Synthesis of spiroindolenine derivatives by a tandem radical-oxidation process

Article abstract of DOI:10.1016/j.tetlet.2009.07.037

In the present work, a novel stereoselective radical cyclization/oxidation/spirocyclization cascade process using a mixture of n-Bu₃SnH/ dilauroyl peroxide is described. The proposed mechanism for this later process combines a 6-endo cyclizatio

Full text of DOI:10.1016/j.tetlet.2009.07.037

Tetrahedron Letters 50 (2009) 5336–5339
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Synthesis of spiroindolenine derivatives by a tandem radical-oxidation process
*
Holber Zuleta-Prada, Luis D. Miranda
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacan, México, D.F. 04510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present work, a novel stereoselective radical cyclization/oxidation/spirocyclization cascade process
using a mixture of n-Bu3SnH/ dilauroyl peroxide is described. The proposed mechanism for this later pro-
cess combines a 6-endo cyclization of an aryl radical onto an enamide double bond, and a consecutive
oxidative-ionic spirocyclization at C-3 of an indole nucleus. All processes led to the construction of
new spiroindolenine derivatives in a one-step synthesis starting from relatively simple starting materials.
The organic peroxide appears to act as the initiator and the oxidant.
Received 2 June 2009
Revised 2 July 2009
Accepted 2 July 2009
Available online 10 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Indole alkaloids have been the object of numerous studies due
to their structural diversity and significant biological and pharma-
cological activities.1 The pentacyclic system common to several
natural product families, such as yohimbane2–5 and its isomers,
which possesses an aromatic E-ring 6 (Scheme 1), has been the
subject of several synthetic approaches by different methodolo-
gies.6 During the course of our ongoing studies on the radical-oxi-
dative addition to heteroaromatic systems, we recently embarked
on an investigation of the radical cascade process depicted in
Scheme 1. Ishibashi has previously used a 6-endo cyclization for
the synthesis of a variety of fused heterocyclic systems,7 and we
envisioned that a similar process might afford radical 2 from the
initial radical 1. Earlier, we showed that a radical alpha to a nitro-
gen atom could be oxidized under tin hydride-mediated condi-
tions.8 Thus, the use of a mixture of n-Bu3Sn/dilauroyl peroxide
(DLP) suggested the possible combination of this 6-endo radical
cyclization with a Pictet–Spengler type ring closure of the acyli-
minium ion 3, which would be derived from oxidation of the inter-
mediate radical 2.9 Based on the pioneering work of van Tamelen
et al.6a,b,10 on related acyliminium ion cyclizations (e.g., 3), kinetic
cyclization could take place at C-3 of the indole system, affording
the indolenine 5, which could undergo a Wagner–Meerwein rear-
rangement to the pentacyclic, thermodynamic product 6.11,12
The direct cyclization of radical 2 to radical 4 is also possible,
but the mismatched polarity resulting from the nucleophilic nature
of both the radical and the aromatic system is likely to disfavor this
reaction pathway. Regardless of whether this latter process oc-
curred, the outcome of the overall reaction would be the same,
with the DLP serving to oxidize the radical 4 to the indolenine 5
in a pathway similar to that reported previously.8 Our initial re-
sults of such a process are described herein.
The enamides 11a–b necessary for the tandem reaction process
were prepared in four steps (Scheme 2) from the corresponding o-
bromoaldehydes 8a–c. The amines 9a–c were synthesized by
reductive amination of 2-thiophenylethylamine 713 and aldehydes
8a–c. Acylation of amines 9a–c with 3-indolacetic acid provided
the amides 10a–c, which were sequentially oxidized to the sulfox-
ides and then subjected to thermolysis in refluxing xylene to give
the enamides 11a–b (Scheme 2).
Optimization of the conditions for the radical reaction was
examined using enamide 11a. Using a syringe pump, a solution
of n-Bu3SnH and DLP in benzene or toluene was slowly added to
a refluxing solution of 11a. In the first experiment using 1.3 equiv
O
O
N
6-endo
N
N
H
N
H
2
1
DLP
O
O
R1
R2
N
N
N
H
3
4
N
H
DLP
-H
-H
O
O
N
A
C
N
D
B
N
H
E
N
5
6
* Corresponding author. Tel.: +52 55 56 22 44 40; fax: +52 55 56 16 22 17.
E-mail address: lmiranda@unam.mx (L.D. Miranda).
Scheme 1. Radical-oxidative process.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.037

H. Zuleta-Prada, L. D. Miranda / Tetrahedron Letters 50 (2009) 5336–5339
5337
HN
SPh
11a
R1
R2
R1
R2
SPh
O
i
see
table 1
NH2
Br
Br
O
7
8a
8b
R1= OCH3 R2= OCH3
R1= R2 OCH2O
9a R1= OCH3 R2=OCH3 96%
O
9b
9c
R1= R2 OCH2O
R1= R2 = H
94%
95%
N
N
H
H
8c R1= R2 = H
N
O
N
H
OH
N
N
14
ii
H
12
O
OMe
OMe
N
H
OMe
OMe
O
13
OMe
O
O
N
OMe
O
SPh
N
N
iii, iv
N
H
N
OMe
OMe
N
H
H
N
Br
Br
OMe
R1
R1
6a
N
5a
OMe
R2
R2
11a R1= OCH3 R2= OCH3 79%
Scheme 3. Tandem radical-oxidation process.
10a
R1= OCH3 R2= OCH3 90%
11b R1= R2 OCH2O
11c
77%
76%
10b R1= R2 OCH2O
10c
94%
90%
R1= R2 = H
R1= R2 = H
formed in all the experiments. This product was formed presum-
ably as a consequence of the lauric acid produced from the perox-
ide during the oxidation process. Attempts to avoid this side
product by the addition of Na2CO3 to the reaction mixture, did
not improve the yields. We also searched for the dimers and/or tri-
mers of the indolenine 5a by HPLC/MS analysis of the crude reac-
tion mixture, but they were not present. To gain insights into the
reaction mechanism, the process was carried out using a catalytic
amount of ACN (1,10-azobis(cyclohexanecarbonitrile) as the initia-
tor (entry 9). Interestingly, the major product formed in this exper-
iment was the tetrahydroisoquinoline 13, and no trace of the
product which would be formed by reduction of the radical 4
was observed. The lack of this latter product suggests that the
cyclization of the radical 2 to the spiro-radical 4 is slower than for-
mation of iminium ion 5 in the presence of excess of DLP or reduc-
tion to 13 in the presence of Bu3SnH, when a catalytic amount of
ACN is used. These results are not conclusive, however, and more
experiments must be performed to firmly establish the actual
mechanistic pathway.
Scheme 2. Reagents and conditions: (i) MeOH, 8 h, rt, then NaBH4, 1 equiv, 12 h. rt;
(ii) DCC, CH2Cl2, rt 3 h; (iii) MCPBA, 1.5 equiv CH2Cl2, rt, 3 h; (iv) NaHCO3, 1 equiv,
120 h, xylene, reflux.
of n-Bu3SnH and 1.5 equiv of DLP in benzene at reflux temperature,
12, the compound of premature reduction, was obtained as the
major product (Table 1, entry 1, Scheme 3), accompanied by a min-
or amount (5%) of 13, another product of premature reduction
(Scheme 3), as well as starting material (ꢀ20%). Interestingly, the
desired pentacyclic product 6a was not observed in the reaction
mixture, but the indolenine 5a was isolated as a single diastereo-
isomer (18%). In an attempt to minimize premature reduction of
the intermediate radicals, and thus improve the yield of 5a, the
reaction was carried out using [(CH3)3Si]3SiH as the propagating
agent, but the reaction profile did not change (entry 2). Prolonging
the addition time of the n-Bu3SnH/DLP solution and the utilization
of 2 equiv of DLP both served to favor the production of 5a (entries
3 and 4). Finally, compound 5a was produced most efficiently
when toluene was used as the solvent (entries 4 and 6).14 Further
increases in both reaction time and DLP neither reduced the forma-
tion of 12 and 13, nor increased the production of 5a. Dibenzoyl
peroxide and dicumyl peroxide were also examined. Although
the desired product was isolated, these peroxides proved to be less
efficient than DLP in the production of 5a (entries 7 and 8).
A significant amount of the product 14, which comes from the
hydrolysis of the enamide moiety in the starting material, was
Under the optimized conditions (entry 4),14 acyl enamides 11b
and 11c also afforded the corresponding indolenines 5b and 5c as
the major products (Scheme 4).
The structure of 5a was confirmed by its NMR spectral features.
The 1H NMR spectrum of compound 5a showed a signal at d
8.26 ppm (singlet 1H), and two groups of signals at d 4.05–
4.02 ppm and d 2.9–2.49, typical for an A2X system for protons at
100 and 10a0. The 13C NMR spectrum exhibits the signals at d
Table 1
Optimization of product yield
Entry
Conditionsa
t (h)
Yield (%)
5a
12
13
14
1
2
3
4
5
6
7
8
9
n-Bu3SnH (1.3 equiv) DLP, (1.5 equiv), benzene, reflux
[(CH3)3Si]3SiH (1.5 equiv) DLP, (1.5 equiv), benzene, reflux
n-Bu3SnH (1.5 equiv) DLP, (2.0 equiv), benzene, reflux
n-Bu3SnH (1.5 equiv) DLP, (2.0 equiv), toluene reflux
[(CH3)3Si]3SiH (1.5 equiv) DLP, (2.0 equiv), benzene, reflux
[(CH3)3Si]3SiH (1.5 equiv) DLP, (2.0 equiv), toluene, reflux
n-Bu3SnH (1.5 equiv) DBP, (2.0 equiv), toluene, 95 °C
n-Bu3SnH (1.5 equiv) DCP, (2.0 equiv), chlorobenzene
n-Bu3SnH (1.5 equiv) ACCN (0.5 equiv), toluene
3
3
5
5
5
5
5
5
5
18
20
25
40
32
37
20
24
25
20
nd
15
nd
10
nd
nd
23
5
5
nd
11
10
12
10
nd
nd
28
15
16
12
15
14
nd
nd
Traces
a
Concentration: 0.1 mmol/mL for both the starting material and the added solution of n-Bu3SnH/DLP.

5338
H. Zuleta-Prada, L. D. Miranda / Tetrahedron Letters 50 (2009) 5336–5339
sions. We also thank H. Rios, R. Patiño, J. Pérez, L. Velasco, N. Zavala,
O
E. Hernandez, I. Chavez, and A. Peña for technical support.
n-Bu3SnH (1.5 eq)
DLP, (2.0 eq)
N
R1
R2
References and notes
11b, 11c
Toluene,
reflux, 5h
N
1. (a) Cordell, G. A.. Introduction to Alkaloids. In A Biogeneric Approach; Wiley
Interscience: New York, 1981. pp 574–832; (b)The Alkaloids, Chemistry and
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Indole Alkaloids; Saxton, J. E., Ed.; Vol 25; Wiley: New York, 1983; pp 147–199.
part 4.
5b R1= R2 OCH2O 40%
5c R1= R2 = H 35%
Scheme 4. Spirocyclization of 11b and 11c.
3. Merlini, L.; Mondelli, R.; Nasini, G.; Hesse, M. Tetrahedron 1967, 23, 3129.
4. Peube-Locou, N.; Plat, M. Phytochemistry 1973, 12, 199.
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Am. Chem. Soc. 1958, 80, 5006; (b) van Tamelen, E. E.; Shamma, M.; Burgstahler,
A. W.; Wolinsky, J.; Tamm, R.; Aldrich, P. E. J. Am. Chem. 1969, 91, 7315–7333;
(c) Stork, G.; Guthikonda, R. N. J. Am. Chem. Soc. 1972, 94, 5109–5110; (d)
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A. I.; Miller, D. B.; White, F. H. J. Am. Chem. Soc. 1988, 110, 4778; (h) Cobas, A.;
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Miyata, O.; Ninomiya, I. Chem. Pharm. Bull. 1991, 39, 2216; (j) Aube, J.; Gosh, S.;
Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009; (k) Padwa, A.; Beall, L. S.;
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Tanaka, M.; Toyofuku, E.; Demizu, Y.; Yoshida, O.; Nakazawa, K.; Sakai, K.;
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W. S.; Tasi, M. R.; Wang, Y. S.; Chang, N. C. Tetrahedron 2005, 61, 585; (n)
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NH
HN
MeO
MeO
MeO
MeO
N
N
O
O
Endo
Exo
N
H
2
N
H
10'
NOE
3
10a'
MeO
MeO
MeO
MeO
H
H
H
H
N
N
5'
O
O
7. (a) Ishibashi, H.; Inomata, M.; Ohba, M.; Ikeda, M. Tetrahedron Lett. 1999, 40,
1149; (b) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem.
Commun. 2000, 1527; (c) Ohba, M.; Kubo, H.; Ishibashi, H. Tetrahedron 2000, 56,
7751; (d) Ishibashi, H.; Ishita, A.; Tamura, O. Tetrahedron Lett. 2002, 43, 473; (e)
Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.; Tanabe, G.;
Ishibashi, H. J. Org. Chem. 2005, 70, 1922; (f) Taniguchi, T.; Iwasaki, K.;
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T.; Ishibashi, H. Org. Lett. 2008, 10, 4129.
Unfavored
Favored
Figure 1. Stereoselectivity in the spirocyclization process.
172.9 ppm (C-2) and d 59.9 ppm (C-3), assigned to a C-imine and C-
spiro quaternary carbon, respectively, values confirmed by a dis-
tortionless enhancement by polarization transfer (DEPT) experi-
ment. The heteronuclear single quantum correlation (HSQC)
experiment showed the correlation C-H 172.9–8.26 ppm and
established the occurrence of the C–H imine. The stereochemistry
of 5a was supported by a NOESY experiment which confirmed the
correlation between protons C-2 and one of the C-100protons and
the C-50 proton (Fig. 1). The high diastereoselectivity of the process
can be rationalized on the basis of the endo/exo models in the
cyclization process as depicted in Figure 1. It is likely that there
is a strong steric repulsion between the hydroisoquinoline ring
and the aromatic ring of the indole nucleus in the endo model. In
contrast, these stereoelectronic interactions are alleviated in the
exo model, facilitating the formation of 5a. In a previous study of
related systems, the mixture of the two possible diastereoisomers
was observed. Apparently, the presence of the fused benzene ring
in the piperidine moiety (isoquinoline moiety) is responsible for
the repulsive interactions in the present system.
8. (a) Guerrero, M. A.; Cruz-Almanza, R.; Miranda, L. D. Tetrahedron 2003, 59,
4953; (b) Miranda, L. D.; Zard, S. Z. Org. Lett. 2002, 4, 1135; See also: (c)
Friestad, G. K.; Wu, Y. Org. Lett. 2009, 11, 819; For
a related oxidative
spirocyclization using DLP see: (d) Guindeuil, S.; Zard, S. Z. Chem. Commun.
2006, 665.
9. For reviews in the area of radical-ionic processes: (a) Zard, S. Z. Radical
Reactions in Organic Synthesis; Oxford, 2003. p 193; (b) Godineau, E.; Landais, Y.
Chem. Eur. J. 2009, 15, 3044; (c) Murphy, J. A.. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, p 298;
Selected recent publications: (d) Korapala, C. S.; Qin, J.; Friestad, G. K. Org. Lett.
2007, 9, 4243; (e) Bertrand, M. P. Tetrahedron 2005, 61, 4261; (f) Ueda, M.;
Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem., Int. Ed. 2005, 44,
6190; (g) Denes, F.; Cutri, S.; Perez-Luna, A.; Chemla, F. Chem. Eur. J. 2006, 12,
6506; (h) Maruyama, T.; Suga, S.; Yoshida, J. Tetrahedron 2006, 62, 6519; (i)
Maruyama, T.; Mizuno, Y.; Shimizu, I.; Suga, S. J. Am. Chem. Soc. 2007, 129, 1902.
10. Van Tamelen, E. E.; Weber, J.; Schiemenz, G. P.; Baker, W. Bioorg. Chem. 1976, 5,
283.
11. Wenkert, E.; Orito, K.; Simmons, D. P.; Kunesch, N.; Ardisson, J.; Poisson, J.
Tetrahedron 1983, 39, 3719.
12. King, F. D. J. Heterocycl. Chem. 2007, 44, 1459.
13. Ishibashi, H.; Uegaki, M.; Sakai, M.; Takeda, Y. Tetrahedron 2001, 57, 2115.
14. General
procedure.
70,80-dimethoxy-100,10a0-dihydro-20H-spiro[indole-3,10-
pyrrolo[1,2-b]isoquinolin]-30(50H)-one (5a): To
a
deaerated solution of
enamide 11a (0.15 g, 0.35 mmol) and Na2CO3 (0.03 g, 0.35 mmol) in 5 mL of
toluene at 95 °C, a solution of n-Bu3SnH (0.15 g, 0.52 mmol) (0.1 mmol/mL)
and 0.27 g (0.72 mmol) of dilauroyl peroxide in toluene (5 mL), was added
dropwise (syringe pump) over 5 h. The reaction mixture was then cooled and
the solvent was removed under reduced pressure. The crude residue was
stirred with an 8% solution of KF in water (10 mL) over night. Then, saturated
solution of NaHCO3 was added (250 mL) and the resulting mixture was
extracted with CH2Cl2 (3 ꢁ 25 mL). The organic layer was dried over Na2SO4.
The solvent was then removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (Hexanes–EtOAc) to give 5a
(0.049 g, 40% yield) as yellow oil. 1H NMR (500 MHz, CDCl3) d ppm: 8.26 (s,
1H), 7.70 (d, J = 7.50 Hz, 1H), 7.45–7.42 (m, 2H), 7.33 (dd, J = 7.5, 15 Hz, 1H),
6.64 (s, 1H), 6.49 s, 1H), 4.96 (d, J = 17.0 Hz, 1H), 4.41 (d, J = 17.0 Hz, 1H), 4.03
(dd, J = 4.0, 11.5 Hz, 1 H), 3.86 (s, 3H), 3.77 (s, 3H), 2.91–2.75 (m, 3H), 2.51 (dd,
J = 4.0, 15.0, Hz, 1H). 13C NMR (125 MHz, CDCl3) d ppm: 172.9, 171.6, 154.6,
148.4, 148.0, 139.6, 129.1, 127.3, 124.1, 122.9, 121.6, 121.3, 111.6, 109.2, 60.3,
59.9, 56.0, 55.9, 42.9, 36.4, 31.3. IR (film): 3342, 3010, 2925, 2854, 1684, 1516,
1462, 1264, 1107, 753. MS (EI) m/z = 348 (100%). HRMS calcd for C21H20O3N2:
349.1552. Found 349.1542.
Finally, several reaction conditions, such as p-toluenesulfonic
acid or BF3–Et2O in refluxing toluene, or trifluoromethanesulfonic
acid in hot dioxane (100 °C)11 all failed to transform the spirocyclic
system 5a into the corresponding pentacyclic system 6a. Initially,
no reaction was observed and only decomposition of the starting
material occurred after longer reactions times (5 h).
In summary, in the present work, we report a novel, stereose-
lective, tandem 6-endo radical cyclization–oxidation-ionic spiro-
cyclization process, using a n-Bu3SnH/DLP mixture, which has
given access to new spiroindolenines. The organic peroxide acts
as both the initiator and the oxidant.
Acknowledgments
9a,10-Dihydro-5H-spiro[[1,3]dioxolo[4,5-g]pyrrolo[1,2-b]isoquinoline-9,30-indol]-
7(8H)-one (5b) (40% yield) as yellow oil. 1H NMR (500 MHz, CDCl3) d ppm: 8.24
We thank CONACYT (J42673Q, 82643) for generous financial
support and Dr. Joseph M. Muchowski for many helpful discus-

H. Zuleta-Prada, L. D. Miranda / Tetrahedron Letters 50 (2009) 5336–5339
5339
(s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.45–7.42 (m, 2H), 7.33 (dd, J = 7.5, 15.0 Hz, 1H),
6.62 (s, 1H), 6.46 (s, 1H), 5.92 (s, 1H), 4.91 (d, J = 17 Hz, 1H), 4.39 (d, J = 17 Hz,
1H), 4.01 (dd, J = 4.0, 11.5 Hz, 1H), 2.87–2.75 (m, 3H), 2.47 (dd, J = 4.0, 15 Hz, 1
H). 13C NMR (125 MHz, CDCl3) d ppm: 172.7, 171.5, 154.7, 147.1, 146.7, 139.1,
129.1, 127.3, 125.2, 124.1, 121.7, 121.3, 108.7, 106.4, 101.5, 60.1, 59.1, 43.2,
36.4, 31.7. IR (film): 3323, 3054, 2923, 2849, 1688, 1484, 1239, 1037. MS (EI)
m/z = 332 (20%). HRMS calcd for C20H16O3N2: 333.1239. Found 333.1241.
100,10a0-Dihydro-20H-spiro[indole-3,10-pyrrolo[1,2-b]isoquinolin]-30(50H)-one
(5c) (30% yield) as yellow oil. 1H NMR (500 MHz, CDCl3) d ppm: 8.26 (s, 1H),
7.70 (d, J = 7.5 Hz, 1H), 7.47–7.42 (m, 2H), 7.33 (dd, J = 7.5, 15 Hz, 1H), 7.23–
7.15 (m, 3H), 7.04–7.01 (m, 1H), 5.02 (d, J = 17 Hz, 1H), 4.51 (d, J = 17 Hz, 1H),
4.06 (dd, J = 4.0, 11.5 Hz, 1H), 2.96–2.77 (m, 3H), 2.59 (dd, J = 4.0, 15 Hz, 1H).
13C NMR (125 MHz, CDCl3) d ppm: 172.7, 171.6, 154.6, 139.3, 132.1, 131.0,
129.1, 129.0, 127.3, 127.2, 127.0, 126.7, 121.6, 121.3, 60.1, 59.9, 43.2, 36.4,
31.7. IR (film): 3340, 3026, 2927, 2855, 1687, 1478, 1243, 1039. MS (EI) m/
z = 288 (70%). HRMS calculated for C19H16ON2: 289.1341. Found 289.1343.