Manganese(III)-mediated oxidative radical addition of malonates to 2-cyanoindoles

Article abstract of DOI:10.1016/j.tetlet.2013.09.012

2-Cyanoindole and N-methyl-2-cyanoindole undergo manganese(III)-mediated radical addition with activated methylene and methine compounds. Products of the methylene addition underwent additional oxidation during the course of the reaction to furnish the corresponding acetoxy compounds. Several structures were confirmed by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2013.09.012

Tetrahedron Letters 54 (2013) 6142–6145
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Manganese(III)-mediated oxidative radical addition of malonates to
2-cyanoindoles
a
a
b
a
a,
⇑
Justin M. Lopchuk , William L. Montgomery , Jerry P. Jasinski , Sayeh Gorjifard , Gordon W. Gribble
a
Department of Chemistry, Dartmouth College, Hanover, NH 03755-3564, USA
Department of Chemistry, Keene State College, Keene, NH 03435-2001, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Cyanoindole and N-methyl-2-cyanoindole undergo manganese(III)-mediated radical addition with
activated methylene and methine compounds. Products of the methylene addition underwent additional
oxidation during the course of the reaction to furnish the corresponding acetoxy compounds. Several
structures were confirmed by X-ray crystallography.
Received 16 August 2013
Revised 29 August 2013
Accepted 4 September 2013
Available online 10 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2
-Cyanoindole
Manganese(III) oxidation
Captodative effect
Radical addition
Malonate
Since the seminal reports disclosing the manganese(III) acetate-
promoted oxidative addition of acetic acid to alkenes in 1968,
2-Cyano-N-methylindole (6) was synthesized in one-pot via
1
sequential addition of n-butyllithium, DMF, and aqueous ammo-
1
3
manganese(III)-based free-radical reactions continue to find new
applications in organic synthesis.2 In just the last few years, new
reports include the synthesis of sterically congested cyclopen-
2
nia/I to 5 (Scheme 1). With these compounds in hand, as well
3
tane-lactones, (Z)-selective exo-alkylidene pyrrolidinones and
4
trifluoromethylated dihydrofurans,5 2-thienyl-
pyrrolidines,
6
7
substituted dihydrofurans, and fluoroacylated 4,5-dihydrofurans.
i) LDA, THF
NHt-Bu
Given our longstanding interest in the chemistry of electron-
8
ii) t-BuNCO
deficient indoles, we previously reported the manganese(III) ace-
N
N
O
tate-promoted radical addition of activated methylene and
methine compounds to 2-nitroindoles which furnish either the
corresponding 3-substituted-2-nitroindoles or 2-oxoindolin-3-yli-
86%
SO2Ph
2
SO Ph
1
2
9
POCl3
87%
denes; the latter product is isolated after an in situ Nef reaction.
In order to expand this methodology, we began to investigate
cyanoindoles as possible substrates for the radical additions. The
cyano group provides an orthogonal chemical handle for further
elaboration when compared to the nitro group, and would circum-
vent the Nef reaction seen previously.
According to a literature procedure, N-phenylsulfonyl-2-cyano-
indole (3) was prepared in two steps from 1 by installation of the
amide with t-butyl isocyanate (2) followed by treatment with
phosphorus oxychloride.10 Deprotection with TBAF delivered
TBAF, THF
82%
CN
CN
N
N
H
SO Ph
3
2
4
i) n-BuLi
ii) DMF
2
-cyanoindole (4) in good yield while avoiding hydrolysis of the
CN
1
1,12
nitrile which has been observed with other bases.
N
N
Me
iii) aq. NH , I
3
2
Me
6
5
53%
⇑
Corresponding author.
E-mail address: ggribble@dartmouth.edu (G.W. Gribble).
Scheme 1. Preparation of 2-cyanoindoles.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.012

J. M. Lopchuk et al. / Tetrahedron Letters 54 (2013) 6142–6145
6143
MeO2C
MeO2C
malonate to the indole requires a stabilized radical be formed at
either -2 C-2 or -3. C-3. The more stable radical 7 will be located
on the carbon which has both an electron-withdrawing and elec-
tron-donating group immediately attached (in this case, at -2). C-
CO Me
CO Me
2
2
CN
CN
N
N
2
). Moreover, installation of the phenylsulfonyl group on nitrogen
7
H/Me
8
SO Ph
2
withdraws enough electron density from -2 C-2 that the captoda-
tive effect is eliminated in 8 (Fig. 1).
Optimum yields were obtained with either unprotected indole
CN
4
or N-methylindole 6 and Mn(OAc)
3
Á2H
2
O in refluxing acetic acid.
CO Me
2
The addition of copper(II) acetate as a co-oxidant did not have a
noticeable effect on either the yield or rate. If the initial product
(12) still contains an enolizable malonate proton, a second radical
was generated (13) by the deprotonation of the remaining C–H
bond, oxidation of the resulting enolate, and trapping with ace-
N
CO Me
2
H
9
Figure 1. Possible radicals generated on 2- and 3-cyanoindoles.
2
tate. This second oxidation proved unavoidable during the course
1
5
of the reaction (Scheme 2).
OAc
CO Me
MeO2C
(
CO Me) CH
A variety of unsubstituted and monosubstituted malonate-type
compounds successfully engaged in the radical reaction (Table 1)
in moderate to good yields, although reaction times were notice-
ably longer than was observed with the corresponding nitroin-
doles. It is noteworthy that when diethyl bromomalonate is used
as a reaction partner (Table 1, entry 6), the bromide is displaced
by acetate to furnish 18 as the final product. This stands in contrast
to previous examples in the literature where the bromide remains
2
2
2
2
2
Mn(OAc) ⋅2H O
3
CN
N
Me
CN
AcOH
10
N
92%
11
Me
1
6
in the isolated radical addition product. Single crystals were ob-
tained for products 14, 15, and 16 which also serves to confirm the
uptake of acetate with unsubstituted malonates (Fig. 2).
In conclusion, we have developed the Mn(III)-based oxidative
free radical addition of malonate-type compounds to 2-cyanoin-
doles in moderate to good yields. This approach provides a comple-
mentary substrate set to our nitroindole chemistry and expands
the possibilities for further elaboration of the indole radical addi-
tion products.
MeO C
MeO C
2
2
CO Me
CO Me
2
2
steps
CN
CN
N
N
Me
13 Me
12
Scheme 2. Radical addition to cyanoindole 10 via captodative radical 12 and
malonate radical 13.
Acknowledgments
as the analogous 3-cyano compounds, we screened the indole sub-
strates under our standard radical addition conditions.9
The 3-cyanoindoles were unreactive, returning only starting
material. The same was true of N-phenylsulfonyl-2-cyanoindole
JML acknowledges support from a Department of Education
GAANN fellowship. GWG acknowledges support by the Donors of
the Petroleum Research Fund (PRF), and administered by the
American Chemical Society, and by Wyeth. J.P.J. acknowledges
the NSF MRI program (grant No. CHE-1039027) for funds to pur-
chase the X-ray diffractometer.
(
3). This falls in line with our previous observations of nitroindoles
14
and can be explained by the captodative effect. Addition of
Table 1
Scope of radical additions1
7–25
R4
R5
R2
R3
R2
R3
CN
N
R1
CN
Mn(OAc) ⋅2H O
3
2
N
R1
AcOH
Entry
R1
R2
R3
R4
R5
Time (h)
Compd18–25
Yield (%)a
91 (63)b
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
H
H
H
H
H
CO
CO
CO
CO
CO
CO
CO
CO
CO
2
2
2
2
2
2
2
2
2
Me
Et
Et
Me
Et
Et
Me
Me
Et
CO
CO
CO
CO
CN
CO
COMe
CO
CO
2
2
2
2
Me
Et
Et
Me
Me
H
(CH
H
Me
Br
H
Me
OAc
2
2
2
4
24
4
4
1.5
48
14
15
16
11
17
18
19
20
21
b
90 (73)
78 (71)b
2
)
2
CN
(CH
OAc
Me
OAc
OAc
OAc
Ph
)
2 2
CN
92 (57)b
58
72
67
81
0
2
Et
2
Me
Et
H
Ph
2
a
For general procedure, see note 17a.
b
Yield from reactions with Cu(OAc)
2
Á2H
2
O as co-oxidant, see note 17b.

6
144
J. M. Lopchuk et al. / Tetrahedron Letters 54 (2013) 6142–6145
Figure 2. ORTEP diagrams of radical addition products 14, 15, and 16.
vacuo to an off-white solid. The product was purified by flash chromatography
silica gel, hexanes:EtOAc 4:1) to afford 4 as a white solid, 827 mg (82%); 1
References and notes
(
H
NMR (300 MHz, CDCl
3
) 1d18.66 (br s, 1H), 7.68 (d, 1H, J = 8.1 Hz), 7.44–7.36 (m,
1
2
.
.
(a) Heiba, E. I.; Dessau, R. M.; Koehl, W. J., Jr. J. Am. Chem. Soc. 1968, 90, 5905–
906; (b) Bush, J. B., Jr.; Finkbeiner, H. J. Am. Chem. Soc. 1968, 90, 5903–5905.
2H), 7.25–7.20 (m, 2H).
5
1
1
1
3. Ushijima, S.; Moriyama, K.; Togo, H. Tetrahedron 2011, 67, 958–964.
4. Viehe, H. G.; Janousek, Z.; Merenyi, R. Acc. Chem. Res. 1985, 18, 148–154.
5. Linker, T.; Kersten, B.; Linker, U.; Peters, K.; Peters, E.-M.; von Schnering, H. G.
Synlett 1996, 468–470.
(a) Snider, B. B. Chem. Rev. 1996, 96, 339–363; (b) Snider, B. B. In
Manganese(III)-based Oxidative Free-Radical Cyclizations in Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds., 2nd ed.; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim Germany, 2004; pp 483–490. Vol. 1; (c)Radicals in Organic
Synthesis; Vol. 1, Basic Principles, Vol. 2, Applications; Renaud, P., Sibi, M. P., Eds.;
Wiley-CCH: New York, 2001.
1
1
6. (a) Zhang, T.-H.; Lu, P.; Wang, F.; Wang, G.-W. Org. Biomol. Chem. 2003, 1,
4403–4407; (b) Wang, G.-W.; Zhang, T.-H.; Cheng, X.; Wang, F. Org. Biomol.
Chem. 2004, 2, 1160–1163.
3
.
Logan, A. W. J.; Parker, J. S.; Hallside, M. S.; Burton, J. W. Org. Lett. 2012, 14,
7. General procedure for the synthesis of 3-substituted-2-cyanoindoles: Cyanoindole
2
940–2943.
6
(40 mg, 0.256 mmol, 1 equiv.), Mn(OAc)
3
Á2H
2
O (345 mg, 1.29 mmol, 5 equiv),
4
5
6
7
8
.
.
.
.
.
Keane, H. A.; Hess, W.; Burton, J. W. Chem. Commun. 2012, 6496–6498.
Bicer, E. Yilmaz, M. ARKIVOC 2013, iii, 304–316.
Bicer, E.; Yilmaz, M.; Karatas, M.; Pekel, A. T. Helv. Chim. Acta 2012, 95, 795–804.
Yilmaz, M.; Yilmaz, E. V. B.; Pekel, A. T. Helv. Chim. Acta 2011, 94, 2027–2038.
(a) Roy, S.; Gribble, G. W. Tetrahedron Lett. 2007, 48, 1003–1007; (b) Roy, S.;
Kishbaugh, T. L. S.; Jasinski, J. P.; Gribble, G. W. Tetrahedron Lett. 2007, 48,
and diethyl malonate (205 mg, 1.28 mmol, 5 equiv) were dissolved in acetic
acid (10 mL) and heated to reflux for 2 h. After TLC indicated complete
consumption of the starting indole, the reaction was poured into water
(
200 mL) and extracted with ethyl acetate (3 Â 50 mL). The combined organic
extracts were washed with water (3 Â 100 mL), brine (1 Â 100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The
product was purified via flash chromatography (silica gel, hexanes:EtOAc 4:1)
1313–1316; (c) Roy, S.; Roy, S.; Gribble, G. W. Tetrahedron Lett. 2008, 49, 1531–
1533; (d) Alford, P. E.; Kishbaugh, T. L. S.; Gribble, G. W. Heterocycles 2010, 80,
831–840; (e) Qian, D. C.; Alford, P. E.; Kishbaugh, T. L. S.; Jones, S. T.; Gribble, G.
20
to afford 15 as a white solid (90%);
General procedure for the synthesis of 3-substituted-2-cyanoindoles with co-
W. ARKIVOC 2010, iv, 66–73.
Androsov, D. A.; Kishbaugh, T. L. S.; Gribble, G. W. Tetrahedron Lett. 2005, 49,
oxidant: Cyanoindole 6 (40 mg, 0.256 mmol, 1 equiv), Mn(OAc)
.29 mmol, 5 equiv), diethyl malonate (205 mg, 1.28 mmol, 5 equiv),
Cu(OAc) (5 mg, 0.025 mmol, 0.1 equiv), and NaOAcÁ3H (350 mg,
Á2H
.57 mmol, 10 equiv) were dissolved in acetic acid (10 mL) and heated to
3
Á2H
2
O (345 mg,
9
.
1
6
621–6623.
2
2
O
2
O
1
1
0. Gribble, G. W.; Barden, T. C.; Johnson, D. A. Tetrahedron 1988, 44, 3195–3202.
1. Lin, C.-D.; Fang, J.-M. J. Chin. Chem. Soc. 1993, 40, 571–579; (b) Iyer, P.; Lucas, M.
C.; Schoenfeld, R. C.; Villa, M.; Welkert, R. J. U.S. Patent 7 446 118, 2008.
2. 2-Cyanoindole 4: To a solution of N-phenylsulfonyl-2-cyanoindole (3, 2.0 g,
2
reflux for 2 h. After TLC indicated complete consumption of the starting indole,
the reaction was poured into water (200 mL) and extracted with ethyl acetate
1
(
(
3 Â 50 mL). The combined organic extracts were washed with water
7
1
.1 mmol, 1 equiv) in THF (30 mL) was added a solution of TBAF (10.6 mL,
.0 M in THF, 1.5 equiv). After heating at reflux for 3 h, the mixture was cooled
3 Â 100 mL), brine (1 Â 100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo to give a brown oil. The product was purified via flash
to room temperature and concentrated in vacuo. The residue was dissolved in
ethyl acetate (100 mL) and water (100 mL) and the layers separated. The
organic layer was washed with brine, dried over Na SO , and concentrated in
2 4
chromatography (silica gel, hexanes:EtOAc 4:1) to afford 15 as a white solid
(
73%).

J. M. Lopchuk et al. / Tetrahedron Letters 54 (2013) 6142–6145
6145
+
1
1
8. Dimethyl 2-acetoxy-2-(2-cyano-1-methyl-1H-indol-3-yl)malonate 11: The
C
20
H
N
22 3
O
4
(MH ) 368.1610, found 368.1612. Single crystals suitable for X-ray
product was purified via flash chromatography (silica gel, hexanes:EtOAc
crystallography were grown from 100% ethanol.
1
4
:1) to afford 11 as a white solid, 111 mg (92%), mp 138–140 °C; H NMR
22. Ethyl 2-cyano-2-(2-cyano-1H-indol-3-yl)propanoate 17: The product was
purified via flash chromatography (silica gel, hexanes:EtOAc 3:1) to afford 17
(
300 MHz, CDCl ) d 7.85 (d, 1H, J = 8.5 Hz), 7.46–7.33 (m, 2H), 7.26–7.21 (m,
3
13
as a pale yellow oil, 55 mg (58%); 1H NMR (300 MHz, CDCl
1
1
3
3
H), 3.92 (s, 3H), 3.81 (s, 6H), 2.35 (s, 3H); C NMR (75 MHz, CDCl
3
) d 169.7,
3
) d 9.14 (br s, 1H),
7.93 (d, 1H, J = 9.0 Hz), 7.44–7.42 (m, 2H), 7.30–7.25 (m, 1H), 4.37–4.29 (m,
65.8, 138.0, 126.5, 123.8, 122.4, 122.4, 117.7, 112.7, 110.5, 109.4, 80.8, 53.8,
+
+
13
1.9, 20.6; HRMS (ESI ) calcd for C17
H
16
N
2
O
6
Na (MNa ) 367.0906, found
2H), 2.30 (s, 3H), 1.39–1.33 (m, 3H); C NMR (75 MHz, CDCl
3
) d 165.8, 136.8,
67.0899.
135.4, 127.2, 124.1, 122.7, 122.4, 120.9, 116.6, 112.4, 109.9, 64.4, 49.0, 20.4,
+
+
9. Dimethyl 2-(2-cyano-1-methyl-1H-indol-3-yl)-2-methylmalonate 14: The
13 3 2
14.1; HRMS (ESI ) calcd for C15H N O Na (MNa ) 290.0905, found 290.0903.
product was purified via flash chromatography (silica gel, hexanes:EtOAc
23. Diethyl 2-acetoxy-2-(2-cyano-1H-indol-3-yl)malonate 18: The product was
1
4
:1) to afford 14 as a white solid, 49 mg (63%), mp 124–125 °C; H NMR
purified via flash chromatography (silica gel, hexanes:EtOAc 4:1) to afford 18
1
(
300 MHz, CDCl
3
) d 7.51 (d, 1H, J = 8.3 Hz), 7.43–7.32 (m, 2H), 7.18 (t, 1H,
as a light yellow solid, 91 mg (72%), mp 124–126 °C; H NMR (300 MHz, CDCl
3
)
1
3
J = 6.8 Hz), 3.88 (s, 3H), 3.81 (s, 6H), 2.11 (s, 3H); C NMR (75 MHz, CDCl
1
3
3
) d
70.9, 138.1, 126.1, 124.9, 122.9, 122.1, 121.6, 113.4, 110.6, 108.8, 54.9, 53.4,
1.7, 23.0; HRMS (ESI ) calcd for C16
d 9.66 (br s, 1H), 7.89 (d, 1H, J = 8.3 Hz), 7.41–7.31 (m, 2H), 7.22-7.16 (m, 1H),
4.32–4.24 (m, 4H), 2.35 (s, 3H), 1.26–1.20 (m, 6H); 13C NMR (75 MHz, CDCl
3
) d
+
+
H
17
N
2
O
4
(MH ) 301.1188, found 301.1190.
169.8, 165.2, 136.9, 126.5, 123.7, 122.2, 122.1, 118.6, 113.4, 112.2, 105.4, 80.4,
+
+
Single crystals suitable for X-ray crystallography were grown from 100%
ethanol.
63.2, 20.5, 13.9; HRMS (ESI ) calcd for C18
H
18
2
N O
6
Na (MNa ) 381.1063, found
381.1055.
2
0. Diethyl 2-acetoxy-2-(2-cyano-1-methyl-1H-indol-3-yl)malonate 15: The product
24. Methyl 2-acetoxy-2-(2-cyano-1H-indol-3-yl)-3-oxobutanoate 19: The product
was purified via flash chromatography (silica gel, hexanes:EtOAc 4:1) to afford
was purified via flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford
19 as a light orange solid, 74 mg (67%), mp 132–134 °C; H NMR (300 MHz,
1
1
1
7
4
1
6
5 as a white solid, 70 mg (90%), mp 91–93 °C; H NMR (300 MHz, CDCl
3
) d
.90 (d, 1H, J = 8.3 Hz), 7.44–7.32 (m, 2H), 7.26–7.19 (m, 1H), 4.31–4.27 (m,
CDCl
3
) d 9.72 (br s, 1H), 7.70 (d, 1H, J = 8.3 Hz), 7.42–7.34 (m, 2H), 7.26–7.18
1
3
13
H), 3.91 (s, 3H), 2.35 (s, 3H), 1.30–1.21 (m, 6H); C NMR (75 MHz, CDCl
3
) d
(m, 1H), 3.88 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H); C NMR (75 MHz, CDCl ) d
3
69.6, 165.2, 138.1, 126.4, 123.8, 122.8, 122.2, 117.7, 112.8, 110.4, 109.4, 80.4,
196.7, 170.4, 166.7, 137.1, 126.5, 123.8, 122.9, 122.1, 117.4, 113.2, 112.5, 105.6,
+
+
+
+
3.1, 31.8, 20.6, 14.1; HRMS (ESI ) calcd for C19
H
20
2
N O
6
Na (MNa ) 395.1219,
85.8, 53.6, 26.4, 20.7; HRMS (ESI ) calcd for C16
H
14
2
N O
5
Na (MNa ) 337.0800,
found 395.1223. Single crystals suitable for X-ray crystallography were grown
from 100% ethanol.
found 337.0791.
25. Dimethyl 2-acetoxy-2-(2-cyano-1H-indol-3-yl)malonate 20: The product was
2
1. Diethyl 2-(2-cyano-1-methyl-1H-indol-3-yl)-2-(2-cyanoethyl)malonate 16: The
product was purified via flash chromatography (silica gel, hexanes:EtOAc 4:1)
purified via flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford 20
1
as a white solid, 94 mg (81%), mp 145–147 °C; H NMR (300 MHz, CDCl
3
) d 9.64
1
to afford 16 as a white solid, 67 mg (71%), mp 104–106 °C; H NMR (300 MHz,
(br s, 1H), 7.84 (d, 1H, J = 8.3 Hz), 7.42–7.33 (m, 2H), 7.26–7.18 (m, 1H), 3.81 (s,
6H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl
) d 170.1, 165.9, 137.0, 126.8, 123.8,
122.6, 121.9, 118.4, 113.4, 112.4, 105.5, 80.8, 54.0, 20.6; HRMS (ESI ) calcd for
CDCl
.82 (t, 2H, J = 7.6 Hz), 2.38 (t, 2H, J = 7.6 Hz), 1.27 (t, 6H, J = 7.1 Hz); C NMR
75 MHz, CDCl ) d 168.6, 138.1, 126.6, 124.6, 122.1, 121.4, 119.3, 119.1, 112.8,
3
) d 7.46–7.36 (m, 2H), 7.23–7.18 (m, 1H), 4.44–4.24 (m, 4H), 3.92 (s, 3H),
3
13
+
2
+
(
1
3
16 14 2 6
C H N O Na (MNa ) 353.0750, found 353.0740.
+
11.0, 109.9, 74.0, 63.1, 58.0, 32.0, 31.6, 14.0, 13.9; HRMS (ESI ) calcd for