Tandem michael addition/cyclization reaction of 2,3-allenoates with organozincs: Facile synthesis of isocoumarins

Article abstract of DOI:10.1021/ol401625t

A series of isocoumarin derivatives have been synthesized via the reaction of 2-(o-(methoxycarbonyl)phenyl)-2,3-allenoates with organozincs in CH ₂Cl₂ at room temperature (for dialkylzinc) or 100 C (for Ph₂Zn) through a tandem Michael addition/intramolecular cyclization process.

Full text of DOI:10.1021/ol401625t

ORGANIC
LETTERS
2013
Vol. 15, No. 15
3884–3887
Tandem Michael Addition/Cyclization
Reaction of 2,3-Allenoates with
Organozincs: Facile Synthesis
of Isocoumarins
Bo Chen† and Shengming Ma*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. China, and Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal University, 3663 North Zhongshan Lu,
Shanghai, 200062, P. R. China
masm@sioc.ac.cn
Received June 9, 2013
ABSTRACT
A series of isocoumarin derivatives have been synthesized via the reaction of 2-(o-(methoxycarbonyl)phenyl)-2,3-allenoates with organozincs in
CH2Cl2 at room temperature (for dialkylzinc) or 100 °C (for Ph2Zn) through a tandem Michael addition/intramolecular cyclization process.
Isocoumarins have attracted the attention of synthetic
and medicinal chemists due to their diverse biological
activities, including antifungal, antitumor, antiallergic,
antimicrobial, anti-inflammatory, antidiabetic, phytotoxic,
and immunomodulatory activities.1 The isocoumarin fra-
mework also represents one of the privileged structures for
the development of natural product-inspired compounds
of potential biological interest. Selected biologically active
isocoumarins are shown in Figure 1.2À4 Besides, there are
many natural products, such as phelligridin D, brevifolin,
sescandelin B, dioscorone A, etc. containing isocoumarins
(Figure 1).5 Therefore, isocoumarins are attractive targets
† Chinese Academy of Sciences.
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Whyte, A. C.; Gloer, J. B.; Scott, J. A.; Malloch, D. J. Nat. Prod. 1996,
59, 765–769. (d) Sappapan, R.; Sommit, D.; Ngamrojanavanich, N.;
Pengpreecha, S.; Wiyakrutta, S.; Sriubolmas, N.; Pudhom, K. J. Nat.
Prod. 2008, 71, 1657–1659.
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Chem. 2003, 81, 284–292. (b) Kojima, K.; Ohno, T.; Inoue, M.;
Mizukami, H.; Nagatsu, A. Chem. Pharm. Bull. 2008, 56, 173–175. (c)
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‡ East China Normal University.
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r
10.1021/ol401625t
Published on Web 07/22/2013
2013 American Chemical Society

On the other hand, allenes are playing a more and
more important role in modern synthetic chemistry.9
Because of their unique structures, allenes show different
reactivity compared with the corresponding alkenyl
and alkynyl compounds. Recently, we have developed
Michael additions of 2,3-allenoates with organomage-
siums or organozincs affording various novel products,
and the key intermediate is the conjugate addition
dienolate.10,11 We envisioned the sequential reaction of
2-(o-(methoxycarbonyl)phenyl)-2,3-allenoate with orga-
nometallic reagents may provide a novel approach to the
isocoumarin skeleton (Scheme 1). However, the subtle
reactivity of the two ester groups in the substrate may be
a problem for this transformation. Herein, we are pleased
to disclose our recent realization of this transformation
using organozincs.
Scheme 1. Allene Approach to Isocoumarins
Figure 1. Some biologically active compounds and natural
products containing an isocoumarin unit.
At first, we treated 2-(o-(methoxycarbonyl)phenyl)-2,3-
allenoate 1a with ethyl magnesium bromide in toluene at
room temperature; however, the expected product was not
observed mainly due to the lack of selectivity caused by the
high reactivity of the Grignard reagent (Scheme 2).
for organic synthesis. Although there are a number of
reports on the preparation of isocoumarins,6À8 there re-
main some limitations such as low yields, poor regioselec-
tivity, and harsh reaction conditions in some cases. Thus, a
simple, mild, efficient, regiocontrolled, and diverse pre-
paration of isocoumarin skeletons with a specific substitu-
tion pattern is still highly desirable.
Scheme 2. Initial Experiment
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5743. (d) Cai, S.; Wang, F.; Xi, C. J. Org. Chem. 2012, 77, 2331–2336. (e)
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2010, 12, 788–791. (f) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch,
K. Org. Lett. 2012, 14, 930–933.
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48, 2030–2032. (b) Yao, T. L.; Larock, R. C. J. Org. Chem. 2003, 68,
5936–5942. (c) Liang, Y.; Xie, Y.-X.; Li, J.-H. Synthesis 2007, 400–406.
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Martinez, J.; Hernandez, J.-F. J. Org. Chem. 2009, 74, 4158–4165.
(9) For most recent reviews on the chemistry of allenes, see: (a) Yu,
Next, we treated 2-(o-(methoxycarbonyl)phenyl)-2,3-
allenoate 1a with diethyl zinc 2a in toluene at 100 °C10a
(entry 1, Table 1), and interestingly the isocoumarin 3a
was formed as the sole product in 76% yield as judged
by 1H NMR analysis, which indicates that the organozincs
undergo exclusively 1,4-conjugated addition first. The
reaction could also proceed smoothly at room temperature
(entry 2, Table 1). A study on solvent effects revealed that
polar solvents, such as DMF and DMSO, are inferior
to nonpolar solvents. CH2Cl2 affords the best result
(entries 3À10, Table 1). Thus, we defined the reaction of
ꢀ
S.; Ma, S. Angew. Chem., Int. Ed. 2012, 51, 3074–3112. (b) Lopez, F.;
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Mascarenas, J. L. Chem.;Eur. J. 2011, 17, 418–428. (c) Aubert, C.;
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2011, 111, 1954–1993. (d) Alcaide, B.; Almendros, P.; Campo, T. M. d.
Chem.;Eur. J. 2010, 16, 5836–5842. (e) Ma, S. M. Acc. Chem. Res. 2009,
42, 1679–1688. (f) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem.
Res. 2008, 42, 45–56. (g) Ma, S. M. Aldrichimica Acta 2007, 40, 91–102.
(10) (a) Chai, G.; Wu, S.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2011, 133,
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(c) Lu, Z.; Chai, G.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 6045–6048.
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14547. (b) Lu, Z.; Chai, G.; Zhang, X.; Ma, S. Org. Lett. 2008, 10, 3517–
3520. (c) Chai, G.; Lu, Z.; Fu, C.; Ma, S. Adv. Synth. Catal. 2009, 351,
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€
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A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196–1216. (j) Yu, S.;
Ma, S. Chem. Commun. 2011, 47, 5384–5418. (k) Krause, N.; Winter, C.
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Weinheim, 2004.
Org. Lett., Vol. 15, No. 15, 2013
3885

2-(o-(methoxycarbonyl)phenyl)-2,3-allenoate 1a with 1.5
equiv of diethyl zinc in CH2Cl2 at room temperature for 3 h
as the standard reaction conditions (entry 10, Table 1).
good yields (3aÀ3j). The R4 in organozinc may be alkyl
(Et, i-Pr, n-Bu) or Ph (3aÀ3d). It should be noted that the
reaction of 1a with Ph2Zn needs to be conducted at an
elevated temperature of 100 °C mainly due to the relatively
lower reactivity of diaryl zinc. R1, R2 may be a cycloalkyl
or n-alkyl group (3eÀ3g). Ethyl allenoate 1e also reacted
smoothly with diethyl zinc affording the corresponding
product 3h in 70% yield. When trisubstituted allenoate 1f
was used as the substrate, the Z/E selectivity of the product
was moderate (4.3/1). However, with a bulky dialkylzinc
reagent (i.e., iPr2Zn), the Z/E selectivity of the isocoumarin
product is >96/4, while the Michael adduct 4j was isolated in
8% yield as the side product. The substituent on the benzene
ring may be an alkyl or a halide, affording the corresponding
isocoumarins 3kÀ3m in good yields (Scheme 3).
Table 1. Optimization of the Reaction Conditionsa
temp
time
(h)
yield of
3a (%)b
recovery of
1a (%)b
entry
solvent
toluene
(°C)
1c
2
100
rt
rt
rt
rt
rt
rt
rt
rt
rt
0.75
1
76
73
75
67
64
80
À
0
toluene
THF
0
3
10.5
10
10
2
14
0
4
1,4-dioxane
Et2O
5
23
0
6
tBuOMe
DMF
7
22
22
5
66
72
0
8
DMSO
CH3CN
CH2Cl2
À
9
58
81
Scheme 3. Further Substrate Scope on the Benzene Ring
10
3
0
a The reaction was carried out using 1a (0.1 mmol) in the indicated
solvent (1.25 mL) in a dry Schlenk tube. b The yields were determined by
1H NMR using mesitylene as the internal standard. c The reaction was
carried out using 1a (0.2 mmol) in 2.5 mL of toluene.
The scope of this transformation was investigated under
the standard conditions (Table 2). The reaction of fully
substituted 2,3-allenoates with different organozincs af-
forded the corresponding isocoumarins in moderate to
The structure of the products was further confirmed
by the X-ray single-crystal diffraction analysis of 3d
(Figure 2).12 In addition, the reaction could be easily
conducted affording product 3a on gram scale in a similar
yield (entry 2 vs 1, Table 2).
Table 2. Substrate Scopea
yield of
entry
R1
R2
R3
R4
Et
3 (%)
1
2
3
4
5
6
7
8
9
10
Me
Me
Me
Me
Me
Me
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1b)
Me (1c)
Me (1d)
Et (1e)
81(3a)
Me
Et
76 (3a)b
84 (3b)
82 (3c)
58 (3d)c
81 (3e)
80 (3f)
Me
i-Pr
n-Bu
Ph
Et
Me
Me
-(CH2)5-
-(CH2)4-
Et
Et
Et
Me
H
Et
82 (3g)d
70 (3h)
82 (3i)e
Figure 2. ORTEP of 3d.
Me
Et
Me
Me (1f)
Et
a The reaction was conducted with 1.0 mmol of 2,3-allenoates, 4 mL
of toluene, and 1.5 equiv of R52Zn (1.5 M solution in toluene for Et2Zn,
1.0 M solution in toluene for i-Pr2Zn, 1.0 M solution in heptanes for n-
Bu2Zn, or pure Ph2Zn). b The reaction was conducted with 5 mmol of 1a
for 12.5 h affording a gram scale of product. c The reaction was
conducted in toluene under 100 °C for 1 h. d The reaction was conducted
for 10 h. e The Z/E ratio was 4.3/1 by crude 1H NMR analysis.
(12) Crystal data for 3d: C20H18O3, MW = 306.34, monoclinic; space
group p2(1)/c, final R indices [I > 2σ(I)], R1 = 0.0374, wR2 = 0.0934; R
˚
indices (all data) R1 = 0.0638, wR2 = 0.1216, a = 13.1393(16) A, b =
˚
˚
9.7705(12) A, c = 27.212(3) A, R = 90.00°, β = 110.152(5)°, γ = 90.00°,
V = 3279.5(7) A , T = 296(2) K, Z = 8, Reflections collected/unique
3
˚
37301/5790 [R(int) = 0.0352], number of observations [>2σ(I)] 4152,
parameters: 421. Supplementary crystallographic data have been depos-
ited at the Cambridge Crystallographic Data Center. CCDC 940122.
3886
Org. Lett., Vol. 15, No. 15, 2013

A possible reaction mechanism was proposed as
shown in Scheme 4. At first, the conjugate addition with
2-(o-(methoxycarbonyl)phenyl)-2,3-allenoate 1a would
form 1,3-dienolate intermediate Int 1. It is interesting to
note that Int 1 did not undergo the intramolecular reaction
with the CO2Me group in the allenic moiety affording
a cyclobutenone, which was observed in our previous
report.10a Instead, the subsequent intramolecular addi-
tion of zinc dienolate to aryl ester functionality leads to
the formation of Int 2. Subsequent 1,2-elimination of
MeOZnEt furnishes the isocoumarin 3a.
2-(o-(methoxycarbonyl)phenyl)-2,3-alenoates and orga-
nozincs at room temperature (for dialkylzinc) or 100 °C
(for Ph2Zn). This method allows the introduction of an
alkoxy group in the heterocyclic portion of the isocoumar-
in ring. Because of the potential of the isocoumarin
products1 and the ready availability of the starting
materials,13 this method would be useful in organic synth-
esis and medicinal chemistry. Further studies in this area
are being actively conducted in our laboratory.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (21232006) and
the National Basic Research Program of China
(2011CB808700) is greatly appreciated. We thank Mr.
Luo Hongwen in this group for reproducing the synthesis
of compounds (3b, 3d, 3k) and Prof. Yu Yihua (East China
Normal University) for helpful discussions.
Scheme 4. Possible Mechanism of the Tandem Michael
Addition/Cyclization Reaction of 1a with Organozincs
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all the
products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) The starting materials may be easily prepared according to the
reported methods: (a) Li, Y.; Zou, H.; Gong, J.; Xiang, J.; Luo, T.;
Quan, J.; Wang, G.; Yang, Z. Org. Lett. 2007, 9, 4057–4060. (b) Marshall,
J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997, 62, 367–371.
In summary, we have developed an efficient and novel
method for the synthesis of isocoumarin derivatives from
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 15, 2013
3887