Unexpected formation of fluorine-containing tetrahydrocarbazole during the reaction of indole, paraformaldehyde, and fluorine-containing β-ketoesters

Article abstract of DOI:10.1016/j.tet.2011.06.007

A surprise and mild method to prepare fluorine-containing indole derivatives through a one-pot three-component condensation reaction sequence is presented. To our surprise, during the reaction of preparation of fluorine-containing indole derivatives, unex

Full text of DOI:10.1016/j.tet.2011.06.007

Tetrahedron 67 (2011) 6334e6339
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Unexpected formation of fluorine-containing tetrahydrocarbazole during the
reaction of indole, paraformaldehyde, and fluorine-containing b-ketoesters
,
,
b,
Wan Pang a b, Yong Xin b, Shi-fa Zhu c, Huan-feng Jiang c , Shi-zheng Zhu
*
*
a School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 120 Caobao Lu, Shanghai 200235, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
c School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 May 2011
Received in revised form 31 May 2011
Accepted 3 June 2011
Available online 13 June 2011
A surprise and mild method to prepare fluorine-containing indole derivatives through a one-pot three-
component condensation reaction sequence is presented. To our surprise, during the reaction of preparation
of fluorine-containing indole derivatives, unexpected formation of fluorine-containing tetrahydrocarbazole
was found. Moreover, this method has been demonstrated in the preparation of functionalized polycyclic
indole derivatives in a straightforward and atom-economical manner.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Paraformaldehyde
b-Ketoesters
Tetrahydrocarbazole
Fluorine-containing
1. Introduction
there are few reports about the synthesis of fluorine-containing
indole derivatives. Herein, we wish to report a new and efficient
Indoles represent a prominent class of heterocyclic compounds
with varied and often potent biological activities.1 Consequently,
there are a large number of methodologies for the synthesis and
structural modification of indole scaffold, including acid-induced
Fischer indole synthesis from arylhydrazine and ketones,2 transi-
tion metal-catalyzed intramolecular alkylation of alkenyl indoles
with unactivated olefins,3 and Lewis acid-promoted internal olefins
in FriedeleCrafts alkylation of indoles.4 Nevertheless, many of them
suffered from some of the following disadvantages, such as diffi-
culty in preparation of complex starting materials, harsh reaction
conditions, trouble with operation (excluding air and moisture),
expensive reagents (e.g., metal-complex catalysis) and long re-
action times, multistep operation, and low overall yields. Thus, in
spite of the diverse synthetic routes developed so far, there still
remains a need to develop a more concise, benign one-pot option
for the synthesis of indole derivatives, especially the fluorinated
ones. It is well documented that the introduction of fluorine-
containing group into organic molecules can make a profound
and unexpected influence on the physical and biological properties
of organic compounds.5 However, to the best of our knowledge,
method for the synthesis of fluorine-containing indole derivative
through a one-pot three-component condensation reaction se-
quence, which involves a Knoevenagel condensation of para-
formaldehyde and fluorine-containing
trapping with indoles via a Michael-type reaction. Depending on
different indoles and fluorine-containing -ketoesters, different
products can be formed through carbonecarbon double-bond
isomerization, -H elimination, or cyclization.
-Keto polyfluoroalkanesulfones have a moderately active
b-ketoesters, followed by
b
b
b
methylene moiety and have been widely used in the synthesis of
heterocycles and unsaturated sulfonyl esters. The Knoevenagel
condensation reaction between
b-keto aryl sulfones or a-per-
fluoroalkanesulfonyl acetate esters and aldehydes is well-known.6
Our laboratory has also studied some chemical transformations of
these compounds.7 For instance, in 2004, we reported an un-
expected formation of tetrasubstituted trans-2,3-dihydrofurans
under basic conditions when b-keto polyfluoroalkanesulfones are
reacted with aromatic aldehydes (Scheme 1).7a
* Corresponding authors. Fax: þ86 21 64166128; e-mail addresses: jianghf@
Scheme 1. The formation of tetrasubstituted trans-2,3-dihydrofurans.
scut.edu.cn (H.-feng Jiang), zhusz@mail.sioc.ac.cn (S.-zheng Zhu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.007

W. Pang et al. / Tetrahedron 67 (2011) 6334e6339
6335
Recently, we studied a one-pot three-component condensation
reaction under acidic conditions. As an example, reaction of 1,2-
derivative, 2-bromodifluromethy substituted tetrahydrocarbazole,
by X-ray crystallography (Scheme 3, Fig. 1).
dimethyl-1H-indole,
2-(trifluoromethane
sulfonyl)-1-
A possible mechanism is outlined in Scheme 4. Under acidic
condition, ethyl 4,4,4-trifluoromethyl-3-oxobutanoate first reacts
with paraformaldehyde through a Knoevenagel condensation, fol-
lowed by an in situ trapping of the vinyl product (I) with 1,2-
phenylethanone, and paraformaldehyde in the presence of ace-
tic acid in DCM at room temperature for 1 h led to isolation of 4
in 56% yield (Scheme 2).
Scheme 2. The reaction of 1,2-dimethyl-1H-indole, 2-(trifluoromethane sulfonyl)-1-phenylethanone and paraformaldehyde.
Scheme 3. The formation of tetrahydrocarbazole derivative.
dimethyl-1H-indole via a Michael-type reaction. The addition
product (II) is unstable, which undergoes double-bond isomeriza-
tion, b-H elimination, cyclization to form tetrahydrocarbazole as
the final product. To the best of our knowledge,2a,8 this might
represent the first report on the formation of tetrahydrocarbazole
derivatives via a one-pot three-component reaction sequence.
As can been seen in Table 1, the reaction did not proceed without
acid (Table 1, entry 4). Moreover, use of Lewis acids instead of
€
Bronsted acids resulted in the formation of different products
(Table 2).9,10
As mentioned above (Scheme 4), product 5 was formed due to
the presence of 2-methyl group on the indole motif. So we
employed 1b to react with ethyl 4,4,4-trifluoroacetoacetate 2b and
paraformaldehyde 3. However, under the same condition, an un-
expected six-membered ring product 8 formed instead of the
expected product 9 (Scheme 5). The structure of 8 was fully con-
firmed by spectroscopic method and single-crystal X-ray diffraction
analysis. Its molecular structure was showed in Fig. 2.
A possible mechanism for the formation of compound 8 is
proposed in Scheme 6. In the presence of acetic acid, the unstable
Michael-type addition indole intermediate (III) further reacted
with two formaldehyde molecules, followed by cyclization to give
the 1,3-dioxane product.
In summary, we have developed a novel and mild method to
prepare fluorine-containing indole derivatives through a one-pot
three-component condensation reaction sequence. Moreover, this
method has been demonstrated in the preparation of functional-
ized polycyclic indole derivatives in a straightforward and atom-
economical manner. Further studies to expand the scope of this
new methodology are underway in our laboratory.
Fig. 1. Molecular structure of 5c.
In order to examine the generality of this reaction, 2-(tri-
fluoromethanesulfonyl)-1-phenylethanone 2a was replaced by
ethyl 4,4,4-trifluoro-3-oxobutanoate 2b to react with 1,2-dimethyl-
1H-indole and paraformaldehyde under the same reaction condi-
tions. To our surprise, the structure of the product was not con-
sistent with what we expected. From the 1H NMR spectrum, the
single signal at 2.55 ppm of 2-methyl group of indole molecular
disappeared and a diagnostic single signal at ꢀ80.1 ppm was found
for the 19F NMR spectrum, which suggested that the tri-
fluoromethyl group was quite close to an electron-donating group.
Next, ethyl 4-bromo-4,4-difluoro-3-oxybutaneoate 2c was used to
repeat the reaction under the same conditions. The structure of the
isolated product was determined to be a fused polycyclic indole
2. Experimental procedure and spectral data
2.1. General
To
a
solution of paraformaldehyde (2.5 mmol), fluorine-
-ketoesters (0.5 mmol), and indole (0.5 mmol) in DCM
containing
b
ꢀ
(3.0 mL) were added acetic acid (50 mol %) and molecular sieves 4 A
(100 mg). The reaction mixture was stirred by magnetic stirrer at

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W. Pang et al. / Tetrahedron 67 (2011) 6334e6339
Scheme 4. The possible mechanism of formation of tetrahydrocarbazole derivative.
Table 1
Reaction results of 1a, 2bed, and 3
COR2
R1
O
O
OH
4 Å molecular sieves
AcOH, CH2Cl2, R.T.
(HCHO)n
+
CH3
+
R1
R2
N
N
CH3
5(b-d)
CH3
2(b-d)
1a
3
Entry
2
Acid
Product
Yielda (%)
R1
R2
1
2
3
4
CF3
OEt (2b)
OEt (2c)
tBu (2d)
OEt (2b)
AcOH
AcOH
AcOH
d
5b
5c
5d
d
50
63
47
d
CF2Br
C3F7
CF3
a
Isolate yield based on 2.
room temperature for about 2 h. The progress of reaction was moni-
tored by TLC. After satisfactoryconversion, the product was separated
from molecular sieves by filtration. The solvent was removed in
vacuum and the residue was purified on silica gel using ethyl aceta-
teehexane as eluent to afford the pure corresponding products.
J1¼3.6 Hz, J2¼14.1 Hz, 1H), 3.43 (s, 3H, CH3), 2.19 (s, 3H, CH3) ppm.
19F NMR (282 MHz, CDCl3)
CDCl3)
d
ꢀ74.7 (s, 3F) ppm. 13C NMR (100 MHz,
d
190.0, 136.9, 136.2, 135.0, 134.4, 128.6, 128.3, 126.5, 121.4,
1
119.9 (q, JCF¼329.7 Hz), 119.9, 116.7, 109.1, 102.9, 64.7, 29.5, 23.8,
10.0 ppm. MS (EI) m/z (%): 409 (Mþ, 20), 276 (72), 170 (18), 158
(C11H12Nþ, 100), 105 (93), 77 (36). Anal. Calcd for C20H18F3NO3S: C,
58.67, H, 4.43, N, 3.42. Found: C, 58.73, H, 4.58, N, 3.30.
2.1.1. 3-(1,2-Dimethyl-1H-indol-3-yl)-1-phenyl-2-(trifluoromethyl-
sulfonyl)propan-1-one (4).
2.1.2. (2S,3R)-Ethyl 2-hydroxy-9-methyl-2-(trifluoromethyl)-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylate (5b).
SO2CF3
COPh
CO2Et
CF3
OH
N
N
Colorless solid. Mp 105e107 ꢁC. IR (KBr)
1684, 1594, 1580, 1476, 1448, 1411, 1363, 1338, 1259, 1237, 1207,
1153, 1109, 934, 773, 741 cmꢀ1 1H NMR (300 MHz, CDCl3)
7.53e7.40 (m, 4H), 7.24e7.11 (m, 5H), 5.57 (dd, J1¼3.6 Hz,
J2¼11.1 Hz, 1H), 3.91 (dd, J1¼11.1 Hz, J2¼14.1 Hz, 1H), 3.72 (dd,
n
3435, 3046, 2941,
Colorless solid. Mp 136e138 ꢁC. IR (KBr)
1616,1474,1395,1383,1375,1345,1295,1277,1189,1163,1106,1062,
1022, 859, 743 cmꢀ1. 1H NMR (300 MHz, CDCl3)
1H), 7.25 (d, J¼7.8 Hz, 1H), 7.18 (t, J¼7.2 Hz, 1H), 7.09 (t, J¼6.9 Hz,
1H), 4.71 (s, 1H), 4.38e4.20 (m, 2H, CH2), 3.59 (s, 3H, CH3),
n 3465, 2975, 1747, 1709,
.
d
7.43 (d, J¼7.8 Hz,
d

W. Pang et al. / Tetrahedron 67 (2011) 6334e6339
6337
Table 2
Reaction results of 1a, 2b, and 3 in the presence of different Lewis acids
H3C
N
H3C
CH3
CH3
N
O
O
6
4 Å molecular sieves
Lewis acid, CH2Cl2, R.T.
(HCHO)n
CH3
CH3
F3C
OEt
OH
N
F3C
CO2Et
CH3
1a
2b
3
N
CH3
7
Entry
Acid
Product
Yielda (%)
1
2
3
4
5
6
7
BF3$OEt2
FeCl3
AlCl3
Cu(OTf)2
Yb4(OTf)3
ZnCl2
6
6
6
6
6
7
7
20
24
34
42
32
35/59b
41
Sm(OTf)3
a
Isolate yield based on 2.
Reaction without 3 and molecular sieves.
b
Scheme 5. The formation of unexpected six-membered ring product 8.
3.19e2.97 (m, 5H), 1.34 (t, J¼7.2 Hz, 3H, CH3) ppm. 19F NMR
(282 MHz, CDCl3)
d
ꢀ81.1 (s, 3F) ppm. 13C NMR (100 MHz, CDCl3)
1
d
175.4, 137.5, 130.0, 125.9 (q, JCF¼286.4 Hz), 125.9, 121.4, 119.3,
117.9, 108.9, 105.0, 74.4 (q, 2JCF¼27.0 Hz), 62.0, 42.3, 29.3, 28.7, 22.9,
14.0 ppm. MS (EI) m/z (%): 341(Mþ, 32), 323 (15), 296 (3), 272 (1),
268 (10), 250 (MþꢀMeꢀPh, 100), 230 (17), 198 (9), 181 (11), 168 (4),
157 (23). Anal. Calcd for C17H18F3NO3: C, 59.82, H, 5.32, N, 4.10.
Found: C, 59.75, H, 5.26, N, 4.05.
2.1.3. (2S,3R)-Ethyl 2-(bromodifluoromethyl)-2-hydroxy-9-methyl-
2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate (5c).
CO2Et
CF2Br
OH
N
Fig. 2. Molecular structure of 8.

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W. Pang et al. / Tetrahedron 67 (2011) 6334e6339
Scheme 6. The possible mechanism of formation of product 8.
Colorless solid. Mp 138e140 ꢁC. IR (KBr)
n
3463, 2976,1745,1708,
C
21H22F7NO2: C, 55.63, H, 4.89, N, 3.09. Found: C, 55.57, H, 4.90, N,
1618,1473,1449,1442,1375,1342,1299,1283,1265,1188,1167,1131,
1102, 1060, 1018, 1000, 976, 908, 860, 815, 741 cmꢀ1 1H NMR
(300 MHz, CDCl3)
2.94.
.
d
7.44 (d, J¼8.1 Hz, 1H), 7.27 (d, J¼8.1 Hz, 1H), 7.19
2.1.5. Bis(1,2-dimethyl-1H-indol-3-yl)methane (6).
(t, J¼8.4 Hz, 1H), 7.09 (t, J¼7.5 Hz, 1H), 4.90 (s, 1H), 4.38e3.63 (m,
2H, CH2), 3.63 (s, 3H, CH3), 3.23e3.03 (m, 5H), 1.35 (t, J¼7.2 Hz, 3H,
CH3) ppm. 19F NMR (282 MHz, CDCl3)
d
ꢀ58.5 (d, J¼18.0 Hz,
2F) ppm. 13C NMR (100 MHz, CDCl3):
d 175.5, 137.5, 130.3, 127.3 (t,
1JCF¼313.9 Hz), 125.8, 121.4, 119.3, 108.9, 105.0, 104.9, 79.2 (q,
2JCF¼20.5 Hz), 62.0, 42.8, 30.7, 29.4, 23.8, 14.1 ppm. MS (EI) m/z (%):
403 (Mþ, 35), 401 (34), 383 (2), 356 (4), 328 (9), 304 (96), 276 (36),
230 (MþꢀMeꢀPhꢀBr, 100), 210 (15), 198 (29), 182 (28), 157 (56).
Anal. Calcd for C17H18BrF2NO3: C, 50.76, H, 4.51, N, 3.48. Found: C,
50.76, H, 4.51, N, 3.38.
N
2.1.4. 1-((2S,3R)-2-Hydroxy-9-methyl-2-(1,1,1,2,2,3,3-heptafluoro)-
2,3,4,9-tetrahydro-1H-carbazole-3-yl)-2,2-dimethylpropan-1-one
(5d).
N
Colorless solid. 1H NMR (300 MHz, CDCl3)
d
7.42(d, J¼7.9 Hz, 2H),
O
7.22 (d, J¼7.8 Hz, 2H), 7.06 (t, J¼7.1 Hz, 2H), 6.96 (t, J¼7.0 Hz, 2H),
3.65 (s, 6H), 3.60 (s, 2H), 2.40 (s, 6H) ppm.
C3F7
OH
2.1.6. Ethyl 3-(1,2-dimethyl-1H-indol-3-yl)-4,4,4-trifluoro-3-hydroxo-
butanoate (7).
N
OH
F3C
CO2Et
Colorless solid. Mp 175e177 ꢁC. IR (KBr)
1476, 1345, 1262, 1223, 1187, 1107, 1068, 1016, 813, 750, 723 cmꢀ1
1H NMR (300 MHz, CDCl3)
n 3409, 2964, 1684,
.
N
d
7.43 (d, J¼7.8 Hz, 1H), 7.27 (d, J¼8.1 Hz,
1H), 7.19 (t, J¼8.4 Hz,1H), 7.09 (t, J¼7.5 Hz,1H), 5.77 (s,1H, OH), 3.62
(s, 3H, CH3), 3.19e2.88 (m, 5H), 1.27 (s, 9H) ppm. 19F NMR
Colorless solid. Mp 114e116 ꢁC. 1H NMR (300 MHz, CDCl3)
(282 MHz, CDCl3)
d
ꢀ80.8 (t, J¼9.9 Hz, 3F), ꢀ116.4 to ꢀ116.8 (m, 2F),
d
7.69(d, J¼7.8 Hz, 1H), 7.25 (d, J¼7.8 Hz, 1H), 7.15 (t, J¼7.2 Hz, 1H),
ꢀ122.9 to ꢀ123.0 (m, 2F) ppm. 13C NMR (100 MHz, CDCl3)
d
222.3,
7.07 (t, J¼6.9 Hz, 1H), 5.37 (s, 1H), 4.11e4.00 (m, 2H), 3.65 (s, 3H),
3.61 (d, J¼16.5 Hz, 1H), 3.25 (d, J¼16.5 Hz, 1H), 2.64 (s, 3H), 1.08 (t,
137.5, 129.9, 125.6, 121.4, 119.3, 117.7, 108.9, 105.2, 58.5, 45.9, 41.0,
29.3, 27.0, 25.6, 18.5 ppm. MS (ESI): 454 (Mþþ1). Anal. Calcd for
J¼7.2 Hz, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
ꢀ81.5 (s, 3F) ppm.

W. Pang et al. / Tetrahedron 67 (2011) 6334e6339
6339
Anal. Calcd for C16H18F3NO3: C, 58.35, H, 5.51, N, 4.25. Found: C,
References and notes
58.44, H, 5.33, N, 4.29.
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N
Colorless solid. Mp 117e119 ꢁC. IR (KBr)
n 3366, 2994, 2958, 2892,
ꢁ
ꢁ
1703, 1474, 1456, 1378, 1326, 1294, 1258, 1223, 1196, 1184, 1160, 1132,
1114, 1095, 1031, 1015, 970, 951, 746 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
7.85 (d, J¼7.8Hz,1H), 7.24 (t, J¼6. 6 Hz, 2H), 7.15(t, J¼6.9 Hz,1H), 6.99
(s, 1H), 5.38 (d, J¼5.4 Hz, 1H), 5.21 (s, 1H), 5.14 (d, J¼5.7 Hz, 1H),
4.34e4.12 (m, 3H), 3.97 (d, J¼11.7 Hz, 1H), 3.78 (s, 3H), 3.61 (dd,
J1¼15.0 Hz, J2¼6.0 Hz, 2H), 1.30 (t, 3H, J¼7.2 Hz) ppm. 19F NMR
(282 MHz, CDCl3)
d
d
ꢀ79.1 (s, 3F) ppm. 13C NMR (100 MHz, CDCl3)
172.1, 136.5, 129.4, 129.1, 122.2 (q, 1JCF¼286.6 Hz), 121.5, 119.7, 118.9,
108.9,108.1, 95.2(q, 2JCF¼32.0Hz), 87.3, 66.8, 62.8, 62.2, 51.7, 32.7, 23.1,
13.8 ppm. MS (EI) m/z (%): 387 (Mþ, 2), 184 (6), 144 (C10H10Nþ, 100),
131 (4), 128 (4), 115 (5), 77 (8), 42 (5). Anal. Calcd for C18H20F3NO5: C,
55.81, H, 5.20, N, 3.62. Found: C, 55.79, H, 5.27, N, 3.64.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (NNSFC) (Nos. 20625205 and 20972178) and Scientific Start-
up Project of Shanghai Institute of technology (No. YJ2011-51) for
financial support.
9. (a) Pradhan, P. K.; Dey, S.; Giri, V. S.; Jaisankar, P. Synthesis 2005, 11, 1779; (b)
McDougal, A.; Gupta, M. S.; Morrow, D.; Ramamoorthy, K.; Lee, J.-E.; Safe, S. H.
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Supplementary data
€ €
10. (a) Abid, M.; Torok, B. Tetrahedron: Asymmetry 2005, 16, 1547; (b) Abid, M.;
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.06.007.
€ €
Torok, B. Adv. Synth. Catal. 2005, 347, 1797.