One-pot cascade trifluoromethylation/cyclization of imides: Synthesis of α-trifluoromethylated amine derivatives

Article abstract of DOI:10.1021/jo5002998

Tryptamine- and phenethylamine-derived imides were selectively monotrifluoromethylated using CF₃TMS. Subsequent methanesulfonic acid mediated cyclization of the intermediate hemiaminals afforded the α-trifluoromethylated amine derivatives via the formation of trifluoromethylated acyliminium ions, in one pot. The strategy was applicable to the both inter- and intramolecular versions. Furthermore, the utility of the present method was demonstrated through the synthesis of trifluoromethylated analogues of harmicine and crispine A.

Full text of DOI:10.1021/jo5002998

Note
pubs.acs.org/joc
One-Pot Cascade Trifluoromethylation/Cyclization of Imides:
Synthesis of α‑Trifluoromethylated Amine Derivatives
Vinay Kumar Pandey and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai - 600036, India
S
* Supporting Information
ABSTRACT: Tryptamine- and phenethylamine-derived
imides were selectively monotrifluoromethylated using
CF3TMS. Subsequent methanesulfonic acid mediated cycliza-
tion of the intermediate hemiaminals afforded the α-
trifluoromethylated amine derivatives via the formation of
trifluoromethylated acyliminium ions, in one pot. The strategy
was applicable to the both inter- and intramolecular versions.
Furthermore, the utility of the present method was
demonstrated through the synthesis of trifluoromethylated
analogues of harmicine and crispine A.
any synthetic bioactive molecules, both in pharmaceut-
icals and agrochemicals, contain fluorine in the form of
ubiquitous natural products associated with diverse biological
functions, particularly, in the brain as neurotoxins and
neuroprotectants.10 Introduction of trifluoromethyl groups in
these therapeutically important natural product motifs at a
specific site may improve their biological profile11 and are
highly desirable. Inspired by the reactivity of trifluoromethy-
lated hemiaminals and the unique properties of trifluoromethy-
lated compounds in biological systems, we herein disclose a
new cascade trifluoromethylation/cyclization of imides for the
synthesis of trifluoromethylated heterocycles and nitrogen-
based building blocks.
For the present study, the phthalimide derivative 1a derived
from tryptamine was chosen as a suitable starting material.
Next, selective monotrifluoromethylation of imide 1a with
CF3SiMe3 was examined.12 After optimization, the monotri-
fluoromethylated product, hemiaminal 2, was isolated from the
reaction of imide 1a and CF3SiMe3 with a catalytic amount of
tetrabutylammonium fluoride (TBAF) in 81% yield (Scheme
2).
M
either fluoro, trifluoromethyl (CF3), or thiotrifluoromethyl
(SCF3) groups.1 The presence of fluorine in the important
structural backbone can profoundly alter the biological and
physicochemical properties of compounds through concurrent
changes in steric, electronic, lipophilic, and metabolic character-
istics.2 Consequently, over the last few decades, fluorinated
compounds have attracted significant attention in various fields,
such as organic synthesis, medicinal chemistry, and materials.3
Among them, trifluoromethylated compounds are of great
interest since the trifluoromethyl group is an excellent
bioisostere of the methyl group, which is stable under metabolic
oxidative conditions. Although trifluoromethylated compounds
and/or building blocks can be synthesized employing both
nucleophilic trifluoromethylating reagents4 and electrophilic
trifluoromethylating reagents5 with appropriate substrates, the
well-practiced strategies utilize a nucleophilic trifluoromethylat-
ing reagent, like (trifluoromethyl)trimethylsilane (CF3SiMe3)
and trifluoromethylated hemiaminals.6
After synthesizing the hemiaminal 2, acid-mediated cycliza-
tion of 2 to the trifluoromethylated heterocycle 3a through
formation of the trifluoromethylated acyliminium ion 2′ was
investigated (Table 1 and Scheme 3).8 Reaction of hemiaminal
2 with Lewis acids, such as BF3·OEt2 and TiCl4, known to
generate iminium ions from hemiaminals,7 in chlorinated
solvents at room temperature did not afford the expected
cyclized product 3a; instead, decomposition of the starting
material was observed (Table 1, entries 1 and 2). Similar results
were obtained with Brønsted acids, such as trifluoroacetic acid
(TFA) or triflic acid (TfOH) (Table 1, entries 3 and 4). To our
delight, treatment of hemiaminal 2 with methanesulfonic acid
(MsOH) in dichloromethane (DCM) at room temperature
Trifluoromethylated hemiaminals possess unique reactivity
under different conditions. Thus, under basic conditions,
trifluoromethylated hemiaminals produce nucleophilic “CF3 ”;
−
in contrast, the trifluoromethylated iminium ions, efficient
trifluoromethylated synthons, are generated under acidic
conditions. The latter phenomenon was utilized in the synthesis
of various N-based trifluoromethylated building blocks.7
However, the generation of related trifluoromethylated
acyliminium ions8 from hemiaminals derived from imides and
their application to the synthesis of trifluoromethylated
heterocycles and building blocks, which are precursors for the
synthesis of trifluoromethylated natural product analogues of
therapeutic importance, are yet to be studied (Scheme 1).
Among the currently marketed drugs, ∼40% are of natural
product origin or inspired.9 The tetrahydro-β-carboline and the
tetrahydroisoquinoline families of alkaloids are classes of
Received: February 12, 2014
Published: April 3, 2014
© 2014 American Chemical Society
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Note
Scheme 1. Generation and Functionalization of Trifluoromethylated Acyliminium Ion from Imides
Scheme 2. Synthesis of Trifluoromethylated Hemiaminal 2
from Imide 1a
Scheme 3. One-Pot Cascade Trifluoromethylation/
Cyclization of Imide 1a
a
Table 1. Optimization of Acid-Mediated Cyclization of 2
b
entry
acid (X equiv)
solvent temp (°C) time (h) yield (%)
c
1
2
BF3·OEt2 (1.5)
TiCl4 (2)
DCM
DCE
DCM
DCM
DCM
DCM
DCE
DCE
DCE
DCE
rt
20
24
24
24
12
12
24
12
10
12
0
0
0
0
its subsequent cyclization, we envisaged a one-pot synthesis of
trifluoromethylated cyclized product 3a from imide 1a (Scheme
3).
d
rt
3
TFA (2)
rt
4
TfOH (1.5)
MsOH (2)
MsOH (5)
MsOH (5)
MsOH (2)
MsOH (2)
MsOH (5)
rt
The reaction of imide 1a and CF3SiMe3 with a catalytic
amount of TBAF in THF for 1 h at 0 °C to rt afforded the
mixture of hemiaminal 2 and its TMS ether. Evaporation of the
THF and treatment of the residue with MsOH in DCE for 3 h
at 55 °C afforded the expected cyclized product 3a in 80%
yield, through the formation of trifluoromethylated acyliminium
ion 2′ (Scheme 3). The formation of product was further
confirmed by X-ray analysis (see the Supporting Informa-
tion).13
5
rt
23
6
rt
35
7
rt
34
8
55
70
55
42
9
55
e
10
84 (80)
a
Reaction conditions: 2 (0.13 mmol), acid (X equiv), solvent (1 mL),
temp, time. Isolated yield. Starting material decomposed. Starting
b
c
d
e
material was recovered. 3 h.
After obtaining the optimized conditions for one-pot
trifluoromethylation/cyclization, the scope and limitations of
the substituted tryptamines and imides were investigated.14 As
shown in Scheme 4, various substituted tryptamine derivatives
were tolerated under the optimized conditions. The halo-
genated tryptamine derivatives, which are amenable for the
subsequent functionalization, also underwent smooth reaction
to furnish the corresponding cyclized products 3b−3d in
excellent yield. Interestingly, the electron-withdrawing trifluor-
omethyl substituted tryptamine derivative also gave the cyclized
product 3e. Reaction of a mixture of 4- and 6-methyl
tryptamine derivatives in a ∼1:1 ratio under the optimized
conditions afforded the trifluoromethylated heterocycles 3f/f′
in good yield in the ratio of ∼1:2, due to the possible steric
effect present in the 4-methyltryptamine derivative. Changing
the phthalimide to succinimide also gave the corresponding
afforded the cyclized product 3a in 23% yield (Table 1, entry
5).
Subsequently, increasing the equivalents of MsOH to 5 equiv
showed only a slight improvement in the yield (Table 1, entry
6). However, increasing the temperature to 55 °C in 1,2-
dichloroethane (DCE) gave the product in 42% yield (Table 1,
entry 8). A further increase in the temperature did not show a
profound effect on the outcome of the reaction (Table 1, entry
9). Next, keeping the temperature at 55 °C, followed by
increasing the equivalents of acid (5 equiv), furnished the
cyclized product in 84% yield. Interestingly, an 80% yield of
product 3a was obtained after 3 h under the same reaction
conditions (Table 1, entry 10). After identifying the suitable
conditions for the synthesis of hemiaminal 2 from imide 1a and
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Note
Scheme 4. One-Pot Cascade Trifluoromethylation/
Scheme 5. One-Pot Cascade Trifluoromethylation/
Cyclization of Imides 4 Derived from Arylethylamines
Cyclization of Imides 1 Derived from Tryptamine
a
Derivatives
a
84% of corresponding detosylated compound 3a was isolated.
product 3g in 75% yield. Next, substitution on the nitrogen was
also examined. A N-methyltryptamine derivative gave the
product 3h in good yield, but N-tosyltryptamine derivative did
not afford the expected cyclized product 3i; instead, the
detosylated product 3a was observed in 84% yield.
Scheme 6. One-Pot Cascade Trifluoromethylation/
Next, the synthesis of various trifluoromethylated tetrahy-
droisoquinolines was envisioned by replacing the indole with a
simple aromatic system. After synthesizing the suitable starting
material 4a derived from phenethylamine and phthalic
anhydride,15 the one-pot trifluoromethylation/cyclization was
investigated employing the optimized conditions used for the
synthesis of 3. Delightfully, the one-pot trifluoromethylation/
cyclization of 4a under the optimized conditions furnished the
expected trifluoromethylated tetrahydroisoquinoline 5a in 76%
yield (Scheme 5). Substitution at ortho, meta, and para
positions are tolerated and afforded the cyclized products
5b−5d in good yield. 3,4-Dimethoxy- and 3,4-methylenedioxy
substituted trifluoromethylated tetrahydroisoquinolines (5e and
5f, respectively) were also achieved employing the optimized
conditions. Halogenated phenethylamines were tolerated under
the trifluoromethylation/cyclization conditions and furnished
the cyclized products 5g−5j in good yields. Subsequently,
replacement of phthalimide with other imides was also studied.
Treatment of the succinimide derivative with CF3SiMe3,
followed by MsOH, afforded the cyclized product 5k, a
potential precursor for the synthesis of the trifluoromethylated
analogue of crispine A, in 86% yield. Similarly, the imides
derived from glutaric acid and cyclohexyl-1,2-dicarboxylic acid
also underwent smooth reaction and afforded the cyclized
products 5l and 5m in 78% and 83% yield, respectively; the
latter gave a mixture of diastereomers in a 1.6:1 ratio.
Cyclization of Imide 4n
After exploring the intramolecular version of the trifluor-
omethylative functionalization, intermolecular versions were
also investigated. N-Phenylphthalimide 6 was chosen as the
substrate for the intermolecular reaction. Reaction of 6 with
CF3SiMe3 gave 7 in 93% yield (Scheme 7). Methanesulfonic
acid mediated generation of the acyliminium ion from the
hemiaminal 7, followed by trapping with N-methylindole 8,
furnished the product 9 in 62% yield. Similarly, trapping with
1,3-dimethoxybenzene 10 afforded the product 11 in 92% yield.
This demonstrates that the present methodology can also be
applied to the synthesis of a wide range of α-trifluoromethy-
lated nitrogen-based building blocks and heterocycles.
After the successful demonstration of a one-pot trifluor-
omethylation/cyclization of an imide, the utility of the
synthesized trifluoromethylated heterocycles was also revealed
by the synthesis of trifluoromethylated natural products and
analogues such as harmicine16 and crispine A,8a therapeutically
important tetrahydro-β-carboline and tetrahydroisoquinoline
natural products, respectively. Reduction of lactam 3g with
lithium aluminum hydride (LiAlH4) in THF furnished the
trifluoromethylated harmicine 12 in excellent yield (Scheme 8).
Similarly, synthesis of the trifluoromethylated analogue of
crispine A 13 was also achieved from the lactam 5k in 80%
yield. Furthermore, reduction of lactam 5e gave the
Next, phthalimide derivative 4n derived from (S)-phenyl-
alaninol was synthesized and subjected to the present
conditions. Trifluoromethylation/cyclization of imide 4n with
CF3SiMe3 and MsOH afforded the cyclized product 5n in 72%
yield (Scheme 6). Although the absolute configuration of the
1
newly formed stereocenter was not determined, the H NMR
spectra showed the presence of a single diastereomer.
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Note
as eluent to afford hemiaminal 2 (0.5 g, 81% yield) as a pale yellow
solid. mp: 174−176 °C; IR (KBr): 3417, 3257, 2933, 1695, 1401, 1181
Scheme 7. Intermolecular Functionalization of a
Trifluoromethylated Acyliminium Ion
1
cm−1; H NMR (400 MHz, DMSO-d6): δ 10.88 (brs, 1H), 8.35 (brs,
1H) 7.82 (d, 1H, J = 7.2 Hz), 7.77 (d, 2H, J = 4.2 Hz), 7.74−7.69 (m,
1H), 7.64 (d, 1H, J = 7.7 Hz), 7.37 (d, 1H, J = 8.0 Hz), 7.25 (d, 1H, J
= 2.1 Hz), 7.10 (td, 1H, J = 7.0, 1.0 Hz), 7.30 (td, 1H, J = 7.9, 1.0 Hz),
3.74 (td, 1H, J = 13.7, 5.3 Hz), 3.63 (td, 1H, J = 12.7, 4.9 Hz), 3.17
(td, 1H, J = 13.4, 4.9 Hz), 2.98 (td, 1H, J = 12.1, 5.2 Hz); 13C{1H}
NMR (125 MHz, DMSO-d6): δ 167.1, 140.8, 136.3, 133.0, 131.4,
131.3, 127.0, 123.9, 123.6 (q, J = 286.1 Hz), 122.9, 122.8, 121.0, 118.4,
118.0, 111.5, 111.0, 87.1 (q, J = 31.0 Hz), 40.2, 24.2; 19F NMR (470
MHz, CDCl3/C6F6): δ −78.76 (s, 3F); HRMS: calcd. for C19H15-
N2F3O2 + Na: 383.0983; found: 383.0992.
Acid-Mediated Cyclization of Hemiaminal 2. Hemiaminal 2
(0.17 mmol) was dissolved in 1 mL of solvent (see Table 1 and the
Supporting Information); then the acid was added (equivalents as
specified in Table 1 and the Supporting Information) under a N2
atmosphere. The reaction tube was sealed with a stopper and stirred at
the temperature mentioned in Table 1 and the Supporting
Information. After completion, the reaction mixture was cooled to
room temperature, quenched with aqueous NaHCO3, and extracted
with CH2Cl2 (3 × 2 mL). The organic layer was dried (Na2SO4) and
evaporated under reduced pressure, and the crude product was
purified by column chromatography using ethyl acetate:hexane (1:4)
as eluent to afford the trifluoromethylated heterocycle 3.
General Procedure for One-Pot Cascade Trifluoromethyla-
tion/Cyclization of Imides 1. Tryptamine-derived phthalimide 1
(0.17−0.20 mmol) was dissolved in dry THF (2 mL) in a reaction
tube under a N2 atmosphere and cooled to 0 °C. CF3SiMe3 (0.26−0.3
mmol) was added, followed by a 1 M solution of TBAF in THF (1−2
mol %, ∼34 μL), and the reaction mixture was warmed to rt and
stirred for 1 h. After 1 h, the THF was evaporated under reduced
pressure and DCE (1 mL) and methanesulfonic acid (0.85−1.0 mmol)
were added. The reaction tube was sealed with a stopper and kept at
55 °C using a preheated oil bath. After completion of the reaction, it
was cooled to rt, quenched with aqueous NaHCO3, and extracted with
CH2Cl2 (3 × 4 mL). The organic layer was dried (Na2SO4) and
evaporated under reduced pressure, and the crude product was
purified by column chromatography using ethyl acetate/hexane as
eluent to afford trifluoromethylated heterocycles 3.
Scheme 8. Synthesis of Trifluoromethylated Analogues of
Natural Product and Related Compounds
3a: 47 mg, 80% yield; pale yellow solid; mp: 258−260 °C; IR
1
(KBr): 3410, 2927, 1693, 1561, 1165 cm−1; H NMR (400 MHz,
CDCl3): δ 8.53 (brs, 1H), 7.92 (d, 2H, J = 6.5 Hz), 7.66 (t, 1H, J = 7.6
Hz), 7.58 (t, 1H, J = 7.6 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.41 (d, 1H, J =
8.0 Hz), 7.29−7.21 (m, 1H), 7.13 (t, 1H, J = 7.4 Hz), 4.94−4.82 (m,
1H), 3.70−3.54 (m, 1H), 3.02−2.87 (m, 2H); 13C{1H} NMR (125
MHz, DMSO-d6): δ 168.0, 139.9, 136.8, 133.2, 130.8, 125.1, 124.5 (q,
J = 286.5 Hz), 124.0, 123.8, 123.0, 119.3, 118.9, 111.7, 110.9, 64.8 (q, J
= 30.9 Hz), 36.8, 20.5; 19F NMR (470 MHz, CDCl3/C6F6): δ −77.06
(s, 3F); HRMS: calcd. for C19H13N2F3O + Na: 365.0878; found:
365.0865.
trifluoromethylated tetrahydroisoquinoline natural product
analogue 14 in good yield.
In conclusion, we developed the new one-pot cascade
trifluoromethylation/cyclization strategy for the synthesis of α-
trifluoromethylated amine derivatives. Efficacy of the trifluor-
omethylated hemiaminal to form an acyliminium ion and its
application is the key feature of the present strategy.
Interestingly, the developed strategy is applicable to both
intra- and intermolecular transformations, where a number of
indole and arene derivatives were employed as trapping agents
to lead to the synthesis of trifluoromethylated heterocycles and
building blocks. Furthermore, the synthesis of trifluoromethy-
lated analogues of harmicine and crispine A was described to
demonstrate the utility of the present method.
3b: 64 mg, 89% yield; white solid; mp: 208−210 °C; IR (KBr):
1
3410, 2972, 1697, 1561, 1169 cm−1; H NMR (400 MHz, CDCl3): δ
8.56 (brs, 1H), 7.92 (t, 2H, J = 7.7 Hz), 7.69 (td, 1H, J = 7.6, 1.2 Hz),
7.64 (d, 1H, J = 1.8 Hz), 7.61 (td, 1H, J = 7.5, 1.0 Hz), 7.33 (dd, 1H, J
= 8.6, 1.7 Hz), 7.28 (d, 1H, J = 8.6 Hz), 4.93−4.82 (m, 1H), 3.67−
3.54 (m, 1H), 2.95−2.82 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 169.2, 140.2, 135.5, 133.0, 131.9, 130.7, 127.8, 126.8, 126.0,
125.0, 124.7 (q, J = 288.0 Hz), 123.0, 122.0, 113.6, 113.0, 112.7, 65.4
(q, J = 31.6 Hz), 37.3, 21.1; 19F NMR (470 MHz, CDCl3/C6F6): δ
−76.94 (s, 3F); HRMS: calcd. for C19H12N2F3OBr + H: 421.0163;
found: 421.0145.
EXPERIMENTAL SECTION
■
Synthesis of Trifluoromethylated Hemiaminal 2 from Imide
1a. Phthalimide derived from tryptamine (1a)14 (0.5 g, 1.7 mmol) was
dissolved in dry THF (10 mL) in a reaction tube under a N2
atmosphere and cooled to 0 °C. (Trifluoromethyl)trimethyl silane
(CF3TMS, 0.3 g, 2.6 mmol) was added, followed by a 1 M solution of
TBAF in THF (1−2 mol %, 20−34 μL), and the reaction mixture was
warmed to room temperature and stirred for 1 h. The THF was
evaporated under reduced pressure, and the crude product was
purified by column chromatography using ethyl acetate:hexane (1:3)
3c: 49 mg, 77% yield; white solid; mp: 268−270 °C; IR (KBr):
1
3350, 2920, 1693, 1459, 1158 cm−1; H NMR (400 MHz, CDCl3): δ
8.61 (brs, 1H), 7.92 (d, 2H, J = 7.8 Hz), 7.68 (t, 1H, J = 7.7 Hz), 7.60
(t, 1H, J = 7.7 Hz), 7.44−7.38 (m, 2H), 7.10 (dd, 1H, J = 8.4, 1.7 Hz),
4.93−4.82 (m, 1H), 3.68−3.53 (m, 1H), 2.97−2.85 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 169.3, 140.2, 137.2, 133.0, 132.0, 130.7,
129.7, 125.4, 125.0, 124.8, 124.7 (q, J = 286.0 Hz), 123.0, 121.3, 120.2,
113.3, 111.6, 65.3 (q, J = 31.1 Hz), 37.3, 21.1; 19F NMR (470 MHz,
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Note
CDCl3/C6F6): δ −77.01 (s, 3F); HRMS: calcd. for C19H12N2F3OCl +
H: 377.0669; found: 377.0685.
CDCl3/C6F6): δ −76.13 (s, 3F); HRMS: calcd. for C17H12NOF3 + H:
304.0949; found: 304.0936.
5b: 47 mg, 73% yield; orange liquid; IR (Neat): 2928, 1706, 1614,
1466, 1382, 1176 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J
= 7.7 Hz), 7.91−7.81 (m, 2H), 7.65 (td, 1H, J = 7.6, 1.0 Hz), 7.55 (t,
1H, J = 7.5 Hz), 7.13 (d, 1H, J = 7.9 Hz), 7.01 (s, 1H), 4.72 (dd, 1H, J
= 13.5, 6.8 Hz), 3.56 (td, 1H, J = 12.6, 4.6 Hz), 3.09−2.97 (m, 1H),
2.84 (dd, 1H, J = 16.6, 4.4 Hz), 2.31 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 168.5, 142.2, 139.1, 135.3, 132.6, 132.1, 130.7, 130.1,
127.8, 127.3, 126.4, 125.1 (q, J = 287.0 Hz), 124.3, 124.2, 66.7 (q, J =
30.0 Hz), 36.1, 28.9, 21.0; 19F NMR (470 MHz, CDCl3/C6F6): δ
−76.29 (s, 3F); HRMS: calcd. for C18H14NOF3 + H: 318.1106; found:
318.1097.
3d: 57 mg, 82% yield; white solid; mp: 282−284 °C; IR (KBr):
3420, 2972, 1700, 1609, 1470, 1190 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.59 (brs, 1H), 7.98 (d, 1H, J = 7.7 Hz), 7.94 (d, 1H, J =
7.7 Hz), 7.72 (t, 1H, J = 7.5 Hz), 7.62 (t, 1H, J = 7.5 Hz), 7.39 (s, 1H),
7.23 (s, 1H), 4.88 (dd, 1H, J = 14.0, 5.5 Hz), 3.68−3.51 (m, 1H),
2.99−2.78 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.1,
139.8, 133.2, 132.7, 131.9, 130.8, 127.9, 127,0, 126.4, 125.1, 124.6 (q, J
= 285.0 Hz), 123.4, 123.1, 117.7, 117.4, 114.0, 65.1, 37.1, 21.2; 19F
NMR (470 MHz, CDCl3/C6F6): δ −76.93 (s, 3F); HRMS: calcd. for
C19H11N2F3OCl2 + H: 411.0279; found: 411.0299.
3e: 51 mg, 73% yield; brown solid; mp: 166−168 °C; IR (KBr):
3413, 2924, 1693, 1620, 1466, 1176 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.58 (br s, 1H), 7.94 (d, 1H, J = 7.5 Hz), 7.88 (d, 1H, J =
7.5 Hz), 7.78−7.66 (m, 2H), 7.62 (t, 1H, J = 7.5 Hz), 7.51 (d, 1H, J =
7.5 Hz), 7.22 (t, 1H, J = 7.5 Hz), 4.90 (d, 1H, J = 13.6 Hz), 3.71−3.54
(m, 1H), 3.04−2.86 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ
169.1, 140.0, 133.2, 132.4, 131.9, 130.8, 127.7, 126.2, 125.1, 124.9 (q, J
= 273 Hz), 124.7 (q, J = 289 Hz), 123.4, 122.8, 121.4 (q, J = 4.4 Hz),
120.1, 114.0 (t, J = 33.3 Hz), 113.6, 65.3 (q, J = 31.1 Hz), 37.2, 21.0;
19F NMR (470 MHz, CDCl3/C6F6): δ −63.31 (s, 3F), −77.01 (s, 3F);
HRMS: calcd. for C20H13N2F6O + H: 411.0932; found: 411.0944.
3g: 38 mg, 75% yield; white solid; mp: 198−200 °C; IR (KBr):
3413, 2969, 1686, 1620, 1564, 1179 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.16 (brs, 1H), 7.51 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J =
8.0 Hz), 7.24 (t, 1H, J = 7.7 Hz), 7.14 (t, 1H, J = 7.7 Hz), 4.64−4.52
(m, 1H), 3.37−3.24 (m, 1H), 2.91−2.81 (m, 2H), 2.80−2.69 (m, 2H),
2.55−2.41 (m, 1H), 2.28−2.13 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 174.1, 136.8, 127.4, 126.3 (q, J = 287 Hz), 126.2, 123.6,
120.4, 119.1, 111.7, 111.5, 63.7 (q, J = 28.7), 36.6, 30.4, 28.0, 20.7; 19F
NMR (470 MHz, CDCl3/C6F6): δ −79.52 (s, 3F); HRMS: calcd. for
C15H13N2OF3 + H: 295.1058; found: 295.1067.
3h: 49 mg, 81% yield; yellow solid; mp: 128−130 °C; IR (KBr):
2924, 1717, 1620, 1466, 1368, 1260, 1169 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.14 (d, 1H, J = 7.6 Hz), 7.95 (d, 1H, J = 7.6 Hz), 7.68 (t,
1H, J = 7.8 Hz), 7.61 (t, 1H, J = 7.8 Hz), 7.25 (d, 1H, J = 7.8 Hz),
7.37−7.26 (m, 2H), 7.14 (t, 1H, J = 7.5 Hz), 4.89 (dd, 1H, J = 13.4,
6.5 Hz), 4.11 (s, 3H), 3.62 (dt, 1H, J = 12.5, 5.0 Hz), 3.17−3.02 (m,
1H), 2.98 (dd, 1H, J = 15.8, 5.2 Hz); 13C{1H} NMR (100 MHz,
CDCl3): δ 168.3, 139.7, 138.6, 132.8, 132.3, 130.5, 126.7, 125.6, 125.2,
125.0, 124.8 (q, J = 285 Hz), 123.8, 120.1, 119.2, 114.3, 109.7, 68.1,
36.5, 33.0, 21.5; 19F NMR (470 MHz, CDCl3/C6F6): δ −77.61 (s,
3F); HRMS: calcd. for C20H15N2F3O + Na: 379.1034; found:
379.1016.
General Procedure for One-Pot Cascade Trifluoromethyla-
tion/Cyclization of Imides 4. Phenethylamine-derived phthalimide
4 (0.17−0.20 mmol) was dissolved in dry THF (2 mL) in a reaction
tube under a N2 atmosphere and cooled to 0 °C. CF3SiMe3 (0.26−0.3
mmol) was added, followed by a 1 M solution of TBAF in THF (1−2
mol %, ∼34 μL), and the reaction mixture was warmed to rt and
stirred for 1 h. After 1 h, the THF was evaporated under reduced
pressure and DCE (1 mL) and methanesulfonic acid (0.85−1.0 mmol)
were added. The reaction tube was sealed with a stopper and kept at
55 °C using an oil bath. After completion of the reaction, it was cooled
to rt, quenched with aqueous NaHCO3, and extracted with CH2Cl2 (3
× 4 mL). The organic layer was dried (Na2SO4) and evaporated under
reduced pressure, and the crude product was purified by column
chromatography using ethyl acetate/hexane as eluent to afford
trifluoromethylated heterocycles 5.
5a: 46 mg, 76% yield; white solid; mp: 110−112 °C; IR (KBr):
2927, 2848, 1711, 1385, 1253, 1161 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.03 (d, 1H, J = 7.7 Hz), 7.97 (d, 1H, J = 6.0 Hz), 7.89 (d,
1H, J = 7.7 Hz), 7.66 (t, 1H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5 Hz),
7.36−7.27 (m, 2H), 7.24−7.17 (m, 1H), 4.73 (dd, 1H, J = 13.6, 7.0
Hz), 3.59 (dt, 1H, J = 4.6, 13.0 Hz), 3.13−3.01 (m, 1H), 2.89 (dd, 1H,
J = 16.6, 4.6 Hz); 13C{1H} NMR (125 MHz, CDCl3): δ 168.5, 141.9,
135.6, 132.7, 132.2, 130.3, 130.2, 129.4, 129.1, 127.5, 126.9, 125.0 (q, J
= 286.7 Hz), 124.4, 124.3, 66.8, 36.1, 28.9; 19F NMR (470 MHz,
5c: 48 mg, 75% yield; white solid; mp: 134−136 °C; IR (KBr):
1
2963, 1713, 1643,1254, 1157 cm−1; H NMR (500 MHz, CDCl3): δ
8.04 (d, 1H, J = 7.7 Hz), 7.88 (d, 1H, J = 7.7 Hz), 7.75 (s, 1H), 7.67
(td, 1H, J = 7.6, 1.0 Hz), 7.57 (td, 1H, J = 7.6, 1.0 Hz), 7.13 (dd, 1H, J
= 7.8, 1.0 Hz), 7.08 (d, 1H, J = 7.8 Hz), 4.71 (dd, 1H, J = 13.6, 6.8
Hz), 3.56 (td, 1H, J = 12.5, 4.6 Hz), 3.06−2.96 (m, 1H), 2.84 (dd, 1H,
J = 16.4, 4.4 Hz), 2.39 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
168.5, 142.0, 136.5, 132.6, 132.4, 132.2, 130.1, 130.0, 129.1, 127.8,
125.1 (q, J = 286.5 Hz), 124.4, 124.3, 66.8 (q, J = 29.5 Hz), 36.2, 28.5,
20.4; 19F NMR (470 MHz, CDCl3/C6F6): δ −76.05 (s, 3F); HRMS:
calcd. for C18H14NOF3 + Na: 340.0925; found: 340.0937.
5d: 44 mg, 70% yield; white solid; mp: 146−148 °C; IR (KBr):
2924, 2861, 1717, 1508, 1263, 1169 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.03 (d, 1H, J = 7.7 Hz), 7.90−7.83 (m, 2H), 7.64 (td, 1H,
J = 7.6, 1.0 Hz), 7.56 (td, 1H, J = 7.6, 1.0 Hz), 7.24 (d, 1H, J = 8.0
Hz), 7.20 (t, 1H, J = 7.1 Hz), 4.86−4.74 (m, 1H), 3.65−3.51 (m, 1H),
2.93−2.78 (m, 2H), 2.24 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3):
δ 168.3, 142.1, 137.7, 134.0, 132.6, 132.2, 130.6, 130.1, 129.3, 126.3,
125.2, 125.1 (q, J = 288.0 Hz), 124.4, 124.3, 66.8 (q, J = 30.0 Hz),
35.5, 26.2, 20.1; 19F NMR (470 MHz, CDCl3/C6F6): δ −76.02 (s,
3F); HRMS: calcd. for C18H14NOF3 + H: 318.1106; found: 318.1093.
5e: 61 mg, 84% yield; white solid; IR (Neat): 2930, 1710, 1518,
1260, 1168, 1151 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.97 (d, 1H, J
= 7.8 Hz), 7.88 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.6 Hz), 7.57 (t,
1H, J = 7.6 Hz), 7.39 (s, 1H), 6.63 (s, 1H), 4.73 (dd, 1H, J = 13.6, 7.0
Hz), 3.95 (s, 3H), 3.84 (s, 3H), 3.54 (dt, 1H, J = 12.7, 4.6 Hz), 3.06−
2.94 (m, 1H), 2.78 (dd, 1H, J = 16.3, 4.6 Hz); 13C{1H} NMR (125
MHz, CDCl3): δ 168.5, 149.7, 147.9, 142.2, 132.6, 132.2, 130.1, 128.5,
125.1 (q, J = 287 Hz), 124.5, 123.8, 120.8, 112.1, 110.4, 66.3 (q, J =
28.9 Hz), 56.3, 55.9, 36.2, 28.5; 19F NMR (470 MHz, CDCl3/C6F6): δ
−76.19 (s, 3F); HRMS: calcd. for C19H16NO3F3 + H: 364.1161;
found: 364.1149.
5f: 62 mg, 88% yield; pale yellow semisolid; IR (Neat): 2924, 2854,
1
1792, 1710, 1487, 1177 cm−1; H NMR (400 MHz, CDCl3): δ 7.96
(d, 1H, J = 7.7 Hz), 7.88 (d, 1H, J = 7.7 Hz), 7.65 (td, 1H, J = 7.7, 1.0
Hz), 7.57 (t, 1H, J = 7.5 Hz), 7.40 (brs, 1H), 6.61 (s, 1H), 5.98 (d, 1H,
J = 1.2 Hz), 5.93 (d, 1H, J = 1.2 Hz), 4.68 (dd, 1H, J = 13.5, 6.7 Hz),
3.52 (dt, 1H, J = 13.0, 4.5 Hz), 3.04−2.91 (m, 1H), 2.76 (dd, 1H, J =
16.2, 4.1 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 168.5, 148.3,
146.9, 142.0, 132.7, 132.1, 130.2, 129.7, 125.0 (q, J = 286.7 Hz), 124.4,
124.1, 121.9, 109.5, 107.3, 101.6, 66.8 (q, J = 30.1 Hz), 36.0, 29.0; 19F
NMR (470 MHz, CDCl3/C6F6): δ −76.23 (s, 3F); HRMS: calcd. for
C18H12NO3F3 + Na: 370.0667; found: 370.0677.
5h: 43 mg, 64% yield; colorless solid; mp: 124−126 °C; IR (KBr):
2962, 1714, 1603, 1473, 1295, 1162 cm−1; 1H NMR (500 MHz,
CDCl3): δ 8.03−7.94 (m, 2H), 7.91−7.86 (m, 1H), 7.66 (td, 1H, J =
7.6, 1.2 Hz), 7.63−7.56 (m, 2H), 7.20 (t, 1H, J = 8.0 Hz), 4.78 (dd,
1H, J = 13.9, 7.4 Hz), 3.61−3.52 (m, 1H), 3.09 (dd, 1H, J = 17.5, 4.7
Hz), 2.96−2.85 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.1,
141.5, 135.3, 133.5, 132.8, 132.1, 131.8, 130.4, 127.8, 126.7, 126.4,
124.9 (q, J = 285.7 Hz), 124.5, 124.3, 66.5, 35.4, 29.9; 19F NMR (470
MHz, CDCl3/C6F6): δ −75.75 (s, 3F); HRMS: calcd. for C17H11-
NOBrF3 + H: 382.0054; found: 382.0065.
5g: 52 mg, 68% yield; colorless solid; mp: 146−148 °C; IR (KBr):
1
2942, 1716, 1519, 1263, 1164 cm−1; H NMR (400 MHz, CDCl3): δ
8.00 (d, 1H, J = 7.7 Hz), 7.95−7.86 (m, 2H), 7.66 (td, 1H, J = 7.6, 1.0
Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.41 (d, 1H, J = 7.8 Hz), 7.28 (t, 1H, J =
4158
dx.doi.org/10.1021/jo5002998 | J. Org. Chem. 2014, 79, 4154−4160

The Journal of Organic Chemistry
Note
7.8 Hz), 4.79 (dd, 1H, J = 13.8, 7.4 Hz), 3.56 (td, 1H, J = 12.9, 5.0
Hz), 3.12 (dd, 1H, J = 17.3, 4.8 Hz), 2.9−2.84 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 168.4, 141.8, 135.9, 134.2, 133.1, 132.4,
131.9, 130.7, 130.4, 127.7, 126.3, 125.2 (q, J = 285.6 Hz), 124.8, 124.6,
66.8 (q, J = 29.8 Hz), 35.5, 27.2; 19F NMR (470 MHz, CDCl3/C6F6):
δ −76.29 (s, 3F); HRMS: calcd. for C17H11NOClF3 + H: 338.0560;
found: 338.0560.
5j: 63 mg, 73% yield; colorless solid; mp: 158−160 °C; IR (KBr):
2924, 2861, 1717, 1633, 1508, 1169 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.01 (d, 1H, J = 7.7 Hz), 7.93 (s, 1H), 7.90 (d, 1H, J = 7.8
Hz), 7.70 (td, 1H, J = 7.6, 1.0 Hz), 7.60 (t, 1H, J = 7.6 Hz), 7.29 (dd,
1H, J = 8.2, 2.0 Hz), 7.14 (d, 1H, J = 8.2 Hz), 4.73 (dd, 1H, J = 13.5,
6.7 Hz), 3.55 (td, 1H, J = 13.1, 4.4 Hz), 3.07−2.93 (m, 1H), 2.87 (dd,
1H, J = 16.3, 4.2 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 168.3,
141.3, 134.0, 132.9, 132.6, 132.1, 131.4, 131.0, 130.4, 129.4, 127.5,
124.8 (q, J = 286.5 Hz), 124.5, 124.1, 66.5, 35.8, 28.3; 19F NMR (470
MHz, CDCl3/C6F6): δ −76.07 (s, 3F); HRMS: calcd. for C17H11-
NOClF3 + H: 338.0560; found: 338.0560.
5i: 47 mg, 69% yield; colorless solid; mp: 126−128 °C; IR (KBr):
2926, 2858, 1705, 1385, 1254, 1172 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.04−7.96 (m, 2H), 7.89 (t, 2H, J = 6.9 Hz), 7.66 (td, 1H, J
= 7.6, 1.0 Hz), 7.58 (t, 1H, J = 7.6 Hz), 7.04 (t, 1H, J = 7.8 Hz), 4.75
(dd, 1H, J = 13.9, 7.0 Hz), 3.62−3.51 (m, 1H), 3.05−2.82 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 168.1, 141.4, 140.3, 138.0,
132.8, 132.1, 131.5, 130.4, 128.2, 127.6, 124.9 (q, J = 288.3 Hz), 124.5,
124.3, 103.4, 66.6 (q, J = 30.1 Hz), 36.0, 35.7; 19F NMR (470 MHz,
CDCl3/C6F6): δ −75.67 (s, 3F); HRMS: calcd. for C17H11NOIF3 + H:
429.9916; found: 429.9934.
N-methylindole 8 (1 equiv). mp: 170−172 °C; IR (KBr): 2858, 1713,
1
1486, 1377, 1353, 1166, 712, cm−1; H NMR (400 MHz, CDCl3): δ
8.01 (d, 1H, J = 7.4 Hz), 7.55 (td, 1H, J = 7.4, 0.9 Hz), 7.46 (td, 1H, J
= 7.5, 1.2 Hz), 7.29 (d, 1H, J = 7.7 Hz), 7.24 (d, 1H, J = 8.2 Hz),
7.17−7.07 (m, 5H), 6.79−6.74 (m, 1H), 6.72−6.67 (m, 2H), 6.32 (d,
1H, J = 8.1 Hz), 3.71 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
168.6, 142.7, 137.1, 135.7, 133.0, 132.0, 130.3, 130.1 (q, J = 3.3 Hz),
129.1, 128.8, 128.2, 125.7, 125.0 (q, J = 287.1 Hz), 124.8, 124.4, 122.6,
120.5, 119.7, 109.8, 104.9, 71.6 (q, J = 29.0 Hz), 33.3; 19F NMR (470
MHz, CDCl3/C6F6): δ −72.68 (s, 3F); HRMS: calcd. for C24H17-
N2OF3 + H: 407.1371; found: 407.1386.
Synthesis of 11. Employing the acid-mediated cyclization
procedure, 11 was isolated (65 mg, 92% yield) from 7 (1 equiv)
and 1,3-dimethoxybenzene (1 equiv). mp: 182−184 °C; IR (KBr):
2941, 2842, 1702, 1607, 1360, 1164, 1039, cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.92−7.87 (m, 1H), 7.49−7.43 (m, 2H), 7.43−7.37 (m,
1H), 7.38−7.15 (m, 4H), 6.90−6.85 (m, 2H), 6.41 (dd, 1H, J = 8.8,
2.5 Hz), 6.33 (d, 1H, J = 2.5 Hz), 3.74 (s, 3H), 3.21 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 169.4, 161.8, 159.4, 144.0, 136.3, 133.0,
132.3, 130.2 (q, J = 3.7 Hz), 129.3, 128.9, 128.5, 127.9, 124.8 (q, J =
286.7 Hz), 123.7, 122.7, 113.7, 104.3, 100.3, 73.1 (q, J = 27.3 Hz),
55.5, 54.4; 19F NMR (470 MHz, CDCl3/C6F6): δ −80.18 (s, 3F);
HRMS: calcd. for C23H18NO3F3 + H: 414.1317; found: 414.1329.
General Procedure for the Synthesis of Trifluoromethylated
Harmicine, Cripsine, and Related Compounds. Lactam 3 or 5
(0.13 mmol) was dissolved in dry THF (2 mL) under a N2
atmosphere and cooled to 0 °C. Next, LiAlH4 (15 mg, 0.40 mmol)
was added portionwise; after the addition, the reaction mixture was
heated at reflux for 4 h. The reaction mixture was cooled to rt,
quenched with aqueous Na2SO4, stirred for 15 min at room
temperature, and then filtered. The solid residue was washed with
ethyl acetate, filtered, and dried (Na2SO4). Evaporation of the solvent
under reduced pressure and purification of the crude product by
column chromatography using ethyl acetate/hexane as eluent afforded
the reduced products in good yield.
5k: 54 mg, 86% yield; pale yellow liquid; IR (Neat): 2919,
1
2851,1705, 1517, 1265, 1158 cm−1; H NMR (400 MHz, CDCl3): δ
6.74 (brs, 1H), 6.61 (s, 1H), 4.38 (dd, 1H, J = 13.5, 7.0 Hz), 3.87 (s,
3H), 3.86 (s, 3H), 3.34−3.22 (m, 1H), 2.97−2.64 (m, 4H), 2.51−2.39
(m, 1H), 2.22−2.08 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
174.0, 149.4, 148.1, 127.0, 126.8 (q, J = 288.4 Hz), 124.0, 111.5, 109.0,
64.9 (q, J = 27.9 Hz), 56.2, 55.9, 35.3, 30.4, 29.4, 27.2; 19F NMR (470
MHz, CDCl3/C6F6): δ −78.25 (s, 3F); HRMS: calcd. for C15H16-
NO3F3 + H: 316.1161; found: 316.1153.
5l: 51 mg, 78% yield; colorless liquid; IR (Neat): 2919, 2851,1705,
1517, 1265, 1158 cm−1; 1H NMR (500 MHz, CDCl3): δ 6.82 (s, 1H),
6.61 (s, 1H), 5.06 (dd, 1H, J = 13.2, 5.2 Hz), 3.87 (s, 3H), 3.86 (s,
3H), 3.00 (td, 1H, J = 13.0, 3.3 Hz), 2.90−2.72 (m, 2H), 2.70−2.59
(m, 2H), 2.51−2.39 (m, 1H), 2.11−1.97 (m, 1H), 1.93−1.74 (m, 2H);
13C{1H} NMR (125 MHz, CDCl3): δ 170.3, 149.0, 147.8, 128.1, 126.4
(q, J = 290.0 Hz), 124.6, 111.7, 108.9, 63.6 (q, J = 26.0 Hz), 56.2, 55.9,
36.3, 33.2, 31.2, 28.2, 16.6; 19F NMR (470 MHz, CDCl3/C6F6): δ
−70.60 (s, 3F); HRMS: calcd. for C16H18NO3F3 + H: 330.1317;
found: 330.1327.
5n: 48 mg, 72% yield; colorless liquid; IR (Neat): 1739, 1460, 1174
cm−1; 1H NMR (500 MHz, CDCl3): δ 7.82−7.77 (m, 1H), 7.72−7.68
(m, 1H), 7.65 (td, 1H, J = 7.4, 1.3 Hz), 7.61 (td, 1H, J = 7.4, 1.3 Hz),
7.36−7.26 (m, 4H), 4.51−4.43 (m, 1H), 4.43−4.37 (m, 1H), 4.36−
4.30 (m, 1H), 3.37 (dd, 1H, J = 13.6, 6.2 Hz), 2.94 (dd, 1H, J = 13.6,
9.0 Hz); 13C{1H} NMR (125 MHz, CDCl3): δ 174.1, 140.4, 137.1,
133.9, 133.6 132.6, 131.9, 129.3, 129.0, 128.8, 127.0, 125.0, 124.1,
123.9 (q, J = 288.2 Hz), 97.7 (q, J = 33.5 Hz), 77.4, 58.4, 40.5; 19F
NMR (470 MHz, CDCl3/C6F6): δ −80.54 (s, 3F); HRMS: calcd. for
C18H14NO2F3 + Na: 356.0874; found: 356.0891.
12: 30 mg, 82% yield; pale yellow liquid; IR (Neat): 3418, 2939,
1
1458, 1323, 1295, 1179 cm−1; H NMR (500 MHz, CDCl3): δ 7.93
(brs, 1H), 7.55 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.22 (td,
1H, J = 8.0, 1.0 Hz), 7.13 (td, 1H, J = 8.0, 1.0 Hz), 3.40−3.29 (m, 2H),
3.15−3.09 (m, 1H), 3.00−2.90 (m, 2H), 2.63−2.53 (m, 2H), 2.03−
1.91 (m, 2H), 1.81−1.74 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 136.5, 130.4, 127.2 (q, J = 284.6 Hz), 126.5, 122.9, 119.8,
118.8, 111.6, 111.2, 63.8 (q, J = 28.3 Hz), 51.3, 44.2, 35.3, 23.8, 16.0;
19F NMR (470 MHz, CDCl3/C6F6): δ −79.50 (s, 3F); HRMS: calcd.
for C15H15N2F3 + H: 281.1266; found: 281.1254.
13: 32 mg, 80% yield; pale yellow liquid; IR (Neat): 2925, 2852,
1
1514, 1259, 1138, 1106 cm−1; H NMR (500 MHz, CDCl3): δ 6.80
(brs, 1H), 6.60 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.39 (ddd, 1H, J =
12.6, 8.4, 4.5 Hz), 3.28−2.21 (m, 1H), 2.94−2.76 (m, 4H), 2.73−2.61
(m, 2H), 2.10−1.95 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ
148.5, 147.6, 129.5, 127.6 (q, J = 285.7 Hz), 126.4, 111.4, 110.9, 66.9
(q, J = 26.3 Hz), 56.2, 55.9, 54.0, 46.3, 36.9, 25.1, 23.7 ; 19F NMR (470
MHz, CDCl3/C6F6): δ −79.02 (s, 3F); HRMS: calcd. for C15H18-
NO2F3 + H: 302.1368; found: 302.1381.
14: 35 mg, 75% yield; orange solid; mp: 124−126 °C; IR (KBr):
2933, 2361, 1518, 1464, 1261, 1165 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.75−7.67 (m, 1H), 7.34−7.25 (m, 3H), 7.25−7.18 (m,
1H), 6.58 (s, 1H), 4.40 (d, 1H, J = 13.1 Hz), 4.27 (d, 1H, J = 13.1 Hz),
3.89 (s, 3H), 3.83 (s, 3H), 3.64−3.51 (m, 1H), 3.32−3.21 (m, 1H),
3.09 (ddd, 1H, J = 16.4, 11.9, 5.5 Hz), 2.48 (ddd, 1H, J = 16.4, 4.0, 1.7
Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 148.8, 147.4, 140.1, 139.8,
131.0, 129.0, 128.6, 127.4, 126.7 (q, J = 286.2 Hz), 123.9, 122.9, 111.8,
111.2, 71.3 (q, J = 28.4 Hz), 56.2, 55.8, 43.6, 22.5; 19F NMR (470
MHz, CDCl3/C6F6): δ −75.82 (s, 3F); HRMS: calcd. for C19H18-
NO2F3 + H: 350.1368; found: 350.1363.
Synthesis of 7. The product 7 was isolated (245 mg, 93% yield) as
a white solid from 6 employing the procedure developed for the
synthesis of 2. mp: 166−168 °C; IR (KBr): 3252, 2862, 1703, 1498,
1
1377, 1156, 763, 703 cm−1; H NMR (400 MHz, CDCl3): δ 7.68 (d,
1H, J = 7.4 Hz), 7.60 (td, 1H, J = 0.7, 7.48 Hz), 7.46 (t, 1H, J = 7.1
Hz), 7.37 (d, 1H, J = 7.4 Hz), 7.34−7.27 (m, 3H), 7.20−7.14 (m, 2H),
4.95 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.6, 140.2,
134.0, 133.4, 131.4, 131.2, 129.3, 128.7, 128.6, 124.1, 122.7 (q, J =
287.5 Hz), 89.2 (q, J = 32.7 Hz); 19F NMR (470 MHz, CDCl3/C6F6):
δ −80.30 (s, 3F); HRMS: calcd. for C15H10NO2F3 + H: 294.0742;
found: 294.0728.
Synthesis of 9. Employing the acid-mediated cyclization
procedure, 9 was isolated (43 mg, 62% yield) from 7 (1 equiv) and
4159
dx.doi.org/10.1021/jo5002998 | J. Org. Chem. 2014, 79, 4154−4160

The Journal of Organic Chemistry
Note
Dandepally, S. R.; Oldham, C.; Williams, A.; Ibeanu, G. Cell. Mol.
Neurobiol. 2010, 31, 145. (c) Yamaguchi, T.; Saneyoshi, M. Nucleic
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ASSOCIATED CONTENT
■
S
* Supporting Information
Supporting Information containing 1H and 13C NMR spectra of
all the new compounds and crystallographic data of compound
3a is provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) CCDC 978788 (3a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via http://www.
ccdc.cam.ac.uk/data_request/cif.
(14) For synthesis of starting materials 1, see: (a) Raheem, I. T.;
Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007,
129, 13404. (b) Mangalaraj, S.; Ramanathan, C. R. RSC Adv. 2012, 2,
12665.
(15) For synthesis of starting materials 4, see: (a) Selvakumar, J.;
Makriyannis, A.; Ramanathan, C. R. Org. Biomol. Chem. 2010, 8, 4056.
(b) Braun, U.; Shulgin, A. T.; Braun, G.; Sargent, T., III J. Med. Chem.
1977, 20, 1543.
AUTHOR INFORMATION
Corresponding Author
*E-mail: anbarasansp@iitm.ac.in. Fax: +91-44-22574202.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Council of Scientific & Industrial Research
(CSIR), the Board of Research in Nuclear Sciences (BRNS)
through DAE Young Scientist Award, and the Indian Institute
of Technology Madras (IITM) through New Faculty Scheme
for funding this work. V.K.P. thanks CSIR for a fellowship. We
thank Mr. Ramkumar for single-crystal analysis support.
(16) Chakraborty, I.; Jana, S. Synthesis 2013, 3325.
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