Cy2NH·HX-promoted cyclizations of o-(alk-1-ynyl)benzoates and (Z)-alk-2-en-4-ynoate with copper halides to synthesize isocoumarins and α-pyrone

Article abstract of DOI:10.1055/s-2006-958960

Cy₂NH·HX was found to improve the cyclization reactions of o-(alk-1-ynyl)benzoates and (Z)-alk-2-en-4-ynoate with CuX₂ (X = Cl, Br) to synthesize the corresponding 4-haloisocoumarins and 5-bromo-2-pyrone, respectively. In the presenc

Full text of DOI:10.1055/s-2006-958960

400
PAPER
Cy2NH·HX-Promoted Cyclizations of o-(Alk-1-ynyl)benzoates and (Z)-Alk-2-
en-4-ynoate with Copper Halides to Synthesize Isocoumarins and a-Pyrone
C
y
N
H·H
X
-Promo
u
te
d
Cyclizat
nions Liang, Ye-Xiang Xie, Jin-Heng Li*
2
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and
Chemical Engineering, Hunan Normal University, Changsha 410081, P. R. of China
Fax +86(731)8872531; E-mail: jhli@hunnu.edu.cn
Received 1 September 2006; revised 19 October 2006
still depended on both the electrophilic reagents (I2 or ICl)
Abstract: Cy2NH·HX was found to improve the cyclization reac-
and solvents (CH2Cl2 or MeCN). Larock and Yao5d,e have
successfully employed both 2-(alk-1-ynyl)benzoates and
5-substituted (Z)-alk-2-en-4-ynoates as the starting mate-
tions of o-(alk-1-ynyl)benzoates and (Z)-alk-2-en-4-ynoate with
CuX2 (X = Cl, Br) to synthesize the corresponding 4-haloisocou-
marins and 5-bromo-2-pyrone, respectively. In the presence of two
equivalents of CuCl2, cyclization of methyl 2-(2-phenylethy- rials in the iodolactonization reaction to selectively con-
nyl)benzoate was conducted smoothly to afford the corresponding
struct the corresponding 4-iodoisocoumarins and 5-iodo-
desired product in 83% yield after 24 hours, whereas the yield was
2-pyrones in CH2Cl2. To the best of our knowledge, only
enhanced to 91% in eight hours when 0.1 equivalent of Cy2NH·HCl
two examples of 4-bromoisocoumarins by bromocycliza-
was added. Under the standard reaction conditions, a variety of o-
tion of the corresponding acetylenic esters using Br2 and
(alk-1-ynyl)benzoates and (Z)-alk-2-en-4-ynoate underwent the cy-
clization reaction with CuX2 to provide the corresponding 4-ha-
LiBr as the electrophilic reagents are known,5a and the
synthesis of 4-chloroisocoumarins from a similar route re-
mains unexplored. Thus, development of a new and sim-
ple method to selectively construct these 4-
haloisocoumarins and 5-halo-2-pyrones (halo = Br Cl) is
still significant. Here, we wish to report that 4-haloisocou-
marins and 5-bromo-6-phenyl-2H-pyran-2-one were ob-
tained in moderate to excellent yields using CuX2
(X = Br, Cl) as the electrophilic reagent and the corre-
sponding Cy2NH·HX (X = Br, Cl) as the promoter
(Equation 1).
loisocoumarins and 5-bromo-2-pyrone, respectively, in moderate to
excellent yields.
Key words: cyclization, o-(alk-1-ynyl)benzoate, (Z)-alk-2-en-4-
ynoate, 4-haloisocoumarin, 5-bromo-2-pyrone, Cy2NH·HX, cop-
per(II) halide
Isocoumarins and a-pyrones1 are found in numerous nat-
ural products2 and synthetic compounds of vital medicinal
value.3 Accordingly, many excellent synthetic methods
have been reported for their direct preparation.4–6 Among
these efficient methods, mainly the electrophilic cycliza-
tions of 2-(alk-1-ynyl)benzoic acids, 5-substituted (Z)-
alk-2-en-4-ynoic acids and their analogous esters to con-
struct the corresponding isocoumarins and a-pyrones
have been attractive. Thus, this method has been success-
ful in the selective synthesis of many isocoumarins and a-
pyrones containing diverse functional groups under mild
and simple conditions.4–6 In particular, isocoumarins and
2-pyrones with a halide group (I, Br or Cl) are of great val-
ue for the introduction of new groups in the synthesis of
natural products.4,5 However, recently much attention was
focused on the synthesis of 4-iodoisocoumarins and 5-
iodo-2-pyrones. Initially, a variety of 4-haloisocoumarins
and 5-halo-2-pyrones were prepared by the halolactoniza-
tion of the corresponding 2-(alk-1-ynyl)benzoic acids and
5-substituted (Z)-alk-2-en-4-ynoic acids with X2 or NXS
(X = I, Br, Cl), but the selectivity of these reactions was
not satisfactory because a mixture of five- and six-mem-
ber-ring products was formed.4 Recently, Rossi and co-
workers5b,c have disclosed the synthesis of 4-iodoisocou-
marins and 5-iodo-2-pyrones via the iodocyclization of
the corresponding acetylenic esters, but their selectivity
O
CuX2 (2 equiv)
CO2Me
Cy2NH HX (0.1 equiv)
O
CH2ClCH2Cl, 80 °C
R'
R'
R
R
X
X = Br, Cl
Equation 1
The reaction of methyl 2-(2-phenylethynyl)benzoate
(1a)5e,7 with CuCl2 in the presence of some additives was
first tested as a model reaction, and the results are summa-
rized in Table 1. Very recently, we have reported a novel
and selective method for the synthesis of 2-disubstituted
3-halobenzo[b]furans in the presence of PdX2 and CuX2.8
In that paper, Et3N·HX was found as a switch to shift the
selectivity. Thus, we applied these conditions in the cy-
clization of methyl 2-(2-phenylethynyl)benzoate (1a). As
expected, 4-chloro-3-phenyl-1H-isochromen-1-one (2a),
a target product, was isolated in 48% yield together with
a 28% yield of a by-product 3a in the presence of PdCl2 (5
mol%), CuCl2 (4 equiv) and Et3N·HCl (0.1 equiv) (entry
1). However, the following results indicated that the pres-
ence of PdCl2 and/or Et3N·HCl disfavored the selectivity
of 2a (entries 1–3). Without PdCl2, treatment of substrate
1a with CuCl2 and Et3N·HCl provided the desired product
2a regiospecifically in 77% yield in 12 hours (entry 2),
whereas the yield of 2a was enhanced to 83% in the ab-
SYNTHESIS 2007, No. 3, pp 0400–0406
x
x
.
x
x
.2
0
0
7
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958960; Art ID: F13706SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cy2NH·HX-Promoted Cyclizations
401
sence of both PdCl2 and Et3N·HCl after prolonging the re- Table 1 Cyclization of Methyl 2-(2-Phenylethynyl)benzoate (1a)
with Copper(II) Chloridea
action time (entry 3). Subsequently, a series of other
additives, such as LiCl, K3PO4 and Cy2NH·HCl, were
O
O
CO2Me
evaluated to further enhance the selectivity toward to 2a
(entries 4–7). Gratifyingly, we found that both the selec-
tivity and the rate could be promoted by Cy2NH·HCl, but
either LiCl or K3PO4 affected the reaction slightly. Treat-
ment of substrate 1a with CuCl2 (4 equiv) and
Cy2NH·HCl (0.1 equiv) afforded the desired product 2a in
91% yield in eight hours (entry 7), whereas only 72% or
68% yield of 2a was obtained in the presence of LiCl and
K3PO4, respectively (entries 4 and 6). We also discovered
that the amount of CuCl2 affected the reaction to some ex-
tent (entries 7–9). Identical results to those of entry 7 were
observed in the presence of Cy2NH·HCl when the amount
of CuCl2 was reduced to two equivalents (entry 8). How-
ever, the yield of 2a was decreased to 55% when one
equivalent of CuCl2 was added (entry 9) and without
CuCl2 no reaction takes place even in the presence of four
equivalents of LiCl (entry 5).
CuCl2, additive
O
O
+
CH2ClCH2Cl,
80 °C
Ph
Ph
Ph
Cl
2a
H
3a
1a
Entry
Additive
Time (h) Yield (%)b
2a
3a
1
PdCl2 (5 mol%)/Et3N·HCl
(0.1 equiv)
8
48
28
2
Et3N·HCl (0.1 equiv)
–
12
20
18
24
18
8
77
83
72
–
–
3
15
5
4
LiCl (2 equiv)
5c
6
LiCl (4 equiv)
–
K3PO4 (2 equiv)
Cy2NH·HCl (0.1 equiv)
Cy2NH·HCl (0.1 equiv)
Cy2NH·HCl (0.1 equiv)
68
91
92
55
10
6
With the standard reaction conditions in hand, the scope
of the substrates was then examined. As demonstrated in
Table 2, the reaction tolerated a set of functional groups in
the benzene rings or at the terminal of alkynes. To our de-
light, methyl 2-(2-phenylethynyl)benzoate (1a) could also
react with CuBr2 in the presence of Cy2NH·HBr to give
the corresponding desired product 4-bromo-3-phenyl-1H-
isochromen-1-one (4a) in a 95% yield (entry 1). Other 2-
ethynylbenzoates 1b–e bearing different groups, such as
long-chain alkyl, bulky alkyl, olefin and hydroxy groups,
at the terminus of alkynes underwent both the chlorocy-
clization and bromocyclization reactions with CuCl2 or
CuBr2 smoothly to selectively afford the corresponding
products in good yields (entries 2–9). Gratifyingly the
corresponding ethyl ester 1f was also cyclized by CuCl2
smoothly to generate the target product 2a in a 93% yield
(entry 10).
7
8d
9e
8
5
12
28
a Reaction conditions: 1 (0.3 mmol), CuCl2 (4 equiv) and additive in
CH2ClCH2Cl (3 mL) at 80 °C.
b Isolated yield.
c Without CuCl2.
d With only 2 equivalents CuCl2.
e With only 1 equivalent CuCl2.
a
Table 2 Cy2NH·HX-Promoted Cyclization Reaction in the Presence of CuX2
O
CuX2 (2 equiv)
CO2R''
Cy2NH HX (0.1 equiv)
CH2ClCH2Cl, 80 °C
O
R'
R'
R
R
X
1
2 (X = Cl) or 4 (X = Br)
Entry
1c
Substrate
Additive
Time (h)
1
Yield (%)b
CO2Me
CuBr2/Cy2NH·HBr
95 (4a)
R
R = Ph (1a)
2
3
4
5
R = n-C8H17 (1b)
CuCl2/Cy2NH·HCl
CuBr2/Cy2NH·HBr
CuCl2/Cy2NH·HCl
CuBr2/Cy2NH·HBr
5
3
4
1
99 (2b)
97 (4b)
89 (2c)
78 (4c)
1b
R = t-Bu (1c)
1c
Synthesis 2007, No. 3, 400–406 © Thieme Stuttgart · New York

402
Y. Liang et al.
PAPER
Table 2 Cy2NH·HX-Promoted Cyclization Reaction in the Presence of CuX2a (continued)
O
CuX2 (2 equiv)
CO2R''
Cy2NH HX (0.1 equiv)
CH2ClCH2Cl, 80 °C
O
R'
R'
R
R
X
1
2 (X = Cl) or 4 (X = Br)
Entry
Substrate
Additive
Time (h)
Yield (%)b
6
7d
8
R = cyclohex-1-enyl (1d)
CuCl2/Cy2NH·HCl
CuBr2/Cy2NH·HBr
CuCl2/Cy2NH·HCl
CuBr2/Cy2NH·HBr
CuCl2/Cy2NH·HCl
20
14
3
99 (2d)
76 (4d)
77 (2e)
60 (4e)
93 (2a)
1d
R = CH2OH (1e)
9
1e
3
10
8
CO2Et
Ph
1f
11
CuBr2/Cy2NH·HBr
3
88 (4g)
O2N
CO2Me
R
R = Ph (1g)
12
13e
14
R = n-C8H17 (1h)
CuCl2/Cy2NH·HCl
CuBr2/Cy2NH·HBr
CuCl2/Cy2NH·HCl
26
2
87 (2h)
68 (4h)
90 (2i)
1h
6
CO2Me
MeOOC
Ph
1i
1i
15f
16
CuBr2/Cy2NH·HBr
CuCl2/Cy2NH·HCl
3
6
54 (4i)
99 (2j)
MeO
CO2Me
Ph
1j
1j
17
18
CuBr2/Cy2NH·HBr
CuBr2/Cy2NH·HBr
3
6
77 (4j)
47 (4k)
CO2Et
Ph
1k
a Reaction conditions: 1 (0.3 mmol), CuX2 (2 equiv) and Cy2NH·HX (0.1 equiv) in CH2ClCH2Cl (3 mL) at 80 °C under N2.
b Isolated yield.
c The by-product 3a was isolated in 4% yield.
d The by-product 3d was isolated in 9% yield.
e The by-product 3h was isolated in 29% yield.
f The by-product 3i was isolated in 35% yield.
The substrates 1g–j having an electron-withdrawing of CuBr2 with (Z)-ethyl 5-phenylpent-2-en-4-ynoate (1k)
group or an electron-donating group on the benzene rings was decreased to some extent, a moderate yield of the tar-
have also worked well with CuX2 (X = Cl, Br), respec- get product 4k was still achieved (entry 18).
tively, to give the target products in moderate to excellent
On the basis of the previous work4,5,8 and our results, a
yields (entries 11–17). For example, the cyclization of
working mechanism was proposed for the present reaction
methyl 5-methoxy-2-(2-phenylethynyl)benzoate (1j) with
CuBr2 or CuCl2 was conducted successfully to offer the
corresponding products 2j and 4j in 99% and 77% yields,
respectively (entries 16 and 17). Although the reactivity
to elucidate the role of Cy2NH·HX (Scheme 1). Firstly,
the complex of CuX2 with a C≡C bond on substrate 1
formed intermediate 5, which was followed by the addi-
Synthesis 2007, No. 3, 400–406 © Thieme Stuttgart · New York

PAPER
Cy2NH·HX-Promoted Cyclizations
403
1H NMR (400 MHz, CDCl3): d = 8.35 (d, J = 8.0 Hz, 1 H), 7.96 (d,
J = 8.4 Hz, 1 H), 7.88–7.84 (m, 3 H) 7.61 (t, J = 8.0 Hz, 1 H), 7.50–
7.48 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.9, 150.4, 135.9, 135.3, 131.4,
130.2, 129.8, 129.3, 129.1, 128.2, 124.0, 120.1, 111.3.
tion of intermediate 5 with X– and oxygen to generate in-
termediate 6. Intermediate 6 then reacted with water to
yield products 2 or 4. We deduced that Cy2NH⋅HX may
play two roles in the reaction, including: (1) phase-trans-
fer catalyst for the CuX2/solvent/substrate/product phas-
es; (2) provide free active X– to induce and improve the
occurrence of the reaction (Equation 2). Further studies
on the exact roles of Cy2NH·HX is in progress.
LRMS (EI, 20 eV): m/z (%) = 258 (M+ + 2, 29), 256 (M+, 84), 228
(57), 193 (M+ – 28 – Cl, 61), 165 (48), 105 (68), 77 (100).
4-Chloro-3-octyl-1H-isochromen-1-one (2b)
Slightly yellow oil.
IR (CH2Cl2): 1716 cm–1.
OR
OR
O
CuX2
O
O
OR
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 7.6 Hz, 1 H), 7.81–
7.77 (m, 2 H), 7.54 (t, J = 7.6 Hz, 1 H), 2.77 (t, J = 7.6 Hz, 2 H),
1.76–1.72 (m, 2 H), 1.41–1.27 (m, 10 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.3, 154.7, 135.5, 135.1, 129.7,
128.3, 123.1, 120.1, 110.9, 31.7, 31.2, 29.2, 29.1, 29.0, 26.7, 22.6,
14.0.
R'
CuX
R'
X
R'
RO
X2Cu
5
1
6
O
X
OH2
H2O
O
O
LRMS (EI, 20 eV): m/z (%) = 294 (M+, 32) 292 (M+, 93), 257
R'
R'
ROH
(M+ – Cl, 11), 194 (64), 162 (52), 132 (77), 104 (100).
X
7
2 or 4
HRMS (EI): m/z calcd for C17H2135ClO2 (M+): 292.1230; found:
292.1229.
Scheme 1
3-tert-Butyl-4-chloro-1H-isochromen-1-one (2c)
White solid; mp 137.0–138.2 °C.
IR (film): 1720 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.26 (d, J = 8.4 Hz, 1 H), 7.89 (d,
J = 8.4 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H),
1.52 (s, 9 H).
O
O
CuCl2 (2 equiv)
CO2Me
Cy2NH⋅HBr (0.1 equiv)
O
O
+
CH2ClCH2Cl, 80 °C
Ph
Ph
Ph
Br
4a (6%)
Cl
2a (91%)
1a
13C NMR (100 MHz, CDCl3): d = 160.9, 159.4, 136.7, 135.0, 129.3,
128.4, 123.2, 120.0, 110.7, 37.8, 28.2.
Equation 2 A control reaction was monitored by GC-MS analysis
LRMS (EI, 20 eV): m/z (%) = 238 (M+, 13), 236 (M+, 39), 221 (28),
In summary, we have described a simple and efficient pro-
tocol for the Cy2NH⋅HX-promoted cyclizations of o-(alk-
1-ynyl)benzoates and (Z)-alk-2-en-4-ynoate with CuX2
(X = Cl, Br) to give the corresponding 4-haloisocou-
marins and 5-bromo-2-pyrone in moderate to excellent
yields. This represents a useful addition to the growing ap-
plications of isocoumarins and a-pyrones in preparative
organic chemistry and medicinal industry.
194 (42), 159 (M+ – 42 – Cl, 100).
HRMS (EI): m/z calcd for C13H1335ClO2 (M+): 236.0604; found:
236.0604.
4-Chloro-3-cyclohexenyl-1H-isochromen-1-one (2d)
Yellow solid; mp 150.0–151.2 °C.
IR (film): 1740 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 7.6 Hz, 1 H), 7.87 (d,
J = 8.0 Hz, 1 H), 7.81 (t, J = 8.4 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H),
6.42 (t, J = 1.6 Hz, 1 H), 2.41–2.39 (m, 2 H), 2.27–2.25 (m, 2 H),
1.78–1.69 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 161.1, 152.8, 136.2, 135.2, 135.1,
129.6, 128.5, 123.8, 120.3, 109.8, 26.3, 25.5, 22.3, 21.5, 18.2.
NMR spectroscopy was performed on an INOVA-400 (Varian)
spectrometer operating at 400 MHz (1H NMR) and 100 MHz (13C
NMR). TMS was used an internal standard and CDCl3 was used as
the solvent. All melting points are uncorrected.
LRMS (EI, 20 eV): m/z (%) = 262 (M+ + 2, 34), 260 (M+, 100), 225
Cy2NH·HX-Promoted Cyclizations of o-(Alk-1-ynyl)benzoates
and (Z)-Alk-2-en-4-ynoate with Copper Halides; General Pro-
cedure
(M+ – Cl, 32).
HRMS (EI): m/z calcd for C15H1335ClO2 (M+): 260.0604; found:
A mixture of substrate 1 (0.3 mmol), CuX2 (2 equiv), Cy2NH⋅HCl
(0.1 equiv) and CH2ClCH2Cl (3 mL) was stirred at 80 °C under N2
for the desired time until complete consumption of starting material
as monitored by TLC (Table 2). The mixture was filtered over a
short column of silica gel and the solvent was evaporated. The res-
idue was purified by flash column chromatography over silica gel
(hexane–EtOAc) to afford the corresponding coupled products 2,
3a, 3d, 3h or 4.
260.0603.
4-Chloro-3-(hydroxymethyl)-1H-isochromen-1-one (2e)
White solid; mp 151 °C.
IR (film): 1737 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.26 (d, J = 7.2 Hz, 1 H), 7.81 (t,
J = 6.4 Hz, 2 H), 7.58 (t, J = 8.4 Hz, 1 H), 4.75 (s, 2 H), 3.73 (br s,
1 H).
13C NMR (100 MHz, CDCl3): d = 160.8, 150.2, 135.4, 134.8, 128.7,
129.3, 124.0, 120.6, 112.1, 59.3.
4-Chloro-3-phenyl-1H-isochromen-1-one (2a)4a
White solid; mp 150.0 °C.
IR (film): 1742 cm–1.
LRMS (EI, 20 eV): m/z (%) = 212 (M+ + 2, 12), 210 (M+, 37), 181
(M+ – H2O, 100), 165 (M+ – Cl, 38), 151 (46), 123 (84), 89 (38).
Synthesis 2007, No. 3, 400–406 © Thieme Stuttgart · New York

404
Y. Liang et al.
PAPER
HRMS (EI): m/z calcd for C10H735ClO3 (M+): 210.0084; found:
210.0080.
1H NMR (400 MHz, CDCl3): d = 8.23 (d, J = 8.4 Hz, 1 H), 7.65 (t,
J = 8.0 Hz, 1 H), 7.44–7.38 (m, 2 H), 6.82–6.80 (m, 1 H), 6.36 (s, 1
H), 2.30–2.25 (m, 4 H), 1.79–1.76 (m, 2 H), 1.67–1.65 (m, 2 H).
4-Chloro-7-nitro-3-octyl-1H-isochromen-1-one (2h)
Yellow solid; mp 97 °C.
IR (film): 1740 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.11 (s, 1 H), 8.60 (d, J = 8.8 Hz,
1 H), 7.98 (d, J = 8.8 Hz, 1 H), 2.83 (d, J = 8.0 Hz, 2 H), 1.79–1.75
(m, 2 H), 1.42–1.25 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.4, 154.3, 137.8, 134.6, 130.1,
129.5, 128.2, 127.5, 125.7, 120.5, 100.0, 25.6, 24.1, 22.2, 21.7.
LRMS (EI, 20 eV): m/z (%) = 226 (M+, 100).
7-Nitro-3-octyl-1H-isochromen-1-one (3h)
Yellow solid; mp 54.1–56.0 °C.
13C NMR (100 MHz, CDCl3): d = 159.4, 158.8, 147.1, 140.3, 129.3,
125.7, 125.0, 120.7, 110.2, 31.8, 31.6, 29.2, 29.1 (2 C), 26.6, 22.6,
14.0.
IR (film): 1724 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.09 (s, 1 H), 8.48 (d, J = 8.8 Hz,
1 H), 7.52 (d, J = 8.8 Hz, 1 H), 6.38 (s, 1 H), 2.59 (t, J = 7.6 Hz, 2
H), 1.74–1.72 (m, 2 H), 1.39–1.25 (m, 10 H), 0.88 (t, J = 6.4 Hz, 3
H).
LRMS (EI, 20 eV): m/z (%) = 339 (M+ + 1, 2), 337 (M+, 36), 302
(M+ – Cl, 44), 239 (43), 57 (100).
HRMS (EI): m/z calcd for C17H2035ClO4 (M+): 337.1081; found:
337.1080.
13C NMR (100 MHz, CDCl3): d = 162.6, 161.1, 146.5, 142.6, 128.9,
126.3, 125.6, 120.3, 102.2, 33.8, 31.7, 29.2, 29.1, 29.0, 26.7, 22.6,
14.0.
Methyl 4-Chloro-1-oxo-3-phenyl-1H-isochromene-6-carboxy-
late (2i)
White solid; mp 150.9–151.3 °C.
IR (film): 1738, 1727 cm–1.
LRMS (EI, 20 eV): m/z (%) = 303 (M+, 30), 205 (45), 57 (100);
HRMS (EI): m/z calcd for C17H21NO4 (M+): 303.1471; found:
303.1469.
1H NMR (400 MHz, CDCl3): d = 8.60 (s, 1 H), 8.41 (d, J = 8.0 Hz,
1 H), 8.21 (d, J = 8.0 Hz, 1 H), 7.89–7.87 (m, 2 H), 7.51–7.50 (m, 3
H), 4.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.5, 160.2, 151.1, 136.2, 136.1,
131.0, 130.5, 130.2, 129.4, 129.3, 128.3, 125.6, 123.3, 111.0, 52.9.
LRMS (EI, 20 eV): m/z (%) = 316 (M+ + 2, 33), 314 (M+, 99), 286
(38), 171 (24), 227 (30), 199 (16), 163 (M+ – Cl, 32), 105 (62), 77
(70), 44 (100).
HRMS (EI): m/z calcd for C17H1135ClO4 (M+): 314.0346; found:
314.0345.
Methyl 1-Oxo-3-phenyl-1H-isochromene-6-carboxylate (3i)
White solid; mp 199.0 °C.
IR (film): 1739, 1724 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.37 (d, J = 8.0 Hz, 1 H), 8.19 (s,
1 H), 8.09 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 7.6 Hz, 2 H), 7.49–7.46
(m, 3 H), 7.02 (s, 1 H), 4.00 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.8, 161.6, 154.4, 137.5, 135.7,
131.5, 130.3, 130.0, 128.9, 128.2, 127.5, 125.3, 123.3, 101.5, 52.8.
LRMS (EI, 20 eV): m/z (%) = 282 (M+ + 2, 5), 280 (M+, 100), 252
(60), 105 (35), 77 (40) 44 (90).
HRMS (EI): m/z calcd for C17H12O4 (M+): 280.0736; found:
280.0735.
4-Chloro-7-methoxy-3-phenyl-1H-isochromen-1-one (2j)
White solid; mp 170.0 °C.
IR (film): 1727 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.90–7.85 (m, 3 H), 7.76 (s, 1 H),
7.50–7.41 (m, 4 H), 3.95 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.1, 160.2, 148.3, 131.5, 129.9,
129.5, 129.2, 128.2, 125.8, 125.6, 121.7, 111.3, 110.4, 55.9.
LRMS (EI, 20 eV): m/z (%): 288 (M+ + 2, 33), 286 (M+, 95), 256
(18), 258 (52), 223 (M+ – 28 – Cl, 23), 215 (36), 152 (49), 105 (100),
77 (100).
4-Bromo-3-phenyl-1H-isochromen-1-one (4a)4a
White solid; mp 99.5–101.0 °C (Lit.11 mp 100.0–101.5 °C).
IR (film): 1739 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.34 (d, J = 8.0 Hz, 1 H), 7.96 (d,
J = 8.0 Hz, 1 H), 7.85 (t, J = 8.8 Hz, 1 H), 7.81–7.78 (m, 2 H), 7.60
(t, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.1, 151.8, 136.6, 135.4, 132.8,
130.2, 129.8, 129.6, 129.1, 128.1, 126.6, 120.6, 101.3.
HRMS (EI): m/z calcd for C16H1135ClO3 (M+): 286.0397; found:
286.0396.
LRMS (EI, 20 eV): m/z (%) = 332 (M+ + 2, 80), 330 (M+, 86), 304
(36), 302 (37), 223 (M+ – 28 – Br, 26), 152 (54), 105 (100).
3-Phenyl-1H-isochromen-1-one (3a)6m
4-Bromo-3-octyl-1H-isochromen-1-one (4b)
Slightly yellow oil.
IR (CH2Cl2): 1723 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.26 (d, J = 8.0 Hz, 1 H), 7.78 (d,
J = 8.8 Hz, 2 H), 7.54–7.50 (m, 1 H), 2.81 (t, J = 7.2 Hz, 2 H), 1.77–
1.72 (m, 2 H), 1.40–1.27 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.4, 155.7, 136.3, 135.2, 129.6,
128.4, 125.6, 120.2, 101.1, 33.4, 31.7, 29.2, 29.1, 29.0, 26.8, 22.6,
14.0.
White solid; mp 88.0 °C (Lit.5e mp 87–89 °C).
IR (film): 1696 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.26 (d, J = 8.4 Hz, 1 H), 7.84 (d,
J = 8.4 Hz, 2 H), 7.68 (t, J = 7.2 Hz, 1 H), 7.47–7.39 (m, 5 H), 6.91
(s, 1 H).
13C NMR (100 MHz, CDCl3): d = 162.2, 153.5, 137.4, 134.8, 131.8,
129.8, 129.5, 128.7, 128.0, 125.9, 125.1, 120.4, 101.7.
LRMS (EI, 20 eV): m/z (%) = 222 (M+, 80), 194 (58), 105 (70), 77
(100).
LRMS (EI, 20 eV): m/z (%) = 338 (M+ + 2, 70), 336 (M+, 72), 257
(M+ – Br, 35), 159 (100).
3-Cyclohexenyl-1H-isochromen-1-one (3d)9
Slightly yellow oil.
IR (CH2Cl2): 1732 cm–1.
HRMS (EI): m/z calcd for C17H2179BrO2 (M+): 336.0725; found:
336.0723.
Synthesis 2007, No. 3, 400–406 © Thieme Stuttgart · New York

PAPER
Cy2NH·HX-Promoted Cyclizations
405
4-Bromo-3-tert-butyl-1H-isochromen-1-one (4c)
White solid; mp 123.0–125.5 °C.
IR (film): 1731 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.26 (d, J = 8.0 Hz, 1 H), 7.95 (d,
J = 8.4 Hz, 1 H), 7.79 (t, J = 8.4 Hz, 1 H), 7.53 (t, J = 8.4 Hz, 1 H),
1.56 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 161.1, 160.1, 137.4, 135.1, 129.3,
128.5, 125.8, 120.1, 100.4, 38.5, 28.5.
1H NMR (400 MHz, CDCl3): d = 9.11 (s, 1 H), 8.58 (d, J = 8.8 Hz,
1 H), 7.99 (d, J = 8.0 Hz, 1 H), 2.87 (t, J = 8.0 Hz, 2 H), 1.79–1.76
(m, 2 H), 1.43–1.31 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.9, 159.6, 147.1, 141.1, 129.3,
127.5, 125.6, 120.7, 99.9, 33.9, 31.8, 29.2, 29.1, 29.0, 26.8, 22.6,
14.0.
LRMS (EI, 20 eV): m/z (%) = 383 (M+ + 2, 18), 381 (M+, 17), 302
(M+ – Br, 42), 204 (46), 86 (55), 57 (100).
HRMS (EI): m/z calcd for C17H2079BrNO4 (M+): 381.0576; found:
381.0575.
LRMS (EI, 20 eV): m/z (%): 282 (M+ + 2, 25), 280 (M+, 24), 267
(8), 285 (9), 201 (26), 159 (M+ – Br, 100).
HRMS (EI): m/z calcd for C13H1379BrO2 (M+): 280.0099; found:
280.0098.
Methyl 4-Bromo-1-oxo-3-phenyl-1H-isochromene-6-carboxy-
late (4i)
White solid; mp 156.0–156.6 °C.
IR (film): 1738, 1730 cm–1.
4-Bromo-3-cyclohexenyl-1H-isochromen-1-one (4d)
Yellow solid; mp 105.0 °C.
1H NMR (400 MHz, CDCl3): d = 8.61 (s, 1 H), 8.40 (d, J = 8.0 Hz,
1 H), 8.20 (d, J = 7.6 Hz, 1 H), 7.82 (d, J = 7.2 Hz, 2 H), 7.51–7.49
(m, 3 H), 4.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.5, 160.4, 152.5, 136.8, 136.3,
132.4, 130.4, 130.2, 129.6, 129.4, 128.2, 123.4, 100.9, 52.9.
LRMS (EI, 20 eV): m/z (%) = 360 (M+ + 2, 100), 358 (M+, 95), 332
(45), 330 (46), 273 (22), 271 (23), 192 (M+ – Br, 12), 163 (22), 105
(96), 77 (88).
HRMS (EI): m/z calcd for C17H1179BrO4 (M+): 357.9841; found:
357.9839.
IR (film): 1736 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 7.6 Hz, 1 H), 7.88 (d,
J = 8.4 Hz, 1 H), 7.81 (t, J = 8.4 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 1 H),
6.32–6.29 (m, 1 H), 2.38–2.36 (m, 2 H), 2.26–2.23 (m, 2 H), 1.78–
1.76 (m, 2 H), 1.76–1.69 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 161.4, 154.3, 136.8, 135.2, 135.1,
131.1, 129.6, 128.6, 126.5, 120.5, 99.9, 26.3, 25.3, 22.2, 21.5.
LRMS (EI, 20 eV): m/z (%) = 306 (M+ + 2, 100), 304 (M+, 100), 252
(34), 250 (33), 197 (96), 179 (M+ – 56 – Br, 50).
HRMS (EI): m/z calcd for C15H1379BrO2 (M+): 304.0099; found:
304.0099.
4-Bromo-7-methoxy-3-phenyl-1H-isochromen-1-one (4j)
White solid; mp 162.0–164.0 °C.
IR (film): 1732 cm–1.
4-Bromo-3-(hydroxymethyl)-1H-isochromen-1-one (4e)
White solid; mp 124.5 °C.
1H NMR (400 MHz, CDCl3): d = 7.89 (d, J = 9.2 Hz, 1 H), 7.81–
7.78 (m, 2 H), 7.76 (s, 1 H), 7.48–7.45 (m, 3 H), 7.41 (d, J = 9.2 Hz,
1 H), 3.95 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.3, 160.3, 149.7, 132.8, 130.2,
129.9, 129.7, 128.5, 128.1, 124.7, 121.7, 110.4, 101.2, 56.0.
LRMS (EI, 20 eV): m/z (%) = 302 (M+ – 28, 86), 300 (M+ – 28, 85),
274 (52), 272 (50), 193 (M+ – 58 – Br, 60), 165 (63), 105 (78), 77
(100).
HRMS (EI): m/z calcd for C16H1179BrO3 (M+): 329.9892; found:
329.9891.
IR (film): 1733 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.29 (d, J = 7.6 Hz, 1 H), 7.83 (d,
J = 4.0 Hz, 2 H), 7.62–7.58 (m, 1 H), 4.78 (s, 2 H), 2.88 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 160.9, 151.8, 135.6 (2 C), 129.9,
129.5, 126.2, 120.8, 102.0, 61.5.
LRMS (EI, 20 eV): m/z (%) = 256 (M+ + 2, 18), 254 (M+, 19), 227
(29), 229 (32), 197 (26) 195 (26), 169 (53), 167 (55), 147 (M+ –
29 – Br, 48), 88 (100).
HRMS (EI): m/z calcd for C10H779BrO3 (M+): 253.9579; found:
253.9578.
5-Bromo-6-phenyl-2H-pyran-2-one (4k)10
White solid; mp 93.0–94.5 °C (Lit.10 mp 91–92 °C).
4-Bromo-7-nitro-3-phenyl-1H-isochromen-1-one (4g)
Yellow solid; mp 187.0–191.0 °C.
IR (film): 1733 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.17 (s, 1 H), 8.63 (d, J = 8.8 Hz,
1 H), 8.17 (d, J = 8.8 Hz, 1 H), 7.85–7.82 (m, 2 H), 7.54–7.52 (m, 3
H).
13C NMR (100 MHz, CDCl3): d = 159.3, 155.2, 147.5, 141.5, 131.9,
131.1, 129.7, 129.4, 128.5, 128.3, 125.6, 121.1, 99.8.
LRMS (EI, 20 eV): m/z (%) = 347 (M+ + 2, 100), 345 (M+, 89), 319
(42), 317 (40), 273 (21), 271 (23), 192 (M+ – 74 – Br, 39), 163 (52),
105 (64), 77 (100).
IR (film): 1732 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.82 (d, J = 8.0 Hz, 2 H), 7.51–
7.47 (m, 4 H), 6.23 (d, J = 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 160.5, 158.2, 148.5, 131.6, 130.9,
129.0, 128.3, 115.2, 98.0.
LRMS (EI, 20 eV): m/z (%) = 252 (M+ + 2, 13), 250 (M+, 14), 224
(59), 222 (58), 195 (7), 193 (7), 115 (M+ – 55 – Br, 37), 105 (60),
77 (100).
Acknowledgment
HRMS (EI): m/z calcd for C15H879BrNO4 (M+): 344.9637; found:
344.9637.
The authors thank Hunan Provincial Natural Science Foundation of
China (No. 05JJ1002), the National Natural Science Foundation of
China (No. 20572020), Fok Ying Dong Education Foundation (No.
101012), the Key Project of Chinese Ministry of Education (No.
206102) and Scientific Research Fund of Hunan Provincial Educa-
tion Department (No. 05B038) for financial support.
4-Bromo-7-nitro-3-octyl-1H-isochromen-1-one (4h)
Yellow solid; mp 71.2–72.0 °C.
IR (film): 1729 cm–1.
Synthesis 2007, No. 3, 400–406 © Thieme Stuttgart · New York

406
Y. Liang et al.
PAPER
(5) For papers on the synthesis of isocoumarins and a-pyrones
by electrophilic cyclization of the corresponding esters, see:
(a) Oliver, M. A.; Gandour, R. D. J. Org. Chem. 1984, 49,
558. (b) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.;
Rossi, R. Tetrahedron 2002, 58, 5023. (c) Rossi, R.;
Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron
2003, 59, 2067. (d) Yao, T.; Larock, R. C. Tetrahedron Lett.
2002, 43, 7401. (e) Yao, T.; Larock, R. C. J. Org. Chem.
2003, 68, 5936.
(6) For selected recent papers on the synthesis of isocoumarins
and a-pyrones by other methods, see: (a) Sashida, H.;
Kawamukai, A. Synthesis 1999, 1145. (b) Larock, R. C.;
Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
(c) Fringuelli, F.; Piermatt, O.; Pizzo, F. Heterocycles 1999,
50, 611. (d) Sashida, H.; Kawamukai, A. Tetrahedron 2000,
56, 4777. (e) Rossi, R.; Bellina, F.; Biagetti, M.; Catanese,
A.; Mannina, L. Tetrahedron Lett. 2000, 41, 5281.
(f) Kotrestou, S. I.; Georgiadis, M. P. Org. Prep. Proced. Int.
2000, 32, 161. (g) Bellina, F.; Ciucci, D.; Vergamini, P.;
Rossi, R. Tetrahedron 2000, 56, 2533. (h) Thibonnet, J.;
Abarbri, M.; Parrain, J.-L.; Duchene, A. J. Org. Chem. 2002,
67, 3941. (i) Nakamura, Y.; Ukita, T. Org. Lett. 2002, 4,
2317. (j) Ma, S.; Yu, S.; Yin, S. J. Org. Chem. 2003, 68,
8996. (k) Cherry, K.; Parrain, J.-L.; Thibonnet, J.; Duchene,
A.; Abarbri, M. J. Org. Chem. 2005, 70, 6669.
References
(1) For reviews, see: (a) Barry, R. D. Chem. Rev. 1964, 64, 229.
(b) Shusherina, N. P. Russ. Chem. Rev. 1974, 43, 851.
(c) Posner, G. H.; Afarinkia, K.; Vinader, V.; Nelson, T. D.
Tetrahedron 1992, 48, 9111. (d) Kvita, V.; Fischer, W.
Chimia 1992, 46, 457. (e) Kvita, V.; Fischer, W. Chimia
1993, 47, 3.
(2) (a) Larsen, T. O.; Breinholt, J. J. Nat. Prod. 1999, 62, 1182.
(b) Dumontet, V.; Hung, N. V.; Adeline, M.-T.; Riche, C.;
Chiaroni, A.; Sevenet, T.; Gueritte, F. J. Nat. Prod. 2004, 67,
858.
(3) For selected recent examples, see: (a) Abraham, W. R.;
Arfmann, H. A. Phytochemistry 1988, 27, 3310.
(b) Schlingmann, G.; Milne, L.; Carter, G. T. Tetrahedron
1988, 54, 13013. (c) Simon, A.; Dunlop, R. W.; Ghisalberti,
E. L.; Sivasithamparam, K. Soil Biol. Biochem. 1988, 20,
263. (d) Vara Prasad, J. V. N.; Para, K. S.; Lunney, E. A.;
Ortwine, D. F.; Dunbar, J. B. Jr.; Ferguson, D.; Tummino, P.
J.; Hupe, D.; Tait, B. D.; Domagala, J. M.; Humblet, C.;
Bhat, T. N.; Liu, B.; Guerin, D. A. M.; Baldwin, E. T.;
Erickson, J. W.; Sawyer, T. K. J. Am. Soc. Chem. 1994, 116,
6989. (e) Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.;
Meinwald, J. Tetrahedron Lett. 1995, 36, 71.
(f) Thaisrivongs, S.; Romero, D. L.; Tommasi, R. A.;
Janakiraman, M. N.; Strohbach, J. W.; Turner, S. R.; Biles,
C.; Morge, R. R.; Johnson, P. D.; Aristoff, P. A.; Tomich, P.
K.; Lynn, J. C.; Horng, M.-M.; Chong, K.-T.; Hinshaw, R.
R.; Howe, W. J.; Finzel, B. C.; Watenpaugh, K. D. J. Med.
Chem. 1996, 39, 4630. (g) Hagen, S. E.; Vara Prasad, J. V.
N.; Boyer, F. E.; Domagala, J. M.; Ellsworth, E. L.; Gajda,
C.; Hamilton, H. W.; Markoski, L. J.; Steinbaugh, B. A.;
Tait, B. D.; Lunney, E. A.; Tummino, P. J.; Ferguson, D.;
Hupe, D.; Nouhan, C.; Gracheck, S. J.; Saunders, J. M.;
VanderRoest, S. J. Med. Chem. 1997, 40, 3707. (h) Judge,
T. M.; Phillips, G.; Morris, J. K.; Lovasz, K. D.; Romines,
K. R.; Luke, G. P.; Tulinsky, J.; Tustin, J. M.; Chrusciel, R.
A.; Dolak, L. A.; Mizsak, S. A.; Watt, W.; Morris, J.; Vander
Velde, S. L.; Strohbach, J. W.; Gammill, R. B. J. Am. Chem.
Soc. 1997, 119, 3627. (i) Deck, L. M.; Baca, M. L.; Salas, S.
L.; Hunsaker, L. A.; Vander Jagt, D. L. J. Med. Chem. 1999,
42, 4250.
(l) Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J.
Org. Chem. 2005, 70, 4778. (m) Zhu, X.-F.; Schaffner,
A.-P.; Li, R. C.; Kwon, O. Org. Lett. 2005, 7, 2977. (n) Li,
X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett.
2005, 7, 5437. (o) Wang, Y.; Burton, D. J. J. Org. Chem.
2006, 71, 3859.
(7) o-(Alk-1-ynyl)benzoates 1a–i were prepared from the
reaction of the corresponding 2-iodobenzoates with terminal
alkynes and (Z)-alk-2-en-4-ynoate(1j) was obtained from
the reaction of (Z)-2-iodo-1-phenylalkene with ethynyl
propionate by known procedures, see: (a) Arcadi, A.;
Marinelli, F. Synthesis 1986, 749. (b) Arcadi, A.; Cacchi,
S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org. Chem.
1996, 61, 9280. (c) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. Rev. 2004, 104, 3079.
(8) Liang, Y.; Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.;
Li, J.-H. Org. Lett. 2006, 8, 3017.
(4) For papers on the synthesis of isocoumarins and a-pyrones
by electrophilic cyclization of the corresponding acids, see:
(a) Nagarajan, A.; Balasubramanian, T. R. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1988, 27, 380.
(b) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R.
Tetrahedron Lett. 2001, 42, 2859. (c) Bellina, F.; Biagetti,
M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857.
(9) Liao, H.-Y.; Cheng, C.-H. J. Org. Chem. 1995, 60, 3711.
(10) Patel, M. G.; Sethna, S. J. Indian Chem. Soc. 1962, 39, 595.
(11) Krafft, G. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc.
1981, 103, 5459.
Synthesis 2007, No. 3, 400–406 © Thieme Stuttgart · New York