanol gave 2-methylsulfonyl-4-fluor-
obenzonitrile 14 in 86% isolated yield (Scheme 2). The nitrile 14 was hydrogen-
ated with 10% Pd/C in ethanolic hydrogen chloride to give 2-methylsulfonyl-4-
fluorobenzylamine 2 as the hydrochloride salt, with an overall yield of 41% in
three steps from commercially available 2,4-difluorobenzonitrile 8.
Scheme 3 outlines the preparation of sulfonamide 3. Reaction of the
commercially available 5-fluoro-2-methylbenzenesulfonyl chloride 15 with
dimethylamine in THF provided the corresponding 5-fluoro-N,N,2-trimethylben-
zenesulfonamide 16. Sequential bromination of 16 with N-bromosuccinimide

4-Fluoro-2-(methylthio)benzylamine
1891
Scheme 2. Reagents and conditions: a) MCPBA (2.2 equiv), CH2Cl2, rt, 16 h; b) H2
(50 psi), EtOH–conc. HCl, 5 : 1 v/v, 10% Pd/C.
followed by conversion to the corresponding azide 17 and catalytic hydrogen-
ation with 5% Pd/C in ethanol produced the required 1-(aminomethyl)-5-
fluoro-N,N-dimethyl-benzenesulfonamide 3 as yellow oil with an overall
yield of 34% from 15.
Scheme 3. Reagents and conditions: a) excess dimethylamine gas, THF, rt, 1 h; b)
NBS (1.1 equiv), CCl4, 778C, 16 h; c) sodium azide (2.5 equiv), DMF, rt, 1 h; d) H2,
5% Pd/C, EtOH, rt, 1 h.
In summary, practical syntheses of 4-fluoro-2-(methylthio)benzylamine 1
and the corresponding 2-methylsulfonyl analog 2 were established. The
methylthio moiety was introduced via either a regioselective lithiation or a
selective nucleophilic aromatic substitution. The analogous sulfonamide 3
was prepared from 5-fluoro-2-methylbenzenesulfonyl chloride using
standard chemical transformations.
EXPERIMENTAL
4-Fluoro-2-(methylthio)benzoic Acid (6)
To a cold (08C) solution of 2-bromo-4-fluorobenzoic acid (4) (15.0 g,
68.5 mmol) in anhydrous THF (150 mL) under argon, a solution of
methylmagnesium chloride (26 mL, 75.3 mmol, 2.9 M) in THF was added

1892
D. S. Perlow et al.
over 5 min. The reaction temperature was maintained below 108C throughout
the addition. After the resulting solution was cooled to 2788C, a solution of
n-butyllithium (60.3 mL, 150.7 mmol, 2.5 M) in hexanes was added over
10 min. The reaction temperature was kept below 2658C during the
addition. The reaction mixture was stirred at 2788C for 1 h. Complete
formation of the bis-anion was confirmed by quenching an aliquot in
methanol, evaporating the mixture, partitioning the crude between acidic
water and chloroform, and observing the NMR spectrum of the organic
layer (1H NMR 4-fluorobenzoic acid (CDCl3, 400 MHz) d 8.13 (m, 2H),
7.15 (t, J ¼ 8.6 Hz, 2H)). A cold (2788C) solution of dimethyl disulfide
(38.7 g, 410.9 mmol) in anhydrous THF (20 mL) was added via cannula.
The resulting mixture was stirred for 10 min, warmed to 08C, and stirred for
2 h. The course of the reaction was followed by quenching aliquots in
MeOH and observing the NMR ratio between 4-fluorobenzoic acid and the
product. Warming the reaction to room temperature gave complete conver-
sion. The salt of the product precipitated from the reaction and was
collected by filtration. This solid was suspended in a mixture of ethyl acetate
(400 mL) and water (400 mL) and acidified with 12 N HCl to pH , 1.
The aqueous portion was separated and extracted with ethyl acetate
(4 ꢁ 500 mL). The organic extracts were combined, dried over Na2SO4,
filtered, and concentrated to a small volume in vacuo. The desired product
crystallized and was filtered and dried in vacuo to afford 10.2 g (80% yield)
of the title compound.
1H NMR (d-DMSO, 400 MHz) d 7.98 (1H, dd, J ¼ 8.8, 6.4 Hz), 7.15
(1H, d, J ¼ 10.8 Hz), 7.05 (1H, dd, J ¼ 8.8, 6.4 Hz), 2.41 (3H, bs) ppm. EI
HRMS exact mass calcd. for C8H7FO2S 186.0151 (M); found 186.0151.
4-Fluoro-2-(methylthio)benzamide (7)
To a solution of 4-fluoro-2-(methylthio)benzoic acid (6) (8.1 g, 43.6 mmol) in
degassed anhydrous DMF (100 mL) under nitrogen, ammonium chloride
(4.7 g, 87.2 mmol), 1-hydroxy-7-azabenzotriazole (11.9 g, 87.2 mmol),
N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride (16.7 g,
87.2 mmol), and N,N,-diisopropylethylamine (30.4 mL, 174.4 mmol) were
added successively. The resultant mixture was stirred at rt for 4 h and
concentrated under vacuum. The residual oil was partitioned between
methylene chloride (800 mL) and 5% aqueous HCl (400 mL). The organic
extract was washed with saturated aqueous sodium bicarbonate (400 mL)
and then with brine (400 mL). The organic solution was dried over Na2SO4,
filtered, and reduced to a small volume in vacuo. The resulting crystalline
solids were filtered and dried in vacuo to afford 8.0 g (99% yield) of the
title compound.
1H NMR (CDCl3, 400 MHz) d 7.67 (1H, dd, J ¼ 8.4, 5.9 Hz), 7.00
(1H, dd, J ¼ 9.9, 2.4 Hz), 6.88 (1H, dd, J ¼ 8.4, 2.4 Hz), 2.48 (3H, s) ppm.

4-Fluoro-2-(methylthio)benzylamine
1893
APCI HRMS exact mass calcd. for C8H8FNOS 186.0783 (MHþ); found
186.0365.
4-Fluoro-2-(methylthio)benzylamine (1)
A solution of lithium aluminum hydride (199.2 mL, 1.0 M in diethyl ether)
was added dropwise to a cold (08C) suspension of 4-fluoro-2-(methylthio)ben-
zamide (7) (12.3 g, 66.4 mmol) in anhydrous diethyl ether (500 mL) under
nitrogen over 5 min. The reaction mixture was stirred at rt for 16 h. The
product mixture was cooled to 08C and treated successively with water
(7.5 mL), 15% aqueous NaOH solution (7.5 mL), and water (23 mL). The sus-
pension was filtered through a pad of Celitew and washed with diethyl ether.
The filtrate was washed with brine (300 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The residual brown oil turned into a crystalline solid
upon standing to afford 9.0 g (79% yield) of the title product.
1H NMR (d-DMSO, 400 MHz) d 7.43 (1H, t, J ¼ 7.0 Hz), 7.03 (1H, dd,
J ¼ 10.0, 2.4 Hz), 6.94 (1H, ddd, J ¼ 8.8, 6.4, 2.4 Hz), 3.64 (2H, s), 2.50
(3H, s) ppm. APCI HRMS exact mass calcd. for C8H10FNS 172.0591
(MHþ); found 172.0566.
4-Fluoro-2-(methylthio)benzonitrile (9)
To a stirred suspension of sodium methanethiolate (2.54 g, 36 mmol) in
anhydrous toluene (50 mL) under an atmosphere of nitrogen in a sealed
flask (350 mL), a solution of 2,4-difluorobenzonitrile (8) (5.0 g, 36 mmol)
in toluene (100 mL) was added by cannula. The flask was sealed, and the
mixture was heated at 608C for 16 h. The resulting reaction mixture was
filtered and concentrated in vacuo, and the residue was partitioned between
methylene chloride (400 mL) and water (400 mL). The organic extract was
washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated
under vacuum. The residual solid was concentrated three times from aceto-
nitrile and pumped on for 2 h in vacuo to remove the remaining starting
material. The desired 4-fluoro-2-(methylthio)benzonitrile (4.3 g) was
obtained in 71% yield. The resulting purity of the desired product was 97%
by HPLC. Further purification at this scale was found to be more effective
after oxidation to the corresponding sulfone (10).
Note: When this reaction was run in an unsealed vessel, we observed that the
rate of reaction was significantly slower, although regioselectivity remained
the same.
Compound 9: 1H NMR (CDCl3, 400 MHz) d 7.56 (1H, dd, J ¼ 8.5, 5.6 Hz), 6.95
(1H, dd, J ¼ 9.4, 2.4 Hz), 6.88 (1H, dt, J ¼ 8.2, 2.4 Hz), 2.54 (3H, s) ppm. EI
HRMS exact mass calcd. for C8H6FNS 167.0203 (MHþ); found 167.0205.

1894
D. S. Perlow et al.
Compound 10: 1H NMR (CDCl3, 400 MHz) d 7.46 (1H, dd, J ¼ 8.2, 6.8 Hz),
7.03 (1H, dd, J¼ 8.4, 1.8 Hz), 6.97 (1H, dt, J ¼ 8.2, 1.8 Hz), 2.50 (3H, s) ppm.
Compound 11:1HNMR(CDCl3, 400 MHz)d7.45(1H, d,J ¼ 8.2 Hz),7.07(1H,
d, J ¼ 1.7 Hz), 6.98 (1H, dd, J¼ 8.2, 1.7 Hz), 2.54 (3H, s), 2.50 (3H, s) ppm.
2-Methylsulfonyl-4-fluorobenzonitrile (14)
To a solution of the mixture of 4-fluoro-2-(methylthio)benzonitrile (9) and
2-fluoro-4-(methylthio)benzonitrile (10) (5.6 g, 33.5 mmol) in methylene
chloride (50 mL), 3-chloroperoxybenzoic acid (19.3 g, 67.0 mmol, 60% by
weight) was added. The reaction mixture was stirred at room temperature
for 16 h. The organic extract was washed with saturated aqueous sodium
bicarbonate solution (2 ꢁ 100 mL), dried over MgSO4, filtered, and concen-
trated under vacuum. Crystallization of the residue from methanol provided
pure 2-methylsulfonyl-4-fluorobenzonitrile (14) as a white crystalline solid
(5.6 g, 86% yield).
1H NMR (CDCl3, 400 MHz) d 7.93 (1H, dd, J ¼ 8.5, 4.8 Hz), 7.90
(1H, dd, J ¼ 7.7, 2.4 Hz), 7.45 (1H, ddd, J ¼ 8.5, 7.2, 2.4 Hz), 3.28 (3H, s)
ppm. EI HRMS exact mass calcd. for C8H6FNSO2 199.0103 (MHþ); found
199.0103.
4-Fluoro-2-(methylsulfonyl)benzylamine Hydrogen Chloride (2)
A mixture of 2-methylsulfonyl-4-fluorobenzonitrile (14) (5.6 g, 28.11 mmol),
10% Pd/C (1 g), and 12 N HCl (10 mL) in ethanol (50 mL) in a Parr vessel
was shaken at rt under an atmosphere of hydrogen (50 psi) for 16 h. A ratio
of 50:50 starting material to desired product was observed. The mixture was
filtered through a bed of Celitew and concentrated slightly. Additional 10%
Pd/C (1 g) and 12 N HCl (10 mL) were added, and the reaction was again
put under H2 (50 psi) and shaken for 16 h. The completed reaction was
filtered through Celitew and concentrated to afford 3.8 g (67% yield) of the
desired material as a white crystalline solid.
1H NMR (CDCl3, 400 MHz) d 7.86 (1H, dd, J ¼ 8.2, 2.7 Hz), 7.74 (1H,
dd, J ¼ 8.5, 5.0 Hz), 7.57 (1H, dt, J ¼ 8.2, 2.7 Hz), 4.45 (2H, s), 3.27 (3H, s)
ppm. EI HRMS exact mass calcd. for C8H10FNO2S 203.0410 (MHþ); found
203.0416. C, H, N calcd. for C8H10FNO2S 1.1 HCl C, 39.49%; H, 4.6%; N,
5.76%; found C, 39.50%; H, 4.34%; N, 5.56%.
5-Fluoro-N,N,2-trimethylbenzenesulfonamide (15)
A solution of 5-fluoro-2-methyl-benzenesulfonyl chloride 14 (5.0 g,
24.0 mmol, Lancaster) in THF (100 mL) was saturated with dimethylamine

4-Fluoro-2-(methylthio)benzylamine
1895
gas and stirred at room temperature for 1 h. The ammonium chloride salts
were removed by filtration, and the filtrate was concentrated under vacuum.
The residual oil was subjected to column chromatography on silica gel
(110 g), eluting with a gradient of 90% hexanes/10% ethyl to 75%
hexanes/25% ethyl acetate over 40 min. Collection and concentration of
appropriate fractions afforded 5.2 g (99% yield) of the desired material.
1H NMR (CDCl3, 400 MHz) d 7.60 (1H, dd, J ¼ 8.6, 2.8 Hz), 7.29 (1H,
dd, J ¼ 8.4, 2.8 Hz), 7.16 (1H, m), 2.93 (6H, s), and 2.59 (3H, s) ppm. LCMS
calcd. for C9H12FNO2S 218.1 (MHþ); found 218.0.
2-(Bromomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide (16)
A mixture of 5-fluoro-N,N,2-trimethylbenzenesulfonamide (15) (5.2 g,
24.0 mmol) and N-bromosuccinimide (4.69 g, 26.4 mmol) in dry CCl4
(100 mL) was refluxed overnight under nitrogen. After the reaction was
allowed to cool to room temperature, the succinimide by-product was
removed by filtration. The filtrate was concentrated, and the residue was
subjected to column chromatography on silica gel (110 g), eluting with a
gradient of 100% hexanes to 80% hexanes/20% ethyl acetate over 40 min.
Collection and concentration of appropriate fractions afforded 4.3 g (60%
yield) of desired product (16).
1H NMR (CDCl3, 400 MHz) d 7.64 (2H, m), 7.31 (1H, m), 4.87 (2H, s),
and 2.88 (6H, s) ppm. LCMS calcd. for C9H11BrFNO2S 297.1 (MHþ); found
297.0.
2-(Azidomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide (17)
A solution of 2-(bromomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide
(16) and sodium azide (2.36 g, 36.3 mmol) in DMF (100 mL) was stirred
at rt under nitrogen for 1 h. The product mixture was filtered, and the
filtrate, was concentrated under vacuum. The residual brown oil was sub-
jected to column chromatography on silica gel (110 g), eluting with a
gradient of 100% hexanes to 80% hexanes/20% ethyl acetate over 40 min.
Collection and concentration of appropriate fractions afforded the desired
material (17).
1H NMR (CDCl3, 400 MHz) d 7.61 (2H, m), 7.32 (1H, m), 4.79 (2H, s),
and 2.85 (6H, s) ppm.
2-(Aminomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide (3)
A mixture of the 2-(azidomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide
(3.57 g, 13.8 mmol) and 5% Pd/C (890 mg) in absolute ethanol (100 mL) was

1896
D. S. Perlow et al.
stirred under a hydrogen gas balloon at rt for 1 h. The reaction mixture was
filtered through a bed of Celitew. The filtrate was concentrated in vacuo to
a yellow oil, which was subjected to preparative reverse-phase chromato-
graphy (Waters Deltapak, 3 serial (10 ꢁ 40-mm I.D.) column cartridges,
C18, 15 mm pore size) eluting with 5–65% acetonitrile/water gradient
(0.1% TFA at 30 mL/min) over 30 min. The appropriate fractions were
collected and concentrated under vacuum. The residue was partitioned
between ethyl acetate (100 mL) and 10% sodium bicarbonate (100 mL).
The organic extract was washed with brine, dried over Na2SO4, filtered, and
concentrated to afford 2.15 g (67% yield) of the desired product (3).
1H NMR (d-DMSO, 400 MHz) d 8.24 (2H, bs), 7.75 (2H, m), 7.67 (1H,
dd, J ¼ 8.6, 2.5 Hz), 4.34 (2H, s) and 2.78 (6H, s) ppm.
ACKNOWLEDGMENTS
The authors thank Charles W. Ross and Art Coddington for high-resolution
mass spectrometry analysis and Steven Pitzenberger and Sandor Varga for
NMR determinations. Thanks are also extended to Peter D. Williams and
Donnette D. Staas for helpful discussion and Joseph P. Vacca and Steven
D. Young for their support.
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