Tandem Blaise-Nenitzescu reaction: One-pot synthesis of 5-hydroxy-α-(aminomethylene)benzofuran-2(3H)-ones from nitriles

Article abstract of DOI:10.1039/c0ob01024c

In contrast to the reaction of benzoquinones with β-enaminoesters providing indoles (Nenitzescu reaction), the tandem one-pot reaction of the Blaise reaction intermediate, zinc bromide complex of β-enaminoesters, with benzoquinone affords 5-hydroxy-α-(ami

Full text of DOI:10.1039/c0ob01024c

View Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 1317
www.rsc.org/obc
COMMUNICATION
Tandem Blaise–Nenitzescu reaction: one-pot synthesis of
5-hydroxy-a-(aminomethylene)benzofuran-2(3H)-ones from nitriles†
Yu Sung Chun,a Ka Yeon Ryu,a Ju Hyun Kim,a Hyunik Shin*b and Sang-gi Lee*a
Received 18th August 2010, Accepted 29th November 2010
DOI: 10.1039/c0ob01024c
In contrast to the reaction of benzoquinones with b-
enaminoesters providing indoles (Nenitzescu reaction), the
tandem one-pot reaction of the Blaise reaction intermedi-
ate, zinc bromide complex of b-enaminoesters, with benzo-
quinone affords 5-hydroxy-a-(aminomethylene)benzofuran-
2(3H)-ones in good to excellent yields (tandem Blaise–
Nenitzescu reaction).
Tandem bond formations are highly attractive in modern synthetic
design, as they enable the synthetic steps to be minimized, while
also maximizing molecular complexity.1 With regard to this arena,
we have recently become interested in the possible use of the Blaise
Scheme
reactions.
1 The Blaise, Nenitzescu, and tandem Blaise–Nenitzescu
reaction intermediate, a zinc bromide complex of b-enaminoester
2, as a potential platform for tandem reaction development.2
During these studies, we observed that the chemoselectivity of
the Blaise reaction intermediate 2 is quite different from the
isolated Blaise reaction adduct, b-enaminoester 3, providing an
opportunity to discover a novel synthetic method that would not
be generally feasible with 3. Herein, we report an unprecedented
novel tandem reaction of the Blaise reaction intermediate 2
with 1,4-benzoquinones (the Blaise–Nenitzescu reaction), afford-
ing the 5-hydroxy-(a-aminomethylene)benzofuran-2(3H)-ones 5
(Scheme 1).
The condensation of a 1,4-benzoquinone with b-enaminoesters
3, usually prepared by the Blaise reaction, affording the sub-
stituted 3-carboxylated 5-hydroxyindole derivatives 4, is known
as the Nenitzescu indole synthesis,3 which has been applied
to the synthesis of biologically active indole derivatives.4 In
literature, there are very limited precedents for one-pot synthesis
of 5-hydroxy-a-(aminomethylene)-benzofuran-2(3H)-ones 5 from
nitriles: the recently developed Re-catalyzed cross-coupling of
nitrile with benzofuranones is the only general one-pot method
for this class of lactone compounds.5 Although a stepwise
reaction of b-aminocroton anilides with benzoquinone has also
been reported, though the yields were low, to afford 5-hydroxy-
a-(1-phenylaminoethyleidene)-benzofuran-2(3H)-one,6 this case
simply reflect the effects of N-substituent on chemoselectivity for
the specific b-enamino anilides, which is not generally observed
in the b-enaminoesters 3. In that context, our tandem process not
only discloses the distinctive reactivity profile of the Blaise reaction
intermediate, but also provides a one-pot method to synthesize
benzofuranone derivatives 5 from nitriles with minimal steps.
In our first investigation, a solution of 1,4-benzoquinone
(1.1 equiv) in THF was added to the Blaise reaction intermediate
2a (R = Ph), formed from benzonitrile and a Reformatsky reagent,
for 30 min at reflux temperature.‡
We initially anticipated that the tandem reaction of the Blaise
reaction intermediate 2 with 1,4-benzoquinone would provide 5-
hydroxyindoles 4 via sequential nucleophilic reactions of a-carbon
and b-nitrogen as demonstrated in its reaction with propiolates
affording 2-pyridones.2d Surprisingly, a lactonized product, 5-
hydroxy-a-(aminomethylene)-benzofuran-2(3H)-one 5a was iso-
lated as a major product in 87% yield along with a trace amount
of indole 4a (R = Ph) (entry 1, Table 1). Later, we found that the
Blaise reaction intermediate is reactive enough to carry out the
the tandem reaction at room temperature with a slightly increased
yield of 90% for 1.5 h (entry 2, Table 1). In contrast, the reaction
between the isolated Blaise adduct b-enaminoester 3a (R = Ph)
and 1,4-benzoquinone in THF afforded the N-cyclized indole 4a
in 64% yield after 24 h at reflux temperature. Addition of 1.0
equiv of ZnBr2 did not change the reaction pathway at all, but did
increase the reaction rate and yield to afford the indole 4a in 86%
yield within 1 h at room temperature.
aDepartment of Chemistry and Nano Science (BK21), Ewha Womans
University, Seoul, 120-750, Korea. E-mail: sanggix@ewha.ac.kr; Fax: +82-
23277-3419; Tel: +82-2-3277-4505
bChemical Development Division, LG Life Sciences, Ltd./R&D, Daejeon,
305-380, Korea
† Electronic supplementary information (ESI) available: Experimental
details and spectral data of 5a~5n and their 1H and 13C NMR spectra.
See DOI: 10.1039/c0ob01024c
These results clearly suggested that the reaction profile of the
Blaise reaction intermediate 2a towards 1,4-benzoquinone is quite
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1317–1319 | 1317
©

View Online
Table 1 The tandem Blaise–Nenitzescu reactions with various nitrilesa
to the enamino zinc complex B via fast proton transfer of the
acidic a-proton. In the zinc bromide complex B, the carbonyl
group of the ester may become highly electrophilic via activation
by zinc coordination, which favors the O-cyclization affording the
lactone ring in C instead of the nucleophilic condensation by the
nitrogen atom to the carbonyl group of quinone, as observed with
the isolated b-enaminoester 3a affording indole 4a.
This novel tandem reaction showed a broad range of substrate
generality (Table 1). The tandem reactions with aromatic and het-
eroaromatic nitriles provided the corresponding benzofuranones
5a–5i (entries 1~11, Table 1) in good to excellent yields.
Electronic and steric properties of the substituents did not sig-
nificantly effect reactivity. The yields were substantially increased
in prolonged reaction times at lowered reaction temperatures
(compare entries 1 and 2, 3 and 4, 10 and 11, 12 and 13). All
aliphatic nitriles also converted to the corresponding benzofura-
nones in high yields (entries 12~14, Table 1). The tandem reactions
of other substituted 1,4-benzoquinones such as 2,5-dimethyl- and
2,6-dimethylbenzoquinones with the Blaise reaction intermediate
derived from benzonitrile also proceeded well to give the corre-
sponding 5-hydroxy-(a-aminomethylene)benzofuran-2(3H)-ones
5m (76%) and 5n (82%), respectively, at 40 ◦C for 48 h (Scheme 3a).
b
Entry
R1(1)
t1/t2
T/◦C
5 Yield (%)c
1
2
3
4
5
6
7
8
9
Ph(1a)
1 h/30 min
1 h/1.5 h
5 h/30 min
5 h/1.5 h
1 h/30 min
1 h/30 min
1 h/15 min
1 h/20 min
1 h/30 min
1.5 h/40 min
Reflux
25
Reflux
25
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
5a (87)
5a (90)
5b (77)
5b (86)
5c (78)
5d (80)
5e (88)
5f (84)
5g (80)
5h (70)
1a
o-CH3C6H4 (1b)
1b
m-CH3C6H4 (1c)
p-CH3C6H4 (1d)
p-FC6H4 (1e)
p-CF3C6H4 (1f)
p-OCH3C6H4 (1g)
10
11
12
1.5 h/6 h
1 h/30 min
40
Reflux
5h (82)
5i (67)
13
14
15
16
1 h/1.5 h
1 h/30 min
1 h/4 h
25
Reflux
35
5i (74)
5j (78)
5k (82)
5l (80)
PhCH2 (1j)
CH3CH2 (1k)
(CH3)2CHCH2 (1l)
1 h/4 h
35
a Reaction conditions: see footnotes. b t1: time for >98% conversion of
nitrile to the Blaise intermediate, t2:time for the disappeareance of the
Blaise intermediate. c After silica column chromatography.
different from that of the isolated b-enaminoester 3a. For isolated
b-enaminoester 3a, the added ZnBr2 may activated the carbonyl
group of the benzoquinone, and the indole 4a was formed more
efficiently according to the original Nenitzescu reaction mecha-
nism. In contrast, the zinc bromide complex of the Blaise reaction
intermediate 2a could activate the ester carbonyl group favoring
formation of benzofuranone 5a, which implies that the Blaise
reaction intermediate 2a possesses dual nucleophilic/electrophilic
character: i.e., the C2-carbon is nucleophilic and the carbonyl of
the ester group is electrophilic allowing tandem C–C/C–O bond
formations. As shown in Scheme 2, the first step would be the
Michael addition of the Blaise reaction intermediate 2a to the 1,4-
benzoquinone providing the imino ester A, which could isomerize
Scheme
1,4-benzoquinones.
3
Tandem Blaise–Nenitzescu reaction with substituted
In conclusion, we have demonstrated an unprecedented,
highly efficient tandem one-pot synthesis of 5-hydroxy-a-
(aminomethylene)benzofuran-2(3H)-ones from nitriles. These re-
sults underscore the high potential of the Blaise reaction in-
termediate as an amphiphilic organozinc complex for forming
carbon-carbon bonds and provides a divergent synthetic platform
towards benzofuran-2(3H)-ones and 5-hydroxyindoles from ni-
triles. Further studies extending the range of tandem reactions
by modulating the Blaise reaction intermediate are currently
underway in our laboratory.
This work was supported by the Korea Research Foundation
funded by the Ministry of Education, Science and Technology
(KRF-20090070898 and KRF-20090063004), and RP-supporting
from Ewha Womans University (Y. S. Chun). We thank Profes-
sor J. Hong for HRMS.
Notes and references
‡ Typical procedure: To a stirred suspension of zinc dust (1.0 g, 15.3 mmol)
in anhydrous THF (4.0 mL) was added methanesulfonic acid (3.7 mg).
After 10 min reflux, benzonitrile (1a, 7.6 mmol) was added. To the solution,
ethyl bromoacetate (11.4 mmol) was slowly added over 1 h, and the reaction
mixture was heated at reflux for an additional 1 h to afford the Blaise
reaction intermediate (>98% conversion by GC analysis). To this reaction
mixture, a solution of 1,4-benzoquinone (7.6 mmol) in anhydrous THF
Scheme 2 Proposed mechanism for the formation of 5.
1318 | Org. Biomol. Chem., 2011, 9, 1317–1319
This journal is
The Royal Society of Chemistry 2011
©

View Online
(8.0 mL) was added for 10 min at either reflux or at room temperature.
The reaction was continued for the given time in Table 1, and quenched by
addition of saturated aqueous NH4Cl. The reaction mixture was extracted
with ethyl acetate (3 ¥ 40 mL), and the combined organic layer was
dried with anhydrous MgSO4, filtered, and concentrated. The residue was
purified by silica column chromatography to afford benzofuranone 5a
(1.94 g, 90%).
(c) Y. S. Chun, Y. O. Ko. H. Shin and S.-g. Lee, Org. Lett., 2009, 11,
3414; (d) Y. S. Chun, K. Y. Ryu, Y. O. Ko, J. Y. Hong, J. Hong, H. Shin
and S.-g. Lee, J. Org. Chem., 2009, 74, 7556.
3 C. D. Nenitzescu, Bull. Soc. Chim. Romania, 1929, 11, 37.
4 (a) L. Ku¨rti and B. Czako´, “Strategic Applications of Named Reactions
in Organic Synthesis”, Elsevier Inc. 2005, pp 312-313; (b) V. S. Velezheva,
A. G. Kornienko, S. V. Topilin, A. D. Turashev, A. S. Peregudov and P. J.
Brenna, J. Heterocycl. Chem., 2006, 43, 873; (c) G. R. Allen, in Org. Rect.,
1973, 20, 337–454; (d) H. D. Beal, S. Winski, E. Swann, A. R. Hudnott,
A. S. Cotril, N. O’Sullivan, S. J. Green, R. Bien, D. Siegel, D. Ross and
C. J. Moody, J. Med. Chem., 1998, 41, 4755; (e) T. M. Bohme, C. E.
Augelli-Szafran, H. Hallak, T. Pugsley, K. Serpa and R. D. Schwartz,
J. Med. Chem., 2002, 45, 3094.
5 H. Takaya, M. Ito and S.-I. Murahashi, J. Am. Chem. Soc., 2009, 131,
10824.
6 E. K. Panisheva, L. M. Alekseeva, A. S. Shashkov and V. D. Granik,
Chem. Heterocycl. Compd., 2003, 39, 1013.
1 (a) T.-L. Ho, Tandem Organic Reactions, Wiley, New York, 1992;
(b) L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006; (c) K. C. Nicolaou,
D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134;
(d) A. Fu¨rstner, Angew. Chem., Int. Ed., 2009, 48, 1364; (e) P. J. Parsons,
C. S. Penkett and A. J. Shell, Chem. Rev., 1996, 96, 195.
2 (a) Y. S. Chun, K. K. Lee, Y. O. Ko, H. Shin and S.-g. Lee, Chem.
Commun., 2008, 5098; (b) Y. O. Ko, Y. S. Chun, C.-L. Park, Y. Kim, H.
Shin, S. Ahn, J. Hong and S.-g. Lee, Org. Biomol. Chem., 2009, 7, 1132;
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1317–1319 | 1319
©