N-Alkylation of 1H-indoles and 9H-carbazoles with alcohols

Article abstract of DOI:10.1016/S0040-4039(02)00217-4

A comparative study of N-alkylation of 1H-indole and 9H-carbazole derivatives with alcohol derivatives was performed using classic Mitsunobu reaction conditions, i.e. DEAD/PPh₃, azodicarboxamide derivatives such as TMAD in the presence of PBu

Full text of DOI:10.1016/S0040-4039(02)00217-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2187–2190
N-Alkylation of 1H-indoles and 9H-carbazoles with alcohols
Agnes Bombrun* and Giulio Casi
Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland
Received 18 December 2001; accepted 25 January 2002
Abstract—A comparative study of N-alkylation of 1H-indole and 9H-carbazole derivatives with alcohol derivatives was
performed using classic Mitsunobu reaction conditions, i.e. DEAD/PPh3, azodicarboxamide derivatives such as TMAD in the
presence of PBu3, or using phosphorane derivatives such as CMMP. © 2002 Elsevier Science Ltd. All rights reserved.
entries 1–3). This result might be explained by the weak
acidity of 5-bromo-1H-indole.6 The use of TMAD/
PBu3 enhanced the reactivity of 5-bromo-1H-indole
towards primary alcohols and compounds 1a and 1b
were obtained in a poor to moderate yield. In contrast
no reaction was observed with ( )-octan-2-ol under the
same reaction conditions. The use of CMMP improved
dramatically the reactivity of 5-bromo-1H-indole and
excellent yields were obtained independently of the use
of secondary or primary alcohols (see entries 1 and 3).
However, the reaction with ( )-glycidol was found to
be difficult to control: using strictly 1 equiv. of each
reagent gave the Mitsunobu product 1b in a 49% yield,
while an excess of reagents and/or high temperature
favour the formation of a by-product. This compound
was identified to be the elimination product of the
alcohol derivative which was formed from a second
attack of the indole onto the epoxide 1b.7 It was of
interest to note that the use of TMAD/PBu3 and
CMMP led to an easy work-up, preventing the tedious
separation of PPh3=(O).
The Mitsunobu reaction is a very versatile method for
the alkylation using aliphatic alcohols as electrophilic
partners under mild conditions.1 Yet applications of the
Mitsunobu reaction to achieve N-alkylation with alco-
hols have been rather limited in scope. One example of
N-alkylation using the Mitsunobu reaction was
reported with indole bearing electron withdrawing
groups.2 To our knowledge no Mitsunobu reaction was
reported using 9H-carbazole compounds. Our objective
was to identify and compare experimental conditions
that would allow direct N-alkylation of substituted
1H-indole and 9H-carbazole derivatives. The classic
Mitsunobu set of reagents diethyl azodicarboxylate/
triphenylphosphine (DEAD/PPh3) was compared to the
use of the N,N,N%,N%-tetramethylazodicarboxamide/
tributylphosphine (TMAD/PBu3) tandem and to the
use of cyanomethylenetrimethyl phosphorane (Me3P=
CH(CN), CMMP). Tsunoda and co-workers showed
the efficiency of TMAD/PBu3 over DEAD/PPh3 for the
preparation of secondary amines.3 Ito and co-workers
reported that phosphoranes such as CMMP were the
most powerful C-alkylating agents for the weak acidic
nucleophiles.4 And recently Zaragosa reported that
CMMP could promote N-alkylation of secondary
amines by alcohols.5
Encouraged by these results, the chemical reactivity of
carbazole derivatives was evaluated under the same set
of experiments. Using the classic Mitsunobu conditions
(DEAD/PPh3), 3,6-dibromo-9H-carbazole and 3-nitro-
9H-carbazole, which were reported to be slightly better
acids than indoles,8 exhibited varying reactivity with
benzyl alcohol, ( )-glycidol and ( )-octan-2-ol (entries
4–9). The reactivity with benzyl alcohol was signifi-
cantly increased using the TMAD/PBu3 tandem. As it
was observed for the 5-bromo-1H-indole derivative, the
reactivity of carbazole derivatives with the secondary
alcohol was sluggish when using the DEAD/PPh3 or
TMAD/PBu3 tandem (entries 8 and 9). The use of
CMMP could improve significantly the reactivity of
carbazoles with the secondary alcohol and afforded
Our initial experiments began by studying the Mit-
sunobu reaction of 5-bromo-1H-indole with primary
alcohols such as benzyl alcohol and ( )-glycidol, and
secondary alcohols such as ( )-octan-2-ol. The reaction
with ( )-glycidol was attractive due to possible further
functionalisation on the Mitsunobu adduct 1b. The
standard Mitsunobu conditions (DEAD/PPh3) failed to
give any expected condensation product (Table 1,
* Corresponding author. Tel.: +41 22 706 9823; fax: +41 22 794 6965;
e-mail: agnes.bombrun@serono.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00217-4

2188
A. Bombrun, G. Casi / Tetrahedron Letters 43 (2002) 2187–2190
Table 1. N-Alkylation of 1H-indole and 9H-carbazole derivatives with alcohols
a
DEAD (2 equiv.), PPh3 (2 equiv.), alcohol (2 equiv.) and amine in THF, 40°C, 15 h.9
b
TMAD (2 equiv.), PBu3 (2 equiv.), alcohol (2 equiv.) and amine in toluene, 40°C, 15 h.10
c
CMMP (2 equiv.), alcohol (2 equiv.) and amine (1 equiv.) in toluene, 110°C, 15 h.11
The temperature was maintained at 25°C and one equiv. of each reagent was used.
A THF solution of 3,6-dibromo-9H-carbazole and cyanomethyl-trimethyl-phosphonium chloride was treated with t-BuOK at 0°C, and the
d
e
reaction mixture was then stirred at 80°C for 15 h.

A. Bombrun, G. Casi / Tetrahedron Letters 43 (2002) 2187–2190
2189
similar yields with benzyl alcohol compared with the
TMAD/PBu3 tandem.
4. Tsunoda, T.; Ito, S. Pure Appl. Chem. 1999, 71, 1053–
1057.
5. Zaragosa, F.; Stephensen, H. J. Org. Chem. 2001, 66,
2518–2521 and Tetrahedron Lett. 2000, 41, 1841–1844.
6. The calculated pKa of substituted-1H-indole is about
15–17 in water according to the ACD/pKa DB version
3.5, and 21 in DMSO according to Bordwell, F. G. Acc.
Chem. Res. 1988, 21, 456–463.
To extend the scope of the use of CMMP with carba-
zole derivatives, the reactivity with tertiary alcohol was
evaluated. Preliminary results showed that 3,6-
dibromo-9H-carbazole could undergo N-alkylation
with tert-butanol using a one-pot protocol of CMMP
(entry 10) to give the product 1j in 70% yield. The
one-pot protocol of CMMP was found to be conve-
nient and was compared to the previously described
general procedure. For instance, the compounds 1a and
1d were obtained with similar yields performing or not
the initial preparation of the phosphorane.12 Further-
more, N-alkylation of 3,6-dibromo-9H-carbazole could
be performed to a supported (S)-3-hydroxy-pyrrolidine
derivative, as outlined in Scheme 1. p-Nitrophenylcar-
bonate Wang resin was attached to (S)-3-pyrrolidinol
to give the resin bound compound 2. Then the Mistus-
nobu coupling with 3,6-dibromo-9H-carbazole using
the TMAD/PBu3 tandem gave, after cleavage with
TFA:CH2Cl2, the desired compound 3 in a 60% yield in
99.8% ee.
7. The following by-products, which were fully character-
ized, were obtained for entries 2, 6 and 7, respectively.
In conclusion we demonstrated that CMMP is the
reagent of choice for the N-alkylation of 1H-indole and
9H-carbazole derivatives with alcohol derivatives. In
addition the TMAD/PBu3 tandem can efficiently N-
alkylate 1H-indole derivatives with primary and sec-
ondary alcohols, and DEAD/PPh3, TMAD/PBu3 and
CMMP can efficiently N-alkylate 9H-carbazole deriva-
tives with primary and secondary alcohols. Further SPS
applications and the scope of alcohols, especially ter-
tiary alcohols, are under investigation.
8. Zherebtsov, I. P.; Lopatinskii, V. P. Izv. Tomsk. Politekh.
Inst. 1970, 163, 12–17. [CA 75, 117862x (1971)].
9. General procedure using the classic Mitsunobu conditions.
9-Benzyl-3,6-dibromo-9H-carbazole 1d. At 25°C in a 25
mL Schlenk flask under an argon atmosphere, benzyl
alcohol (0.134 g, 1.24 mmol, 0.13 mL) was added into an
anhydrous THF solution (5 mL) of 3,6-dibromo-9H-car-
bazole (0.2 g, 0.62 mmol) and PPh3 (0.325 g, 1.24 mmol).
At 0°C, DEAD (0.216 g, 1.24 mmol, 0.19 mL) was added
neat and the reaction mixture was stirred for 15 h at
40°C. TLC monitoring (SiO2, petroleum ether/DCM, 48/
1) showed formation of a new UV active compound
(Rf=0.12). Flash chromatography (SiO2, PE/DCM, 48/1)
gave 80 mg of 1d as a white powder in a 31% yield. Mp
1
155–160°C. H NMR: (300 MHz, DMSO-d6) l (ppm) 8.5
(m, 2H), 7.6 (m, 4H), 7.3 (m, 3H), 7.1 (m, 2H), 5.7 (s,
2H). 13C NMR: (75.5 MHz, DMSO-d6) l (ppm) 140.2,
138.1, 129.9, 129.6, 128.3, 127.5, 124.5, 124.0, 112.8,
112.5, 46.7. Anal. calcd for C19H13Br2N: C, 54.97; H,
3.16; N, 3.37. Found: C, 55.21; H, 3.33; N, 3.44%.
9-Benzyl-3-nitro-9H-carbazole 1e. Yield 65%. Yellow
Scheme 1. SPS application. (i) 3,6-Dibromo-9H-carbazole,
TMAD, PBu3; (ii) TFA/CH2Cl2 (5/1).
1
Acknowledgements
powder. Mp 120.5°C. H NMR: (300 MHz, DMSO-d6) l
(ppm) 9.2 (m, 1H), 8.5 (m, 1H), 8.3 (dd, J=9.2, 2.4 Hz,
1H), 7.85 (m, 1H) 7.8 (m, 1H), 7.6 (m, 1H), 7.3 (m, 6H),
5.8 (s, 2H). 13C NMR: (75.5 MHz, DMSO-d6) l (ppm)
144.3, 142.4, 141.1, 137.8, 129.6, 128.4, 127.6, 123.2,
123.0, 122.4, 122.4, 121.7, 118.3, 111.5, 110.7, 46.9. Anal.
calcd for C19H14N2O2 C, 75.48; H, 4.67; N, 9.27. Found:
C, 75.36; H, 4.73; N, 9.27%. 3,6-Dibromo-9-oxiranyl-
methyl-9H-carbazole 1f. Yield 65%. White solid. Mp
We would like to thank Pierre-Andre Pittet and Fabi-
enne Charvillon-Burgat for their technical support, and
Patrick Gerber and Dominique Swinnen for helpful
discussions.
1
References
147.5°C. H NMR: (300 MHz, CDCl3) l (ppm) 8.1 (m,
2H), 7.6 (dd, J=8.7, 1.9 Hz, 2H), 7.3 (d, J=8.7 Hz, 2H),
4.7 (dd, J=15.8, 2.6 Hz, 1H), 4.3 (dd, J=15.8, 5.2 Hz,
1H), 3.3 (m, 1H), 2.8 (t, J=4.3 Hz, 1H), 2.5 (dd, J=4.9,
2.6 Hz, 1H). 13C NMR: (75.5 MHz, CDCl3) l (ppm)
139.9, 129.6, 123.9, 123.5, 112.9, 110.9, 50.7, 45.3, 45.1.
Anal. calcd for C15H11Br2NO2 (c-hexane): C, 59.43; H,
1. Mitsunobu, O. Synthesis 1981, 1–28.
2. Bhagwat, S. S.; Gude, C. Tetrahedron Lett. 1994, 35,
1847–1850.
3. Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem.
Lett. 1994, 539–542.

2190
A. Bombrun, G. Casi / Tetrahedron Letters 43 (2002) 2187–2190
6.54; N, 2.51. Found: C, 59.84; H, 6.55; N, 2.53%.
matography (SiO2, PE/DCM, 3/1) gave 350 mg of 1d as
a white powder in a 97% yield. 9-(2-Octyl)-3-nitro-9H-
carbazole 1i. Yield 82%. Yellow oil. 1H NMR: (300
MHz, CDCl3) l (ppm) 9.0 (d, J=2.26 Hz, 1H), 8.3 (dd,
J=9.2, 2.4 Hz, 1H), 8.2 (m, 1H), 7.6 (m, 3H), 7.3 (m,
1H), 4.8 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.7 (d, J=7.2
Hz, 3H), 1.4–1.0 (m, 8H), 0.9–0.7 (m, 3H). 13C NMR:
(75.5 MHz, CDCl3) l (ppm) 140.6, 127.4, 123.6, 123.3,
121.6, 121.3, 120.8, 117.5, 111.3, 109.8, 109.4, 52.6, 35.2,
31.8, 29.2, 27.1, 22.8, 19.7, 14.3. Anal. calcd for
C20H24N2O2: C, 74.05; H, 7.46; N, 8.63. Found: C, 73.94;
H, 7.48; N, 8.60%. 1-Benzyl-5-bromo-1H-indole 1a. Yield
88%. White powder. Mp 70.5°C. 1H NMR: (300 MHz,
DMSO-d6) l (ppm) 7.8 (m, 1H), 7.5 (d, J=3.2 Hz, 1H),
7.4 (m, 1H), 7.2 (m, 6H), 6.5 (m, 1H), 5.4 (s, 2H). 13C
NMR: (75.5 MHz, DMSO-d6) l (ppm) 138.9, 135.4,
131.6, 131.0, 129.5, 128.3, 127.9, 124.5, 123.6, 113.1,
112.7, 101.6, 50.1. Anal. calcd for C15H12BrN: C, 62.96;
H, 4.23; N, 4.89. Found: C, 62.99; H, 4.37; N, 4.95%.
5-Bromo-1-(2-octyl)-1H-indole 1c. Yield 93%. Colourless
3-Nitro-9-oxiranylmethyl-9H-carbazole 3g. Yield 95%.
Yellow solid. Mp 153.5°C. H NMR: (300 MHz, CDCl3)
1
l (ppm) 9.2 (d, J=2.3 Hz, 1H), 8.4 (m, 1H), 8.4 (dd,
J=9.0, 2.2 Hz, 1H), 7.9 (d, J=9.0 Hz, 1H), 7.8 (m, 1H),
7.6 (m, 1H), 7.3 (t, J=7.5 Hz, 1H), 4.9 (dd, J=15.8, 3.0
Hz, 1H), 4.5 (dd, J=15.6, 5.8 Hz, 1H), 3.4 (m, 1H), 2.8
(t, J=7.5 Hz, 1H), 2.5 (dd, J=4.9, 2.6 Hz, 1H).
10. General procedure using TMAD/PBu3. 9-Benzyl-3,6-
dibromo-9H-carbazole 1d. At 25°C in a 25 mL Schlenk
flask, under an argon atmosphere, benzyl alcohol (0.134
g, 1.24 mmol, 0.13 mL) was added into a solution of
3,6-dibromo-9H-carbazole (0.2 g, 0.62 mmol) and PBu3
(0.25 g, 1.24 mmol, 0.31 mL) in anhydrous toluene (5
mL). At 0°C, TMAD (0.21 g, 1.24 mmol) was added neat
and the reaction mixture was stirred at 40°C for 15 h.
TLC monitoring (SiO2, PE/DCM, 48/1) showed forma-
tion of a new UV active compound (Rf=0.12). Filtration
on a silica bed using EtOAc/c-hexane as eluant gave 244
mg of 1d as a white solid in a 95% yield. 3,6-Dibromo-9-
1
1
oil. H NMR: (300 MHz, CDCl3) l (ppm) 7.8 (m, 1H),
(2-octyl)-9H-carbazole 1h. Yield 25%. Colourless oil. H
7.3 (m, 2H), 7.2 (d, J=3.2 Hz, 1H), 6.5 (d, J=3.2 Hz,
1H), 4.5 (m, 1H), 2.0–1.7 (m, 2H), 1.5 (d, J=6.8 Hz, 3H),
1.4–1.0 (m, 8H), 0.9 (t, J=7.1 Hz, 3H). 13C NMR:
(CDCl3, 75.5 MHz) l (ppm) 134.9, 130.9, 125.5, 124.3,
123.7, 112.7, 111.2, 101.3, 52.2, 37.5, 32.0, 29.4, 26.6,
22.9, 21.7, 14.4. Anal. calcd for C16H22BrN: C, 62.34; H,
7.19; N, 4.54. Found: C, 62.38; H, 7.24; N, 4.61%.
3,6-Dibromo-9-tert-butyl-9H-carbazole 1j. In a 15 mL
dried ACE pressure tube under an argon atmosphere, a
solution of 3,6-dibromo-9H-carbazole (0.100 g, 0.308
mmol) and cyanomethyl-trimethyl-phosphonium chloride
(0.584 g, 3.85 mmol) in anhydrous THF (5 mL) was
treated with t-BuOK (0.380 g, 3.39 mmol) at 0°C. After
4.5 h at rt, the reaction mixture was stirred at 80°C. TLC
monitoring (EtOAc/c-hexane, 1/6) showed formation of a
new UV active compound (Rf=0.42). Flash chromato-
graphy (SiO2, PE/DCM, 3/1) gave 1j as a white powder
in a 70% yield. Mp: 170.5°C. 1H NMR: (300 MHz,
DMSO-d6) l (ppm) 8.5 (m, 2H), 7.9 (m, 2H), 7.5 (m, 2H),
1.9 (s, 9H). 13C NMR: (DMSO-d6, 75.5 MHz) l (ppm)
139.8, 129.3, 127.2, 125.6, 123.8, 117.0, 112.1, 60.4, 31.3.
12. The one-pot protocol using a solution of cyanomethyl-
trimethyl-phosphonium chloride (2.5 equiv.), amine (1
equiv.), alcohol (2 equiv.) and KH (2.2 equiv.) in THF
gave similar yields to those observed in entries 1 and 4
using the above described protocol of CMMP.
NMR: (300 MHz, CDCl3) l (ppm) 8.1 (m, 2H), 7.5 (m,
2H), 7.4 (m, 2H), 4.6 (m, 1H), 2.2 (m, 1H), 2.0–1.8 (m,
1H), 1.6 (d, J=7.0 Hz, 3H), 1.3–0.9 (m, 8H), 0.8 (t,
J=6.6 Hz, 3H). 13C NMR: (75.5 MHz, CDCl3) l (ppm)
139.0, 129.1, 124.2, 123.5, 112.1, 52.2, 35.2, 31.9, 29.3,
27.1, 22.8, 19.7, 14.3. Anal. calcd for C20H23Br2N: C,
54.94; H, 5.30; N, 3.20. Found: C, 54.93; H, 5.33; N,
3.41%. 5-Bromo-1-oxiranylmethyl-1H-indole 1b. Yield
1
25%. Colourless oil. H NMR: (300 MHz, DMSO-d6) l
(ppm) 7.7 (m, 1H), 7.6 (m, 1H), 7.4 (d, J=3.4 Hz, 1H),
7.3 (dd, J=8.7, 1.9 Hz, 1H), 6.5 (m, 1H) 4.6 (dd, J=15.3,
3.2 Hz, 1H), 4.2 (dd, J=15.1, 6.0 Hz, 1H), 3.3 (m, 1H),
2.8 (m, 1H), 2.6 (m, 1H). Anal. calcd for C11H10BrNO: C,
52.41; H, 4.00; N, 5.56. Found: C, 52.48; H, 4.09; N,
5.52%.
11. General procedure using CMMP. 9-Benzyl-3,6-dibromo-
9H-carbazole 1d. In a 15 mL dried ACE pressure tube
under an argon atmosphere, CMMP (prepared according
to the protocol of Tsunoda, T.; Nagiro, C.; Oguri, M.;
Ito, S. Tetrahedron Lett. 1996, 37, 2459–2462) (0.200 g,
1.74 mmol) was added into a solution of benzyl alcohol
(0.188 g, 1.74 mmol, 0.18 mL) and of 3,6-dibromo-9H-
carbazole (0.282 g, 0.87 mmol) in toluene (10 mL). The
reaction mixture was stirred at 110°C for 15 h. TLC
monitoring (SiO2, PE/DCM, 48/1) showed the formation
of a new UV active compound (Rf=0.12). Flash chro-