Synthesis of indolines, indoles, and benzopyrrolizidinones from simple aryl azides

Article abstract of DOI:10.1021/ol301120w

A simple approach to prepare indolines and benzopyrrolizidinones from ortho-azidoallylbenzenes via a tandem radical addition/cyclization is described. The use of triethylborane to initiate and sustain the process provides the best results. Indolines are easily converted into the corresponding indoles by oxidation with manganese dioxide.

Full text of DOI:10.1021/ol301120w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Indolines, Indoles, and
Benzopyrrolizidinones from Simple Aryl
Azides
Franc-ois Brucelle and Philippe Renaud*
€
Universitat Bern, Departement fur Chemie und Biochemie, Freiestrasse 3, CH-3012
Bern, Switzerland
€
philippe.renaud@ioc.unibe.ch
Received April 26, 2012
ABSTRACT
A simple approach to prepare indolines and benzopyrrolizidinones from ortho-azidoallylbenzenes via a tandem radical addition/cyclization is
described. The use of triethylborane to initiate and sustain the process provides the best results. Indolines are easily converted into the
corresponding indoles by oxidation with manganese dioxide.
Indoline and indole derivatives are ubiquitous in nat-
ure as well as in compounds of pharmaceutical interest.1
Their preparation and functionalization are widely re-
cognized as a privileged field of investigation.2 Benzopyr-
rolizidines represent an important subclass of this family
of heterocycles, encompassing for instance the mitomycin
alkaloids.3 In the past 30 years, radical chemistry has
become a powerful tool for organic synthesis.4 Of parti-
cular interest, CÀN bonds have been shown to be readily
formed when organic azides were used as radical traps.5
In 1994, Kim et al. reported efficient radical cyclizations
onto aliphatic azides to prepare N-heterocycles using
tributyltin or tris(trimethylsilyl)silyl radicals and haloalk-
yl azides.6 A related strategy was applied by Murphy et al.
to the synthesis of the tetracyclic core of Aspidosperma
and Vinca alkaloids involving iodoaryl azides as key
intermediates.7 Radical cyclizations involving aromatic
azides are muchless documented.8 Spagnolo et al. reported
the formation of indoles by addition of sulfanyl or silyl
radicals onto (o-azidophenyl)acetylenes to generate vinyl
radicals which undergo intramolecular 5-exo cyclization.9
Here, we report a cascade reaction onto o-azidoallylben-
zenes involving a radical addition to the terminal double
bond followed by a cyclization onto the azido group in the
absence of a H-donor reagent (Scheme 1).
(1) For selected reviews, see: (a) Saxton, J. E. Nat. Prod. Rep. 1997,
14, 559–590. (b) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem.
Rev. 2010, 110, 4489–4497. (c) Ruiz-Sanchis, P.; Savina, S. A.; Albericio,
Indoline Synthesis. In a preliminaryexperiment, the con-
version of 2-allylaniline 3a to indoline 2a was attempted by
ꢀ
F.; Alvarez, M. Chem.;Eur. J. 2011, 17, 1388–1408.
(2) For selected reviews, see: (a) Humphrey, G. R.; Kuethe, J. T.
Chem. Rev. 2006, 106, 2875–2911. (b) Bandini, M.; Eichholzer, A.
Angew. Chem., Int. Ed. 2009, 48, 9608–9644. (c) Anas, S.; Kagan,
H. B. Tetrahedron: Asymmetry 2009, 20, 2193–2199. (d) Liu, D.; Zhao,
G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975–3984.
(3) For a recent review on the chemistry and biology of mitomycins,
see: Andrez, J.-C. Beilstein J. Org. Chem. 2009, 5, 33.
(4) (a) Renaud, P., Sibi, M. P., Eds. Radicals in Organic Synthesis;
Wiley-VCH: Weinheim, 2001. (b) Chatgilialoglu, C; Studer, A., Eds.
Synthetic Applications and Strategies. Encyclopedia of Radicals in Chem-
istry, Biology and Materials, Vol. 2; Wiley: Chichester, 2012.
(5) (a) Panchaud, P.; Chabaud, L.; Landais, Y.; Ollivier, C.; Renaud,
P.; Zigmantas, S. Chem.;Eur. J. 2004, 10, 3606–3614. (b) Minozzi, M.;
Nanni, D.; Spagnolo, P. Chem.;Eur. J. 2009, 15, 7830–7840.
(6) Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116, 5521–
5522.
(7) (a) Kizil, M.; Murphy, J. A. J. Chem. Soc., Chem. Commun. 1995,
1409–1410. (b) Kizil, M.; Patro, B.; Callaghan, O.; Murphy, J. A.;
Hursthouse, M. B.; Hibbs, D. J. Org. Chem. 1999, 64, 7856–7862. (c)
Patro, B.; Murphy, J. A. Org. Lett. 2000, 2, 3599–3601. (d) Zhou, S.;
Bommezijn, S.; Murphy, J. A. Org. Lett. 2002, 4, 443–445.
(8) Before publication of ref 9, only two papers were reported in the
literature: (a) Benati, L.; Montevecchi, P. C.; Spagnolo, P. Tetrahedron
Lett. 1978, 19, 815–818. (b) Benati, L.; Montevecchi, P. C. J. Org. Chem.
1981, 46, 4570–4573.
(9) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. Eur. J. Org.
Chem. 1998, 1219–1226.
r
10.1021/ol301120w
XXXX American Chemical Society

the desired 2-substituted indoline 2a in moderate yield
(Scheme 3).6 Attempts to optimize the cyclization reac-
tion by varying the initiator and by using Bu3SnH failed
to afford a higher yield.
Scheme 1. Radical Cascade onto ortho-Azidoallylbenzenes
Scheme 3. Initial Cascade Reaction Attempt
a two-step process consisting of the addition of ethyl
iodoacetate 4 under iodine atom transfer conditions
followed by an intramolecular nucleophilic substitution
(Scheme 2).10 However, the radical process did not take
place since N-alkylation of the aniline by the highly
reactive iodoacetate rapidly took place affording a mix-
ture of N-alkylated products. This simple approach was
therefore abandoned in favor of a radical cascade ap-
proach starting from 2-allyl-1-azidobenzene.
The use of triethylborane was investigated next. In the
presence of oxygen, Et3B efficiently produces ethyl radi-
cals that initiate radical chain processes, even at low tem-
perature.14 Moreover, it can also act as a chain transfer
reagent since it undergoes homolytic substitution with
aminyl radicals15 (such an intermediate aminyl radical is
expected in our proposed cascade; see Scheme 1). Based
on the tin-free conditions developed in our group for the
radical carboazidation,16 we first tried to prepare indoline
2a from azide 1a and iodide 4 in the presence of an excess
of Et3B in EtOH/H2O. Under these conditions, only the
iodine atom transfer product 5a was obtained (Table 1,
entry 1). With an open to air system the radical cascade
was still unsuccessful in EtOH/H2O. However, indoline
2a was obtained in 63% yield along with a small amount
of the corresponding indole 6a when benzene and 4 equiv
of Et3B were used (entry 2). Increasing the amount of
borane did not give a higher yield, and using less than 4
equiv resulted in the incomplete conversion of 5a to 2a.
Indeed, 5a was always formed after addition of the first
equivalent of Et3B, and its complete conversion to the
cyclized product occurred only after further addition 3
equiv of Et3B. Working with a slight excess of aryl azide
(ratio 1.5:1) afforded 2a in 88% yield contaminated by
9% of 6a (entry 3). The influence of the ratios of starting
materials on the yield is explained by minor side reactions
involving the azide.17 A rapid screening of solvents
(Table 1, entries 4À7) showed a significant reduction of
the formation of 6a when the reaction was carried out in
Scheme 2. Preliminary Experiment onto 2-Allylaniline
Several substituted 2-allyl-1-azidobenzenes 1 were read-
ily prepared according to literature procedures from com-
mercially available anilines via either a sequence involving
N-alkylation, aza-Claisen rearrangement, and mild con-
version into aryl azides or a two-step procedure using Stille
coupling.11 The tandem radical addition/cyclization was
then investigated using the model reaction between 1a
and ethyl iodoacetate 4 as a radical precursor. The reac-
tion temperature was critical for this transformation since
ortho-azidoallylbenzene derivatives are known to under-
go intramolecular cycloaddition at temperatures above
80 °C.9,12 In an initial attempt, the use of hexabutylditin
as a chain transfer reagent was tested (Scheme 3).13 This
reaction afforded exclusively the product of iodine atom
transfer 5a without cyclization. Treatment of the iodide
5a with (Me3Si)3SiH and AIBN as an initiator afforded
(14) Darmency, V.; Renaud, P. Top. Curr. Chem. 2006, 263, 71–106.
(15) For selected examples, see: (a) Bertrand, M. P.; Feray, L.;
Nouguier, R.; Stella, L. Synlett 1998, 780–782. (b) Miyabe, H.; Ueda,
M.; Naito, T. J. Org. Chem. 2000, 65, 5043–5047. (c) Ueda, M.; Miyabe,
H.; Miyata, O.; Naito, T. Tetrahedron 2009, 65, 1321–1326. (d) Valpuesta,
(10) For Et3B-induced halogen atom transfer reactions, see: (a)
Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.; Omoto,
K.; Fujimoto, H. J. Am. Chem. Soc. 2000, 122, 11041–11047. (b)
Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K.; Omoto,
K.; Fujimoto, H. J. Org. Chem. 2001, 66, 7776–7785.
(11) For detailledpreparation ofazides 1, see SupportingInformation.
(12) Smith, P. A. S.; Chou, S. P. J. Org. Chem. 1981, 46, 3970–3977.
(13) (a) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717–
4727. (b) Panchaud, P.; Ollivier, C.; Renaud, P.; Zigmantas, S. J. Org.
Chem. 2004, 69, 2755–2759.
~
M.; Munoz, C.; Dı
´
az, A.; Torres, G.; Suau, R. Eur. J. Org. Chem. 2010,
1934–1942.
(16) Panchaud, P.; Renaud, P. J. Org. Chem. 2004, 69, 3205–3207.
(17) Trace amounts of 2-propylindoline resulting from the addition
of an ethyl radical to the double bond of 1a followed by cyclization were
observed. By running the reaction in the absence of iodide 4, 2-propy-
lindoline could be isolated in 5À10% yield. Products resulting from an
intramolecular dipolar cycloaddition of the azidoalkene 1a could not be
identified, but this process could also be responsible for a partial
decomposition of 1a.
B
Org. Lett., Vol. XX, No. XX, XXXX

good H-donor solvents such as toluene (entry 4) or Et2O
(entry 7).
A plausible mechanism for our radical cascade is out-
lined in Scheme 5. Experimentally, we observed that the
intermediate iodine atom transfer product 5 accumulates
in the mixture during the first part of the reaction. Its
formation is optimal when 1 equiv of Et3B and a small
quantity of oxygen (<10 mol %) are used. The 5-exo
cyclization starts only when most of the ethyl iodoacetate
4 is consumed. To achieve an efficient cyclization, an ex-
cess of Et3B and oxygen is required. The chain is propa-
gated by reaction of the aminyl radical with triethylbor-
ane. Hydrolysis of the aminoborane during the reaction
(open flask) or during the workup procedure affords the
indoline 2. As previously reported, Et3B is proposed to
act as a radical initiator and a chain propagator.15 For-
mation of indole 6 presumably occurs by disproportiona-
tion of the aminyl radical or by H-atom abstraction
involving an ethyl radical.19 Indole 6 may also be gener-
ated from 2 since our open to air conditions should favor
the presence of radical species (oxygen-centered radicals
for instance) able to perform such oxidative side reac-
tions. This hypothesis is supported by a control experi-
ment furnishing a small quantity of indole 6a when 2a and
triethylborane were mixed together in benzene, in a flask
open to air without ethyl iodoacetate. Solvents able to
undergo competitive H-atom abstraction, like toluene or
Et2O, protect the indoline against such oxidations.
Table 1. Optimization of the Et3B-Mediated Cascade Reaction
Converting Azidoalkene 1a into Indoline 2a
1a/4
Et3B
(equiv)a
product
(yield)b
ratio
2a/6ac
entry
1
(equiv)
solvent
1/2
5
EtOH/H2O
2.3:1
5a (52%)
À
2d
3d
4d
5d
6d
7d
1/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
4
4
4
4
5
5
benzene
benzene
toluene
CH2Cl2
t-BuOH
Et2O
2a (63%)e
2a (88%)e
2a (82%)e
2a (82%)e
2a (62%)e
2a (40%)e
97:3
91:9
96:4
92:8
94:6
99:1
a 2 M solution of Et3B in EtOH used (entry 1) or 1 M in hexane
(entries 2À7). b Isolated yield based on the limiting reagent. c Determined
by 1H NMR on the purified mixture. d Open to air reaction. e Combined
yield of 2a and 6a.
2-Allyl-1-azidobenzenes 1bÀf were then submitted to
the radical cascade according to the optimized procedure
(Scheme 4). As expected, indolines 2 were obtained
in good yields when a slight excess (1.5 equiv) of the
azidoalkene 1 was used. Aryl azides bearing an electron-
donating group gave lower yields than those bearing an
electron-withdrawing group. Traces of the corresponding
indoles (<12%) were detected in all examples excepted
when azide 1f was used. Unsurprisingly, indole formation
is apparently favored by electron-donating substituents
and disfavored by electron-withdrawing substituents.18
Scheme 5. Proposed Mechanism
Scheme 4. Radical Cascade with Azidoalkenes 1bÀf
(18) Amounts of indoles
Information.
6 are reported in the Supporting
(19) A similar disproportionation event was observed by Zard et al.
during a radical cascade: Biechy, A.; Zard, S. Z. Org. Lett. 2009, 11,
2800–2803.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 6. Oxidation into Indoles
Scheme 7. Benzopyrrolizidinone Synthesis
Indole Synthesis. The formation of indole side products
during our radical cascade prompted us to investigate
conditions for the oxidation of our indolines. Manganese
dioxide was reported in the literature to be suitable for the
oxidation of indolines to indoles.20 After optimization of
the reaction conditions, 2a was efficiently converted into
6a in 84% yield (Scheme 6). Other indoles were also
prepared in good to high yields, except 6b which decom-
posed partly under our oxidation conditions. Attempts to
prepare indoles from azides 1 via a one-pot procedure
involving the radical cascade and the MnO2 oxidation
resulted in complex mixtures of products.
1a in 86% yield. This method compares favorably with
previous approaches.24
In conclusion, we have developed a mild and efficient
procedure to selectively prepare indolines and indoles via
a radical cascade starting from 2-allyl-1-azidobenzene
derivatives using tin-free conditions. The 2-substituted
indolines prepared by this process are readily transfor-
med by lactamization into benzopyrrolizidinones, the core
of several alkaloids.
Acknowledgment. We thank the Swiss National Science
Foundation (20020_135087) and the University of Bern
for financial support. We are grateful to Andreas Wenger
(University of Bern) for technical assistance. We thank
BASF Corporation for the generous gift of Et3B.
Benzopyrrolizidinone Synthesis. Benzopyrrolizidines
constitute the core structure of several natural products
such as mitomycins,3,21 a class of very potent antibiotic
and antitumor alkaloids, or flinderoles,22 which possess
selective antimalarial activity. Interestingly, the indoline
2a furnished the tricyclic lactam 7a in 90% yield by
simple treatment with camphorsulfonic acid (CSA) in
refluxing toluene (Scheme 7).23 The same benzopyrro-
lizidinone 7a was prepared in a one-pot sequence from
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) Jansen, A. B. A.; Johnson, J. M.; Surtees, J. R. J. Chem. Soc.
1964, 5573–5577.
(21) For a recent example of work related to mitomycins, see: Trost,
B. M.; O’Boyle, B. M.; Torres, W.; Ameriks, M. K. Chem.;Eur. J. 2011,
17, 7890–7903.
(23) Danishefsky, S. J.; Regan, J.; Doehner, R. J. Org. Chem. 1981,
46, 5255–5261.
(24) Danishefsky, S. J.; Doehner, R. Tetrahedron Lett. 1977, 35,
3029–3030.
(22) (a) Dethe, D. H.; Erande, R. D.; Ranjan, A. J. Am. Chem. Soc.
2011, 133, 2864–2867. (b) Zeldin, R. M.; Toste, F. D. Chem. Sci. 2011, 2,
1706–1709.
The authors declare no competing financial interest.
D
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