Reactions of carbazole with dimethyl alkanedisulfonates

Article abstract of DOI:10.1134/S1070363217070337

Reaction of carbazole with dimethyl alkanedisulfonates in the presence of sodium hydride resulted in the formation of three main products: 2-(9H-carbazol-9-yl)alkylmethanesulfonates, 1,2-di-(9H-carbazol-9-yl)alkanes, and 9-alkenyl-9H-carbazoles.

Full text of DOI:10.1134/S1070363217070337

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 7, pp. 1641–1644. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, T.A. Epishina, T.V. Goreva, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 7,
pp. 1214–1217.
LETTERS
TO THE EDITOR
Reactions of Carbazole with Dimethyl Alkanedisulfonates
V. B. Sokolov, A. Yu. Aksinenko*, T. A. Epishina, and T. V. Goreva
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, 142432 Russia
*
e-mail: alaks@ipac.ac.ru
Received April 19, 2017
Abstract―Reaction of carbazole with dimethyl alkanedisulfonates in the presence of sodium hydride resulted
in the formation of three main products: 2-(9H-carbazol-9-yl)alkylmethanesulfonates, 1,2-di-(9H-carbazol-9-
yl)alkanes, and 9-alkenyl-9H-carbazoles.
Keywords: carbazole, dimethyl alkanedisulfonates, alkylation, conjugates, olefination, sodium hydride
DOI: 10.1134/S1070363217070337
N-Substituted derivatives of carbazoles are a pro-
mising class of biologically active compounds, among
which substances have been found showing anti-
microbial [1], antifungal [2], antitumor [3], antioxidant
isolated as the main substance (Scheme 1). Thus, when
carrying out the reaction in THF with an equimolar
ratio of the reagents, carbazoles 3a and 3b formed
predominantly. When using a double excess of car-
bazole 1 and sodium hydride, carbazoles 4a and 4b
were obtained in high yields. The reaction of equi-
molar amounts of carbazole 1 and dimethyl alkane-
disulfonates 2a and 2b at boiling in the presence of a
twofold excess of sodium hydride led to the formation
of N-vinyl- and N-allylcarbazoles 5a and 5b.
[4], anti-inflammatory [5], and neuroprotective pro-
perties [6–12 ]. In this regard, the development of
preparative methods for the functionalization of
carbazoles at the NH function seems to be one of the
promising and relevant areas of medical chemistry.
A prerequisite for this study was the data on the
synthesis of three types of N-substituted carbazoles: 2-
Compounds 3–5 were crystalline substances whose
composition and structure were confirmed by ele-
mental analysis and NMR spectroscopy methods. In
(
9H-carbazol-9-yl)ethylmethanesulfonate obtained by
alkylation of carbazole with 2-iodoethanol and sub-
sequent mesylation of the resulting 2-(9H-carbazol-9-
yl)ethanol [13], 1,2-di-(9H-carbazol-9-yl)ethane syn-
thesized by alkylating carbazole with dibromoethane
1
the H NMR spectra of compounds 3–5 there were
characteristic signals of aromatic protons of the
carbazole ring in the range of 7.1–8.1 ppm. The spectra
of compounds 3a and 3b contained the signals of
methanesulfonic group at 2.4–2.7 ppm. The signals of
the ethylene spacer in the spectra of compounds 4a and
4b were observed in the range of 2.43–4.92 ppm. In
the NMR spectra of compounds 5a and 5b there were
the signals of vinyl protons at 4.8–7.2 ppm.
[14], and 9-vinyl-9H-carbazole obtained by alkylating
carbazole with vinyl bromide [15 ]. The aim of the
present work was to study the synthetic possibilities of
the reaction of available carbazole and dimethyl
alkanedisulfonates to obtain N-substituted carbazole
derivatives of the three above-mentioned structural
types, including promising synthetic blocks.
The structure of compound 3a was also confirmed
by chemical transformations. Thus, carbazole 3a reacted
with 3,5-dimethylaminoadamantane 6 in isopropanol
under reflux to produce carbazole and amino-ada-
We found that carbazole 1 in the presence of
sodium hydride reacted with dimethyl alkanedi-
sulfonates 2a and 2b to form three reaction products:
1
mantane conjugate 7 (Scheme 2). The H NMR spec-
2
-(9H-carbazol-9-yl)ethylmethanesulfonates 3a and
trum contained a superposition of the signals of
carbazole and adamantane fragments.
3
9
b, 1,2-di-(9H-carbazol-9-yl)alkanes 4a and 4b,
-alkenyl-9H-carbazoles 5a and 5b; depending on the
stoichiometric ratio of the reagents and the reaction
conditions, each of three products can be obtained and
In conclusion, an original approach towards the
synthesis of N-substituted carbazoles of three structural
1
641

1
642
SOKOLOV et al.
Scheme 1.
MeO SO
(CH )
OSO Me
2
2
2 n
NaH
2a, 2b
N
(CH2)n
OSO Me
2
3a, 3b
0
.5 MeO SO
(CH )
OSO Me
2
2 n
2
N
NaH
2a, 2b
(CH2)n
N
H
N
1
4a, 4b
MeO SO
(CH )
OSO Me
2
2 n
2
2
NaH
2a, 2b
N
(CH2)n
5a, 5b
n = 0 (а), 1 (b).
Scheme 2.
NH2
2
N
6
N
NH
OSO Me
2
3
a
7
types by reacting carbazole and dimethyl alkanedisulfo-
nates in the presence of sodium hydride was developed.
2-(9H-Carbazol-9-yl)ethylmethanesulfonate (3a).
A mixture of 1.1 mmol of NaH and 1 mmol of
carbazole 1 in 20 mL of THF was stirred for 1 h, then
0.1 mmol of dimethyl sulfonate 2a was added, and the
mixture was stirred for 2 h at 20°C. After the reaction
completed the mixture was poured into 100 mL of
Dimethyl alkanedisulfonates 2a and 2b were
prepared according to the procedure described in [16];
carbazole 1 was purchased from Aldrich.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 7 2017

REACTIONS OF CARBAZOLE WITH DIMETHYL ALKANEDISULFONATES
1643
water, the precipitate formed was filtered off and re-
C 86.79; H 5.91; N 7.06. C H N. Calculated, %: C
1
4
11
crystallized from ethanol. Yield 0.24 g (83%), mp 162–
87.01; H 5.74; N 7.25.
1
1
64°C. Н NMR spectrum (CDCl ), δ, ppm: 2.48 s
3
8
-(Propen-2-yl)-9Н-carbazole (5b) was prepared
(
(
3H, CH SO O), 4.46–4.72 m (4Н, СН ), 7.14–7.32 m
1
3
2
2
similarly. Yield 0.14 g (68%), mp 71–72°С. Н NMR
spectrum (CDCl ), δ, ppm (J, Hz): 4.83 d.t (2H, CH ,
2Н, CH ), 7.36–7.52 m (4Н, CH ), 8.07 d (2Н,
Ar
Ar
3
3
2
CH , J = 7.6 Гц). Found, %: C 62.41; H 5.45; N
3
4
3
Ar
HH
JHH = 4.9, J = 1.5), 4.98 d.d.t (1H, CH =, J
=
HH
2
HH
4
.71. C H NO S. Calculated, %: C 62.26; H 5.23; N 4.84.
2
4
15
15
3
1
7.1, J = 1.5, J = 1.5), 5.11 d.d.t (1H, CH =,
HH HH 2
3
2
4
2-(9Н-Carbazol-9-yl)propylmethanesulfonate (3b)
JHH = 10.4, JHH = JHH = 1.5), 5.93 d.d.d (1H, CH=,
3
3
3
was prepared similarly. Yield 0.24 g (79%), mp 107–
JHH = 17.1, J = 10.4, J = 4.9), 7.10–7.27 m (2Н,
HH
HH
1
1
2
3
5
09°С. Н NMR spectrum (CDCl ), δ, ppm (J, Hz):
CH ), 7.28–7.52 m (4Н, CH ), 8.08 d (2Н, CH ,
3
Ar Ar Ar
3
3
.19 q (2Н, СН , J = 5.8), 2.67 s (3H, CH SO O),
.27 t (2H, СН , J = 5.8), 3.46 t (2H, СН , J
.8), 7.44–7.64 m (4Н, CH ), 7.71–7.87 m (4Н,
JHH = 7.6). Found, %: C 86.74; H 6.48; N 6.53.
2
HH
3
2
3
3
=
C H N. Calculated, %: C 86.92; H 6.32; N 6.76.
15 13
2
HH
2
HH
Ar
N-[2-(9Н-Carbazol-9-yl)ethyl]-3,5-dimethylada-
mantyl-1-amine (7). A solution of 0.01 mmol of ethyl
methanesulfonate 3a and 0.02 mmol of 3,5-dimethyl-
adamantane-1-amine 6 in 10 mL of isopropanol was
CH ). Found, %: C 63.17; H 5.86; N 4.43. C H NO S.
Ar
16 17
3
Calculated, %: C 63.34; H 5.65; N 4.62.
1
,2-Di-(9Н-carbazol-9-yl)ethane (4a). To a solu-
tion of 1 mmol of carbazole 1 in 20 mL of THF was
added 1.1 mmol of NaH. The reaction mixture was
stirred for 1 h, then 0.05 mmol of dimethyl sulfonate
refluxed for 8 h, then poured into 100 mL of H O. The
2
precipitate formed was filtered off and recrystallized
1
from ethanol. Yield 0.31 g (83%), mp 178–180°С. Н
2a was added and stirring was continued for 2 h at 20°С.
NMR spectrum (CDCl ), δ, ppm (J, Hz): 0.77 s (6Н,
3
After the reaction completed the mixture was poured
СН ), 0.96–1.09 m (2Н, СН ), 1.09–1.26 m (9Н, СН +
3
2
2
into 100 mL of H O. The precipitate formed was
NH), 1.30–1.42 m (2Н, СН ), 1.99–2.12 m (1Н, СН),
2
2
3
3
filtered off and recrystallized from ethanol. Yield 0.27 g
3.01 t (2H, СН , J = 7.0), 4.36 t (2H, СН , J
=
2
HH
2
HH
1
(
75%), mp 300°С. Н NMR spectrum (CDCl ), δ, ppm
7.0), 7.16–7.31 m (2Н, CH ), 7.40–7.53 m (4Н, CH ),
3
Ar Ar
3
(
7
J, Hz): 4.92 s (4Н, СН ), 7.01–7.14 m (4Н, CH ),
8.08 d (2Н, CH , J = 7.6). Found, %: C 83.61; H
Ar HH
2
Ar
3
.18–7.27 m (8Н, CH ), 8.01 d (4Н, CH , J
=
8.84; N 7.33. C H N . Calculated, %: C 83.82; H 8.66;
Ar
Ar
HH
26 32 2
7
.8). Found, %: C 86.86; H 5.75; N 7.98. C H N .
N 7.52.
26
20
2
Calculated, %: C 86.65; H 5.59; N 7.77.
1
H NMR spectra were recorded on a Bruker DPX
1
,2-Di-(9Н-carbazol-9-yl)propane (4b) was pre-
200 spectrometer, reference SiMe . Melting points
4
pared similarly. Yield 0.27 g (72%), mp 181–183°С.
were determined in a glass capillary.
1
Н NMR spectrum (CDCl ), δ, ppm (J, Hz): 2.43 q
3
3
3
(
2Н, СН , J = 7.3), 4.32 t (4H, СН , J = 7.3),
ACKNOWLEDGMENTS
2 HH 2 HH
3
7
8
6
5
.10–7.30 m (8Н, CH ) 7.39 t (4Н, CH , J = 7.6),
Ar Ar HH
.10 d (4H, CH , J = 7.6). Found, %: C 86.38; H
.11; N 7.31. C H N . Calculated, %: C 86.60; H
3
This work was supported by the Russian Science
Foundation (project no. 14-23-00160).
Ar
HH
2
7
22
2
.92; N 7.48.
REFERENCES
8
-Vinyl-9Н-carbazole (5a). To a solution of
1
2
1
mmol of carbazole 1 in 20 mL of THF was added
.1 mmol of NaH. The reaction mixture was stirred for
h, then 0.1 mmol of dimethyl sulfonate 2a was added
1
2
3
. Yaqub, G., Hannan, A., Akbar, E., Usman, M., Hamid, A.,
Sadiq, Z., and Iqbal, M., J. Chem., 2013, ID 818739. doi
10.1155/2013/ 818739
and the mixture was stirred for 8 h at 60°С. After the
reaction completed the mixture was poured into
1
. Thevissen, K., Marchand, A., Chaltin, P., Meert, E.M.K.,
and Cammue, B.P.A., Curr. Med. Chem., 2009, vol. 16,
no. 17, p. 2205. doi 10.2174/092986709788612701
00 mL of H O. The formed precipitate was filtered
2
off and recrystallized from ethanol. Yield 0.14 g
. Giraud, F., Bourhis, M., Nauton, L., Théry, V.,
Herfindal, L., Døskeland, S.O., Anizon, F., and Moreau, P.,
Bioorg. Chem., 2014, vol. 57, p. 108. doi 10.1016/
j.bioorg.2014.09.004
1
(
73%), mp 101–103°С. Н NMR spectrum (CDCl ), δ,
3
3
ppm (J, Hz): 5.16 d (1Н, СН =, J = 9.0), 5.55 d
2
HH
3
(
1Н, СН =, J = 16.2), 7.18–7.38 m (3Н, CH
+
Ar
2
HH
Ar
3
СН=), 7.48 t (2Н, CH , J = 7.6), 7.67 d (2Н, CH ,
4. Guillonneau, C., Pierre, A., Charton, Y., Guilbard, N.,
Berthier, L.K., Leonce, S., Michael, A., Bisagni, E., and
Ar
HH
3
3
JHH = 8.2), 8.08 d (2Н, CH , J = 7.6). Found, %:
Ar
HH
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 7 2017

1
644
SOKOLOV et al.
10. RF Patent 2608737, 2016.
Atassi, G., J. Med. Chem., 1999, vol. 42, no. 12,
p. 2191. doi 10.1021/jm981093m
1
1. Sokolov, V.B., Aksinenko, A.Yu., Goreva, T.V., Epishi-
na, T.A., Grigor’ev, V.V., Gabrel’yan, A.V., Vinogra-
dova, D.V., Dubova, L.G., Shevtsov, P.N., Shevtso-
va, E.F., and Bachurin, S.O., Russ. Chem. Bull., 2016,
vol. 65, no. 5, p. 1346. doi 10.1007/s11172-016-1460-6
5
. Bandgar, B.P., Adsul, L.K., Chavan, H.V., Jalde, S.S.,
Shringare, S.N., Shaikh, R., Meshram, R.J., Gacche, R.N.,
and Masand, V., Bioorg. Med. Chem. Lett., 2012,
vol. 22, no. 18, p. 5839. doi 10.1016/j.bmcl.2012.07.080
6
7
8
. Zhu, D., Chen, M., Li, M., Luo, B., Zhao, Y., Huang, P.,
Xue, F., Rapposelli, S., Pi, R., and Wen, S., Eur. J. Med.
Chem., 2013, vol. 68, p. 81. doi 10.1016/
j.ejmech.2013.07.029
. Yoon, H.J., Kong, S.-Y., Park, M.-H., Cho, Y., Kim, S.-E.,
Shin, J.-Y., Jung, S., Lee, J., Farhanullah, Kim, H.-J.,
and Lee, J., Bioorg. Med. Chem., 2013, vol. 21, no. 22,
p. 7165. doi 10.1016/j.bmc.2013.08.066
. MacMillan, K. S., Naidoo, J., Liang, J., Melito, L.,
Williams, N.S., Morlock, L., Huntington, P.J., Estill, S.J.,
Longgood, J., Becker, G.L., McKnight, S.L., Pieper, A.A.,
De Brabander, J.K., and Ready, J.M., J. Am. Chem.
Soc., 2011, vol. 133, no. 5, p. 1428. doi 10.1021/
ja108211m
1
2. Sokolov, V.B., Aksinenko, A.Yu., Goreva, T.V., Epishi-
na, T.A., Dubova, L.G., Dubrovskaya, E.S., Klochkov, S.G.,
Shevtsov, P.N., Shevtsova, E.F., and Bachurin, S.O.,
Russ. Chem. Bull., 2016, vol. 65, no. 9, p. 2306. doi
1
0.1007/s11172-016-1582-x
1
1
3. Kim, Y.J., Ryu, J.-H., Cheon, Y.J., Lim, H.J., and Jeon, R.,
Bioorg. Med. Chem. Lett., 2007, vol. 17, no. 12,
p. 3317. doi 10.1016/j.bmcl.2007.04.005
4. Narkhede, H.P., Int. J. Chem. Sci., 2014, vol. 12, no. 2,
p. 551.
15. Lebedev, A.Y., Izmer, V.V., Kazyul’kin, D.N., Belets-
kaya, I.P., and Voskoboynikov, A.Z., Org. Lett., 2002,
vol. 4, no. 4, p. 623. doi 10.1021/ol0172370
9
. Bachurin, S.O., Shevtzova, E.P., Lermontova, N.N.,
Serkova, T.P., and Ramsay, R.R., Neuro Toxicol., 1996,
vol. 17, nos. 3–4, p. 897.
16. Poldy, J., Peakal, R., and Barrow, R.A., Tetrahedron.
Lett., 2008, vol. 49, no. 15, p. 2446. doi 10.1016/
j.tetlet.2008.02.037
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 7 2017