Three-component coupling using arynes and DMF: Straightforward access to coumarins via ortho-quinone methides

Article abstract of DOI:10.1039/c1cc11955a

ortho-Quinone methides, arising from a formal [2+2] cycloaddition between arynes and DMF, were found to facilely undergo a [4+2] cycloaddition with ester enolates or ketenimine anions to produce diverse coumarins in a straightforward manner. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc11955a

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COMMUNICATION
Three-component coupling using arynes and DMF: straightforward
access to coumarins via ortho-quinone methidesw
Hiroto Yoshida,* Yu Ito and Joji Ohshita
Received 7th April 2011, Accepted 5th May 2011
DOI: 10.1039/c1cc11955a
ortho-Quinone methides, arising from a formal [2+2] cycloaddition
between arynes and DMF, were found to facilely undergo a [4+2]
cycloaddition with ester enolates or ketenimine anions to produce
diverse coumarins in a straightforward manner.
ortho-Quinone methides (o-QMs)1 are labile and transient
intermediates, which have been widely utilized as defensive
chemicals in nature. Their structural motifs also play vital
roles in vitamin E chemistry and metabolism,2 and anti-cancer
properties of anthracyclines.3 Despite the universal knowledge
Fig. 1 Biologically active coumarins.
about o-QMs as biologically active components, there should
be a number of unexploited reactions of potential synthetic
value, which would be feasible by suitable combination of o-QMs
and designed reagents.1b In this regard, we have previously
disclosed that a 2 : 1 coupling reaction of arynes with aldehydes
offered straightforwardly xanthene derivatives of structural
diversity,4 where o-QMs, arising from a formal [2+2] cyclo-
addition between arynes and aldehydes, act as key intermediates.5
The six-membered oxygen-containing heterocyclic frameworks
of the xanthenes are assembled by a [4+2] cycloaddition
between the exo enone moieties of o-QMs and arynes, and
thus we envisaged that the use of other combinations of
carbonyl compounds and 2p components in the reaction with
arynes should result in a new type of coupling reactions for
the synthesis of benzo-annulated O-heterocycles. We report
herein that the novel three-component coupling using arynes
and DMF provides direct access to coumarins,6 which constitute
an important class of such biologically active compounds as
carbochromen (coronary heart disease treatment),7 pachyrrhizine
(mosquitocidal activity),8 warfarin (anticoagulant)9 and AP2238
(anti-Alzheimer drug candidate)10 (Fig. 1).
Table 1 Three-component coupling of benzyne, DMF and active
methylene compoundsa
Entry
Z1
Z2
Time/h
Yieldb (%)
3
1
2
3
4
5
6
7
8
9
CO2Et
CO2Et (2a)
CO2n-Bu (2b)
CO2i-Pr (2c)
CO2t-Bu (2d)
CO2Me (2e)
CN (2f)
CO2Et (2g)
CN (2h)
CO2Et (2i)
5
4
10
17
5
1.5
5
6
79
87
79
72
55
39
74
53
44
3a
3b
3c
3d
3e
3f
3g
3h
3i
CO2n-Bu
CO2i-Pr
CO2t-Bu
C(O)Me
CN
P(O)(OEt)2
SO2(p-tol)
SO2Ph
8
a
The reaction was carried out in DMF (4 mL) at 80 1C using 1a
(0.40 mmol), 2 (0.20 mmol) and KF (0.80 mmol). Isolated yield
based on 2.
b
solvents distinctly switch the course of the reaction. As
depicted in Scheme 1, nucleophilic attack of a carbonyl oxygen
of DMF to benzyne would trigger the reaction.14 The resulting
zwitterion (4) undergoes intramolecular cyclization to give
benzoxete 5, which then isomerizes to an o-QM (6) via
electrocyclic ring-opening. Subsequent [4+2] cycloaddition
between 6 and an enolate of 2a,15,16 followed by elimination
of an ethoxide and dimethylamine, furnishes 3a. Other malo-
nates (2b–2d) were also smoothly coupled with benzyne and
DMF to afford the respective coumarins (3b–3d) in high yields
(entries 2–4), and furthermore the three-component coupling
was applicable to b-ketoester (2e) and malononitrile (2f)17
(entries 5 and 6), albeit in moderate yields. The functional
We first conducted the reaction of in situ-generated benzyne
(from 1a11 and KF) with diethyl malonate (2a) in DMF at
80 1C, and observed that 3-(ethoxycarbonyl)coumarin (3a)
was produced in 79% yield (entry 1, Table 1). It should be
noted that the same reaction in THF led to the C–C bond
cleavage of 2a as we reported before,12,13 showing that the
Department of Applied Chemistry, Graduate School of Engineering,
Hiroshima University, Higashi-Hiroshima 739-8527, Japan.
E-mail: yhiroto@hiroshima-u.ac.jp; Fax: +81-82-424-5494;
Tel: +81-82-424-7724
w Electronic supplementary information (ESI) available: Experimental
procedure including spectroscopic and analytical data. See DOI:
10.1039/c1cc11955a
c
8512 Chem. Commun., 2011, 47, 8512–8514
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Table 2 Three-component coupling of benzyne, DMF and arylacetic
acid esters/arylacetonitrilesa
Entry Ar
Z
Time/h Yieldb (%)
3
1
2
3
CO2Et (2j)
CO2Et (2k)
2.5
3
95
70
3j
3k
CO2Et (2l)
CN (2m)
8.5
6.5
28
60
3l
3m
4
Ph
5
CN (2n)
CN (2o)
19
66
99
3n
3o
6
5.5
Scheme 1 A reaction pathway for the formation of 3a.
7
CN (2p)
CN (2q)
CN (2r)
CN (2s)
6
68
64
40
39
3p
3q
3r
3s
group compatibility of the present reaction was high enough,
and thus active methylene compounds bearing a diethyl-
phosphoryl (2g) or an arylsulfonyl group (2h and 2i) were
convertible into the coumarins (3g–3i) with these functional
groups remaining intact throughout the reaction (entries 7–9).
Besides active methylene compounds, arylacetic acid esters
and arylacetonitriles proved to serve efficaciously as third
components in the reaction. As described in Table 2, ethyl
2-pyridylacetate (2j) and ethyl 4-pyridylacetate (2k) smoothly
participate in the reaction to afford 3j and 3k in 95% and 70%
yield (entries 1 and 2), whereas the reaction of ethyl 3-pyridyl-
acetate (2l) resulted in a lower yield (entry 3), suggesting that
facile deprotonation of the methylene moieties, being attributable
to the stable resonance structures of the corresponding enolates,
would be crucial for the efficient coupling. Treatment of phenyl-
acetonitrile (2m) or 2-naphthylacetonitrile (2n) with benzyne and
DMF also provided good yields of the coumarins (3m and 3n)
(entries 4 and 5), and furthermore the reaction of arylacetonitriles
(2o and 2p) having an electron-withdrawing group at the para
position readily took place (entries 6 and 7). Substituted
coumarins containing a benzothiazole (3q) or a benzodioxole
(3r) moiety could be fabricated based on the three-component
coupling (entries 8 and 9), however, the reaction of sterically
demanding nitriles became sluggish (entries 10–12).
8
8.5
3
9
10
5.5
11
12
a
CN (2t)
CN (2u)
6
31
30
3t
10.5
3u
The reaction was carried out in DMF (4 mL) at 80 1C using 1a
b
(0.40 mmol), 2 (0.20 mmol) and KF (0.80 mmol). Isolated yield
based on 2.
The scope of the reaction was further examined by using
substituted arynes (Scheme 2). Similarly to the case of simple
benzyne, 4,5-dimethylbenzyne (from 1b) and 3,6-dimethoxy-
benzyne (from 1c) smoothly reacted with 2j and DMF to
produce high yields of the multisubstituted coumarins (4a and
4b), while the reaction of 2,3-naphthalyne (from 1d) led to the
formation of 4c in 39% yield. Perfect regioselectivity was
observed in the reaction of 3-phenylbenzyne (from 1e), in
which the oxygen atom derived from DMF was attached at
the meta position of the phenyl group.18
On the supposition that salicylaldehyde might be an inter-
mediate species in the present coupling,19,20 we carried out the
Scheme 2 Synthesis of coumarins using substituted arynes.
Chem. Commun., 2011, 47, 8512–8514 8513
c
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Tetrahedron, 2006, 62, 6918; (c) Y. Yamamoto and N. Kirai,
Org. Lett., 2008, 10, 5513.
7 D. Opherk, G. Schuler, W. Waas, R. Dietz and W. Kubler,
Eur. Heart J., 1990, 11, 342.
8 J. J. Magadula and P. Etasto, Nat. Prod. Rep., 2009, 26,
1535.
9 Y. G. Cao, X. Q. Liu, Y. C. Chen, K. Hao and G. J. Wang, Eur. J.
Pharm. Sci., 2007, 30, 175.
10 L. Piazzi, A. Rampa, A. Bisi, S. Gobbi, F. Belluti, A. Cavalli,
M. Bartolini, V. Andrisano, P. Valenti and M. Recanatini, J. Med.
Chem., 2003, 46, 2279.
11 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983,
1211.
12 H. Yoshida, M. Watanabe, J. Ohshita and A. Kunai, Chem.
Commun., 2005, 3292.
Scheme
3 Mechanistic investigation of the three-component
coupling.
13 For other C–C bond cleavage reactions using arynes, see:
(a) U. K. Tambar and B. M. Stoltz, J. Am. Chem. Soc., 2005,
127, 5340; (b) H. Yoshida, M. Watanabe, J. Ohshita and A. Kunai,
Tetrahedron Lett., 2005, 46, 6729; (c) U. K. Tambar, D. C. Ebner
and B. M. Stoltz, J. Am. Chem. Soc., 2006, 128, 11752;
(d) H. Yoshida, M. Watanabe, T. Morishita, J. Ohshita and
A. Kunai, Chem. Commun., 2007, 1505; (e) H. Yoshida,
T. Kishida, M. Watanabe and J. Ohshita, Chem. Commun., 2008,
5963.
14 For a review on nucleophilic coupling with arynes, see: S. V. Kessar, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Flemming,
Pergamon Press, Oxford, 1991, vol. 4, pp. 483–515.
15 At present, we have no decisive evidence for whether the [4+2]
cycloaddition proceeds concertedly or stepwise.
16 A fluoride acts as a base for the formation of an enolate. See
ref. 13d.
reaction of benzyne with DMF (Scheme 3), however, no trace
of salicylaldehyde was formed under our conditions, which
rules out its intermediacy in the three-component coupling.21
Although the reaction of salicylaldehyde with 2m actually
provided 3m, the efficiency is considerably lower than that of
the present reaction.
In conclusion, we have demonstrated that o-QMs, generated
from arynes and DMF, are efficaciously coupled with active
methylene compounds, arylacetic acid esters or arylaceto-
nitriles to offer the direct access to diverse coumarins, which
comprise integral parts of biologically active compounds and
pharmaceuticals. Further studies on novel coupling reactions
using o-QMs as well as on extension of the reaction scope are
in progress.
17 In this case, the [4+2] cycloadditon between an o-QM and a
ketenimine anion provides an iminocoumarin, which is then con-
verted into 3f upon a work-up process.
This work was financially supported by Grants-in-Aid
for Young Scientist (A) (22685021) from the MEXT, Japan.
We thank Central Glass Co. Ltd. for a generous gift of
trifluoromethanesulfonic anhydride.
18 This regioselectivity can be ascribed to avoidance of the unfavourable
steric repulsion between the phenyl moiety and the incoming DMF in
the nucleophilic attack.
19 For the synthesis of coumarins by the Knoevenagel condensation
of salicylaldehyde with active methylene compounds, see: (a) C. Su,
Z.-C. Chen and Q.-G. Zhen, Synthesis, 2003, 555; (b) B. C. Ranu
and R. Jana, Eur. J. Org. Chem., 2006, 3767.
20 For the generation of salicylaldehyde by the reaction of arynes
with DMF in the presence of water, see: (a) S. Yaroslavsky,
Tetrahedron Lett., 1965, 6, 1503; (b) E. Yoshioka, S. Kohtani
and H. Miyabe, Org. Lett., 2010, 12, 1956; (c) K. Okuma,
A. Nojima, Y. Nakamura, N. Matsunaga, N. Nagahora and
K. Shioji, Bull. Chem. Soc. Jpn., 2011, 84, 328.
21 As a referee commented, the following betaine, being the resonance
structure of o-QM 6, may also serve as the key intermediate in the
present reaction.
Notes and references
1 For reviews, see: (a) P. Wan, B. Barker, L. Diao, M. Fischer,
Y. Shi and C. Yang, Can. J. Chem., 1996, 74, 465; (b) R. W. Van
De Water and T. R. R. Pettus, Tetrahedron, 2002, 58, 5367.
2 T. Rosenau, A. Potthast, T. Elder and P. Kosma, Org. Lett., 2002,
4, 4285.
3 S. R. Angle, J. D. Rainier and C. Woytowicz, J. Org. Chem., 1997,
62, 5884.
4 H. Yoshida, M. Watanabe, H. Fukushima, J. Ohshita and
A. Kunai, Org. Lett., 2004, 6, 4049.
5 For other examples on the reactions of o-QMs derived from arynes
and aldehydes, see: (a) H. Heaney and C. T. McCarty, Chem.
Commun., 1970, 123; (b) H. Heaney, J. M. Jablonski and
C. T. McCarty, J. Chem. Soc., Perkin Trans. 1, 1972, 2903;
(c) J. Nakayama, M. Yoshida and O. Simamura, Chem. Lett.,
1973, 451.
6 For selected reports on the synthesis of coumarins, see:
(a) M. K. Potdar, S. S. Mohile and M. M. Salunkhe, Tetrahedron
Lett., 2001, 42, 9285; (b) J. Oyamada and T. Kitamura,
c
8514 Chem. Commun., 2011, 47, 8512–8514
This journal is The Royal Society of Chemistry 2011