Asymmetric Friedel-Crafts reactions of N-tert-butylsulfinyl-3,3,3- trifluoroacetaldimines: General access to enantiomerically pure indoles containing a 1-amino-2,2,2-trifluoroethyl group

Article abstract of DOI:10.1021/jo5012009

We have demonstrated that 3,3,3-trifluoroacetaldimine (S)-1 easily reacts with indole derivatives under Friedel-Crafts reactions to provide reliable and generalized access to biologically interesting compounds containing the CF ₃CH(NH₂)- pharmacophoric group. The reactions proceed with high rates and generally excellent yields (>90%) and stereochemical outcomes (99:1 dr).

Full text of DOI:10.1021/jo5012009

Note
pubs.acs.org/joc
Asymmetric Friedel−Crafts Reactions of N-tert-Butylsulfinyl-3,3,3-
trifluoroacetaldimines: General Access to Enantiomerically Pure
Indoles Containing a 1‑Amino-2,2,2-trifluoroethyl Group
Lingmin Wu,† Chen Xie,† Haibo Mei,† Vadim A. Soloshonok,‡,§ Jianlin Han,*,† and Yi Pan†
†School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian,
Spain
§IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
S
* Supporting Information
ABSTRACT: We have demonstrated that 3,3,3-trifluoroace-
taldimine (S)-1 easily reacts with indole derivatives under
Friedel−Crafts reactions to provide reliable and generalized
access to biologically interesting compounds containing the
CF3CH(NH2)− pharmacophoric group. The reactions pro-
ceed with high rates and generally excellent yields (>90%) and
stereochemical outcomes (99:1 dr).
ndoles represent one of the most abundant classes of
naturally occurring biologically active compounds. From the
To exclude the potential reactivity of the NH function of the
parent indole, as a model compound we chose to study N-
methylindole (3). Friedel−Crafts reactions of 3 with imine (S)-
1 are presented in Table 1. Attempts to use AlCl3 as the catalyst
led to complete decomposition of the starting compounds
(entry 1). Instead, the application of a less strong Lewis acid,
Cu(OTf)2, allowed the preparation of the target products 4 in
60% yield, albeit with rather low diastereoselectivity (entry 2).
We found that the stereochemical outcome could be
I
early days of pharmaceutical science, indole-derived drugs have
played a pivotal role in modern medicine.1 In view of the ever-
increasing importance of fluorine in modern drug develop-
ment,2 the synthesis and medicinal chemistry of fluorine-
containing indoles have received particular attention.3 Con-
sistent with our longstanding interest in the synthesis of
biologically relevant fluorinated compounds,4 we have been
developing the chemistry of (S)- and (R)-N-tert-butylsulfinyl-
3,3,3-trifluoroacetaldimine [(S)-1 and (R)-1, respectively]
(Figure 1)5 as distinctive reagents for wide-ranging preparation
Table 1. Optimization of the Conditions for the Reaction of
a
Indole 3 with Imine (S)-1
time
(h)
yield
b
c
Figure 1. Chiral trifluoromethyl imines 1 and indole derivatives 2.
entry catalyst (mol %)
solvent
CH2Cl2
temp.
(%)
dr
1
2
3
4
5
6
7
8
AlCl3 (20)
rt
rt
rt
rt
rt
rt
4
4
trace
60
−
Cu(OTf)2 (20) CH2Cl2
BF3·Et2O (20) CH2Cl2
BF3·Et2O (100) CH2Cl2
BF3 Et2O (100) toluene
BF3·Et2O (100) Et2O
70:30
4
17
95:5
of various classes of compounds containing the 2,2,2-trifluoro-
1-aminoethyl [CF3CH(NH2)−] pharmacophoric group.6 One
of the still unexplored areas of the reactivity of imines 1 is
Friedel−Crafts-type additions, which can provide direct access
to trifluoromethyl-containing indoles 2 (Figure 1). Therefore,
motivated by the novelty of both Friedel−Crafts reactions of
imines 1 and the type of compounds 2, we decided to
investigate the Lewis acid-catalyzed reactions of (S)-1 with
various indoles. Our results suggest that this approach is
exceptionally successful in granting generalized access to
indoles bearing substituents on both the six- and five-
membered rings.
4
87
93:7
4
47
89:11
94:6
4
50
BF3·Et2O (100) n-hexane rt
BF3·Et2O (100) CH2Cl2 0 °C
4
52
80:20
98:2
10
90
a
Reaction conditions: sulfinylimine 1 (1 mmol), indole 3 (1.2 mmol),
b
catalyst, 5 mL of solvent. Isolated yields of major diastereomers.
c
Determined by 19F NMR analysis of the crude reaction mixtures.
Received: May 29, 2014
Published: July 22, 2014
© 2014 American Chemical Society
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Note
significantly improved to 95:5 with the application of BF3·Et2O
(entry 3) as the catalyst for this reaction. Further optimization
attempts led us to use a stoichiometric amount of BF3·Et2O
(entry 4). The necessity to apply a rather large quantity of
Lewis acid in these reactions can be rationalized by the fact that
the sulfoxide oxygen in imine (S)-1 can act as a Lewis base and
thus neutralize the catalyst effect.7 Attempts to use solvents
other than CH2Cl2 were rather unsuccessful, resulting in both
lower chemical yields and lower diastereoselectivity (entries 5−
7). Finally, we found that lowering the reaction temperature
from ambient to 0 °C afforded the target product in 90% yield
with improved selectivity (entry 8), although the reaction was
slower, taking about 10 h for its completion. These results
clearly demonstrated that the Friedel−Crafts reaction of imine
(S)-1 with indole 3 can be conducted under very mild
conditions and affords the target compounds in synthetically
valuable yields and diastereoselectivity. The next goals of this
study were to explore the structural generality of these reactions
and elucidate a possible mechanistic rationale for the observed
stereochemical outcome.
Table 3. Reactions of Various Substituted N-Methylindoles 7
with Imine (S)-1
a
b
c
entry
R
product
yield (%)
dr
1
2
2-CH3
8a
8b
8c
8d
8e
8f
87
NR
60
80
75
92
96
96:4
−
2-CHO
4-CN
3
99:1
97:3
99:1
99:1
97:3
77:23
90:10
90:10
96:4
99:1
99:1
4
4-MeO
5-CN
5
6
5-MeO
5-COOCH3
5-COOH
6-Cl
7
8g
8h
8i
d
8
90
9
68
64
74
82
94
10
11
12
13
6-Br
8j
7-Br
8k
8l
First, we investigated the effect of the substituent on the
indole nitrogen, and the results are summarized in Table 2. In
7-CH3
2-CH3-5-MeO
8m
a
Reaction conditions: sulfinylimine 1 (1 mmol), indole 7 (1.2 mmol),
b
Table 2. Reactions of N-Substituted Indoles 5 with Imine
BF3·Et2O (1 mmol), CH2Cl2 (5 mL). Isolated yields of major
a
c
diastereomers; NR indicates no reaction. Determined by 19F NMR
(S)-1
d
analysis of the crude reaction mixtures. The yield of two
diastereomers.
CH2Cl2 (5 mL) at 0 °C for 10 h. In the case of 2-substituted
derivatives (entries 1 and 2), we again observed a dramatic
effect of the substituent’s electronic properties on the reaction
outcome. Thus, while the 2-Me derivative 7 reacted efficiently
with imine (S)-1, the 2-formyl-containing 7 failed completely to
undergo the desired transformation, indicating a detrimental
effect of its electron-withdrawing property on the reactivity. By
contrast, the electronic properties of a substituent at the 4-
position (on the phenyl ring) showed just a little effect the
stereochemical outcome. For example, 4-CN and 4-MeO
derivatives 7 (entries 3 and 4) cleanly reacted with imine (S)-1
to afford the corresponding products 8 in 60 and 80% yield,
respectively, both with excellent diastereoselectivity. A similar
trend was observed also in the series of 5-substituted indoles 7.
The reactions of derivatives 7 bearing 5-CN and 5-MeO groups
(entries 5 and 6) gave rise to the corresponding products 8 as
single diastereomers in 75 and 92% yield, respectively.
Unexpectedly, very interesting results were obtained in the
case of derivatives 7 containing an ester (R = CO2Me; entry 7)
and a free carboxylic group (entry 8) at the 5-position. In both
reactions we observed excellent reactivity, and the target
products were isolated in high yields. However, while in the
case of the 5-CO2Me containing indole 7 we obtained virtually
complete stereoselectivity (99:1), the 5-COOH-bearing sub-
strate gave a rather poor stereochemical outcome (77:23). Also,
lower than normal stereoselectivities and chemical yields were
recorded for the reactions of 6-Cl- and 6-Br-substituted
derivatives 7 (entries 9 and 10). The presence of a substituent
in the last possible position on the indole framework (the 7-
position) was quite consistent with the usually very good
stereochemical outcome observed in these reactions. Thus, 7-
Br- and 7-methyl-containing indoles 7 gave the corresponding
products 8k and 8l in 74 and 82% yield with 96:4 and 99:1
diastereoselectivity, respectively (entries 11 and 12). Finally, to
conclude this structural generality part of the study, we
b
c
entry
R
product
yield (%)
dr
1
2
3
4
5
CH3
Et
6a
6b
6c
6d
6e
90
98:2
98:2
96:4
−
82
Bn
85
Cbz
H
NR
d
36
77:23
a
Reaction conditions: sulfinylimine 1 (1 mmol), indole 5 (1.2 mmol),
b
BF3·Et2O (1 mmol), CH2Cl2 (5 mL). Isolated yields of major
c
diastereomers; NR indicates no reaction. Determined by 19F NMR
d
analysis of the crude reaction mixtures. The reaction was run for 18 h.
the reactions of N-ethyl and N-benzyl derivatives 5 we observed
reactivity similar to that of N-methylindole (entries 2 and 3 vs
1), and the corresponding products 6 were isolated in good
yields and diastereomeric purity. In sharp contrast, indole 5
bearing a Cbz protecting group (entry 4) failed to react with
imine (S)-1; not even a trace amount of the expected product 6
was observed in the reaction mixture. Of particular interest was
the reaction of unprotected indole 5 (entry 5), which gave a
rather poor outcome. While the reaction did take place, the
product 6 was isolated in 36% yield with low diastereose-
lectivity. This brief screening allowed us to outline some
general principles and limitations of these Friedel−Crafts
reactions in terms of the electronic properties of the N-
substituent as well as the possibility of using unsubstituted
indole.
Next, we focused on exploring the generality of these
reactions using N-methylindoles 7 (Table 3) bearing
substituents in all possible positions of the indole framework.
For the purpose of comparison, all of the reactions were
conducted under the standard conditions: sulfinylimine 1 (1
mmol), indole 7 (1.2 mmol), and BF3·Et2O (1 mmol) in
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conducted the reaction of 2-methyl-5-methoxy-disubstituted
indole 7 with imine (S)-1. As one can see from entry 13, the
desired product 8 was obtained in high yield (94%) with an
excellent stereochemical outcome (99:1 dr).
Scheme 1. Deprotection of Product 4
Taking advantage of the high crystallinity of product 8l
containing a methyl group at the 7-position, we conducted its
crystallographic analysis to determine the absolute config-
uration of the newly created stereogenic carbon. According to
the X-ray data, the configuration of 8l is (S,S) (Figure 2). The
absolute configurations of the other products 8 were assigned
accordingly as (S,S) on the basis of the close similarity of their
spectral and chiroptical properties.
indole derivatives in the presence of stoichiometric amounts of
BF3·Et2O. The reactions feature a wide range of generality with
good-to-excellent stereochemical outcomes. On the basis of the
experimental data reported here, one may assume that the
developed method is a highly synthetically valuable approach
for the preparation of various novel biologically interesting
indole derivatives containing the CF3CH(NH2)− pharmaco-
phoric group.
EXPERIMENTAL SECTION
■
Typical Procedure for the Friedel−Crafts Reaction of N-
Methylindoles and Sulfinylimine 1. To a solution of indole 7 (1.2
mmol) in anhydrous CH2Cl2 (5 mL) at 0 °C was added BF3·Et2O
(130 μL, 1.0 mmol) dropwise. Then the solution of sulfinylimine 1
(201 mg, 1.0 mmol) in CH2Cl2 (2 mL) was added in one portion.
Stirring was continued at 0 °C for 10 h, and then the reaction was
quenched with H2O (10 mL). The organic layer was removed, and the
aqueous layer was extracted with EtOAc (2 × 20 mL). The combined
organic layers were washed with water (2 × 30 mL) and brine solution
(1× 30 mL) and dried over anhydrous Na2SO4. The solvent was
evaporated, and the crude mixture was charged onto silica gel and
purified through flash chromatography (eluent: 1:1 PE/EtOAc) to
furnish the corresponding product 8.
Figure 2. ORTEP structure of compound 8l.
Taking into account the (S,S) absolute configuration of
products 8, we can discuss a plausible mechanistic rationale for
the observed stereochemical outcome in the reactions under
study. As shown in Figure 3, three possible transition states
(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)-
ethyl)propane-2-sulfinamide (6a). Colorless oil. Yield: 298 mg
(90%). [α]2D5 = +101.12 (c = 0.36, CHCl3). H NMR (400 MHz,
1
CDCl3): δ 7.66 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 (t, J
= 8.0 Hz, 1H), 7.21 (s, 1H), 7.16−7.12 (m, 1H), 5.13 (qd, J = 8.0, 4.0
Hz, 1H), 3.93 (br, 1H), 3.76 (s, 3H), 1.19 (s, 9H). 13C NMR (101
MHz, CDCl3): δ 137.3, 130.5, 126.5, 125.3 (q, JFC = 282.8 Hz), 122.4,
3
120.3, 120.0, 109.7, 104.1, 55.9, 54.7 (q, JFC = 32.3 Hz), 33.0, 22.6.
19F NMR (376 MHz, CDCl3): δ −73.99. IR (cm−1): 2959, 2927, 1552,
1475, 1364, 1336, 1267, 1170, 1133, 1118, 1072, 1014, 743. HRMS
(TOF MS ESI): calcd for C15H19F3N2OSNa [M + Na]+ 355.1068,
found 355.1068.
Figure 3. Possible transition states.
(S)-N-((S)-1-(1-Ethyl-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-methyl-
propane-2-sulfinamide (6b). Colorless oil. Yield: 285 mg (82%).
[α]2D5 = +95.85 (c = 0.48, CHCl3). H NMR (400 MHz, CDCl3): δ
1
(TSs) A, B, and C can be constructed to account for the
experimental results. Considering TSs A−C, one may agree
that TS A seems less sterically crowded, but only TS C can
account for the quite unexpected effect of the substituents at
the 5- and 6-positions in the phenyl ring of the indole on the
observed stereochemical outcome.
Finally, we believed that it would be desirable to demonstrate
the deprotection of the products obtained to confirm the
possibility of preparing free CF3-containing amines by this new
approach. To this end, we conducted the reaction of N-Me
derivative (S,S)-4 (Scheme 1). Under the standard conditions,7
the deprotection step proceeded without any complications,
and amine (S)-9 was isolated in 92% yield. Also, the
enantioselectivity of (S)-9 was been examined, and the ee
value was found to be 99.6%, indicating that no racemization
happened during the deprotection process.
7.66 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26−7.21 (m, 2H),
7.14−7.10 (m, 1H), 5.13 (qd, J = 8.0, 4.0 Hz, 1H), 4.14 (q, J = 8.0 Hz,
2H), 3.94 (s, 1H), 1.46 (t, J = 8.0 Hz, 3H), 1.19 (s, 9H). 13C NMR
(101 MHz, CDCl3): δ 136.4, 128.7, 126.7, 125.3 (q, JFC = 282.8 Hz),
3
122.2, 120.4, 120.0, 109.8, 104.3, 55.9, 54.8 (q, JFC = 32.3 Hz), 41.2.
22.6, 15.3.19F NMR (376 MHz, CDCl3): δ −73.95. IR (cm−1): 2979,
2960, 2927, 1471, 1464, 1363, 1267, 1170, 1134, 1118, 1076, 742.
HRMS (TOF MS ESI): calcd for C16H21F3N2OSNa [M + Na]+
369.1224, found 369.1221.
(S)-N-((S)-1-(1-Benzyl-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-meth-
ylpropane-2-sulfinamide (6c). Colorless oil. Yield: 348 mg (85%).
[α]2D5 = +82.72 (c = 0.49, CHCl3). H NMR (400 MHz, CDCl3): δ
1
7.68 (d, J = 8.0 Hz, 1H), 7.31−7.23 (m, 5H), 7.21−7.17 (m, 1H), 7.13
(t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 5.34−5.24 (m, 2H), 5.15
(qd, J = 8.0, 4.0 Hz, 1H), 3.97 (d, J = 4.0 Hz, 1H), 1.18 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 136.9, 136.7, 129.9, 128.9, 128.9, 127.9,
126.8, 126.8, 125.2 (q, JFC = 282.8 Hz), 122.6, 120.3, 110.2, 105.0,
3
56.0, 54.6 (q, JFC = 32.3 Hz), 50.3, 22.6. 19F NMR (376 MHz,
CDCl3): δ −74.03. IR (cm−1): 3195, 3064, 2960, 2926, 1552, 1469,
To conclude, we have demonstrated that 3,3,3-trifluoroace-
taldimine (S)-1 easily undergoes Friedel−Crafts reactions with
1454, 1363, 1338, 1267, 1172, 1134, 1122, 1072, 742. HRMS (TOF
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Note
MS ESI): calcd for C21H23F3N2OSNa [M + Na]+ 431.1381, found
431.1382.
1347, 1267, 1225, 1168, 1127, 1069, 1037, 797. HRMS (TOF MS
ESI): calcd for C16H21F3N2O2SNa [M + Na]+ 385.1174, found
385.1172.
(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethyl)-
propane-2-sulfinamide (6e). Pale-yellow solid, mp 154−155 °C.
Methyl 3-((S)-1-((S)-1,1-Dimethylethylsulfinamido)-2,2,2-trifluor-
Yield: 114 mg (36%). [α]D25 = +109.17 (c = 0.70, CHCl3). H NMR
1
oethyl)-1-methyl-1H-indole-5-carboxylate (8g). White solid, mp 75−
1
76 °C. Yield: 372 mg (96%). [α]2D5 = +128.96 (c = 0.44, CHCl3). H
(400 MHz, CDCl3): δ 9.38 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.33 (d, J
= 8.0 Hz, 1H), 7.26−7.18 (m, 1H), 7.16−7.12 (m, 2H), 5.16 (qd, J =
8.0, 4.0 Hz, 1H), 4.12 (d, J = 4.0 Hz, 1H), 1.24 (s, 9H). 13C NMR
(101 MHz, CDCl3): δ 136.7, 126.7, 125.9, 125.3 (q, JFC = 282.8 Hz),
NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H),
7.30−7.28 (m, 2H), 5.22−5.15 (m, 1H), 4.36 (s, 1H), 3.85 (s, 3H),
3.69 (s, 3H), 1.18 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 167.8,
139.6, 131.9, 126.0, 125.1 (q, JFC = 282.8 Hz), 123.5, 123.2, 122.0,
109.5, 105.9, 56.1, 54.3 (q, 3JFC = 32.3 Hz), 51.8, 33.0, 22.5. 19F NMR
(376 MHz, CDCl3): δ −74.01. IR (cm−1): 2953, 1715, 1457, 1289,
1266, 1252, 1170, 1115, 1075, 771. HRMS (TOF MS ESI): calcd for
C17H21F3N2O3SNa [M + Na]+ 413.1123, found 413.1120.
3
122.5, 120.1, 119.9, 112.0, 104.9, 56.1, 54.9 (q, JFC = 32.3 Hz), 22.6.
19F NMR (376 MHz, CDCl3): δ −73.90. IR (cm−1): 2957, 2923, 2852,
1462, 1266, 1254, 1174, 1118, 1068, 1032, 750. HRMS (TOF MS
ESI): calcd for C14H17F3N2OSNa [M + Na]+ 341.0911, found
341.0911.
(S)-N-((S)-1-(1,2-Dimethyl-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-
3-((S)-1-((S)-1,1-Dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-
1-methyl-1H-indole-5-carboxylic Acid (8h). White solid, mp 192−
193 °C. Yield: 338 mg (90%). [α]2D5 = +117.25 (c = 0.86, CHCl3).
methylpropane-2-sulfinamide (8a). Yellow oil. Yield: 303 mg (87%).
[α]2D5 = +157.80 (c = 0.53, CHCl3). H NMR (400 MHz, CDCl3): δ
1
1
7.63 (d, J = 8.0 Hz, 1H), 7.24−7.21 (m, 1H), 7.18−7.14 (m, 1H),
7.09−7.05 (m, 1H), 5.13 (d, J = 8.0 Hz, 1H), 3.96 (br, 1H), 3.56 (s,
3H), 2.42 (s, 3H), 1.18 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
138.4, 137.1, 126.2, 125.7 (q, JFC = 282.8 Hz), 121.3, 120.4, 119.8,
Major diastereomer: H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H),
7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.34 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H),
5.27−5.20 (m, 2H), 3.84 (s, 3H), 1.26 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 171.7, 139.8, 131.5, 126.1, 124.1 (q, JFC = 278.8 Hz), 124.0,
3
109.1, 99.9, 55.4, 54.1 (q, JFC = 32.3 Hz), 29.6, 22.6, 10.5. 19F NMR
3
123.7, 121.8, 109.4, 106.4, 56.6, 54.4 (q, JFC = 32.3 Hz), 33.3, 22.6.
(376 MHz, CDCl3): δ −73.38. IR (cm−1): 2957, 1473, 1365, 1268,
1168, 1124, 1075, 744. HRMS (TOF MS ESI): calcd for
C16H21F3N2OSNa [M + Na]+ 369.1224, found 369.1224.
19F NMR (376 MHz, CDCl3): δ −73.62.
Minor diastereomer: 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H),
7.79 (dd, J = 8.8, 1.2 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H),
5.21 (d, J = 4.0 Hz, 1H), 4.70 (d, J = 4.0 Hz, 1H), 3.75 (s, 3H), 1.31
(s, 9H). 13C NMR (101 MHz, CDCl3): δ 171.5, 139.5, 130.0, 126.4,
125.0 (q, JFC = 282.8 Hz), 124.1, 123.7, 121.9, 109.3, 108.5, 56.6, 55.2
(S)-N-((S)-1-(4-Cyano-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroeth-
yl)-2-methylpropane-2-sulfinamide (8c). Pale-yellow solid, mp 167−
168 °C. Yield: 210 mg (60%). [α]2D5 = −64.85 (c = 0.73, CHCl3). H
1
NMR (400 MHz, CDCl3): δ 7.59 (dd, J = 8.0, 4.0 Hz, 1H), 7.51 (d, J
= 8.0 Hz, 1H), 7.45 (s, 1H), 7.29 (t, J = 4.0 Hz, 1H), 5.80 (s, 1H), 4.36
(s, 1H), 3.85 (s, 3H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
136.6, 131.9, 126.9, 126.2, 125.0 (q, JFC = 282.8 Hz), 121.9, 119.4,
115.0, 105.7, 101.7, 56.5, 52.4 (q, 3JFC = 31.3 Hz), 33.4, 22.5. 19F NMR
(376 MHz, CDCl3): δ −73.39. IR (cm−1): 2960, 2927, 2220, 1460,
1365, 1347, 1265, 1172, 1126, 1067, 789. HRMS (TOF MS ESI):
calcd for C16H18F3N3OSNa [M + Na]+ 380.1020, found 380.1021.
(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-(4-methoxy-1-methyl-1H-
indol-3-yl)ethyl)propane-2-sulfinamide (8d). Pale-yellow solid, mp
148−149 °C. Yield: 292 mg (80%). [α]2D5 = −2.50 (c = 0.48, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.18 (t, J = 8.0 Hz, 1H), 7.04 (s, 1H),
3
(q, JFC = 32.3 Hz), 33.1, 22.5. 19F NMR (376 MHz, CDCl3): δ
−73.83.
IR (cm−1): 3295, 3160, 2964, 2925, 2854, 2608, 1705, 1694, 1678,
1616, 1458, 1410, 1389, 1366, 1347, 1318, 1291, 1268, 1246, 1214,
1171, 1138, 1118, 1072, 1051, 1024, 1010, 916, 773, 750, 709. HRMS
(TOF MS ESI): calcd for C16H19F3N2O3SNa [M + Na]+ 399.0966,
found 399.0966.
(S)-N-((S)-1-(6-Chloro-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroeth-
yl)-2-methylpropane-2-sulfinamide (8i). Pale-yellow oil. Yield: 250
mg (68%). [α]2D5 = +110.92 (c = 0.57, CHCl3). H NMR (400 MHz,
1
CDCl3): δ 7.57 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.22 (s,
1H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 5.11 (qd, J = 8.0, 4.0 Hz, 1H), 4.11
(d, J = 3.6 Hz, 1H), 3.65 (s, 3H), 1.18 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 137.8, 131.4, 128.5, 125.1 (q, JFC = 282.8 Hz), 125.0, 121.4,
120.8, 109.9, 104.3, 55.9, 54.5 (q, 3JFC = 32.3 Hz), 33.1, 22.6. 19F NMR
(376 MHz, CDCl3): δ −74.10. IR (cm−1): 3207, 2960, 2928, 2871,
1614, 1549, 1491, 1475, 1458, 1423, 1365, 1330, 1267, 1170, 1146,
1118, 1070, 899, 863, 843, 805. HRMS (TOF MS ESI): calcd for
C15H18ClF3N2OSNa [M + Na]+ 389.0678, found 389.0675.
6.96 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.46 (s, 1H), 4.93
(s, 1H), 3.95 (s, 3H), 3.74 (s, 3H), 1.15 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 153.3, 138.5, 127.5, 125.0 (q, JFC = 282.8 Hz), 123.1, 116.6,
106.5 (d, J = 2.0 Hz), 103.3, 100.5, 56.5, 55.6 (q, 3JFC = 32.3 Hz), 55.4,
33.2, 22.4. 19F NMR (376 MHz, CDCl3): δ −74.28. IR (cm−1): 2958,
1503, 1468, 1346, 1260, 1168, 1124, 1077, 734. HRMS (TOF MS
ESI): calcd for C16H21F3N2O2SNa [M + Na]+ 385.1174, found
385.1171.
(S)-N-((S)-1-(6-Bromo-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroeth-
yl)-2-methylpropane-2-sulfinamide (8j). Yellow oil. Yield: 264 mg
(64%). [α]2D5 = +91.75 (c = 0.61, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.52 (d, J = 8.0, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.23−7.20
(m, 2H), 5.10 (qd, J = 8.0, 4.0 Hz, 1H), 4.08 (s, 1H), 3.66 (s, 3H),
1.18 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 138.1, 131.3, 125.3,
125.2 (q, JFC = 282.8 Hz), 123.3, 121.7, 116.0, 112.9, 104.5, 55.9, 54.5
(S)-N-((S)-1-(5-Cyano-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroeth-
yl)-2-methylpropane-2-sulfinamide (8e). White solid, mp 173−174
°C. Yield: 270 mg (75%). [α]2D5 = +194.09 (c = 0.37, CHCl3). H
1
NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.49 (dd, J = 8.0, 4.0 Hz,
1H), 7.41−7.38 (m, 2H), 5.11 (qd, J = 8.0, 4.0 Hz, 1H), 3.98 (d, J =
4.0 Hz, 1H), 3.84 (s, 3H), 1.22 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 139.0, 133.2, 126.3, 126.2,, 126.1, 125.3, 124.9 (q, JFC
=
3
(q, JFC = 32.3 Hz), 33.0, 22.5. 19F NMR (376 MHz, CDCl3): δ
3
282.8 Hz), 120.4, 110.8, 105.2, 103.4, 56.0, 54.3 (q, JFC = 32.3 Hz),
33.4, 22.5. 19F NMR (376 MHz, CDCl3): δ −74.15. IR (cm−1): 2958,
2928, 2221, 1488, 1379, 1365, 1265, 1171, 1150, 1117, 1072, 804.
HRMS (TOF MS ESI): calcd for C16H18F3N3OSNa [M + Na]+
380.1020, found 380.1017.
−74.11. IR (cm−1): 2959, 2928, 1546, 1474, 1455, 1365, 1329, 1266,
1170, 1146, 1119, 1073, 854, 804. HRMS (TOF MS ESI): calcd for
C15H18BrF3N2OSNa [M + Na]+ 433.0173, found 433.0159.
(S)-N-((S)-1-(7-Bromo-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroeth-
yl)-2-methylpropane-2-sulfinamide (8k). Yellow solid, mp 55−56 °C.
(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-1-methyl-1H-
Yield: 301 mg (74%). [α]D25 = +79.04 (c = 0.79, CHCl3). H NMR
1
indol-3-yl)ethyl)propane-2-sulfinamide (8f). Yellow oil. Yield: 330
mg (92%). [α]2D5 = +116.60 (c = 0.49, CHCl3). H NMR (400 MHz,
1
(400 MHz, CDCl3): δ 7.60 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz,
1H), 7.20 (s, 1H), 6.94 (t, J = 8.0 Hz, 1H), 5.13 (qd, J = 8.0, 4.0 Hz,
1H), 4.13 (s, 3H), 4.10 (s, 1H), 1.19 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 133.6, 133.4, 129.6, 127.5, 125.1 (q, JFC = 282.8 Hz), 121.2,
119.5, 104.3, 104.2, 56.0, 54.3 (q, 3JFC = 32.3 Hz), 37.3, 22.5. 19F NMR
(376 MHz, CDCl3): δ −74.01. IR (cm−1): 2958, 1566, 1471, 1456,
1411, 1365, 1266, 1171, 1113, 1074, 780, 737. HRMS (TOF MS ESI):
calcd for C15H18BrF3N2OSNa [M + Na]+ 433.0173, found 433.0169.
CDCl3): δ 7.23 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J = 2.0 Hz,
1H), 6.92 (dd, J = 8.8, 2.4 Hz, 1H), 5.09 (qd, J = 8.0, 4.0 Hz, 1H), 3.91
(d, J = 4.0 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 1.23 (s, 9H). 13C NMR
(101 MHz, CDCl3): δ 154.4, 132.6, 131.0, 126.9, 125.3 (q, JFC = 282.8
3
Hz), 112.8, 110.5, 103.3, 101.9, 55.7, 55.7, 54.6 (q, JFC = 32.3 Hz),
33.2, 22.6. 19F NMR (376 MHz, CDCl3): δ −74.00. IR (cm−1): 3206,
2957, 2927, 2870, 2834, 1624, 1579, 1548, 1493, 1457, 1426, 1363,
7680
dx.doi.org/10.1021/jo5012009 | J. Org. Chem. 2014, 79, 7677−7681

The Journal of Organic Chemistry
Note
(S)-N-((S)-1-(1,7-Dimethyl-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-
methylpropane-2-sulfinamide (8l). White solid, mp 127−128 °C.
REFERENCES
■
(1) (a) Shaveta; Singh, A.; Kaur, M.; Sharma, S.; Bhatti, R.; Singh, P.
Eur. J. Med. Chem. 2014, 77, 185−192. (b) Brewer, M. R.; Pao, W.
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6745.
Yield: 284 mg (82%). [α]D25 = +98.78 (c = 0.82, CHCl3). H NMR
1
(400 MHz, CDCl3): δ 7.50 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.01 (t, J
= 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.11 (qd, J = 8.0, 4.0 Hz, 1H),
4.06 (s, 3H), 3.91 (d, J = 4.0 Hz, 1H), 2.77 (s, 3H), 1.22 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 136.0, 132.0, 127.6, 125.2 (q, JFC = 282.8
3
Hz), 125.1, 121.7, 120.3, 118.3, 103.8, 55.9, 54.6 (q, JFC = 32.3 Hz),
37.2, 22.6, 19.7. 19F NMR (376 MHz, CDCl3): δ −74.00. IR (cm−1):
2962, 2930, 1459, 1365, 1267, 1168, 1114, 1073, 781, 746. HRMS
(TOF MS ESI): calcd for C16H21F3N2OSNa [M + Na]+ 369.1224,
found 369.1222.
(3) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, Germany, 2004. (b) Chambers, R. D. Fluorine in Organic
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(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-1,2-dimethyl-
1H-indol-3-yl)ethyl)propane-2-sulfinamide (8m). White solid, mp
130−131 °C. Yield: 354 mg (94%). [α]2D5 = +232.8 (c = 0.51, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 8.0 Hz, 2H), 6.83 (dd, J =
́ ́
fluorine Chemistry; Blackwell: Oxford, U.K., 2006. (d) Begue, J. P.;
Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
Wiley: New York, 2008. (e) Ojima, I. Fluorine in Medicinal Chemistry
and Chemical Biology; Blackwell: Oxford, U.K., 2009. (f) Wang, S.; Nie,
J.; Zheng, Y.; Ma, J. A. Org. Lett. 2014, 16, 1606−1609. (g) Gong, Y.
F.; Kato, K. J. Fluorine Chem. 2002, 116, 103−107. (h) Gong, Y. F.;
Kato, K. Tetrahedron: Asymmetry 2001, 12, 2121−2127.
8.0, 4.0 Hz, 1H), 5.11 (d, J = 8.0 Hz, 1H), 3.97 (d, J = 4.0 Hz, 1H),
3.78 (s, 3H), 3.54 (s, 3H), 2.40 (s, 3H), 1.21 (s, 9H). 13C NMR (101
MHz, CDCl3): δ 154.2, 138.8, 132.3, 126.5, 125.8 (q, JFC = 282.8 Hz),
3
111.1, 109.7, 102.8, 99.3, 55.6, 55.2, 54.1 (q, JFC = 32.3 Hz), 29.7,
22.6, 10.5. 19F NMR (376 MHz, CDCl3): δ −73.34. IR (cm−1): 2956,
1489, 1456, 1264, 1230, 1166, 1124, 1074. HRMS (TOF MS ESI):
calcd for C17H23F3N2O2SNa [M + Na]+ 399.1330, found 399.1328.
Procedure for Deprotection of 4. Cleavage of the chiral tert-
butylsulfinyl group was carried out in a 25 mL round-bottom flask, to
which 0.5 mmol of 4 and 5 mL of MeOH were added. Then 1 mL of
aqueous HCl (36%) was added dropwise with stirring at room
temperature. After 4 h, when the reaction was complete as determined
by TLC monitoring, the volatiles were removed under reduced
pressure. The residue was dissolved in CH2Cl2 (10 mL), and Et3N
(15.0 mmol) was added. The mixture was stirred at rt for 1 h, and then
H2O (10 mL) was added. The organic layer was removed, washed with
water and brine, and dried with anhydrous Na2SO4. The mixture was
filtered and concentrated. The crude product was purified by layer
chromatography to give product 9 in 92% yield.
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(S)-2,2,2-Trifluoro-1-(1-methyl-1H-indol-3-yl)ethanamine (9).
Pale-yellow solid, mp 52−53 °C. Yield: 106 mg (92%). [α]D25
=
+2.08 (c = 0.67, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J =
8.0 Hz, 1H), 7.31 (dd, J = 8.0, 0.8 Hz, 1H), 7.27−7.22 (m, 1H), 7.17−
7.13 (m, 2H), 4.73 (q, J = 8.0 Hz, 1H), 3.75 (s, 3H), 1.80 (s, 2H). 13C
NMR (101 MHz, CDCl3): δ 137.0, 127.8, 126.7, 126.5 (q, JFC = 282.8
3
Hz), 122.3, 119.9, 119.4, 109.7, 109.3 (d, J = 2.0 Hz), 51.4 (q, JFC
=
31.3 Hz), 32.8. 19F NMR (376 MHz, CDCl3): δ −76.66. IR (cm−1):
3376, 3283, 3188, 2919, 2855, 1616, 1553, 1477, 1468, 1399, 1277,
1243, 1179, 1160, 1151, 1118, 1090, 945, 809, 741, 712. HRMS (TOF
MS EI+) m/z calcd for C11H11F3N2 228.0874, found 228.0870.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full spectroscopic data and copies of 1H and 13C NMR spectra
for compounds 6−9, HPLC spectra of compound 9, and X-ray
crystallographic data for 8l (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hanjl@nju.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21102071) and
the Fundamental Research Funds for the Central Universities
(1107020522 and 1082020502). The Jiangsu 333 Program (for
Y.P.) and the Changzhou Jin-Feng-Huang Program (for J.H.)
are also acknowledged.
7681
dx.doi.org/10.1021/jo5012009 | J. Org. Chem. 2014, 79, 7677−7681