Facile and Effective Copper-Mediated Cyclization Reaction of Cyclopropylideneacetic Acids (or Esters) and Cyclopropylideneacetonitriles

Article abstract of DOI:10.1021/jo035225h

The full details of the copper-mediated cyclization reaction of cyclopropylideneacetic acids (or esters) and cyclopropylidenenitriles, the synthetic application of this reaction, and the study of the reaction mechanism are reported.

Full text of DOI:10.1021/jo035225h

F a cile a n d Effective Cop p er -Med ia ted Cycliza tion Rea ction of
Cyclop r op ylid en ea cetic Acid s (or Ester s) a n d
Cyclop r op ylid en ea ceton itr iles
Xian Huang,*,†,‡ Hongwei Zhou,† and Wanli Chen†
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, P.R. China, and
State Key Laboratory of Oganometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P.R. China
huangx@mail.hz.zj.cn
Received August 20, 2003
The full details of the copper-mediated cyclization reaction of cyclopropylideneacetic acids (or esters)
and cyclopropylidenenitriles, the synthetic application of this reaction, and the study of the reaction
mechanism are reported.
In tr od u ction
focused on their intermolecular and intramolecular reac-
tions. Usually a phenolic hydroxyl group3a or a CtC or
CdC bond3b-d was employed for intramolecular reactions.
In a preliminary communication, we have reported a
new concept in which the proximal and distal C-C bond
was selectively cleaved with CuX2. The in situ generated
organometallic intermediates were trapped by a COOH
or COOEt group acting as the intramolecular nucleophile,
leading to a CuX2-mediated cyclization reaction of cyclo-
propylideneacetic acids and esters.10
In this paper, we wish to report the full details of the
copper-mediated cyclization reactions of cyclopropyli-
deneacetic acids (or esters) and cyclopropylidenenitriles,
the synthetic application of this reaction, and the study
of the reaction mechanism.
In the past decades, methylenecyclopropanes (MCPs),
which are highly strained but readily available and stable
molecules, have been studied. They are of synthetic
interest due to the attractive feature that MCPs have
multiple possibilities for reaction of the three strained
bonds (two proximal and one distal bonds) in the cyclo-
propane ring.1 Especially, increasing attention has been
paid to the transition-metal-mediated reactions of MCPs,
which have been usually employed for the construction
of complex and interesting organic molecules.2 The re-
activities of MCPs toward various transition metals,
including Pd,3 Ni,4 Pt,5 and Rh,6 have been studied, and
various reaction pathways, including oxidative addition
of the distal or proximal C-C bond7 and regioselective
hydrometalation8 or carbometalation9 of the CdC bond,
have been observed. In addition, attention has being
Resu lts a n d Discu ssion
Cu X2-Med ia ted Cycliza tion Rea ction of Cyclo-
p r op ylid en eca r boxylic Acid s a n d Ester s. The reac-
tions of cyclopropylideneacetic acid (1a ) and CuBr2 in
different solvents and at various temperatures were first
investigated. 4-Bromomethyl-2(5H)-furanone (3a ) was
obtained in 54% yield when 1a was treated with CuBr2
(4 equiv) in acetonitrile at 60 °C. Further optimization
of conditions demonstrated the solvent system CH3CN/
H2O (4:1) at 85°C was more favorable, and 3a was
isolated in 78% yield.
Interestingly, 4-iodo-5,6-dihydro-2H-pyran-2-one (4a )
instead of 4-iodomethyl-2(5H)-furanone (3b) was isolated
when 1a was treated with CuI/I2 (4 equiv) in CH3CN/
H2O (4:1) and at 85 °C. Furthermore, a dramatic tem-
perature effect was observed in the further screening:
4-iodomethyl-2(5H)-furanone (3b) was obtained in aque-
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) Brandi, A.; Goti, A. Chem. Rev. 1998, 98, 589.
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Noyori, R.; Hayashi N.; Kato, M. J . Am. Chem. Soc. 1971, 93, 4948;
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10.1021/jo035225h CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004
J . Org. Chem. 2004, 69, 839-842
839

Huang et al.
SCHEME 1
SCHEME 2
TABLE 2. Syn th esis of
4-Ha lo-5,6-d ih yd r o-2(1H)-p yr id in on es
TABLE 1. Syn th esis of
entry
R
X
time (h)
product (yield %)
4-Ha lo-5,6-d ih yd r o-2H-p yr a n -2-on esa
1
2
3
4
5
6
Bn (5a )
Bn (5a )
Me (5b)
Me (5b)
Et (5c)
Et (5c)
Br
I
Br
I
Br
I
48
56
44
50
44
48
6a (57)
6b (54)
6c (52)
6d (50)
6e (60)
6f (55)
a
Reaction temperature ) 85 °C; CuBr2 (4 equiv), I2 (4 equiv),
CuI (0.1 equiv); 4 equiv of LiBr or LiI was added
entry
R1
R2
X
time (h)
product (yield %)
reaction described above could be extended to cyclo-
propylideneacetonitriles in which the CN group is the
potential intramolecular nucleophile.
1
2
3
4
5
6
7
8
H
H
Me (2a )
Me (2a )
Me (2b)
Me (2b)
Et (2c)
Br
I
Br
I
Br
I
Br
I
24
24
30
30
31
31
30
30
35
35
4b (79)
4c (73)
4b (81)
4c (71)
4d (83)
4e (77)
4f (80)
4g (76)
4h (76)
4i (70)
Et
Et
Et
Et
Et
Et
Et
Et
2-Benzyl-cyclopropylideneacetonitrile14 (5a ) was chosen
as starting material. The cyclization reaction proceeded
slowly and 4-bromo-5,6-dihydro-2(1H)-pyridinone (6a )
was obtained in only 28% yield when 5a was treated with
CuBr2 (4 equiv) in aqueous acetonitrile at 85 °C, even
after heating for 3d . Fortunately, we found that addition
of 4 equiv of LiBr accelerated the reaction,13 and 6a was
obtained in 57% yield (Scheme 2).
Et (2c)
n-Pr (2d )
n-Pr (2d )
Bn (2e)
Bn (2e)
9
10
Br
I
a
Reaction temperature ) 85 °C; CuBr2 (4 equiv), I2 (4 equiv),
CuI (0.1 equiv).
Similarly, in the presence of 4 equiv of LiI, the
corresponding 4-iodo-5,6-dihydro-2(1H)-pyridinone (6b)
was isolated in 54% yield by treating 5a with CuI/I2 at
85 °C for 56 h. The reaction can be extended to other
2-alkyl-cyclopropylideneacetonitriles, and the results
were summarized in Table 2.
ous acetonitrile in 68% yield by treating 1a with CuI/I2
in aqueous acetonitrile at a lower temperature (60 °C)
for 14 h. When the more available ethyl cyclopropylide-
neacetate (2a )11 was used as the substrate, similar results
were also obtained (Scheme 1).
P d (0)/Cu I-Ca ta lyzed Cr oss-Cou p lin g Rea ction of
4-Ha lo-5,6-d ih yd r o-2H-p yr a n -2-on es or 4-Ha lo-5,6-
d ih yd r o-2(1H)-p yr id in on es w ith Ter m in a l Alk yn es.
Because of the potential biological activities of 4-ynyl-
pyranones or 4-ynyl-pyridinones,15 a facile and efficient
synthetic method for prepation of these compounds is
valuable. Transition-metal-catalyzed coupling reactions
of terminal alkynes with organohalides is a very useful
method for the formation of C-C single bonds. Therefore,
4-halo-5, 6-dihydro-2H-pyran-2-ones or 4-halo-5,6-dihy-
dro-2(1H)-pyridinones might be an important class of
building blocks for the synthesis of 4-ynyl-pyranones or
4-ynyl-pyridinones by coupling reactions with alkynes.
Thus, the Pd (0)/CuI-catalyzed cross-coupling reaction
of 4-halo-5,6-dihydro-2H-pyran-2-ones or 4-halo-5,6-di-
The reactions of cyclopropylidenepropanoic acid (2a )
and ethyl cyclopropylidenepropanate (2b) with CuCl2
were also investigated. No reaction was observed when
these reactions were carried out at either 85 or 60 °C in
aqueous acetonitrle.
A series of ethyl 2-alkyl-substitued cyclopropylidene-
acetates (2) were chosen as substrates, and 4-halo-5,
6-dihydro-2H-pyran-2-ones were obtained highly selec-
tively; the results are summarized in Table 1.
Cycliza tion of Cyclop r op ylid en en itr iles. 4-Halo-
5,6-dihydro-2(1H)-pyridinones, as well as pyranones and
furanones, are important classes of compounds because
they are pivotal skeletons in many natural products with
an unusual range of biological activities.12 It can be
envisioned that pyridinones could be obtained if the
(11) Kortmann, I.; Werstermann, B. Synthesis 1995, 931-933.
(12) (a) Topol, I.; Burt, S. K.; Rashin, A. A.; Erickson, J . W. J . Phys.
Chem. A 2000, 104, 866. (b) Takeda, Y.; Okeda, Y.; Masuda, T.; Hirata,
E.; Shieato, T.; Takushi, A.; Yu, Q.; Otsuka, H. P. K.: Warkentin, J .
Chem. Pharm. Bull. 2000, 48, 752. (c) Brady, S. F.; Clardy, J . J . Nat.
Prod. 2000, 63, 1447. (d) Watanabe, H.; Watanabe, H.; Usui, T.;
Kondoh, M.; Osada, H.; Kitahara, T. J . Antibiot. 2000, 53, 540.
(13) Ma, S.; Wu, S. L. J . Org. Chem. 1999, 64, 6314.
(14) Mauduit. M.; Kouklovsky, C.; Langlois, Y. Tetrahedron Lett.
1998, 39, 6857.
(15) (a) Takeda, Y.; Okeda, Y.; Masuda, T.; Hirata, E.; Shieato, T.;
Takushi, A.; Yu, Q.; Otsuka, H. P. K.: Warkentin, J . Chem. Pharm.
Bull. 2000, 48, 752. (b) Brady, S. F.; Clardy, J . J . Nat. Prod. 2000, 63,
1447.
840 J . Org. Chem., Vol. 69, No. 3, 2004

Cyclizations of Cyclopropylideneacetic Acids
TABLE 3. P d (0)/Cu I-Ca ta lyzed Cr oss-Cou p lin g Rea ction
of 4-Ha lo-5,6-d ih yd r o-2H-p yr a n -2-on es or
4-Ha lo-5,6-d ih yd r o-2(1H)-p yr id in on es w ith Ter m in a l
Alk yn esa
SCHEME 3
SCHEME 4
entry
R1
R2
X
Y
time (h) product (yield %)
1
2
3
4
5
6
7
8
H (4a ) n- C5H9
H (4a ) Ph
Me (4c) n- C4H9
Me (4c) Ph
Me (4c) n-C5H11
Me (4c) t-Bu
Me (4c) CH3OCH2
Et (4e) n-C4H9
Et (4e) Ph
I
I
I
I
I
I
I
I
O
O
O
O
O
O
O
O
12
12
12
10
10
10
14
12
12
15
20
7a (92)
7b (95)
7c (90)
7d (88)
7e (87)
7f (89)
7g (80)
7h (95)
7i (92)
7j (83)
7i (45)
9
10
I
I
Br
O
NH
O
Me (6c) Ph
11b Et (4d ) Ph
SCHEME 5
a
The reaction was carried out in CH3CN at 50 °C; substrate
b
was PdCl2(PPh3)2/CuI/K2CO3/alkyne 1:0.02:0.02:2:1.2. The re-
covery of 4d ) 39%.
hydro-2(1H)-pyridinones was studied. Usually the cou-
pling reaction was carried out in the presence of Et3N.16
However, reaction of 4a with 1-hexyne in Et3N catalyzed
by PdCl2(PPh3)2 and CuI afforded an unidentified mix-
ture. Fortunately, 4-(1′-hexynyl-)-5,6-dihydro-2H-pyran-
2-one was obtained in 92% yield by using CH3CN as the
solvent and K2CO3 as the base. Further studies showed
that the reaction is general for a number of substituted
terminal alkynes and pyranones or pyridinones (Table
3): R1 can be H (entries 1 and 2, Table 3) or an alkyl
group (entries 3-11, Table 3); R2 can be an alkyl (entries
1, 3, 5-8, Table 3) or phenyl group (entries 2, 4, 9-11,
Table 3); X can be Br (entry 11, Table 3) or I (entries
1-10, Table 3); Y can be O (entries 1-9, 11, Table 3) or
NH (entry 12, Table 3). When 4-bromo-5,6-dihydro-2H-
pyran-2-one was chosen as substrate, the yield of product
was lower (entry 11, Table 3).
P la u sible Mech a n ism . The reaction of ethyl 2-allyl-
cyclopropylideneacetate (2h ) with CuX2 afforded 6-bromo-
4,5,6,7-tetrahydro-3H-cyclopenta[c]-pyran-1-one (8a ) and
6-iodo-4,5,6,7-tetrahydro-3H-cyclopenta[c]-pyran-1-one
(8b), indicating the possibility of intermediate 9.17 In-
termediate 9, upon intramolecular insertion, would give
the bicyclic organocopper intermediate 10, which would
lead to 6-halo-4,5,6,7-tetrahydro-3H-cyclopenta[c]-pyran-
1-one (8) via oxidative cleavage with CuX2 (Scheme 3).
Ma has proposed an acyclic copper-complex mechanism
for the CuX2-mediated cyclization reaction of 2,3-allenoic
acids,13 and Ito has proposed a metallocyclic intermediate
in the mechanism of the Pd- and Pt-catalyzed silaboration
of MCPs.5 However, considering that Cu(II) is an oxidiz-
ing agent and difficult to be oxidized to Cu(IV), we
suggest the possibility of an acyclic organocopper inter-
mediate in the mechanism for the reaction. Because 3
could not be transformed to 4 under the same conditions,
SCHEME 6
it is concluded that 3 and 4 were formed by parallel
reaction routes. The coordination of CuX2 to 2-alkyl-
substitued cyclopropylideneacetic acid (or ester) may form
an organocopper coordination complex 11 (or 13).5,10 The
carbonyl oxygen atom attacks the δ-position of complex
11 (or 13) to form vinylic copper intermediate 12 (or 14).
Oxidative cleavage of 12 (or 14) with CuX2 affords 4 (or
3)10 (Scheme 4).
However, in the case of cyclopropylideneacetonitriles
it is improbable that the intramolecular nucleophile
attack occurs on the δ-position owing to the lineal
structure of nitriles (Scheme 5).
Thus, we suggest the possibility that the nitrogen atom
of amide, formed in situ by hydrolysis of nitriles, acts as
the nucleophile.18b 2-Benzyl-cyclopropylideneacetamide
(17) was prepared and treated with CuBr2 in aqueous
acetonitrile at 85 °C. As expected, 6a was obtained in
44% yield after 48 h (Scheme 6).
On the other hand, we examined the reaction of
2-benzyl-cyclopropylideneacetonitrile with CuBr2 in an-
hydrous acetonitrile. Surprisingly, 2-benzyl-3,5-dibromo-
pentenitrile instead of 6a was obtained, which further
(18) (a) Ma, S.; Wu, S. L. Tetrahedron Lett. 2001, 42, 4075. (b) Ma,
S.; Xie, H. X. Org. Lett. 2000, 2, 3801. (c) Ma, S.; Hao, X.; Huang, X.
Chem. Commun. 2003, 1082. (d) Chubb, F. L.; Edward, J . T.; Wong,
S. C. J . Org. Chem. 1980, 45, 2315.
(19) (a) Topol, I.; Burt, S. K.; Rashin, A. A.; Erickson, J . W. J . Phys.
Chem. A 2000, 104, 866. (b) Takeda, Y.; Okeda, Y.; Masuda, T.; Hirata,
E.; Shieato, T.; Takushi, A.; Yu, Q.; Otsuka, H. P. K.: Warkentin, J .
Chem. Pharm. Bull. 2000, 48, 752. (c) Brady, S. F.; Clardy, J . J . Nat.
Prod. 2000, 63, 1447. (d) Watanabe, H.; Watanabe, H.; Usui, T.;
Kondoh, M.; Osada, H.; Kitahara, T. J . Antibiot. 2000, 53, 540.
(16) Sonogashira, K. Comprehensive Organic Synthesis; Pergamon:
Oxford, 1990; Vol. 3, pp 521-549.
(17) J ousseaume, B.; Duboudin, J . G. Synth. Commun. 1979, 9, 53.
J . Org. Chem, Vol. 69, No. 3, 2004 841

Huang et al.
SCHEME 7
SCHEME 8
hydro-2(1H)-pyridinones. The synthetic utility of this
reaction and a preliminary study of the reaction mech-
anism were carried out. As a result of the ready avail-
ability of starting materials and the simple and conve-
nient operation, the reaction has potential utility in
organic synthesis.
supported the idea that the in situ formed amide inter-
mediate is crucial for the cyclization of cyclopropy-
lidenenitriles (Scheme 7).
Considering the difficulty of hydrolysis of nitriles, we
propose an equilibrium between nitrile and amide and
that the interception of the copper intermediate involved
in the equilibrium allows the cyclization reaction to be
successful (Scheme 8).
Ack n ow led gm en t . This work was supported by
the National Natural Science Foundation of China
(20332060).
Con clu sion
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for compounds prepared. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed a facile and effective
copper-mediated cyclization reaction of cyclopropylide-
neacetic acids (or esters) and cyclopropylideneacetoni-
triles for the synthesis of 4-halomethyl-2(5H)-furanones,
4-halo-5,6-dihydro-2H-pyran-2-ones, and 4-halo-5,6-di-
J O035225H
842 J . Org. Chem., Vol. 69, No. 3, 2004