Multicomponent reactions involving arynes, quinolines, and aldehydes

Article abstract of DOI:10.1021/ol4023134

The multicomponent reaction involving arynes, quinolines, and aldehydes leading to the diastereoselective synthesis of benzoxazino quinoline derivatives in good yields proceeding via 1,4-zwitterionic intermediates is reported. In addition, the synthetic p

Full text of DOI:10.1021/ol4023134

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Multicomponent Reactions Involving
Arynes, Quinolines, and Aldehydes
Anup Bhunia,† Digvijay Porwal,† Rajesh G. Gonnade,‡ and Akkattu T. Biju*,†
Organic Chemistry Division, and Center for Materials Characterization, CSIR-National
Chemical Laboratory, Dr. Homi Bhabha Road, Pune ꢀ 411008, India
at.biju@ncl.res.in
Received August 13, 2013
ABSTRACT
The multicomponent reaction involving arynes, quinolines, and aldehydes leading to the diastereoselective synthesis of benzoxazino quinoline derivatives
in good yields proceeding via 1,4-zwitterionic intermediates is reported. In addition, the synthetic potential of various carbonyl compounds in this reaction
as well as the utility of isoquinoline as the nucleophilic trigger has been examined.
Multicomponent Reactions (MCRs) are one-pot reac-
tions, in which three or more starting materials react to
form a product, where basically all or most of the atoms
contribute to the newly formed product.1 Speed, diversity,
efficiency, atom economy, and environmental friendliness
are some of the notable features of this class of reactions.2
The most important MCRs are the isocyanide-based reac-
tions such as the Passerini three-component reaction3 and
the Ugi four-component reaction.4 Moreover, a variety of
heterocycles can be constructed using the MCR strategy,
where zwitterionic intermediates are generated by the
addition of a nucleophile to activated CꢀC multiple bonds
followed by their interception with a third component.5
The synthetic utility of arynes in MCRs has been recently
significant, as this method allows a straightforward access to
various multisubstituted arenes of structural complexity
and diversity.6,7 The initial reports on aryne MCRs utilize
the anionic nucleophiles as the nucleophilic trigger.8 How-
ever, in 2004, Yoshida, Kunai and co-workers employed
isocyanides as the neutral nucleophile source and they
reported an efficient MCR involving arynes, isocyanides,
and aldehydes leading to the formation of benzannulated
(6) For recent reviews on arynes, see: (a) Wu, C.; Shi, F. Asian J. Org.
Chem. 2013, 2, 116. (b) Dubrovskiy, A. V.; Markina, N. A.; Larock,
R. C. Org. Biomol. Chem. 2013, 11, 191. (c) Tadross, P. M.; Stoltz, B. M.
Chem. Rev. 2012, 112, 3550. (d) Gampe, C. M.; Carreira, E. M. Angew.
Chem., Int. Ed. 2012, 51, 3766. (e) Bhunia, A.; Yetra, S. R.; Biju, A. T.
Chem. Soc. Rev. 2012, 41, 3140. (f) Okuma, K. Heterocycles 2012, 85,
515. (g) Yoshida, H.; Takaki, K. Synlett 2012, 23, 1725. (h) Yoshida, H.;
Ohshita, J.; Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199. (i) Chen, Y.;
Larock, R. C. Arylation reactions involving the formation of arynes. In
Modern Arylation Methods; Ackermann, L., Ed.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2009; p 401. (j) Sanz, R. Org.
Prep. Proced. Int. 2008, 40, 215. (k) Wenk, H. H.; Winkler, M.; Sander,
W. Angew. Chem., Int. Ed. 2003, 42, 502. (l) Pellissier, H.; Santelli, M.
Tetrahedron 2003, 59, 701.
(7) For a recent highlight on transition-metal-free aryne MCRs, see:
Bhojgude, S. S.; Biju, A. T. Angew. Chem., Int. Ed. 2012, 51, 1520. For
selected recent reports, see: (b) Sha, F.; Huang, X. Angew. Chem., Int.
Ed. 2009, 48, 3458. (c) Allan, K. M.; Gilmore, C. D.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2011, 50, 4488. (d) Yoshioka, E.; Kohtani, S.; Miyabe, H.
Angew. Chem., Int. Ed. 2011, 50, 6638. (e) Yoshioka, E.; Kohtani, S.;
Miyabe, H. Org. Lett. 2010, 12, 1956. (f) Yoshida, H.; Ito, Y.; Ohshita, J.
Chem. Commun. 2011, 47, 8512. (g) Yoshida, H.; Asatsu, Y.; Mimura,
Y.; Ito, Y.; Ohshita, J.; Takaki, K. Angew. Chem., Int. Ed. 2011, 50, 9676.
(8) (a) Meyers, A. I.; Pansegrau, P. D. Tetrahedron Lett. 1983, 24, 4935.
(b) Meyers, A. I.; Pansegrau, P. D. J. Chem. Soc., Chem. Commun. 1985, 690.
(c) Tripathy, S.; LeBlanc, R.; Durst, T. Org. Lett. 1999, 1, 1973.
† Organic Chemistry Division.
‡ Center for Materials Characterization.
(1) For recent reviews on multicomponent reactions, see: (a) Domling,
€
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b) Multicomponent
ꢀ
Reaction; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005.
€
(c) Domling, A. Chem. Rev. 2006, 106, 17. (d) Ruijter, E.; Scheffelaar,
R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234. (e) Graaff, C.
€
de.;Ruijter, E.; Orru, R. V. A. ChemSoc. Rev. 2012, 41, 3969. (f)Domling,
A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
(2) Ruijter, E.; Orru, R. V. A. Drug Discovery Today: Technologies
2013, 10, e15.
(3) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Passerini, M.
Gazz. Chim. Ital. 1922, 52, 432. For a review, see: (c) Banfi, L.; Riva, R.
In Organic Reactions; Charette, A. B., Ed.; Wiley: New York, 2005; Vol. 65,
pp 1ꢀ140.
€
(4) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
€
1959, 71, 386. (b) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267.
(5) For an account, see: Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.;
Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899.
r
10.1021/ol4023134
XXXX American Chemical Society

iminofuran derivatives.9,10 Interestingly, however, the syn-
thetic utility of N-heterocycles as nucleophiles in aryne
MCRs has received only limited attention.11 We have re-
cently reported a unique MCR involving arynes, N-hetero-
cycles, and isatins.12 With isoquinoline as the nucleophilic
trigger, the reaction afforded the spirooxazino isoquino-
line derivatives proceeding via 1,4-dipolar intermediates
(Scheme 1, eq 1). In addition, the use of pyridine as a
nucleophile furnished indolin 2-one derivatives and the reac-
tion is likely to proceed through a pyridylidene intermediate.
inseparable mixtureofdiastereomers in68%yield and 10:1
diastereomeric ratio (Scheme 2).14 The optimization stu-
dies revealed that the use of other fluoride sources such as
tetrabutylammonium fluoride (TBAF) and CsF were not
beneficial, and reactions carried out above ꢀ10 °C were
not efficient.
Scheme 2. MCR Involving Quinoline, Aryne, and
4-Chlorobenzaldehyde
Scheme 1. N-Heterocycle Triggered MCRs of Arynes with
Electrophiles
The major diastereomer 4a was separated by crystalliza-
tion, and its structure and stereochemistry were unequivo-
cally confirmed by single-crystal X-ray analysis (Figure 1).15
Notably, some oxazinoquinoline derivatives are known to
exhibit antimalarial activity and a few of them are possibly
antitumor agents.16
However, the reaction was limited to isatins as the electro-
philic coupling partner. Herein, we report the general MCR
involving quinolines, arynes, and various carbonyl com-
pounds, leading to a diastereoselective synthesis of oxazino-
quinoline derivatives, and the reaction proceeds through a
1,4-dipolar intermediate (eq 2).
The present study commenced by treating quinoline
1a and 4-chlorobenzaldehyde 3a with the aryne generated
in situ from 2-(trimethylsilyl)aryl triflate 2a13 using KF
and 18-crown-6. A facile reaction occurred resulting in the
formation of the benzoxazino quinoline derivatives as an
Figure 1. Crystal structure of 4a (thermal ellipsoids are shown
with 30% probability).
With the new reaction conditions in hand, we then
examined the substrate scope of this quinoline initiated
aryne MCR (Scheme 3). First, we evaluated various
aldehydes. Benzaldehyde worked well and electron-releas-
ing or-withdrawing group atthe 4-position of the aromatic
ring was well tolerated, leading to benzoxazino quinoline
derivatives in good yields and excellent diastereoselectivity
(4bꢀ4d). Moreover, substitution is tolerated at the 3- and
2-position of the aromatic ring of 3 resulting in the smooth
conversion to the product in excellent diastereoselectivity
(4e, 4f). Furthermore, disubstituted aldehyde as well as
(9) (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew.
Chem., Int. Ed. 2004, 43, 3935. (b) Yoshida, H.; Fukushima, H.; Ohshita,
J.; Kunai, A. Tetrahedron Lett. 2004, 45, 8659. (c) Yoshida, H.;
Fukushima, H.; Morishita, T.; Ohshita, J.; Kunai, A. Tetrahedron
2007, 63, 4793.
(10) (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am.
Chem. Soc. 2006, 128, 11040. (b) Yoshida, H.; Morishita, T.; Ohshita, J.
Org. Lett. 2008, 10, 3845. (c) Yoshida, H.; Morishita, T.; Fukushima, H.;
Ohshita, J.; Kunai, A. Org. Lett. 2007, 9, 3367. (d) Morishita, T.;
Fukushima, H.; Yoshida, H.; Ohshita, J.; Kunai, A. J. Org. Chem.
2008, 73, 5452.
(11) (a) Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2006, 2454.
(b) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H. Chem.;Asian J.
2010, 5, 153.
(12) (a) Bhunia, A.; Roy, T.; Pachfule, P.; Rajamohanan, P. R.; Biju,
A. T. Angew. Chem., Int. Ed. 2013, 52, DOI:10.1002/anie.201304278.
For recent reports on aryne chemistry from our lab, see: (b) Kaicharla,
T.; Bhojgude, S. S.; Biju, A. T. Org. Lett. 2012, 14, 6238. (c) Bhojgude,
S. S.; Kaicharla, T.; Bhunia, A.; Biju, A. T. Org. Lett. 2012, 14, 4098.
(13) For the generation of arynes from 2-(trimethylsilyl)aryl triflates,
see: (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211. For a modified procedure for the synthesis of the triflate, see:
(14) For details, see the Supporting Information.
(15) CCDC-954832 (4a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data
request/cif.
ꢀ
(16) March, L. C.; Romanchick, W. A.; Bajwa, G. S.; Joullie, M. M.
J. Med. Chem. 1973, 16, 337. (b) Nasr, M.; Abbasi, M. M.; Nabih, I.
J. Pharm. Sci. 1974, 63, 1314.
~
ꢀ
ꢀ
(b) Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis 2002, 1454.
B
Org. Lett., Vol. XX, No. XX, XXXX

2-naphthaldehyde worked well (4g, 4h). Additionally,
heterocyclic aldehydes furnished moderate to good yields
of the desired products, in a 1:1 diastereomeric ratio, further
expanding the scope of this aryne MCR (4i, 4j). Gratifyingly,
challenging aldehydes such as ferrocenecarboxaldehyde as
well as aliphatic aldehyde also furnished moderate to good
yields of the desired products, in excellent diastereoselectivity
(4k, 4l). Besides, this unique MCR is not limited to quino-
line. 4-Methylquinoline as well as 8-methoxyquinoline
worked well leading to the formation of the desired products
in moderate to good yields thus demonstrating the versatility
of the present reaction (4m, 4n).
The mechanistic rationale for this aryne MCR may be
advanced as follows (Scheme 4). The reaction proceeds via
the initialgeneration ofthe 1,4-dipolarintermediate5 from
quinoline and aryne (generated from 2).17 The zwitterion
5 can add to the electrophilic aldehyde in a concerted
1,4-dipolar cycloaddition reaction leading to the forma-
tion of 4. On the other hand, in a stepwise pathway, 5 can
add to aldehyde generating the tetrahedral intermediate 6,
which undergoes cyclization leading to 4.
Scheme 4. Plausible Reaction Mechanism
Scheme 3. Substrate Scope of the MCR Involving Quinoline,
Aryne, and Aldehydea
In view of these interesting results, we next evaluated
the effect of varying the aldehyde component of this reac-
tion (Scheme 5). Delightfully, benzophenone underwent
efficient cyclization with quinoline and aryne leading to
the formation of the 5,5-diphenyl benzoxazino quinoline
derivative 7a in 54% yield. Moreover, p-benzoquinone can
be used as an effective carbonyl surrogate in this reaction,
and the reaction afforded the spirobenzooxazino quinoline
derivative 7b in 59% yield. Additionally, di(hetero)aryl
1,2-diones including benzil and 2,20-thenil as well as ethyl-
phenyl glyoxylate can also be used as the third component
in this MCR furnishing the desired products as a mixture
of diastereomers in moderate yield (7cꢀ7e).
Scheme 5. MCR Involving Quinoline, Aryne, and Ketonesa
a General conditions: 1 (0.5 mmol), 2 (0.6 mmol), 3 (0.75 mmol), KF
(1.2 mmol), 18-crown-6 (1.2 mmol), THF (2.0 mL), ꢀ10 °C to rt, 12 h.
Total yields of both diastereomers are given, and the major diastereomer
is shown. The diastereomeric ratio is given in parentheses and was
determined by 1H NMR analysis of the crude reaction mixture.
We next examined the effect of varying the substituents
on the aryne precursor 2. Electronically dissimilar 4,5-
disubstituted symmetrical aryne precursors readily furn-
ished the benzoxazino quinoline derivatives in good yields
and diastereoselectivities (4oꢀ4q). Interestingly, the unsym-
metrical naphthalyne underwent efficient MCR to deliver a
single regioisomer, arising from the addition of quinoline to
the less hindered position of naphthalyne, in 67% yield and
an excellent diastereoselectivity of >20:1 (4r).
a General conditions: 1a (0.5 mmol), 2a (0.6 mmol), ketone (0.75 mmol),
KF (1.2 mmol), 18-crown-6 (1.2 mmol), THF (2.0 mL), ꢀ10 °C to rt, 12 h.
The diastereomeric ratio is given in parentheses and was determined by 1H
NMR analysis of the crude reaction mixture.
Encouraged by the interesting results using quinoline as
the nucleophile, we then focused our attention on isoqui-
noline as the nucleophile for the aryne MCRs anticipating
Org. Lett., Vol. XX, No. XX, XXXX
C

ring were well tolerated, leading to the desired heterocycle in
good yields (9aꢀ9g) and a diastereoselectivity up to 3:1.
Moreover, a symmetrical aryne precursor also worked well
leading to the desired product in 68% yield.19
Scheme 6. Scope of the MCR Involving Isoquinoline, Aryne,
and Aldehydea
In conclusion, we have developed a new MCR involving
arynes, quinolines, and aldehydes leading to the formation
of benzoxazino quinoline derivatives and the reaction
proceeds via 1,4-dipolar intermediates. The desired pro-
duct was formed in moderate to good yields with good
diastereoselectivity. In addition, the reaction works well
with various carbonyl compounds as the third component
aswell asisoquinoline asthe nucleophilictrigger. Effortsto
further expand the scope of aryne MCRs are ongoing in
our laboratory.
Acknowledgment. Generous financial support from
CSIR-New Delhi (Network project ORIGIN, CSC0108)
is gratefully acknowledged. A.B. thanks CSIR-New Delhi
for the award of the Junior Research Fellowship, and D.P.
thanks DST for the award of the KVPY fellowship. We
thank Dr. P. R. Rajamohanan (CSIR-NCL) for the NMR
spectra.
a General conditions: 8 (0.5 mmol), 2 (0.6 mmol), 3 (0.75 mmol), KF
(1.2 mmol), 18-crown-6 (1.2 mmol), THF (2.0 mL), ꢀ10 °C to rt, 12 h.
The total yields of the mixture of diastereomers are given. The diaster-
eomeric ratio is given in parentheses and was determined by 1H NMR
analysis of the crude reaction mixture.
that the reaction affords the analogous benzoxazino iso-
quinoline derivatives. Inaninitialexperiment, treatment of
isoquinoline 8 and p-tolualdehyde with aryne precursor 2a
in the presence of the fluoride source afforded the benzox-
azino isoquinoline derivatives as an inseparable mixture of
diastereomers in 80% yield and a 3:2 diastereomeric ratio
(Scheme 6).18 A variety of aromatic aldehydes with elec-
tron-releasing and -withdrawing groups on the aromatic
Supporting Information Available. Detailed experimen-
tal procedures, single crystal X-ray data of 4a, and char-
acterization data of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) For selected reports on the generation of 1,4-dipolar intermedi-
ates from isoquinoline and activated CꢀC triple bonds and their
interception with electrophiles, see: (a) Nair, V.; Sreekanth, A. R.;
Abhilash, N.; Bhadbhade, M. M.; Gonnade, R. C. Org. Lett. 2002, 4,
3575. (b) Nair, V.; Sreekanth, A. R.; Biju, A. T.; Rath, N. P. Tetrahedron
Lett. 2003, 44, 729. (c) Nair, V.; Remadevi, R.; Varma, L. Tetrahedron
Lett. 2005, 46, 5333.
(17) For selected reports on the generation of 1,4-dipolar intermedi-
ates from quinoline and activated CꢀC triple bonds and its interception
with electrophiles, see: (a) Nair, V.; Devipriya, S.; Suresh, E. Tetrahe-
dron 2008, 64, 3567. (b) Nair, V.; Devipriya, S.; Suresh, E. Tetrahedron
Lett. 2007, 48, 3667.
(18) Initial attempts to separate the diastereomers by crystallization
failed.
The authors declare no competing financial interest.
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