Pd-Catalyzed Migratory Cycloisomerization of N-Allyl- o-allenylaniline Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00676

The Pd-catalyzed migratory cycloisomerization of N-allyl-o-allenyl aniline derivatives is first reported to give indoles having a substituent at the 2-position.

Full text of DOI:10.1021/acs.orglett.9b00676

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Migratory Cycloisomerization of
N‑Allyl‑o‑allenylaniline Derivatives
Yasuhiro Ii, Satoru Hirabayashi, Shohei Yoshioka, Hiroshi Aoyama, Kenichi Murai,
Hiromichi Fujioka, and Mitsuhiro Arisawa*
Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The Pd-catalyzed migratory cycloisomerization of N-allyl-o-allenyl aniline derivatives is first reported to give
indoles having a substituent at the 2-position.
ransition-metal-catalyzed migratory cycloisomerization
cyclization to yield complex skeletons.14 Allenes have been
found to possess unique reactivity toward a number of
transition metals, such as Pd,15 Ni,16 Ru,17 Rh,18 and Au.19
Recently, we also reported the Ru-catalyzed [2 + 2] reaction of
N-allenyl-o-vinyl aniline derivatives.17c However, to the best of
our knowledge, there have been no reports of migratory
cycloisomerizations between allenes and amines having a
migrating group on the heteroatom that could lead to a variety
of substituted heterocycles.
1,2
Tprovides a powerful approach in organic synthesis.
In
particular, migratory cycloisomerizations of o-alkynylaryl ethers
and amines having a migrating group on the heteroatom have
been used to the synthesis of 2,3-disubstituted benzofurans and
indoles (Scheme 1, eq 1). As migrating groups, α-alkoxyalkyl,3
allyl,3b,4 propargyl,5 benzyl,3b,6 acyl,3g,7 methyl,8 sulfonyl,4l,9
silyl,10 boryl11 groups, and so on12 have been employed.
Allenes, a class of readily accessible, air- and water-stable
compounds, show interesting and varied reactivity patterns as a
result of their unique chemical properties,13 and are now
becoming an integral part of modern synthetic methods in
In this letter, we report an unprecedented Pd-catalyzed
migratory cycloisomerization of N-allyl-o-allenyl aniline de-
rivatives 1 (Scheme 1, eq 2).
First, the reaction of N-allyl-N-toluenesulfonyl-o-allenyl
aniline 1a with various transition metal catalysts in toluene
as solvent was investigated. When an organometallic catalyst
(Ru, Au, Pt, In, Ni, Rh, and so on), which has worked well in
cycloisomerization or migratory cycloisomerization, was used,
no cyclization proceeded. However, when palladium acetate,
Pd(OAc)2 (10 mol %), and triphenylphosphine, PPh3 (20
mol %), were used, migratory cycloisomerization proceeded to
give 2-butenylindole 2a in 42% yield (Table 1, entry 1).
In entries 1−5, 10 mol % of Pd(OAc)2 was used and the
catalytic amount of PPh3 as ligand was investigated. As a result,
when the amount of ligand was reduced from 20 mol %, the
yield of 2a decreased (entry 2), and 2a was not obtained in the
absence of the ligand (entry 3). When the amount of ligand
was increased from 20 mol %, the yield of 2a increased; when
45 mol % PPh3 was used, the yield of 2a reached 75% (entry
5). In entries 6−8, the Pd catalyst was changed. When
Scheme 1. Migratory Cycloisomerizations
Received: February 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Conditions Optimization; Migratory
Cycloisomerization of 1a
Table 2. Effect of Substituent on Nitrogen(I)
entry
substrate
R =
time (h)
product
yield (%)
a
1
2
3
4
5
1a
1b
1c
1d
1e
Ts
3
5
3
2.5
2.5
2a
2b
2c
2d
2e
83
79
44
0
entry cat. Pd (mol %)
ligand (mol %) time (h) yield of 2a (%)
Ms
Ns
Ac
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd(PPh3)4 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (2)
Pd2(dba)3 (1)
Pd2(dba)3 (10)
PPh3 (20)
PPh3 (15)
−
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
3
42
28
0
Boc
0
PPh3 (30)
PPh3 (45)
PPh3 (45)
−
58
75
83
0
to 44%. From these results, it might be considered necessary to
use a substrate having electron-withdrawing groups at least to
some extent on nitrogen for this reaction to proceed.
Subsequently, the effect of substituents on the aromatic ring
was studied (Table 3). Substrates 1f, 1g, 1h, and 1i had chloro
−
83
0
0
9
P(o-tol)3 (45)
P(t-Bu)3 (45)
PCy3 (45)
P(OPh)3 (45)
P(OMe)3 (45)
PPh3 (9)
PPh3 (4.5)
10
11
12
13
14
15
16
0
Table 3. Effect of Substituent on Aromatic Ring
82
83
77
49
77
b
PPh3 (45)
a
b
Based on the catalyst complex. 1 mmol-scale reaction.
Pd2(dba)3 and 45 mol % PPh3 were used, 2a was obtained in
83% yield (entry 6). When Pd(PPh3)4 was used, 2a was
obtained in the same yield even in the absence of a ligand
(entry 8). These results proved that zerovalent Pd is a reactive
species.20 Subsequently, we decided to study the reaction
solvent and temperature using the conditions of entry 6.
Next, we decided to investigate the effect of the ligand on
this reaction (entries 9−13). In investigations using ligands
bulkier than triphenylphosphine (cone angle θ = 145°)
(entries 9−11),21 the reaction did not proceed. Then we
examined ligands less bulky than triphenylphosphine (entries
12−13). As a result, product 2a was obtained in the same yield
as when triphenylphosphine was used. The bidentate ligands
( )-BINAP and 2,2′-bipyridyl were used, but this reaction did
not proceed. From the above results, it was found that the
reaction did not proceed when the bulkiness of the ligand was
increased above a certain extent, so triphenylphosphine was
selected as the optimum ligand in consideration of its stability.
From entries 6, 14, and 15, we knew that we could reduce the
amount of catalyst to 2 mol % palladium. Also, even in a 1-
mmol-scale reaction, we could obtain the product 2a in almost
the same yield (entry 16).
We continued our experiments to study the scope and
generality of this reaction using the conditions of Table 1,
entry 6. First, the protecting group on nitrogen was studied
(Table 2). The expected product was obtained from a
substrate containing a p-toluenesulfonyl, a methanesulfonyl,
or an o-nitrobenzenesulfonyl group (entries 1−3). But a
substrate containing a less electron-withdrawing group, such as
an acetyl or a tert-butoxycarbonyl group, was recovered
unchanged (entries 4 and 5). From substrates containing a
p-toluenesulfonyl or a methanesulfonyl group, the correspond-
ing products were obtained in high yields of 83% and 79%,
respectively, whereas, for an o-nitrobenzenesulfonyl-containing
substrate, the yield of the corresponding product was reduced
entry
substrate
R1 =
R2 =
R3 =
product
yield (%)
1
2
3
4
5
6
7
8
9
1a
1f
1g
1h
1i
1j
1k
1l
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
2a
2f
2g
2h
2i
2j
2k
2l
83
0
3-Cl
4-Cl
5-Cl
6-Cl
5-Me
5-OMe
5-F
90
82
82
79
30
62
56
66
1m
1n
H
H
2m
2n
10
groups at the 3-, 4-, 5-, and 6-positions on the aromatic ring,
respectively. It was confirmed that 1g, 1h, and 1i were
converted to the corresponding products in 90%, 82%, and
82% yield, respectively (entries 3−5). In stark contrast, 1f, with
a chloro group at the 3-position, was recovered unchanged
(entry 2). In view of the fact that the present cyclization
reaction was carried out in the presence of Pd, when the
substituent is located at the 6-position but not when the
substituent is at the 3-position, although both are 1,2,3-
trisubstituted benzene, it is suggested that the catalyst reacts
initially with the allyl group rather than the allene, and
cyclization proceeds. In other words, when a substituent is
present at the 3-position, the distance between the nitrogen
and the central allene carbon becomes greater, which is
considered to be difficult to cyclize. Substrates 1j, 1k, and 1l
having a methyl, methoxy, or fluoride group at the 5-position,
as an electron-donating or much more electron-withdrawing
group, respectively, reacted in 79%, 30%, and 62% yields
(entries 6−8). Also, 1m and 1n, having a substituent at the
allyl moiety, were converted to 2m and 2n in 56% and 66%
yield, respectively (entries 9 and 10).
B
DOI: 10.1021/acs.orglett.9b00676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Subsequently, the effect of the allyl group on nitrogen was
examined by using substrates substituted with other alkyl
groups (Scheme 2). First, when the allyl group was changed to
Scheme 3. Crossover Experiments
Scheme 2. Effect of Substituent on Nitrogen(II)
a
No catalysists were added.
Scheme 4. Plausible Reaction Mechanism
a vinyl group, a product obtained by migratory cyclo-
isomerization could not be confirmed, and compound 3,
considered to be formed by the [2 + 2] cyclization addition
reaction, was obtained in 93% yield. Compound 3 was
determined by X-ray crystal structure analysis (CCDC
1898621; Figure 1). As a result of various investigations, it
explains the following results: (1) The reaction is an
intramolecular cyclization and does not proceed unless the
ligand is sufficiently small. (2) It is necessary to stabilize the
negative charge on the nitrogen of the π-allyl intermediate with
a group of some electron-withdrawing character; conversely if
the electron-withdrawing property is too high, the yield
decreases. (3) With the substrate having a substituent at the
3-position on the aromatic ring, the reaction did not proceed
due to steric hindrance.
In conclusion, we have developed, for the first time to our
knowledge, a Pd-catalyzed migratory cycloisomerization of 1,
containing allene and allylic amine moieties, to give 2-
substituted indoles 2. We also found that the thermal [2 +
2] cyclization addition reaction of compound 1k, containing
allene and vinyl amine moieties, proceeded preferentially over
the migratory cycloisomerization.
Figure 1. X-ray structure of 3.
was found that this reaction did not require a transition metal
catalyst and proceeded quantitatively by heating. In addition,
when substrates 1p, 1q, and 1r in which the allyl group was
changed to a methyl, a cyclopropylmethyl group, or a benzyl
group, respectively, were subjected to the same reaction
conditions, migratory cycloisomerization did not proceed and
the raw materials were recovered unchanged.
Finally, in order to ascertain whether this reaction is an
intramolecular rearrangement or an intermolecular rearrange-
ment reaction, we decided to carry out a crossover experiment.
Substrate 1b, having a mesyl group and an allyl group on the
aromatic amino group, and substrate 1n, having a p-
toluenesulfonyl group and a 2-butenyl group, were subjected
to reflux heating in toluene in the presence of a Pd catalyst. We
obtained compounds 2b and 2n only, which result from
reaction in the molecule (Scheme 3). This revealed that this
reaction is an intramolecular rearrangement reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00676.
1
Experimental procedures, characterization data, H and
Based on the experimental results, the mechanism of this
reaction is proposed to be as shown in Scheme 4, which
13C NMR spectra for compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b00676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
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(6) (a) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett.
2008, 10, 2649−2651. (b) Sato, T.; Nakamura, I.; Terada, M. Eur. J.
Org. Chem. 2009, 2009, 5509−5512.
CCDC 1898621 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(7) (a) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 10546−10547. (b) Nakamura, I.; Sato, Y.; Konta, S.;
Terada, M. Tetrahedron Lett. 2009, 50, 2075−2077. (c) Wu, C. Y.;
Hu, M.; Liu, Y.; Song, R. J.; Lei, Y.; Tang, B. X.; Li, R. J.; Li, J. H.
Chem. Commun. 2012, 48, 3197−3199. (d) Li, G.; Huang, X.; Zhang,
L. Angew. Chem., Int. Ed. 2008, 47, 346−349. (e) Zhao, F.; Zhang, D.;
Nian, Y.; Zhang, L.; Yang, W.; Liu, H. Org. Lett. 2014, 16, 5124−
5127.
AUTHOR INFORMATION
■
(8) Zeng, X.; Kinjo, R.; Donnadieu, B.; Bertrand, G. Angew. Chem.,
Corresponding Author
*E-mail: arisaw@phs.osaka-u.ac.jp.
ORCID
Int. Ed. 2010, 49, 942−945.
(9) (a) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2007, 46, 2284−2287. (b) Nakamura, I.;
Yamagishi, U.; Song, D.; Konta, S.; Yamamoto, Y. Chem. - Asian J.
2008, 3, 285−295. (c) Zhu, Z.; Chen, K.; Xu, Q.; Shi, M. Adv. Synth.
Catal. 2015, 357, 3081−3090.
(10) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett.
2007, 9, 4081−4083.
Kenichi Murai: 0000-0002-1689-6492
Hiromichi Fujioka: 0000-0002-9970-4248
Mitsuhiro Arisawa: 0000-0002-7937-670X
Notes
(11) (a) Hirner, J. J.; Faizi, D. J.; Blum, S. A. J. Am. Chem. Soc. 2014,
136, 4740−4745. (b) Chong, E.; Blum, S. A. J. Am. Chem. Soc. 2015,
137, 10144−10147. (c) Faizi, D. J.; Issaian, A.; Davis, A. J.; Blum, S.
A. J. Am. Chem. Soc. 2016, 138, 2126−2129. (d) Yuan, K.; Wang, S.
Org. Lett. 2017, 19, 1462−1465.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(12) Maranon, L. A.; Martínez, M. M.; Sarandeses, L. A.; Bengoa, E.
̃
This work was partially supported by a Grant-in-Aid from JSPS
KAKENHI for Precisely Designed Catalysts with Customized
Scaffolding (Grant No. JP 18H04260), T15K149760, and
T15KT00630, by Platform Project for Supporting Drug
Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research
(BINDS)) from AMED under Grant Number
JP18am0101084 and JP19am0101084.
G.; Sestelo, J. P. J. Org. Chem. 2018, 83, 7970−7980.
(13) (a) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.;
Simonneau, A. Chem. Rev. 2011, 111, 1954−1993. (b) Mascaren
̃
as, J.
́
L.; Varela, I.; Lopez, F. Acc. Chem. Res. 2019, 52, 465−479. (c) Yang,
̈
B.; Qiu, Y.; Backvall, J. E. Acc. Chem. Res. 2018, 51, 1520−1531.
̈
(14) (a) Hoffmann-Roder, A.; Krause, N. Angew. Chem., Int. Ed.
2004, 43, 1196−1216. (b) Ma, S. Chem. Rev. 2005, 105, 2829−2872.
(c) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem. Res. 2009, 42,
45−56.
(15) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem.
Rev. 2000, 100, 3067−3126.
REFERENCES
■
(1) Wang, S. Tetrahedron Lett. 2018, 59, 1317−1327.
(2) Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Aldrichimica Acta
2010, 43, 37−46.
(16) Noucti, N. N.; Alexanian, E. J. Angew. Chem., Int. Ed. 2015, 54,
5447−5450.
(17) (a) Kang, S. K.; Ko, B. S.; Lee, D. M. Tetrahedron Lett. 2002,
(3) (a) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem.
́
43, 6693−6696. (b) Gulías, M.; Collado, A.; Trillo, B.; Lopez, F.;
Soc. 2005, 127, 15022−15023. (b) Furstner, A.; Heilmann, E. K.;
̈
Onate, E.; Esteruelas, M. A.; Mascarenas, J. L. J. Am. Chem. Soc. 2011,
̃
̃
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 4760−4763.
(c) Nakamura, I.; Chan, C. S.; Araki, T.; Terada, M.; Yamamoto, Y.
Adv. Synth. Catal. 2009, 351, 1089−1100. (d) Nakamura, I.; Sato, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473. (e) Nakamura,
I.; Okamoto, M.; Sato, T.; Terada, M. Heterocycles 2010, 82, 689−
697. (f) Nakamura, I.; Mizushima, Y.; Yamagishi, U.; Yamamoto, Y.
Tetrahedron 2007, 63, 8670−8676. (g) Obata, T.; Suzuki, S.;
Nakagawa, A.; Kajihara, R.; Noguchi, K.; Saito, A. Org. Lett. 2016,
18, 4136−4139.
133, 7660−7663. (c) Nada, T.; Yoneshige, Y.; Ii, Y.; Matsumoto, T.;
Fujioka, H.; Shuto, S.; Arisawa, M. ACS Catal. 2016, 6, 3168−3171.
(18) (a) Makino, T.; Itoh, K. Tetrahedron Lett. 2003, 44, 6335−
6338. (b) Makino, T.; Itoh, K. J. Org. Chem. 2004, 69, 395−405.
(c) Kawaguchi, Y.; Nagata, A.; Kurokawa, K.; Yokosawa, H.; Mukai,
C. Chem. - Eur. J. 2018, 24, 6538−6542. (d) Haraburda, E.;
́
Fernandez, M.; Gifreu, A.; Garcia, J.; Parella, T.; Quintana, A. P.;
Roglans, A. Adv. Synth. Catal. 2017, 359, 506−512. (e) Liu, C. H.; Yu,
Z. X. Angew. Chem., Int. Ed. 2017, 56, 8667−8671.
(4) (a) Cacchi, S.; Fabrizi, G.; Moro, L. Synlett 1998, 1998, 741−
745. (b) Monteiro, N.; Balme, G. Synlett 1998, 1998, 746−747.
(c) Liang, Z.; Ma, S.; Yu, J.; Xu, R. J. Org. Chem. 2007, 72, 9219−
9224. (d) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63,
1001−1011. (e) Majumdar, K. C.; Hazra, S.; Roy, B. Tetrahedron Lett.
́
(19) Luzung, M. R.; Mauleon, P. F.; Toste, D. J. Am. Chem. Soc.
2007, 129, 12402−12403.
(20) Pd2(dba)3 is easier to handle than Pd(PPh3)4, because
Pd(PPh3)4 is easily oxidized.
(21) Bilbrey, J. A.; Kazez, A. H.; Locklin, J.; Allen, W. D. J. Comput.
2011, 52, 6697−6701. (f) Furstner, A.; Stelzer, F.; Szillat, H. J. Am.
̈
Chem. 2013, 34, 1189−1197.
Chem. Soc. 2001, 123, 11863−11869. (g) Cariou, K.; Ronan, B.;
Mignani, S.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed.
2007, 46, 1881−1884. (h) Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9,
3181−3184. (i) Heugebaert, T. S. A.; Stevens, C. V. Org. Lett. 2009,
11, 5018−5021. (j) Hashmi, A. S. K.; Graf, K.; Ackermann, M.;
̌
́
Rominger, F. ChemCatChem 2013, 5, 1200−1204. (k) Kolundzic, F.;
́
Murali, A.; Galan, P. P.; Bauer, J. O.; Strohmann, C.; Kumar, K.;
Waldmann, H. Angew. Chem., Int. Ed. 2014, 53, 8122−8126. (l) Wu,
C.; Zhao, F.; Du, Y.; Zhao, L.; Chen, L.; Wang, J.; Liu, H. RSC Adv.
2016, 6, 70682−70690.
(5) (a) Taguchi, M.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org.
Lett. 2015, 17, 6250−6253. (b) Cacchi, S.; Fabrizi, G.; Moro, L.
Tetrahedron Lett. 1998, 39, 5101−5104.
D
DOI: 10.1021/acs.orglett.9b00676
Org. Lett. XXXX, XXX, XXX−XXX