Et3B-Mediated radical alkylation of pyrroles and indoles

Article abstract of DOI:10.1016/j.tetlet.2006.02.052

An efficient Et₃B-mediated oxidative radical substitution of substituted pyrroles and indoles using xanthate based radical chemistry in the presence of iron(II) sulfate is described. Unsubstituted indole gave only low yield or failed in the process. 2-Cyanofuran and 2-benzoylthiophene did not afford the corresponding alkylated products under these conditions.

Full text of DOI:10.1016/j.tetlet.2006.02.052

Tetrahedron Letters 47 (2006) 2517–2520
Et3B-Mediated radical alkylation of pyrroles and indoles
Miguel A. Guerrero and Luis D. Miranda*
Instituto de Quı´mica, Universidad Nacional Auto´noma de Me´xico, Circuito Exterior, Ciudad Universitaria, 04510 Coyoacan,
Me´xico D. F., Mexico
Received 20 January 2006; revised 9 February 2006; accepted 9 February 2006
Available online 28 February 2006
Abstract—An efficient Et3B-mediated oxidative radical substitution of substituted pyrroles and indoles using xanthate based radical
chemistry in the presence of iron(II) sulfate is described. Unsubstituted indole gave only low yield or failed in the process. 2-Cyano-
furan and 2-benzoylthiophene did not afford the corresponding alkylated products under these conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
The use of triethylborane in air as an initiator of radical
based processes has become increasingly popular in
recent years.1 Because radical reactions can be initiated
by this reagent at ambient or subambient temperatures,
it has found widespread application, particularly in the
stereoselective addition of alkyl radicals to double
bonds.1c In contrast, there are very few examples of
the use of Et3B to initiate oxidative radical substitution
of aromatic systems,2 a carbon–carbon bond forming
reaction that has considerable preparative value.3,4 We
recently reported an efficient intermolecular oxidative
radical alkylation of various heterocyclic aromatic sys-
tems which included pyrroles, indoles, furans and thio-
phenes, using xanthate based radical chemistry, lauroyl
peroxide as the initiator in 1,2-dichloroethane at reflux
temperature, and near stoichiometric quantities of the
heteroaromatic substrate.5 In order to widen the scope
of this latter methodology it was of interest to attempt
the reaction at room temperature using triethylborane
as an initiator. Herein are described preliminary results
of the alkylation reaction of pyrroles and indoles using
xanthates as the radical source and Et3B as initiator at
room temperature.
using xanthate 2 as the radical source, Et3B in air as
the initiator, and pyrrole-2-carboxaldehyde (1) or
3-methoxycarbonylindole (4) as the heteroaromatic sub-
strates (3 equiv), generated the expected products 3 and
5 (Scheme 1) in low yields (Table 1, entries 1 and 2).
O
Et3B
H
OEt
S
H
+
N
CH2Cl2,
r. t.
N
S
H
O
O
H
O
EtO
O
1
3
2
OEt
CO2Me
CO2Me
Et3B
+
2
CH2Cl2,
r. t.
N
N
H
H
EtO
4
5
Scheme 1.
Table 1.
Entry Substrate Time (h) Et3B
(equiv)
Additive
Yield (%)
1
2
3
4
5
6
7
8
9
1
4
1
1
4
1
1
1
1
4
4
2
2
6
4
—
—
—
—
15
10
35
62
43
65
—
—
44
—
—
A critically important issue in the oxidative radical
alkylation of aromatic systems is the requirement of
an agent to effect the oxidation step. It was considered
possible that boron peroxides, which are reported to
be formed in the reaction of triethylborane with oxy-
gen,1 might accomplish this oxidation. The initial results
4
4
4
4
2
2
2
2
2
2
14
14
14
14
14
14
14
14
—
FeSO4
Fe(ClO4)2
CuCl2
FeSO4
Fe(ClO4)2
CuCl2
10
11
*
Corresponding author. Tel.: +52 55 56 22 44 40; fax: +52 55 56 16 22
17; e-mail: lmiranda@servidor.unam.mx
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.052

2518
M. A. Guerrero, L. D. Miranda / Tetrahedron Letters 47 (2006) 2517–2520
Table 2.
Entry
Substrate
Xanthate
Product
O
Xth
O
1
N
N
H
O
O
H
O
O
6
11
14 (62%)
O
O
OEt
Xth
Xth
Xth
2
3
6
6
N
H
OEt
O
2
15 (16%)
O
O
OEt
OEt
N
H
O
12
16 (57%)
O
O
H
N
H
H
N
O
4
5
6
O
O
O
O
1a
11
17 (60%)
O
O
Xth
Xth
N
OEt
OEt
1a
12
18 (49%)
O
O
O
Cl3C
Cl3C
N
N
H
O
H
O
7
O
11
19 (63%)
O
Xth
O
H
H
O
N
N
H
O
7
8
H
O
O
11
1
20 (57%)
O
O
O
O
H
O
Xth
Xth
N
O
N
H
1
N
O
12
21 (61%)
O
O
OMe
O
OMe
9
O
O
N
N
H
4
H
11
O
22 (54%)
O
OMe
O
O
O
O
Xth
N
10
4
O
N
N
O
H
13
23 (56%)
O
O
Xth
Xth
Xth
11
12
OEt
N
H
N
H
OEt
OEt
OEt
2
8
24 (30%)
O
CN
O
—
—
9
2
O
S
13
O
10
2
Xth = SC(S)OEt.

M. A. Guerrero, L. D. Miranda / Tetrahedron Letters 47 (2006) 2517–2520
2519
Borane reagent (4 equiv) was required to effect full con-
sumption of the radical source 2, a phenomenon which
has previously been observed.2a Further experimenta-
tion revealed that the time addition of the borane had
a significant effect on the product yield and a 14 h addi-
tion period was found to be the optimal for substrates 1
and 4 (Table 1, entries 4 and 5). We then speculated that
borane peroxides might not be efficient in the oxidation
pathway and decided to test some cooxidants. For
instance Fe(III) has been successfully used as an oxidant
in similar processes.2b,6 In this context we hypothesized
that Fe(II) might be oxidized to Fe(III) by the action
of boron peroxides formed during the autoxidation of
triethylborane. Thus, when FeSO4Æ7H2O (1 equiv in a
6:3:1 CH2Cl2–H2O–EtOH solvent mixture) was utilized
in these reactions, only 2 equiv of the borane were
required for complete consumption of the xanthate,
although the product yields were not improved (entries
6 and 9). Neither Fe(ClO4)2 nor CuCl2 functioned as
cooxidants, and only decomposition of the substrates
was observed (entries 7, 8, 10 and 11). It seems evident
that the presence of ferrous sulfate enhances the effi-
ciency of the process, perhaps as expected by acting as
a source of Fe(III) which then participates in the oxida-
tive pathway of the rearomatization process.2b,6 How-
ever, the precise role of this salt is currently not
known and experiments to better understand it are in
progress. It is noteworthy that only 3 equiv of the aro-
matic substrate were used in these experiments, which
represents a distinct advantage in comparison with pre-
viously reported methodology where a large excess was
used (10–30 equiv),2b and approaches the high substrate
economy of our lauroyl peroxide initiated xanthate
based oxidative radical alkylations.5 With these opti-
mized reaction conditions in hand, we examined the
scope of the process with various xanthates and several
different substituted pyrrole and indole substrates (Table
2).7 Generally good yields of the alkylated pyrroles were
obtained with primary and secondary xanthates (Table
2, entries 1–8). Even trichloroacetylpyrrole 7 afforded
the expected alkylated product 19 in good yield (entry
6). Even the isoxazolidinone containing xanthate deriv-
ative 12 furnished the alkylated pyrrole 21 in quite
acceptable yield. Under the same conditions, indole 4
afforded similar yields of the alkylated indoles 23 and
24 along with small quantities of the indole 25 (5–6%),
derived from the direct addition of the ethyl radical onto
the indole (entries 9 and 10). In contrast, the reaction of
indole (8) with xanthate 2 gave a low yield of the
expected 2-alkylated indole 24 (entry 11). Remarkably,
reaction of this latter indole with xanthates 11 and 12
failed to afford the expected products. This is somewhat
surprising, given that the reactions of 3-carbomethoxy-
indole (4) with these xanthate derived radicals are
supposed to be polarity mismatched processes, yet they
are nevertheless much more efficient than the analogous
reaction with indole. This result might be better
explained on the basis that the radical 26 is more
stabilized (benzylic and a- to a carbonyl group) than
27 (only benzylic).
A few experiments were also carried out with 2-cyano-
furano and 2-benzoylthiophene, but all of them failed,
and only the aromatic substrates were recovered (entries
12 and 13).
In closing it has been demonstrated that the xanthate-
mediated intermolecular oxidative radical alkylation of
pyrroles and indoles can be effected in moderate to good
yields at room temperature using Et3B as the initiator
and FeSO4Æ7H2O as a cooxidant. In principle, these
are conditions which could be used in the stereoselective
radical additions to aromatic systems. Work along these
lines is underway.
Acknowledgements
We thank CONACYT (J42673Q), for generous financial
support and Dr. Joseph M. Muchowski, for many
´
helpful discussions. Also we thank R. Patino, J. Perez,
˜
L. Velasco, H. Rios, N. Zavala, E. Hernandez and A.
Pena, for technical support.
˜
References and notes
1. For reviews in this field see: (a) Ollivier, C.; Renaud, P.
Chem. Rev. 2001, 101, 3415; (b) Yorimitsu, H.; Oshima, K..
In Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.;
Wiley-VCH: Weinheim, 2001; Vol. 1, p 11; (c) Sibi, M. P.;
Rheault, T. R. In Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1,
p 461.
2. (a) Artis, D. R.; Cho, I.-S.; Muchowski, J. M. Can. J.
Chem. 1992, 70, 1838; (b) Baciocchi, E.; Muraglia, E.
Tetrahedron Lett. 1993, 34, 5015; (c) Wakabayashi, K.;
Yorimtsu, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2000,
2, 1899.
3. For reviews in this field see: (a) Studer, A. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vol. 2, pp 62–76; (b) Bowman, W.
R.; Bridge, C. F.; Brookes, P. J. Chem. Soc., Perkin Trans.
1 2000, 1–14; (c) Bowman, W. R.; Fletcher, A. J.; Pots, G.
B. S. J. Chem. Soc., Perkin Trans. 1 2002, 2747.
4. Recent publications: (a) Aldabbagh, F.; Bowman, W. R.;
Mann, E.; Slawin, A. M. Z. Tetrahedron 1999, 55, 8111; (b)
Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 4073; (c)
´
´
Marco-Contelles, J.; Rodrıguez-Fernandez, M. Tetrahedron
Lett. 2000, 41, 381; (d) Bowmann, W. R.; Mann, E.; Parr, J.
J. Chem. Soc., Perkin Trans. 1 2000, 2991; (e) Miranda, L.
´
D.; Cruz-Almanza, R.; Pavon, M.; Romero, Y.; Muchow-
ski, J. M. Tetrahedron Lett. 2000, 41, 10181; (f) McCarroll,
A. J.; Walton, J. C. J. Chem. Soc., Perkin Trans. 1 2001,
3215; (g) Bennasar, M.-Ll.; Roca, T.; Griera, R.; Bosch, J.
J. Org. Chem. 2001, 66, 7547; (h) Bennasar, M.-Ll.; Roca,
T.; Griera, R.; Bosch, J. J. Org. Chem. 2002, 67, 6268; (i)
Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; McInally,
T. Tetrahedron Lett. 2002, 43, 4191; (j) Rheault, T. R.; Sibi,
M. P. Synthesis 2003, 803; (k) Beckwith, A. L. J.; Bowry, V.
W.; Bowman, W. R.; Mann, E.; Parr, J.; Storey, J. M. D.
O
O
OMe
OMe
R
R
N
N
N
H
H
H
25
26
27

2520
M. A. Guerrero, L. D. Miranda / Tetrahedron Letters 47 (2006) 2517–2520
Angew. Chem., Int. Ed. 2004, 43, 95; (l) Bennasar, M.-Ll.;
Roca, T.; Ferrando, F. Tetrahedron Lett. 2004, 45, 5605;
(d, J = 4.2 Hz, 1H), 6.19 (d, J = 4.2 Hz, 1H), 4.13 (q,
J = 7.2 Hz, 2H), 3.98 (q, J = 13.5 Hz, 1H), 3.93 (s, 3H),
1.51 (d, J = 13.5 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, CD3COCD3) d ppm: 179.8, 172.8, 143.3,
133.2, 124.5, 108.7, 61.6, 37.5, 32.6, 16.7, 14.3. IR (neat,
cmÀ1) m 1734, 1661, 1468; EM (EI) m/z = M+ (%).
´
Menes-Arzate, M.; Martınez, R.; Cruz-Almanza, R.; Osor-
nio, Y. M.; Muchowski, J. M.; Miranda, L. D. J. Org.
Chem. 2004, 69, 4001.
´
5. Osornio, Y. M.; Cruz-Almanza, R.; Jimenez-Montano, V.;
˜
1
Miranda, L. D. Chem. Commun. 2003, 2316–2317.
6. For examples of the use of Fe(II) in similar processes: (a)
Muchowski, J. M.; Cho, I. S.; Jaime-Figueroa, S.; Artis, R.
D. J. Org. Chem. 1994, 59, 2456; (b) Miranda, L. D.; Cruz-
Almanza, R.; Pavon, M. ARKIVOC 2002, 15–22.
Compound 19: H NMR (200 MHz, CD3COCD3) d ppm:
11.4 (br s, 1H), 7.36–7.34 (m, 1H), 6.39–6.37 (m, 1H), 4.54–
4.36 (m, 2H), 4.23 (dd, J = 11.5, 8.8 Hz, 1H), 2.89–2.78 (m,
1H) 2.68–2.56 (m, 1H); 13C NMR (75 MHz, CD3COCD3) d
ppm: 175.8, 172.9, 139.5, 123.3, 120.3, 96.19, 122.4, 110.9,
67.5, 39.7; IR (neat, cmÀ1) m 3409, 1770, 1668, 1167; EM
(IE), m/z = (M+) 295 (5%), (M++1) 296, 178 (100%).
7. Typical experimental procedure: A solution of Et3B (1.0 M
in THF) was added dropwise (2 equiv/14 h) to a stirred
solution of the xanthate (1 equiv), the aromatic compound
(3 equiv) and FeSO4 (1 equiv) in CH2Cl2/EtOH/H2O (6:3:1,
4 ml/mmol of the xanthate). The organic solvent was
removed under reduced pressure and the crude residue
extracted with EtOAc. The organic layer was dried with
Na2SO4, and solvent removed under reduced pressure. The
product was purified by chromatography on a silica gel
column (ethyl acetate/hexane 8:2) to furnish the desired
product. Selected spectral data. Compound 14: 1H NMR
(200 MHz, CD3COCD3) d ppm: 7.87–7.85 (m, 2H), 7.61–
7.47 (m, 3H), 6.81 (dd, J = 3.9, 2.7 Hz, 1H), 6.28 (dd,
J = 3.9, 2.7 Hz, 1H), 4.56–4.33 (m, 2H), 4.20 (dd, J = 11.0,
9.0 MHz, 1H), 2.9–2.55 (m, 2H). 13C NMR (75 MHz,
CD3COCD3) d ppm: 184.3, 176.2, 139.7, 136.5, 132.4,
132.0, 129.5, 129.1, 119.9, 109.8, 67.5, 39.6, 30.4; IR (neat,
cmÀ1) m 3273, 1767, 1612; MS (EI) (m/z), M+ 255 (90%), 77
(100%). Compound 15: 1H NMR (300 MHz, CDCl3) d
ppm: 10.41 (br s, 1H), 7.89 (dd, J = 8.5, 1.8 Hz, 2H), 7.57–
7.43 (m, 3H), 6.81 (dd, J = 3.8, 2.5 Hz, 1H), 6.18
(dd, J = 3.8, 2.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.77
(s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (300 MHz,
CDCl3) d ppm: 184.2, 169.4, 138.6, 131.9, 131.6, 131.2,
128.9, 128.2, 119.8, 110.6, 61.4, 33.6, 14.1; IR (neat, cmÀ1) m
3286, 2922, 1737, 1606; HRMS FAB+ (M+1, m/z) calcd for
C15H16O3N: 258.1130, found: 258.1130. Compound 16.
1
Compound 20: H NMR (300 MHz, CD3COCD3) d ppm:
11.05 (br s, 1H), 9.46 (s, 1H), 6.93 (dd, J = 3.81, 2.34 Hz,
1H), 6.27 (dd, J = 3.81, 2.34 Hz, 1H), 4.50–4.33 (m, 2H),
4.13 (dd, J = 11.13, 9.09 Hz, 1H), 2.65–2.52 (m, 2H); 13C
NMR (75 MHz, CD3COCD3) d ppm: 179.1, 176.0, 137.2,
134.3, 121.3, 110.0, 67.4, 39.7, 30.3; IR (neat, cmÀ1) m 3259,
1767, 1647; EM (EI), m/z (M+): 179 (100%). Compound 21:
1H NMR (300 MHz, CD3COCD3) d ppm: 10.75 (br s, 1H),
9.43 (s, 1H), 6.88 (dd, 1 = 3.81, 2.34 Hz, 1H), 6.17 (dd,
J = 3.8, 2.34 Hz, 1H), 5.20 (q, J = 7.02 Hz, 1H) 4.52–4.40
(m, 2H), 4.11–3.96 (m, 2H), 1.51 (d, J = 7.02 Hz, 3H); 13C
NMR (75 MHz, CD3COCD3) d 178.9, 173.3, 154.5, 14.6,
133.8, 121.1, 109.6, 63.2, 43.8, 37.5, 17.8; IR (neat, cmÀ1) m
3297, 1776, 1698, 1649; EM (EI), m/z (M+): 236 (15%), 149
1
(100%). Compound 22: H NMR (300 MHz, CD3COCD3)
d ppm: 11.75 (br, 1H), 8.07–8.02 (m, 1H), 7.48–7.42 (m,
1H), 7.25–7.13 (m, 2H), 4.92 (dd, J = 12.0, 9.3 Hz, 1H),
4.58 (td, J = 8.6, 2.3 Hz, 1H), 4.45 (ddd, J = 11.3, 9.8,
6.8 Hz, 1H), 3.87 (s, 3H), 2.79–2.61 (m, 2H). 13C NMR
(300 MHz, CD3COCD3) d ppm: 176.0, 166.5, 143.8, 136.6,
127.83, 123.5, 122.3, 122.2, 112.4, 105.6, 67.4, 51.0, 40.3,
30.8; IR (neat, cmÀ1) m 3452, 2925, 1736, 1624; EM (EI),
m/z (M+): 259 (30%), 227 (100%). Compound 23: 1H NMR
(300 MHz, CD3COCD3) d ppm: 10.95 (br s 1H) 8.07–8.00
(m, 1H), 7.50–7.45 (m, 1H), 7.18–7.12 (m, 2H), 6.13 (q,
J = 7.0 Hz, 1H), 4.49 (t, J = 7.9 Hz, 2H), 4.08–4.032 (m,
2H), 3.8 (s, 3H), 1.64 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CD3COCD3) d ppm: 174.3, 166.2, 154.0, 146.0,
136.4, 127.7, 123.0, 122.1, 121.9, 112.5, 104.5, 63.1, 50.8,
43.7, 37.5, 17.2; IR (neat, cmÀ1) m 3338, 2951, 1779, 1693;
EM (EI), m/z (M+): 316 (10%), 71 (100%). Compound 24:
1H NMR (200 MHz, CD3COCD3) d ppm: 10.08 (br s, 1H),
7.47 (d, J = 7.5Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.10–6.91
(m, 2H), 6.33 (dd, J = 2.0, 1.0 Hz, 1H), 4.14 (q, J = 7 Hz,
2H), 3.84 (d, J = 1 Hz, 2H), 1.22 (t, J = 7 Hz, 3H); 13C
NMR (75 MHz, CD3COCD3) d ppm: 170.6, 137.7, 132.6,
129.5, 121.8, 120.5, 119.9, 111.7, 101.9, 61.3, 34.6, 14.4; IR
1
White solid mp 72–74 °C. H NMR (300 MHz, CDCl3) d
ppm: 10.12 (br s, 1H, NH), 7.86–7.89 (m, 2H), 7.44–7.57
(m, 3H), 6.80 (dd, J = 3.6 Hz, 2.4 Hz, 1H), 6.18 (dd,
J = 3.6 Hz, 2.4 Hz, 1H), 3.91 (q, J = 7.2 Hz, 1H), 3.71 (s,
3H), 1.59 (d, J = 7.2 Hz, 3H); HRMS FAB+ (M+1, m/z)
calcd for C15H16O3N1: 258.1130, found: 258.1125. Com-
1
pound 17. H NMR (300 MHz, CD3COCD3) d ppm: 9.51
(s, 1H), 6.94 (d, J = 4.2 Hz, 1H), 6.25 (dd, J = 3.9, 0.4 Hz,
1H), 4.55–4.37 (m, 2H), 4.27 (dd, J = 10.8, 9.0 Hz, 1H),
4.00 (s, 3H), 2.81–2.73 (m, 1H), 2.66–2.52 (m, 1H); 13C
NMR (75 MHz, CD3COCD3) d ppm: 179.83, 175.6, 139.9,
133.7, 124.3, 108.9, 67.5, 38.1, 32.9, 29.6; IR (neat, cmÀ1) m
1768, 1659; EM (EI) m/z = M+ 193 (100%). Compound 18:
1H NMR (300 MHz, CD3COCD3) d ppm: 9.49 (s, 1H), 6.92
(neat, cmÀ1
C12H13NO2 = 204.1025, found 204.1017.
) m 3397, 2926, 1728; HMRS calcd for