A furoindoline synthesis by remote radical functionalization

Article abstract of DOI:10.1016/j.tetlet.2012.07.115

The preliminary results of an investigation toward a synthesis of furoindolines from 3-(2-hydroxyethyl)indolines by remote radical functionalization are described. Using an oxidative radical cyclization, it was discovered that the intramolecular hydrogen abstraction was only successful when the resulting radical (and hence carbocation) was resonance stabilized by adjacent tertiary amine and phenyl groups. The successful cyclization affords diastereomeric furoindolines, one of which contains a highly strained trans-fused 5,5-ring system. This furoindoline synthesis contains a rare example of an alkoxy radical promoted hydrogen atom transfer of a proton attached to a nitrogen-substituted carbon.

Full text of DOI:10.1016/j.tetlet.2012.07.115

Tetrahedron Letters 53 (2012) 5426–5429
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A furoindoline synthesis by remote radical functionalization
⇑
Matthew B. Calvert, Jonathan Sperry
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The preliminary results of an investigation toward a synthesis of furoindolines from 3-(2-hydroxy-
ethyl)indolines by remote radical functionalization are described. Using an oxidative radical cyclization,
it was discovered that the intramolecular hydrogen abstraction was only successful when the resulting
radical (and hence carbocation) was resonance stabilized by adjacent tertiary amine and phenyl groups.
The successful cyclization affords diastereomeric furoindolines, one of which contains a highly strained
trans-fused 5,5-ring system. This furoindoline synthesis contains a rare example of an alkoxy radical pro-
moted hydrogen atom transfer of a proton attached to a nitrogen-substituted carbon.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 24 May 2012
Revised 13 July 2012
Accepted 27 July 2012
Available online 3 August 2012
Keywords:
Furoindoline
Radical
Remote functionalization
Heterocycle
Indoline
The furoindoline motif (1) is found in several natural products
with interesting biological properties and some members of this
class are shown in Figure 1. Physovenine was first isolated over a
century ago1 and possesses both anticholinergic and miotic activi-
ties2 along with potential for the treatment of Alzheimer’s disease.3
Madindoline A inhibits the growth of IL-6-dependent cell lines by
targeting gp1304 and aspidophylline A reverses drug resistance in
resistant KB cells.5
furoindoline 1 (Scheme 2). To the best of our knowledge, the alk-
oxy radical promoted abstraction of a H-atom attached to a nitro-
gen-substituted carbon under oxidative conditions is not known.13
Attempting the standard oxidative radical cyclization reaction
conditions10 on 3-(2-hydroxyethyl)indoline [( )-10]14 failed to
give the furoindoline ( )-11 and simply caused rapid degradation
of the starting material. This negative result was unsurprising
and attributed to competing N-iodination, and hence the reactive
amine was masked in order to eradicate any unwanted iodin-
ation at this site. Accordingly, triethylsilane-mediated reduction
of N-methyltryptophol (12)15 gave N-methyl-3-(2-hydroxyethyl)
The majority of furoindoline syntheses rely on the cyclization of
a precursor of type 2, which is usually generated from an oxindole
3 or tryptophol 46–9 (Scheme 1).
Although the synthetic methods outlined above have been suc-
cessful in accessing furoindolines, they can require harsh (often
acidic) conditions which may restrict their use with delicate sub-
strates. In what would constitute a novel approach based on re-
mote radical functionalization, we chose to investigate the
synthesis of furoindolines using an alkoxy radical promoted 1,5-
hydrogen atom transfer (1,5-HAT) reaction that has found wide-
spread application in the synthesis of tetrahydrofurans,10 spiroke-
tals,11 and carbohydrates.12 It was envisioned that the reduced
tryptophols [3-(2-hydroxyethyl)indolines, 5] could undergo initial
hypoiodite (6) formation from reaction with acetyl hypoiodite,
which is generated in situ from iodobenzene diacetate and iodine.
Photolytic cleavage of 6 would give the alkoxy radical 7 that, in
what constitutes the key remote functionalization step, would be
expected to undergo an intramolecular hydrogen abstraction
(1,5-HAT) to generate radical 8. Oxidation generates the resonance
stabilized carbocation 9 which undergoes cyclization to the desired
R1
H
Me
N
O
Me
O
O
R2
O
N
H
N
H
1
Me
physovenine
H
N
Me
OHC
O
HO
N
H
O
O
Me
HN
O
N
H
H
Me
CO2Me
O
H
O
aspidophylline A
Me
nBu
madindoline A
⇑
Corresponding author. Tel.: +64 9 373 7599x88269; fax: +64 9 373 7422.
E-mail address: j.sperry@auckland.ac.nz (J. Sperry).
Figure 1. Examples of furoindoline natural products.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.115

M. B. Calvert, J. Sperry / Tetrahedron Letters 53 (2012) 5426–5429
5427
R1
O
O
OH
O
O
(COCl)2
Et3N
O
OEt
Me
Et2O
Cl
Me
R1
R1
EtOH
N
H
Me
OH
R2
N
57%
O
R2
3
or
Me
N
N
15
from
Me
Me
N
N
15
17
H
16
2
1
OH
R2
(or iminium ion)
BH3·DMS
THF
89%
N
CF3
H
separate
OH
H
H
Me
18
O
-COCF3
then
OH
Me
4
O
NOE
NaBH3CN
TFA
NaHCO3
MeOH
Scheme 1. Traditional approaches to furoindolines (1).
3
2
Me
58%
N
N
N
18
from
Me
Me
Me
19
( )-
R1
18
R1
-20
( )
OH
O
R2
R2
Scheme 4. Synthesis of 3-(2-hydroxyethyl)indoline [( )-20].
N
P
N
P
5
1
PhI
2AcOI
PhI(OAc)2
+ I2
Conditions
I2 (2 eq.)
AcOH
PhI(OAc)2 (2.2 eq.), hν
R1
OH
R1
OH
R2
cyclohexane or CCl4
7 °C - r.t, 1-16 h
O
I
H
R2
N
P
9
O
Me
N
P
N
N
Me
P = protecting
group
Me
6
Me
21
( )-
20
( )-
hν
[O]
R1
I
Scheme 5. Failed cyclization of ( )-20.
R1
Intramolecular
hydrogen
O
OH
R2
abstraction
H
oxalyl chloride followed by ethanol. Borane-mediated reduction
of 17 gave tryptophol 18 that underwent reduction using Gribble’s
conditions17 to give trifluoroacetate ( )-19 along with trifluoro-
acetylated starting material ( )-18-COCF3. Chromatographic purifi-
cation of ( )-19 followed by basic hydrolysis gave the desired
reduced tryptophol ( )-20. 2D NMR experiments confirmed the
syn-relationship between the protons at C2 and C3 in compound
( )-20, with no anti-isomer observed (Scheme 4). Even though
the hydroxyethyl side chain (C3) and the proton at C2 were anti,
models suggested this would not have a detrimental effect on
the proposed intramolecular hydrogen abstraction (1,5-HAT)
event.
Disappointingly, the substrate ( )-20 failed to undergo cycliza-
tion, again leading to a complex mixture of products from which
the furoindoline ( )-21 could not be identified (Scheme 5). This
disappointing result suggested that the proton at C2 still did not
possess the requisite reactivity and accordingly, we set out to build
a substrate that would be more susceptible to intramolecular
hydrogen abstraction by the alkoxy radical.
In an analogous synthesis to that outlined in Scheme 4,
1-methyl-2-phenylindole (22)18 underwent reaction with oxalyl
chloride and the resulting intermediate 23 was treated with etha-
nol under basic conditions to give 24. Borane-mediated reduction
gave tryptophol 25 which underwent further reduction to give
the desired reduced tryptophol ( )-27 after basic hydrolysis of
the trifluoroacetate ( )-26 (Scheme 6).
2D NMR experiments again confirmed the syn-relationship be-
tween the protons at C2 and C3 in compound ( )-27, with no
anti-isomer observed (Scheme 6). Gratifyingly, upon subjecting
( )-27 to the standard oxidative radical cyclization conditions,
the furoindolines ( )-28a and ( )-28b were isolated in a 2:1 ratio
(Scheme 7).19
(1,5-HAT)
N
R2
N
P
P
8
7
Scheme 2. Proposed synthesis of furoindolines from 3-(2-hydroxyethyl)indolines
by remote radical functionalization.
OH
Conditions
I2 (2 eq.)
PhI(OAc)2 (2.2 eq.), hν
cyclohexane or CCl4
7 °C - r.t, 1-16 h
H
Conditions
O
2
N
H
( )-10
N
H
H
( )-11
OH
OH
Conditions
i. Et3SiH
TFA
ii. TBAF
THF
H
O
2
80%
N
N
N
H
Me
Me
Me
13
( )-
12
14
( )-
Scheme 3. Failed cyclization of 3-(2-hydroxyethyl)indolines [( )-10] and [( )-13].
indoline [( )-13].16 Disappointingly, subjecting ( )-13 to the same
reaction conditions led to a complex mixture of products, none of
which could be identified as furoindoline ( )-14 (Scheme 3).
At this stage it was considered that the secondary hydrogens
present at C2 in ( )-13 may not possess the requisite reactivity
to undergo successful abstraction by the alkoxy radical. In order
to test this hypothesis, we set out to employ a substrate that would
necessitate abstraction of a tertiary hydrogen, hence forming a
more stable tertiary radical (and tertiary carbocation upon oxida-
tion). 1,2-Dimethylindole (15) was converted into the ethyl gly-
oxylate 17 via glyoxylyl chloride 16 by initial treatment with
Due to the high level of ring strain present in trans-fused 5,5-
ring systems compared to their cis-fused counterparts,20 it was
naturally assumed ( )-28a was the major diastereomer and this

5428
M. B. Calvert, J. Sperry / Tetrahedron Letters 53 (2012) 5426–5429
References and notes
O
O
O
O
(COCl)2
Et2O
Et3N
1. (a) Salway, A. H. J. Chem. Soc. 1911, 99, 2148; (b) Robinson, B. J. Chem. Soc. 1964,
1503; (c) Takano, S.; Ogasawara, K. Alkaloids 1989, 36, 225.
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Neurochem. Int. 1998, 32, 413; (c) Sneader, W. Drug News Perspect. 1999, 12,
433.
OEt
Ph
Cl
Ph
EtOH
Ph
N
94%
N
N
Me
from 22
Me
Me
24
22
23
3. Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi, A. Med. Res. Rev.
1995, 15, 3.
4. (a) Hayashi, M.; Kim, Y.-P.; Takamatsu, S.; Enomoto, A.; Shinose, M.; Takahashi,
Y.; Tanaka, H.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 1091; (b)
Takamatsu, S.; Kim, Y.-P.; Enomoto, A.; Hayashi, M.; Tanaka, H.; Komiyama, K.;
Omura, S. J. Antibiot. 1997, 50, 1069; (c) Omura, S.; Hayashi, M.; Tomoda, H.
Pure Appl. Chem. 1999, 71, 1673.
5. (a) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama, K.; Kam,
T.-S. J. Nat. Prod. 2007, 70, 1783; (b) Subramaniam, G.; Kam, T.-S. Helv. Chim.
Acta 2008, 91, 930.
6. From oxindoles: (a) Horne, S.; Taylor, N.; Collins, S.; Rodrigo, R. J. Chem. Soc.,
Perkin Trans. 1 1991, 1, 3047; (b) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6500; (c) Suarez-Castillo, O. R.; Sanchez-Zavala, M.;
Melendez-Rodriguez, M.; Castelan-Duarte, L. E.; Morales-Rios, M. S.; Joseph-
Nathan, P. Tetrahedron 2006, 62, 3040; (d) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org.
Lett. 2009, 11, 3854.
BH3·DMS
THF
78%
separate
OH
NOE
H
CF3
25
-COCF3
then
OH
O
O
NaHCO3
MeOH
NaBH3CN
TFA
3
H
2
Ph
47%
Ph
N
N
from 25
Ph
Me
Me
N
( )-27
25
Me
( )-26
Scheme 6. Synthesis of 3-(2-hydroxyethyl)indoline [( )-27].
7. From tryptophols: (a) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.;
Hayashi, M.; Komiyama, K.; Ohmura, S.; Smith, A. B., III J. Am. Chem. Soc. 2000,
122, 2122; (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314; (c)
Zhu, Y.; Rawal, V. H. J. Am. Chem. Soc. 2012, 134, 111; An interrupted Fischer
reaction generates intermediates 2 directly from phenylhydrazines and lactols,
see: (d) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458; (e)
Schammel, A. W.; Boal, B. W.; Zu, L.; Mesganaw, T.; Garg, N. K. Tetrahedron
2010, 66, 4687.
8. (a) Kulkarni, M. G.; Dhondge, A. P.; Borhade, A. S.; Gaikwad, D. D.; Chavhan, S.
W.; Shaikh, Y. B.; Nigdale, V. B.; Desai, M. P.; Birhade, D. R.; Shinde, M. P. Eur. J.
Org. Chem. 2009, 3875; For examples of complementary routes that do not rely
on the classical cyclizations outlined in Scheme 1, see: (b) Liu, Y.; Xu, W.;
Wang, X. Org. Lett. 2010, 12, 1448.
9. Outside of the context of furoindoline synthesis, the cyclization of an oxygen
nucleophile onto a carbon atom adjacent to nitrogen is typically achieved by
amine?imine oxidation and subsequent nucleophilic attack. For
representative examples, see: (a) Chen, C.-K.; Hortmann, A. G.; Marzabadi, M.
R. J. Am. Chem. Soc. 1988, 110, 4829; (b) He, F.; Altom, J. D.; Corey, E. J. J. Am.
Chem. Soc. 1998, 121, 6771; (c) Moldvai, I.; Czántay, C., Jr.; Czántay, C.
Heterocycles 2001, 55, 2147.
H
3
O
I2, PhI(OAc)2
hν, cyclohexane
7 °C - r.t
OH
Ph
N
Ph
NOE
H
H
Me
( )-28a
H
45 min
2
H
N
40%
28a:28b
= 2:1
N
Me
NOE
O
Me
27
3
O
( )-
28a
N
Ph
Me
28b
( )-
Scheme 7. Successful furoindoline synthesis and key NOE interactions in ( )-28a
(ent-28a drawn for clarity purposes).19
10. (a) Paquette, L. A.; Sun, L. Q.; Friedrich, D.; Savage, P. B. J. Am. Chem. Soc. 1997,
119, 8438; (b) Chatgilialoglu, C.; Gimisis, T.; Spada, G. P. Chem. Eur. J. 1999, 5,
2866; (c) Bruke, S. D.; Kort, M. E.; Strickland, S. M. S.; Organ, H. M.; Silks, L. A.
Tetrahedron Lett. 1994, 35, 1503; (d) Hatakeyama, S.; Kawamura, M.; Takano, S.
J. Am. Chem. Soc. 1994, 116, 4081.
11. (a) Sperry, J.; Liu, Y.-C.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 29. The
synthesis of spiroaminals by 1,5- or 1,6-HAT is restricted to the cyclization of
an amine nucleophile onto a cation resonance stabilized by oxygen, see:; (b)
Koag, M.; Lee, S. Org. Lett. 2011, 13, 4766. and references therein.
12. (a) Martín, A.; Pérez-Martín, I.; Quintanal, L. M.; Suárez, E. Org. Lett. 2007, 9,
1785; (b) Martín, A.; Quintanal, L. M.; Suárez, E. Tetrahedron Lett. 2007, 48,
5507; (c) Francisco, C. G.; Herrera, A. J.; Suárez, E. J. Org. Chem. 2002, 67, 7439;
(d) Francisco, C. G.; Freire, R.; Herrera, A. J.; Pérez-Martín, I.; Suárez, E. Org. Lett.
2002, 4, 1959.
was confirmed based on the conclusive NOE interactions depicted
in Scheme 7. Despite ( )-28b being the minor diastereomer, the
formation of a strained trans-fused 5,5-ring system20 is notewor-
thy and speaks to the kinetic nature of this cyclization reaction.
In conclusion, we have investigated the synthesis of furoindo-
lines from 3-(2-hydroxyethyl)indolines by a remote intramolecular
free radical functionalization. It was discovered that the intramo-
lecular hydrogen abstraction was only successful when the result-
ing radical (and hence carbocation) was resonance stabilized by
nitrogen and an adjacent phenyl group. Although this appears to
limit this methodology to the synthesis of furoindolines bearing
a quaternary center at C2, the successful cyclization affords diaste-
reomeric furoindolines, one of which contains a highly strained
trans-fused 5,5-ring system. This reaction represents a rare exam-
ple of an alkoxy radical promoted hydrogen atom transfer of a pro-
ton attached to a nitrogen substituted carbon.13 The mild nature of
these cyclization conditions infers potential application in the syn-
thesis of other heterocyclic motifs (such as spiroaminals)21 and
other trans-fused 5,5-ring systems.
13. For an example of related 1,5-HAT under reductive conditions, see: Zhu, H.;
Wickenden, J. G.; Campbell, N. E.; Leung, J. C. T.; Johnson, K. M.; Sammis, G. M.
Org. Lett. 2009, 11, 2019 (see Table 2, compound 1i).
14. Hirose, T.; Sunazuka, T.; Yamamoto, D.; Kojima, N.; Shirahata, T.; Harigaya, Y.;
¯
Kuwajima, I.; Omura, S. Tetrahedron 2005, 61, 6015.
15. Garden, S. J.; da Silva, R. B.; Pinto, A. C. Tetrahedron 2002, 58, 8399.
16. TBAF work-up was required to hydrolyze the TES–ether of 13.
17. Gribble, G. W.; Hoffman, J. H. Synthesis 1977, 859.
18. Ishikura, M.; Terashima, M. J. Org. Chem. 1994, 59, 2634.
19. ( )-cis-Furoindoline (28a) and ( )-trans-furoindoline (28b)
To a solution of ( )-27 (40 mg, 160
added I2 (90 mg, 360 mol) at room temperature. Upon dissolution of iodine,
the solution was cooled to 7 °C and PhI(OAc)2 (100 mg, 320 mol) was added
lmol) in degassed cyclohexane (15 mL) was
l
l
and the reaction mixture irradiated with a desk lamp (60 W) for 45 min. The
reaction mixture was diluted with Et2O (20 mL) and saturated Na2S2O3
solution (50 mL) and the whole extracted with Et2O (3 Â 40 mL). The
combined organic extracts were dried (MgSO4), filtered and concentrated in
vacuo. Purification by preparative TLC eluting with CH2Cl2–MeOH (97.5:2.5)
Acknowledgment
We thank the School of Chemical Sciences, University of Auck-
land for the award of a summer research scholarship (M.B.C.).
gave the title compounds 28a (less polar) and 28b as
a
2:1 mixture of
diastereomers.
Compound 28a, brown solid (11 mg, 44 lmol, 27%); Mp 65–68 °C; m
max/cmÀ1
3260, 3061, 2927, 1703, 1602, 1464, 1361, 1040, 1014, 786, 701; HRMS Found:
[M]+, 251.1317. [C17H17NO]+ requires 251.1305; 1H NMR (400 MHz, acetone-
d6): dH = 8.00 (1 H, d, J = 1.6, ArH), 7.58–7.45 (7 H, m, ArH), 7.28 (1 H, d, J = 8.5,
ArH), 3.74–3.69 (2 H, m, CH + CH of CH2), 3.64–3.61 (1 H, m, CH of CH2), 3.59 (3
H, s, NMe), 2.86 (2 H, t, J = 7.2, CHCH2); 13C NMR (100 MHz, acetone-d6):
dC = 140.5 (C), 137.0 (C), 131.6 (3 Â CH), 130.4 (CH), 129.4 (CH), 129.2 (2 Â CH)
128.6 (CH) 112.8 (CH), 110.3 (C), 82.7 (C), 63.2 (CH2), 31.2 (NMe), 30.3 (CH),
29.2 (CH2); m/z (APCI) 251 (M+, 18%).
Supplementary data
Supplementary data (1H, 13C and associated 2D NMR spectra for
compounds ( )-27, ( )-28a and ( )-28b) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.07.115.

M. B. Calvert, J. Sperry / Tetrahedron Letters 53 (2012) 5426–5429
max/cmÀ1 3387, 3051, 2924,
5429
Compound 28b, brown oil (6 mg, 20
lmol, 13%);
m
20. trans-Fused 5,5-ring systems are quite rare. For examples, see: (a) Paquette, L.
A.; Morwick, T. M. J. Am. Chem. Soc. 1997, 119, 1230; (b) Paquette, L. A.; Hamme,
A. T., II; Kuo, L. H.; Doyon, J.; Kreuzholz, R. J. Am. Chem. Soc. 1997, 119, 1242; (c)
Paquette, L. A.; Kuo, L. H.; Tae, J. J. Org. Chem. 1998, 63, 2010; (d) Molander, G.
A.; Nichols, P. J.; Noll, B. C. J. Org. Chem. 1998, 63, 2292; (e) Jamison, T. F.;
Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1998, 119, 4253;
(f) Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem., Int. Ed. 2007, 46,
6586.
1724, 1604, 1469, 1363, 1046, 1013, 704; HRMS Found: [M+H]+, 252.
[C17H17NO+H]+ requires 252.1383; 1H NMR (400 MHz, acetone-d6): dH = 7.63
(1 H, d, J = 8.1, ArH), 7.57–7.53 (4 H, m, ArH), 7.52–7.45 (1 H, m, ArH), 7.39 (1 H,
d, J = 8.3, ArH), 7.19 (1 H, t, J = 8.0, ArH), 7.08 (1 H, t, J = 7.4 ArH), 3.74 (2 H, dt,
J = 7.5, 5.7, CHCH2), 3.59 (3 H, s, NMe), 3.57 (1 H, t, J = 5.7, CH), 2.90 (2 H, t,
J = 7.5, CH2OC); 13C NMR (75 MHz, acetone-d6): dC = 139.0 (C), 137.5 (C), 130.7
(3 Â CH), 129.6 (C), 128.3 (2 Â CH), 128.0 (CH), 121.4 (CH), 118.9 (C), 118.8
(CH), 109.4 (CH), 62.3 (CH2), 30.1 (CH), 29.1 (NMe), 28.6 (CH2); m/z (ESI)
252.1363 ([M+H]+, 82%), 234 (30), 126 (59).
21. Sinibaldi, M.-E.; Canet, I. Eur. J. Org. Chem. 2008, 4391.