Transition-metal-free multicomponent reactions involving Arynes, N-heterocycles, and Isatins

Article abstract of DOI:10.1002/anie.201304278

Mix and match: With isoquinoline as the nucleophilic trigger, multicomponent reactions afforded spirooxazino isoquinoline derivatives, proceeding through 1,4-dipolar intermediates. The use of pyridine as a nucleophile furnished indolin-2-one derivatives, with the reaction likely proceeding through a pyridylidene intermediate.

Full text of DOI:10.1002/anie.201304278

Angewandte
Chemie
DOI: 10.1002/anie.201304278
Synthetic Methods
Transition-Metal-Free Multicomponent Reactions Involving Arynes,
N-Heterocycles, and Isatins**
Anup Bhunia, Tony Roy, Pradip Pachfule, Pattuparambil R. Rajamohanan, and
Akkattu T. Biju*
Dedicated to Dr. Vijay Nair
Arynes have been recognized as highly reactive intermediates
and they have played significant role in various fundamental
organic transformations.[1] Owing to the pronounced electro-
philicity of arynes and the highly strained triple bond in the
ring system, arynes have found widespread applications in
various bond-forming reactions, including pericyclic reac-
tions,[2] insertion reactions,[3] transition-metal-catalyzed reac-
tions[4] and multicomponent reactions (MCRs).[5] Recent
developments in aryne chemistry have been dedicated to
transition-metal-free reactions, which mainly involve the
initial addition of nucleophiles to arynes followed by the
interception of the aryl anion intermediate with electrophiles.
If the nucleophile and electrophile are separate entities, the
overall process is a unique three-component reaction, where
the aryne is inserted between the other two coupling partners
[Eq. (1)].[6] Isocyanides are commonly used nucleophiles in
of aryne MCRs has received only scant attention.[10] Herein,
we report aryne MCRs triggered by N-heterocycles (pyridine,
isoquinoline, and quinoline) and with N-substituted isatins[11]
as the electrophilic component. Gratifyingly, with isoquino-
line as the nucleophilic trigger, the reaction afforded spi-
rooxazino isoquinoline derivatives, and proceeds through
a 1,4-dipolar intermediate.[12] With pyridine as the nucleo-
phile, the reaction furnished indolin-2-one derivatives, with
the reaction is likely proceeding through a pyridylidene
intermediate [Eq. (2)].[13]
The present study was initiated by treating isoquinoline
1a and N-substituted isatin 3a with the aryne generated
in situ from 2-(trimethylsilyl)aryl triflate 2a[14] using KF and
[18]crown-6. A facile reaction occurred, leading to the
formation of the spirooxazino isoquinoline derivatives as an
inseparable mixture of diastereomers in 63% yield and a 9:1
ratio (Scheme 1).[15] The major diastereomer 4a was sepa-
aryne MCRs;[5,7] however, the utility of imines,[8] amines,[9]
cyclic ethers,[5f] DMF,[5c,d] and others as nucleophiles is also
known, and the trapping agents used are usually carbonyl
compounds, including carbon dioxide.[7–9] Despite this, the
synthetic utility of N-heterocycles as nucleophiles in the realm
[*] A. Bhunia, T. Roy, Dr. A. T. Biju
Organic Chemistry Division, CSIR-National Chemical Laboratory
(CSIR-NCL), Dr. Homi Bhabha Road, Pune (India)
E-mail: at.biju@ncl.res.in
Scheme 1. MCR involving isoquinoline, aryne, and N-methyl isatin.
Homepage: http://academic.ncl.res.in/ncl_1/at.biju
P. Pachfule
Physical/Materials Chemistry Division, CSIR-National Chemical
Laboratory (CSIR-NCL), Pune (India)
rated by crystallization and its structure and stereochemistry
was confirmed by single-crystal X-ray analysis.[16]
Dr. P. R. Rajamohanan
Central NMR Facility, CSIR-National Chemical Laboratory
(CSIR-NCL), Pune (India)
Encouraged by this new three-component coupling reac-
tion, we then examined the substrate scope of this isoquino-
line-triggered aryne MCR. The reaction tolerated various
substituents on the isatin nitrogen, leading to an inseparable
mixture of spirooxazino isoquinoline derivatives in 60–77%
yield and moderate diastereoselectivity (4b–4e; Scheme 2).
Moreover, electron-donating and -withdrawing groups on the
carbocyclic ring of isatin resulted in smooth conversions (4 f–
4h). Additionally, electronically different 4,5-disubstituted
symmetrical arynes readily afforded the spirooxazino isoqui-
[**] This work was supported by CSIR-NCL (start-up grant to A.T.B.,
MLP022426), CSIR-New Delhi (Network project-ORIGIN, CSC0108)
and CSIR-OSDD (HCP0001). A.B. and P.P. thank CSIR-New Delhi
for the award of a Research Fellowship. We thank Dr. Rahul Banerjee
for support with X-ray analysis, and B. Santhakumari for the HRMS
data.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304278.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Scheme 3. Proposed reaction mechanism.
Scheme 4. MCR involving pyridine, aryne, and N-methyl isatin.
Scheme 2. Reaction scope of the MCR involving isoquinoline, arynes,
and N-substituted isatins. General conditions: 1 (0.5 mmol), 2
(0.75 mmol), 3 (0.5 mmol) KF (1.5 mmol), [18]crown-6 (1.5 mmol),
THF (2.0 mL), 708C, 24 h. Total yields of both diastereomers are given
and the major diastereomer is shown. Diastereomeric ratios are given
in parentheses and were determined by 1H NMR analysis of crude
reaction mixture. [a] Reaction was run on a 0.25 mmol scale. [b] Reac-
tion run using quinoline (2.0 equiv) and 2a (2.0 equiv). Bn=benzyl,
Tf =trifluoromethanesulfonyl, TMS=trimethylsilyl.
79% yield (Scheme 4). The reaction proceeds through a con-
ceptually new heteroarylation followed by the arylation of
À
isatin, which involves C H bond functionalization of pyridine
and an intramolecular aryl transfer reaction. No product
derived from the interception of an initially formed 1,4-
dipolar intermediate (from pyridine and aryne; analogous to
5) with isatin was observed.[18] The structure of 8a was
unambiguously confirmed by single-crystal X-ray analysis.[16]
With the optimized reaction conditions in hand, we then
examined the substrate scope of this unprecedented aryne
MCR initiated by pyridine (Scheme 5). Various substituents
noline derivatives in good yields and diastereoselectivities
(4i–4k). An unsymmetric aryne generated from 1-(trimethyl-
silyl)-2-naphthyltriflate furnished the desired product in 76%
yield and a 5:1 ratio of diastereomers (4l). In this case, the
observed regioselectivity may be due to the addition of
isoquinoline to the least hindered position of naphthalyne.[17]
Furthermore, this unique MCR is not limited to isoquinoline;
5-bromoisoquinoline and quinoline both worked well, leading
to the formation of the desired products in moderate to good
yields (4m–4o). The isatin component of the reaction can also
be replaced with trifluoroacetophenone, leading to a good
yield of the trifluoromethylated product, and thereby signifi-
cantly expanding the scope of this MCR (4p).
Mechanistically, the reaction can be considered to pro-
ceed through the initial generation of the 1,4-dipolar inter-
mediate 5 from isoquinoline and aryne (generated from 2;
Scheme 3). The zwitterion 5 can add to the electrophilic
carbonyl group of isatin in a concerted manner, leading to the
formation of 4. Alternatively, in a step-wise path, 5 can add to
isatin, generating the tetrahedral intermediate 6, which
undergoes cyclization to produce 4. The observed diastereo-
selectivity in the process suggests a step-wise path.
Scheme 5. Reaction scope of the MCR involving pyridine, arynes and
N-substituted isatins. General conditions: 7 (0.75 mmol), 2
(0.75 mmol), 3 (0.5 mmol) KF (1.5 mmol), [18]crown-6 (1.5 mmol),
THF (2.0 mL), 308C, 12 h. Yields of isolated products are given.
[a] Yield determined by H NMR spectroscopy. [b] Reaction run on
a 0.25 mmol scale.
1
Prompted by these interesting results, we then focused our
attention on pyridine derivatives as the nucleophilic source
for the aryne MCRs with a expectation that the reaction
would afford the analogous pyridooxazino derivatives. Sur-
prisingly, however, treating pyridine 7a and N-methyl isatin
3b with the aryne generated from 2a through the use of KF
and [18]crown-6 furnished the indolin-2-one derivative 8a in
on the isatin nitrogen resulted in smooth conversion into the
indolin-2-one derivatives (8b–8d). Moreover, electron donat-
ing and -withdrawing groups on the carbocyclic ring of isatin
were well tolerated, leading to the desired products in
moderate to good yields (8e–8h). The nucleophile 4-dime-
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
thylamino pyridine (DMAP) can also be used, affording the
indoline 2-one 8i in 89% yield. Furthermore, 4,5-difluoro-
benzyne furnished the desired product in 71% yield, demon-
strating the versatility of the present reaction.
When the reaction was carried out using 4,5-disubstituted
symmetrical aryne precursor 2c, it did not afford the expected
indolin 2-one derivative (8l), but instead furnished the N-aryl
pyridin-2-one derivative (9a) in moderate yield [Eq. (3)]. As
Scheme 6. Tentative mechanism for the pyridine-initiated MCR.
(SNAr) reaction to furnish indolin-2-one 8 via the s-complex
15.[22]
In conclusion, we have developed a conceptually new
MCR involving arynes, N-heterocycles and N-substituted
isatins. When isoquinoline is used as the nucleophile, the
reaction furnished spirooxazino isoquinoline derivatives and
proceeded through 1,4-dipolar intermediates. When pyridine
was used as the nucleophilic trigger, the reaction afforded
indolin-2-one derivatives and likely proceeded through a pyr-
idylidene intermediate.[23]
9a was formed from pyridine and aryne without incorporating
isatin, we carried out additional experiments without adding
isatin.[19] As expected, just mixing pyridine and the aryne
precursor 2c under the optimized conditions afforded 9a in
79% yield [Eq. (4)].[16] Similar results were obtained with
Received: May 17, 2013
Revised: June 16, 2013
Published online: && &&, &&&&
Keywords: isatins · multicomponent reactions · oxindoles ·
.
synthetic methods
aryne precursor 2b. These results tend to indicate that the
initially generated 1,4-dipolar intermediate between pyridine
and aryne (instead of adding to isatin) undergo an intra-
molecular proton transfer to form highly nucleophilic pyr-
idylidene intermediate 10, which was likely quenched by
atmospheric oxygen to form the pyridine-2-one deriva-
tives.[20,21] Moreover, to obtain further mechanistic insight
into the participation of pyridylidene 10 in this reaction, an
experiment was carried out using [D5]pyridine 11; delight-
fully, the reaction furnished 12 in 65% yield with incorpo-
ration of deuterium at the 2 position of the aryl group
[Eq. (5)].
[1] For reviews on aryne chemistry, see: a) P. M. Tadross, B. M.
Stoltz, Chem. Rev. 2012, 112, 3550; b) C. M. Gampe, E. M.
Carreira, Angew. Chem. 2012, 124, 3829; Angew. Chem. Int. Ed.
2012, 51, 3766; c) A. Bhunia, S. R. Yetra, A. T. Biju, Chem. Soc.
Rev. 2012, 41, 3140; d) K. Okuma, Heterocycles 2012, 85, 515;
e) “Arylation reactions involving the formation of arynes”: Y.
Chen, R. C. Larock in Modern Arylation Methods (Ed.: L.
Ackermann), Wiley-VCH, Weinheim, 2009, p. 401; f) H. Yosh-
ida, J. Ohshita, A. Kunai, Bull. Chem. Soc. Jpn. 2010, 83, 199;
g) C. Wu, F. Shi, Asian J. Org. Chem. 2013, 2, 116; h) A. V.
Dubrovskiy, N. A. Markina, R. C. Larock, Org. Biomol. Chem.
2013, 11, 191; i) R. Sanz, Org. Prep. Proced. Int. 2008, 40, 215.
[2] For selected recent reports, see: a) D. A. Candito, D. Dobrovol-
sky, M. Lautens, J. Am. Chem. Soc. 2012, 134, 15572; b) C. Lu,
A. V. Dubrovskiy, R. C. Larock, J. Org. Chem. 2012, 77, 2279;
c) S. S. Bhojgude, T. Kaicharla, A. Bhunia, A. T. Biju, Org. Lett.
2012, 14, 4098; d) T. Kaicharla, S. S. Bhojgude, A. T. Biju, Org.
Lett. 2012, 14, 6238.
[3] For an account, see: a) H. Yoshida, K. Takaki, Synlett 2012, 1725;
for selected recent reports, see: b) J. Kim, B. M. Stoltz,
Tetrahedron Lett. 2012, 53, 4994; c) Y. Fang, D. C. Rogness,
R. C. Larock, F. Shi, J. Org. Chem. 2012, 77, 6262; d) D.
Rodrꢀguez-Lojo, A. Cobas, D. PeÇa, D. Pꢁrez, E. Guitiꢂn, Org.
Lett. 2012, 14, 1363; e) R. A. Dhokale, P. R. Thakare, S. B.
Mhaske, Org. Lett. 2012, 14, 3994; f) K. Mohanan, Y. Coquerel, J.
Rodriguez, Org. Lett. 2012, 14, 4686.
[4] For selected recent reports, see: a) C. Lu, A. V. Dubrovskiy,
R. C. Larock, J. Org. Chem. 2012, 77, 8648; b) K. Parthasarathy,
H. Han, C. Prakash, C.-H. Cheng, Chem. Commun. 2012, 48,
6580.
Based on the results of our preliminary mechanistic
investigation into this MCR, we propose the mechanism
outlined in Scheme 6. First, nucleophilic attack of pyridine on
aryne generates the 1,4-dipolar intermediate 13. In the
absence of an external proton source, 13 undergoes an
intramolecular proton transfer to generate pyridylidene
intermediate 10. The nucleophilic intermediate 10 adds to
isatin to generate tetrahedral intermediate 14, which under-
goes an intramolecular nucleophilic aromatic substitution
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[5] For selected recent reports, see: a) K. M. Allan, C. D. Gilmore,
B. M. Stoltz, Angew. Chem. 2011, 123, 4580; Angew. Chem. Int.
Ed. 2011, 50, 4488; b) E. Yoshioka, S. Kohtani, H. Miyabe,
Angew. Chem. 2011, 123, 6768; Angew. Chem. Int. Ed. 2011, 50,
6638; c) H. Yoshida, Y. Ito, J. Ohshita, Chem. Commun. 2011, 47,
8512; d) H. Yoshida, Y. Asatsu, Y. Mimura, Y. Ito, J. Ohshita, K.
Takaki, Angew. Chem. 2011, 123, 9850; Angew. Chem. Int. Ed.
2011, 50, 9676.
[6] For a highlight, see: S. S. Bhojgude, A. T. Biju, Angew. Chem.
2012, 124, 1550; Angew. Chem. Int. Ed. 2012, 51, 1520.
[7] a) H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, Angew.
Chem. 2004, 116, 4025; Angew. Chem. Int. Ed. 2004, 43, 3935;
b) H. Yoshida, H. Fukushima, T. Morishita, J. Ohshita, A. Kunai,
Tetrahedron 2007, 63, 4793.
[16] CCDC-938921 (4a), 938922 (8a), 938923 (9a), contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data request/cif.
[17] In this case, the pair of diastereomers arising from the addition
of isoquinoline to the more hindered position of naphthalyne
was also observed in ca. 5% yield.
[18] For related reports on the generation of 1,4-dipolar intermedi-
ꢀ
ates from pyridine and activated C C bonds, see: a) V. Nair,
A. N. Pillai, R. S. Menon, E. Suresh, Org. Lett. 2005, 7, 1189;
b) V. Nair, A. R. Sreekanth, A. U. Vinod, Org. Lett. 2001, 3,
3495.
[19] For an earlier report on the addition of pyridine to aryne, see:
a) E. K. Fields, S. Meyerson, J. Org. Chem. 1966, 31, 3307; see
also: b) N. Dennis, A. R. Katritzky, S. K. Parton, J. Chem. Soc.
Perkin Trans. 1 1976, 2285; c) D. K. Rayabarapu, K. K. Majum-
dar, T. Sambaiah, C.-H. Cheng, J. Org. Chem. 2001, 66, 3646;
d) E. Ihara, A. Kurokawa, T. Koda, T. Muraki, T. Itoh, K. Inoue,
Macromolecules 2005, 38, 2167.
[20] For the oxidation of nucleophilic heterocyclic carbenes in the
presence of atmospheric oxygen, see: a) H.-W. Wanzlick, E.
Schikora, Chem. Ber. 1961, 94, 2389; b) H.-W. Wanzlick, Angew.
Chem. 1962, 74, 129; Angew. Chem. Int. Ed. 1962, 1, 75; c) D.
Enders, K. Breuer, J. Runsink, J. H. Teles, Liebigs Ann. 1996,
2019.
[21] Additionally, treating pyridine and aryne with elemental sulfur
under degassing conditions resulted in the formation of
1-phenylpyridine-2(1H)-thione in 16% yield. Although the
yield is low, this is also an indication of the generation of
a pyridylidene intermediate.
[22] It is reasonable to assume, in the case of electronically different
aryne precursors 2b and 2c, that the electron-rich aryl ring
(intermediate 14, Scheme 6) may hamper the SNAr reaction,
hence the corresponding indolin-2-ones were not formed in
these cases [Eq. (3)].
[8] H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, J. Am. Chem.
Soc. 2006, 128, 11040.
[9] a) H. Yoshida, T. Morishita, J. Ohshita, Org. Lett. 2008, 10, 3845;
b) H. Yoshida, T. Morishita, H. Fukushima, J. Ohshita, A. Kunai,
Org. Lett. 2007, 9, 3367; c) T. Morishita, H. Fukushima, H.
Yoshida, J. Ohshita, A. Kunai, J. Org. Chem. 2008, 73, 5452.
[10] a) M. Jeganmohan, C.-H. Cheng, Chem. Commun. 2006, 2454;
b) M. Jeganmohan, S. Bhuvaneswari, C.-H. Cheng, Chem. Asian
J. 2010, 5, 153.
[11] For recent reviews on isatins, see: a) G. S. Singh, Z. Y. Desta,
Chem. Rev. 2012, 112, 6104; b) R. Dalpozzo, G. Bartolib, G.
Bencivennib, Chem. Soc. Rev. 2012, 41, 7247.
[12] For selected reports on the generation of 1,4-dipolar intermedi-
ꢀ
ates from isoquinoline and activated C C bonds, see: a) V. Nair,
A. R. Sreekanth, N. Abhilash, M. M. Bhadbhade, R. C. Gon-
nade, Org. Lett. 2002, 4, 3575; b) V. Nair, A. R. Sreekanth, A. T.
Biju, N. P. Rath, Tetrahedron Lett. 2003, 44, 729.
[13] For selected reports, see: a) J. A. Cabeza, I. del Rꢀo, E. Pꢁrez-
CarreÇo, M. G. Sꢂnchez-Vega, D. Vꢂzquez-Garciꢂ, Angew.
Chem. 2009, 121, 563; Angew. Chem. Int. Ed. 2009, 48, 555;
b) M. Rosellꢃ-Merino, J. Dꢀez, S. Conejero, Chem. Commun.
2010, 46, 9247; c) K. Hata, Y. Segawa, K. Itami, Chem. Commun.
2012, 48, 6642; for a review, see: O. Schuster, L. Yang, H. G.
Raubenheimer, M. Albrecht, Chem. Rev. 2009, 109, 3445.
[14] a) Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983,
1211; b) D. PeÇa, A. Cobas, D. Pꢁrez, E. Guitiꢂn, Synthesis 2002,
1454.
[23] The mechanistic difference in the reactivity of isoquinoline and
pyridine towards aryne and isatin may be due to the less
aromatic nature of the heterocyclic ring of isoquinoline, which
facilitates the formation of spirooxazino derivatives. Owing to
the relatively high aromaticity of pyridine, the corresponding
spirocyclization is less favored in this case.
[15] For details, see the Supporting Information.
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
A. Bhunia, T. Roy, P. Pachfule,
P. R. Rajamohanan,
A. T. Biju*
&&&& — &&&&
Transition-Metal-Free Multicomponent
Reactions Involving Arynes, N-
Heterocycles, and Isatins
Mix and match: With isoquinoline as the
nucleophilic trigger, multicomponent
reactions afforded spirooxazino isoqui-
noline derivatives, proceeding through
1,4-dipolar intermediates. The use of
pyridine as a nucleophile furnished indo-
lin-2-one derivatives, with the reaction
likely proceeding through a pyridylidene
intermediate.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!