Three-step synthesis of substituted isochromenes

Article abstract of DOI:10.1016/j.tet.2015.12.021

A synthetic route toward isochromenes 6, starting with aldehydes 3, in good to excellent yield is described herein. This novel approach was carried out by the Henry reaction of 3 with NH₄OAc and nitroalkanes (MeNO₂ or EtNO₂), aerobic Wacker-type oxidation of the resulting nitroalkenes 4, followed by K₂CO₃-promoted intramolecular Michael cyclization in modest to good yields.

Full text of DOI:10.1016/j.tet.2015.12.021

Tetrahedron xxx (2015) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Three-step synthesis of substituted isochromenes
*
Chieh-Kai Chan, Yi-Ling Chan, Meng-Yang Chang
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic route toward isochromenes 6, starting with aldehydes 3, in good to excellent yield is de-
scribed herein. This novel approach was carried out by the Henry reaction of 3 with NH4OAc and ni-
troalkanes (MeNO2 or EtNO2), aerobic Wacker-type oxidation of the resulting nitroalkenes 4, followed by
K2CO3-promoted intramolecular Michael cyclization in modest to good yields.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 22 September 2015
Received in revised form 2 December 2015
Accepted 10 December 2015
Available online xxx
Keywords:
Isochromene
Henry reaction
Aerobic Wacker-type oxidation
Intramolecular Michael cyclization
1. Introduction
Many excellent organic chemists are committed to the de-
velopment of efficient and facile ways to synthesize isochromene
Isochromenes are significant classes of heterocyclic compounds,
owing to some natural products and bioactive compound struc-
tures containing meaningful moiety.1 For example, pyr-
anonapthoquinone exhibits pharmaceutical activity: the
carboxamides analog, BCH-2051 (1), acts an anticancer agent in its
ability to fight cancer cell line SKOV3 and methyl 1,5,8-trimethoxy-
1H-isochromene-3-carboxylate (2) displays a moderate antitumor
function.2 It is noteworthy that, the ubiquitous core skeleton, ox-
ygen-/nitrogen-containing hetero-cycles, has appeared in phar-
maceutically important compounds and has also drawn a lot of
attention (see Fig. 1).3
and its derivatives.4 For example, many procedures for the syn-
thetic isochromene, cyclization reaction have been applied using
the metal-catalyzed method.4aed Transition metal-catalyzed cycli-
zation has also been a ubiquitous method, such as the represen-
tative Pd(II) Heck reaction,5 cycloisomerization of Au(I)3b,4e,4k or
Pd(II)4f catalyzed, Os-catalyzed,6 Ru(II)-catalyzed,7 complex with
a tetradentate NeP mixed ligand,8 Ir pincer complexes-catalyzed,9
or Rh(III)-catalyzed oxidative coupling.10
Nitromethyl isochromenes have also drawn attention recently.
In 2011, copper(II)-catalyzed Henry reaction and gold(I)-mediated
cycloisomerization were utilized by Gong’s group to produce
nitromethyl isochromenes.4e Kundu and co-workers developed
a domino reaction to obtain the desired isochromenes.4i
2. Results and discussions
Recently, we have become interested in the development of new
synthetic routes for the construction of a benzofused bicyclic sys-
tem derived from the versatile 2-allylbenzaldehyde 3 including
benzazepines and 2-naphthols, as shown in Scheme 1.11 The
starting skeleton 3 was easily provided by commercially available
isovanillin in moderate overall three-step yields with a reaction
sequence of O-allylation and a Claisen rearrangement followed by
O-alkylation. In 2012, we studied the treatment of 3 via Henry re-
action, reduction and oxidative cleavage annulation providing tet-
rahydro-3-benzazepine analogs.12a Furthermore, we examined the
treatment of 3 by Wacker-type oxidation and intramolecular aldol
cyclization which afforded 2-naphthols derivatives in 2013.12b
Fig. 1. Bioactive isochromene derivatives.
* Corresponding author. Tel.: þ866 7 312 1101x2220; e-mail address: mychang@
cc.kmu.edu.tw (M.-Y. Chang).
http://dx.doi.org/10.1016/j.tet.2015.12.021
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chan, C.-K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.021

2
C.-K. Chan et al. / Tetrahedron xxx (2015) 1e8
Following the experience of our previous work,12 we aim to develop
a facile synthetic route for isochromene based on skeleton 3 by the
above synthetic routes (Henry reaction, Wacker-type oxidation and
Michael cyclization).
the yields were between 70 and 84% (entries 8e12). We have
learned that this oxidation step, PdCl2 (6.5%), CuCl2 (1.5 equiv) in an
oxygen environment is the best condition for this process.
As far as we know, the Michael addition displayed a very com-
mon reaction for cyclization.13 Considering the characteristics of
skeleton 5, a cyclization reaction may be the required task. Fur-
thermore, cyclization of 5 was our goal. In 2012, Fu and co-workers
published a report on K2CO3-catalyzed cyclization to synthesize
chromones and 4-quinolones.14 Moreover, the base-promoted Mi-
chael cyclization was adopted first in this step. 5a was employed as
the model substrate to test the conditions with different bases such
as K2CO3, Cs2CO3, Na2CO3, NaHCO3 and Et3N, following this pro-
tocol. K2CO3 was first tested with the equivalent of 3.5 in acetone at
room temperature, showing only a 65% isolated yield and 15% of the
starting material was recovered (entry 1). Increasing the reaction
temperature to 56 ꢀC, the yield of product 6a was upgraded to 68%
(entry 2). In entry 3, the solvent was changed to THF and the yield
reached 72% at room temperature. This phenomenon can be at-
tributed to the fact that solvent was an important factor, therefore,
THF was more suitable than acetone. When the equivalent of K2CO3
was increased to 4.7, the yield was better than 6.2 in 66 ꢀC reaching
87% (entries 4 and 5). On the basis of these conditions, M2CO3
(M¼Cs, Na) was examined, perhaps the metal radius of Cs was
greater than K, causing the yields of the desired product was not
excellent and an unknown product was isolated (entries 6 and 7).
Intriguingly, changing the smaller radius of metal like Na2CO3, the
reaction took a longer time with no good yields (entry 8). NaHCO3
and Et3N were also not suitable for this strategy, they not only re-
quired a long time but also unknown products appeared (entries 9
and 10). Overviewing the scope of the various bases in THF by
different equivalents, we learned that the K2CO3 was the best one in
this base-mediated strategy (see Table 2).
Scheme 1. Synthetic applications of 3.
Initially, 3a (R1¼OMe, R2¼Me) was selected as the model sub-
strate to conduct the Henry reaction to afford 4a and then, to ex-
plore the oxidation conditions. Wacker-type oxidation was also
employed to promote the allyl group into methylketone 5a. In this
case, there may be a nitrovinyl group besides the allyl group that
enhances the difficulty of the oxidation on the allyl group. Hence,
we wanted to examine the catalytic oxidation condition. Some
Pd(II) catalysts were tried, such as, PdCl2, Pd(OAc)2, PdBr2,
PdCl2(MeCN)2, PdCl2(PPh3)2 and Pd2(dba)3, as shown in Table 1. As
a result, Wacker-type oxidation in this case was not easy under our
previous conditions.12b So, 4a was chosen as the model substrate to
try other conditions, such as catalysts, equivalents of CuCl2 and
oxidants. When the catalyst (PdCl2) and some oxidants (DDQ or
CAN) were selected, only 20% and 18% (entries 1e2) and some
unknown products were obtained. When the reaction was con-
ducted under air or O2, the desired 5a was isolated in 62e87%, and
trace amounts of unknown products were isolated under different
equivalents of PdCl2 and CuCl2 (entries 3e6). When the equivalents
of CuCl2 and PdCl2 were reduced, 5a was isolated in 72% and 4a was
also recovered in 5% (entry 7). Besides PdCl2 being tested, some
other Pd(II) catalysts, including Pd(OAc)2, PdBr2, PdCl2(MeCN)2,
PdCl2(PPh3)2, Pd2(dba)3 were tested under an O2 environment, and
We next explored the scope and generality of the Henry re-
action, Wacker-type oxidation and K2CO3-mediated cyclization
with the optimized reaction conditions in hand. As shown in
Table 3, various substituents (methyl, butyl, cyclopentyl, benzyl or
isopropyl) on the R1 position of 4aej were obtained in moderate
yields (78e85%) via the Henry reaction. The R1 position of 5aee
was a methoxy group, 5fej was a hydrogen atom, and all of their
isolated yields were between 79 and 87%. Base-mediated cycliza-
tion was conducted smoothly, and the desired products were all in
good to excellent performance. Entries 1e5, R1 was an OMe group,
R2 bearing methyl, butyl, cyclopentyl, benzyl and isopropyl groups,
Table 1
Reaction conditions of 4aa
Table 2
Base-mediated cyclization of 5aa
Entry
catalyst (mol %), CuCl2 (equiv), oxidants (equiv)
Yield (%)b
1
2
3
4
5
6
7
8
PdCl2 (5.1), CuCl2 (1.5), DDQ (1.0)
PdCl2 (5.1), CuCl2 (1.5), CAN (1.0)
PdCl2 (5.1), CuCl2 (1.5), air
PdCl2 (5.1), CuCl2 (1.5), O2
PdCl2 (6.5), CuCl2 (1.5), O2
20c
18c
62d
78d
87d
80d
72e
76d
70d
71d
83d
84d
Entry
Base (equiv), solvents, time (h), temp (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
9
K2CO3 (3.5), acetone, 2, 25
K2CO3 (3.5), acetone, 2, 56
K2CO3 (3.5), THF, 2, 25
K2CO3 (4.7), THF, 2, 66
K2CO3 (6.2), THF, 2, 66
Cs2CO3 (3.5), THF, 3, 66
Cs2CO3 (4.7), THF, 2, 66
Na2CO3 (4.7), THF, 30, 66
NaHCO3 (4.7), THF, 70, 66
Et3N (4.7), THF, 4, 66
65c,d
68c
72c,d
87c
80c
25e
20e
53d
25
PdCl2 (8.2), CuCl2 (1.5), O2
PdCl2 (4.3), CuCl2 (1.5), O2
Pd(OAc)2 (6.5), CuCl2 (1.5), O2
PdBr2 (6.5), CuCl2 (1.5), O2
PdCl2(MeCN)2 (6.5), CuCl2 (1.5), O2
PdCl2(PPh3)2 (6.5), CuCl2 (1.5), O2
Pd2(dba)3 (6.5), CuCl2 (1.5), O2
9
10
11
12
10
25
a
a
The reactions were conducted on a 1.0 mmol scale with 4a.
5a was >95% pure as determined by 1H NMR analysis.
Unknown products were obtained (entry1, 5%, entry 2, 6%).
Trace amounts (<5%) of unknown products were obtained.
4a was recovered by 15%.
The reactions were conducted on a 1.0 mmol scale with 5a.
6a was >95% pure as determined by 1H NMR analysis.
Trace amounts (<5%) of unknown products were obtained.
5a was recovered (entry 1, 15%; entry 3, 10%).
b
c
b
c
d
e
d
e
Unknown products were obtained (entry 6, 5%; entry 7, 4%).
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C.-K. Chan et al. / Tetrahedron xxx (2015) 1e8
3
Table 3
Three-step synthesis of substituted isochromenes 6a,b
and 82e87% of 6aee was isolated. As far as we know, the methoxy
group was an electron-donating group, the electron effect brought
about the cyclization conformation. Fortunately, changing the
group of R1 from OMe to H, allowed the cyclization to be conducted
smoothly and the isolated yields of 6fej ranged from 75 to 79%. For
the formation of 6a, we believed that a possible pathway could be
K2CO3-mediated abstraction of benzylic proton of 5a to form
a
more conjugated enolate intermediate followed by intra-
molecular Michael-type cyclization of the resulting stable enolate
that protonation afforded 6a smoothly.
As expected, altering the solvent of the Henry reaction from
nitromethane to nitroethane, followed by Wacker oxidation
resulted in the desired product 5k being isolated in an excellent
yield (88%) and the single-crystal X-ray structure was shown in
(Fig. 2).15 The K2CO3-promoted step was also applied to this con-
figuration forming isochromene derivative 6k (Scheme 2).
Scheme 2. Synthesis of 6k.
Fig. 2. X-ray structure of 5k.
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4
C.-K. Chan et al. / Tetrahedron xxx (2015) 1e8
The isoquinoline nucleus is an important skeleton because many
natural products contain the scaffold exhibiting many biological
activities.16 Therefore, many efficient synthetic ways for substituted
isoquinolines were developed.17 Intriguingly, when NH4OAc was
the additive as a base conducted with 5a in methanol, the iso-
quinoline derivative was obtained in good isolated yield (86%). We
guessed that the mechanism of isoquinoline 7 was that amine
condensed with ketone first to get I. In the basic condition, amine
attacked the double bond to form II. Through the electron ex-
change, III was formed producing compound 7 in a 78% yield
(Scheme 3).
was diluted with water (10 mL) and the mixture was extracted with
EtOAc (3ꢁ20 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated to afford crude product. Puri-
fication on silica gel (hexanes/EtOAc¼10/1e6/1) afforded skeleton
4.
4.2.1. (E)-2-Allyl-3,4-dimethoxy-1-(2-nitrovinyl)benzene
(4a).11 Yield¼85% (635 mg); Yellowish oil; HRMS (ESI, MþþH)
calcd for C13H16NO4 250.1079, found 250.1080; 1H NMR (400 MHz,
CDCl3):
d
8.20 (d, J¼13.2 Hz, 1H), 7.45 (d, J¼13.2 Hz, 1H), 7.35 (d,
J¼8.8 Hz, 1H), 6.86 (d, J¼8.8 Hz, 1H), 6.01e5.91 (m, 1H), 5.07 (dq,
J¼1.6, 10.4 Hz, 1H), 4.90 (dq, J¼1.6, 17.2 Hz, 1H), 3.92 (s, 3H), 3.81 (s,
3H), 3.61 (dt, J¼1.6, 5.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
155.75, 147.68, 136.92, 136.16 (2ꢁ), 135.09, 123.97, 122.34, 116.27,
110.76, 60.99, 55.79, 30.12.
4.2.2. (E)-2-Allyl-3-butoxy-4-methoxy-1-(2-nitrovinyl)benzene
(4b). Yield¼83% (725 mg); Colorless solid; mp¼51e52 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for
C
16H21NO4Na 314.1368, found 314.1363; 1H NMR (400 MHz, CDCl3):
d
8.20 (d, J¼13.2 Hz, 1H), 7.44 (d, J¼13.6 Hz, 1H), 7.33 (d, J¼8.8 Hz,
1H), 6.84 (d, J¼8.8 Hz, 1H), 5.99e5.89 (m, 1H), 5.05 (dq, J¼1.6,
10.0 Hz, 1H), 4.90 (dq, J¼1.6, 17.2 Hz, 1H), 3.91 (t, J¼6.4 Hz, 2H), 3.89
(s, 3H), 3.60 (dt, J¼1.6, 5.6 Hz, 2H), 1.78e1.71 (m, 2H), 1.52e1.47 (m,
Scheme 3. The possible mechanism.
2H), 0.97 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 155.84,
146.91, 137.02, 136.22, 135.96, 135.07, 123.71, 122.24, 116.11, 110.64,
73.19, 55.68, 32.22, 30.14, 19.06, 13.79.
3. Conclusion
4.2.3. (E)-2-Allyl-3-(cyclopentyloxy)-4-methoxy-1-(2-nitrovinyl)
benzene (4c). Yield¼81% (737 mg); Colorless gum; HRMS (ESI,
MþþNa) calcd for C17H21NO4Na 326.1368, found 326.1364; 1H NMR
In summary, a facile and efficient way to synthesize iso-
chromene derivatives was found. Through the Wacker-type oxi-
dation reaction, we obtained ketones 5aej. K2CO3 promoted the
cyclization of ketones 5aej to obtain compound 6aej smoothly.
Interesting, when the base was changed to NH4OAc, the desired
product was not increased; however we acquired the isoquinoline
analogs. The characteristic of the framework of 5 include the ability
to produce substituted isochromenes or isoquinolines with
a change of bases.
(400 MHz, CDCl3):
d
8.23 (d, J¼13.6 Hz, 1H), 7.45 (d, J¼13.2 Hz, 1H),
7.31 (d, J¼8.8 Hz, 1H), 6.84 (d, J¼8.8 Hz, 1H), 5.97e5.87 (m, 1H), 5.07
(dq, J¼2.0, 10.4 Hz, 1H), 4.91 (dq, J¼2.0, 17.2 Hz, 1H), 4.85e4.82 (m,
1H), 3.90 (s, 3H), 3.61 (dt, J¼2.0, 5.6 Hz, 2H), 1.89e1.77 (m, 4H),
1.76e1.67 (m, 2H), 1.64e1.56 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
155.71, 145.81, 137.45, 136.13, 135.98, 135.32, 123.26, 122.51,
116.30, 110.69, 84.90, 55.74, 32.81 (2ꢁ), 30.45, 23.62 (2ꢁ).
4. Experimental section
4.1. General
4.2.4. (E)-2-Allyl-3-(benzyloxy)-4-methoxy-1-(2-nitrovinyl)benzene
(4d). Yield¼78% (814 mg); Colorless solid; mp¼73e74 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for
C
19H19NO4Na 348.1212, found 348.1209; 1H NMR (400 MHz,
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous magnesium sulfate before concentration in vacuo.
Melting points were determined with a SMP3 melting apparatus.
1H and 13C NMR spectra were recorded on a Varian INOVA-400
spectrometer operating at 400 and at 100 MHz, respectively.
CDCl3):
d
8.22 (d, J¼13.2 Hz, 1H), 7.47 (d, J¼13.2 Hz, 2H), 7.48e7.40
(m, 5H), 6.91 (d, J¼8.8 Hz, 1H), 5.96e5.86 (m, 1H), 5.08 (dq, J¼2.0,
10.4 Hz, 1H), 5.00 (s, 2H), 4.90 (dq, J¼2.0, 17.2 Hz, 1H), 3.95 (s, 3H),
3.60 (dt, J¼1.6, 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 155.78,
146.38, 137.23, 136.92, 136.10, 136.08, 135.29, 128.36 (2ꢁ), 128.04
(2ꢁ), 128.02, 124.07, 122.33, 116.23, 110.75, 74.93, 55.77, 30.26.
4.2.5. (E)-2-Allyl-3-isopropoxy-4-methoxy-1-(2-nitrovinyl)benzene
(4e). Yield¼82% (738 mg); Colorless oil; HRMS (ESI, MþþNa) calcd
for C15H19NO4Na 300.1212, found 300.1207; 1H NMR (400 MHz,
Chemical shifts (d) are reported in parts per million (ppm) and the
coupling constants (J) are given in Hertz. High resolution mass
spectra (HRMS) were measured with a mass spectrometer Buker
microTOF-Q. X-ray crystal structures were obtained with an Enraf-
Nonius FR-590 diffractometer (CAD4, Kappa CCD).
CDCl3):
d
8.22 (d, J¼13.6 Hz, 1H), 7.44 (d, J¼13.6 Hz, 1H), 7.31 (d,
J¼8.4 Hz, 1H), 6.60 (d, J¼8.8 Hz, 1H), 5.95e5.85 (m, 1H), 5.05 (dq,
J¼2.0, 10.0 Hz, 1H), 4.90 (dq, J¼2.0, 17.2 Hz, 1H), 4.54e4.48 (m, 1H),
3.88 (s, 3H), 3.63 (dt, J¼2.0, 5.6 Hz, 2H), 1.26 (d, J¼6.0 Hz, 6H); 13C
4.2. A representative synthetic procedure of skeleton 4 is as
follows
NMR (100 MHz, CDCl3): d 155.81, 145.32, 137.35, 136.10, 135.79,
135.31, 123.30, 122.32, 116.18, 110.47, 74.89, 55.61, 30.43, 22.44 (2ꢁ).
Ammonium acetate (NH4OAc, 234 mg, 3.0 mmol) was added to
a solution of skeleton 3 (3.0 mmol) in nitromethane (for 4aej,
MeNO2, 10 mL) or nitroethane (for 4k, EtNO2, 10 mL) at 25 ꢀC. The
reaction mixture was stirred at reflux for 6 h. The reaction mixture
was cooled to 25 ꢀC. Saturated NaHCO3 (5 mL) was added to the
reaction mixture and the solvent was concentrated. The residue
4.2. 6. (E)-2-Allyl-1-methoxy-3-(2-nitrovinyl)benzene
(4f).11 Yield¼84% (552 mg); colorless solid; mp¼55e70 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, MþþH) calcd
for C12H14NO3 220.0974, found 220.0977; 1H NMR (400 MHz,
CDCl3):
d
8.29 (d, J¼13.6 Hz, 1H), 7.48 (d, J¼13.6 Hz, 1H), 7.26 (t,
J¼7.6 Hz,1H), 7.13 (d, J¼7.6 Hz,1H), 7.00 (d, J¼7.6 Hz,1H), 5.98e5.88
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C.-K. Chan et al. / Tetrahedron xxx (2015) 1e8
5
(m, 1H), 5.03 (dq, J¼1.6, 10.0 Hz, 1H), 4.91 (dq, J¼1.6, 16.8 Hz, 1H),
3.85 (s, 3H), 3.58 (dt, J¼1.6, 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
methanol (20 mL, v/v¼9:1) at 25 ꢀC. Then oxygen was bubbled into
the mixture for 3 h, and stirred at 25 ꢀC for 10 h. The residue was
diluted with water (10 mL) and the mixture was extracted with
EtOAc (3ꢁ20 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated to afford crude product. Puri-
fication on silica gel (hexanes/EtOAc¼10/1e6/1) afforded skeleton 5.
d
157.91,138.26,136.95,135.75,130.33,129.41,127.80,119.27,115.66,
113.47, 55.84, 29.83.
4.2.7. (E)-2-Allyl-1-butoxy-3-(2-nitrovinyl)benzene (4g). Yield¼85%
(666 mg); Colorless solid; mp¼40e41 ꢀC (recrystallized from
hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for C15H19NO3Na
4.3.1. (E)-1-(2,3-Dimethoxy-6-(2-nitrovinyl)phenyl)propan-2-one
(5a). Yield¼87% (231 mg); Colorless solid; mp¼103e104 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, MþþH) calcd
for C13H15NO5Na 288.0848, found 288.0840; 1H NMR (400 MHz,
284.1263, found 284.1259; 1H NMR (400 MHz, CDCl3):
d 8.31 (d,
J¼13.6 Hz, 1H), 7.48 (d, J¼13.6 Hz, 1H), 7.23 (t, J¼8.4 Hz, 1H), 7.11 (d,
J¼8.4 Hz, 1H), 6.98 (d, J¼8.4 Hz, 1H), 5.96e5.87 (m, 1H), 5.03 (dq,
J¼1.6, 10.0 Hz, 1H), 4.94 (dq, J¼1.6, 16.8 Hz, 1H), 3.99 (t, J¼6.4 Hz,
2H), 3.59 (dt, J¼1.6, 6.0 Hz, 2H), 1.83e1.76 (m, 2H), 1.56e1.48 (m,
CDCl3):
J¼8.4 Hz,1H), 6.90 (d, J¼8.4 Hz,1H), 3.96 (s, 2H), 3.91 (s, 3H), 3.78 (s,
3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3):
204.97, 155.40,
d
8.00 (d, J¼13.6 Hz, 1H), 7.43 (d, J¼13.6 Hz, 1H), 7.35 (d,
2H), 0.98 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
157.39,
d
138.17, 137.08, 135.83, 130.23, 129.62, 127.72, 119.03, 115.64, 114.30,
68.19, 31.28, 30.03, 19.30, 13.79.
147.63, 136.58, 136.21, 130.43, 123.86, 122.47, 111.58, 60.59, 55.78,
41.17, 29.84.
4.2.8. (E)-2-Allyl-1-(cyclopentyloxy)-3-(2-nitrovinyl)benzene
(4h). Yield¼78% (639 mg); Colorless oil; HRMS (ESI, MþþNa) calcd
for C16H19NO3Na 296.1263, found 296.1260; 1H NMR (400 MHz,
4.3.2. (E)-1-(2-Butoxy-3-methoxy-6-(2-nitrovinyl)phenyl)propan-2-
one (5b). Yield¼85% (261 mg); Colorless solid; mp¼87e88 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd
for C16H21NO5Na 330.1317, found 330.1313; 1H NMR (400 MHz,
CDCl3):
d
8.30 (d, J¼13.6 Hz, 1H), 7.47 (d, J¼13.6 Hz, 1H), 7.21 (t,
J¼8.4 Hz, 1H), 7.08 (d, J¼8.4 Hz, 1H), 6.98 (d, J¼8.4 Hz, 1H),
5.94e5.84 (m, 1H), 5.01 (dq, J¼1.6, 10.0 Hz, 1H), 4.93 (dq, J¼1.6,
17.2 Hz, 1H), 4.82e4.78 (m, 1H), 3.54 (dt, J¼1.6, 5.6 Hz, 2H),
1.82e1.74 (m, 4H), 1.69e1.60 (m, 4H); 13C NMR (100 MHz, CDCl3):
CDCl3):
d
8.01 (d, J¼13.2 Hz, 1H), 7.43 (d, J¼13.2 Hz, 1H), 7.34 (d,
J¼8.8 Hz, 1H), 6.89 (d, J¼8.8 Hz, 1H), 3.98 (s, 2H), 3.92 (t, J¼6.8 Hz,
2H), 3.90 (s, 3H), 2.27 (s, 3H), 1.75e1.68 (m, 2H), 1.50e1.44 (m, 2H),
0.97 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 204.90, 155.52,
d
156.25, 138.10, 137.19, 135.86, 130.31, 130.15, 127.53, 118.74, 115.55,
147.05, 136.56, 136.38, 130.43, 123.67, 122.57, 111.54, 73.01, 55.78,
41.40, 32.28, 29.79, 19.12, 13.82.
115.49, 79.61, 32.78 (2ꢁ), 30.19, 23.94 (2ꢁ).
4.2.9. (E)-2-Allyl-1-(benzyloxy)-3-(2-nitrovinyl)benzene
(4i). Yield¼85% (636 mg); Colorless solid; mp¼84e85 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for
4.3.3. (E)-1-(2-(Cyclopentyloxy)-3-methoxy-6-(2-nitrovinyl)phenyl)
propan-2-one (5c). Yield¼84% (268 mg); Colorless solid;
mp¼100e101 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, MþþNa) calcd for C17H21NO5Na 342.1317, found 342.1314; 1H
C
18H17NO3Na 318.1106, found 318.1103; 1H NMR (400 MHz, CDCl3):
d
8.32 (d, J¼13.6 Hz, 1H), 7.49 (d, J¼13.2 Hz, 1H), 7.45e7.32 (m, 5H),
NMR (400 MHz, CDCl3):
d
7.99 (d, J¼13.2 Hz, 1H), 7.44 (d, J¼13.2 Hz,
7.24 (t, J¼8.0 Hz, 1H), 7.15 (d, J¼8.0 Hz, 1H), 7.05 (d, J¼8.0 Hz, 1H),
6.01e5.91 (m, 1H), 5.12 (s, 2H), 5.06 (dq, J¼1.6, 10.0 Hz, 1H), 4.94
(dq, J¼1.6, 17.2 Hz, 1H), 3.65 (dt, J¼1.6, 5.6 Hz, 2H); 13C NMR
1H), 7.33 (d, J¼8.8 Hz, 1H), 6.89 (d, J¼8.8 Hz, 1H), 4.90e4.88 (m, 1H),
3.98 (s, 2H), 3.90 (s, 3H), 2.24 (s, 3H), 1.80e1.74 (m, 4H), 1.73e1.71
(m, 2H), 1.70e1.59 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 204.89,
(100 MHz, CDCl3):
d
156.95, 138.30, 136.92, 136.64, 135.70, 130.48,
155.30, 145.84, 136.64, 136.51, 130.58, 123.21, 122.76, 111.53, 84.85,
129.81, 128.60 (2ꢁ), 128.01, 127.77, 127.09 (2ꢁ), 119.59, 115.84,
55.78, 41.74, 32.82 (2ꢁ), 29.71, 23.63 (2ꢁ).
114.90, 70.41, 30.09.
4.3.4. (E)-1-(2-(Benzyloxy)-3-methoxy-6-(2-nitrovinyl)phenyl)
propan-2-one (5d). Yield¼86% (293 mg); Colorless solid;
mp¼118e119 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, MþþNa) calcd for C19H19NO5Na 364.1161, found 364.1157; 1H
4.2.10. (E)-2-Allyl-1-isopropoxy-3-(2-nitrovinyl)benzene
(4j). Yield¼83% (540 mg); Colorless oil; HRMS (ESI, MþþNa) calcd
for C14H17NO3Na 270.1106, found 270.1102; 1H NMR (400 MHz,
CDCl3):
d
8.30 (d, J¼13.6 Hz, 1H), 7.47 (d, J¼13.2 Hz, 1H), 7.22 (t,
NMR (400 MHz, CDCl3):
d
7.97 (d, J¼13.2 Hz, 1H), 7.44 (d, J¼13.2 Hz,
J¼8.0 Hz, 1H), 7.09 (d, J¼8.0 Hz, 1H), 6.99 (d, J¼8.0 Hz, 1H),
5.95e5.85 (m, 1H), 5.02 (dq, J¼1.6, 10.4 Hz, 1H), 4.94 (dq, J¼2.0,
17.6 Hz, 1H), 4.60e4.54 (m, 1H), 3.57 (dt, J¼1.6, 6.0 Hz, 2H), 1.35 (s,
1H), 7.40e7.33 (m, 6H), 6.95 (d, J¼8.8 Hz, 1H), 4.98 (s, 2H), 3.96 (s,
3H), 3.87 (s, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
204.86,
155.42, 146.71, 137.14, 136.66, 136.34, 130.75, 128.55 (2ꢁ), 128.24,
128.19 (2ꢁ), 123.97, 122.66, 111.60, 75.04, 55.89, 41.46, 29.79.
3H),1.33 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 156.22,138.09,137.21
(2ꢁ), 135.89, 130.49, 127.60, 119.04, 115.99, 115.64, 70.56, 30.15,
22.03 (2ꢁ).
4.3.5. (E)-1-(2-Isopropoxy-3-methoxy-6-(2-nitrovinyl)phenyl)
propan-2-one (5e). Yield¼82% (240 mg); Colorless solid;
mp¼69e70 ꢀC (recrystallized from hexanes and EtOAc); HRMS (ESI,
MþþNa) calcd for C15H19NO5Na 316.1161, found 316.1158; 1H NMR
4.2.11. (E)-2-Allyl-3,4-dimethoxy-1-(2-nitroprop-1-en-1-yl)benzene
(4k).11 Yield¼86% (226 mg); Yellowish oil; HRMS (ESI, MþþH)
calcd for C14H18NO4 264.1236, found 264.1238; 1H NMR (400 MHz,
(400 MHz, CDCl3):
d
7.98 (d, J¼13.6 Hz, 1H), 7.44 (d, J¼13.6 Hz, 1H),
CDCl3):
d
8.13 (s, 1H), 7.02 (d, J¼8.4 Hz, 1H), 6.86 (d, J¼8.8 Hz, 1H),
7.33 (d, J¼8.8 Hz,1H), 6.88 (d, J¼8.8 Hz,1H), 4.58e4.52 (m,1H), 4.00
5.93e5.84 (m, 1H), 5.02 (dq, J¼1.6, 10.0 Hz, 1H), 4.90 (dq, J¼1.6,
17.2 Hz, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.47 (dt, J¼1.6, 6.0 Hz, 2H),
(s, 2H), 3.89 (s, 3H), 2.24 (s, 3H), 1.23 (d, J¼6.4 Hz, 6H); 13C NMR
(100 MHz, CDCl3):
d 204.93, 155.46, 145.47, 136.68, 136.43, 130.77,
2.32 (d, J¼0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
153.86, 147.47,
123.30, 122.72, 111.34, 74.98, 55.72, 41.75, 29.77, 22.47 (2ꢁ).
135.77 (2ꢁ), 133.88, 132.48, 125.29, 125.01, 115.76, 110.13, 60.95,
55.71, 31.09, 13.91.
4.3.6. (E)-1-(2-Methoxy-6-(2-nitrovinyl)phenyl)propan-2-one
(5f). Yield¼82% (193 mg); Colorless solid; mp¼95e96 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for
4.3. A representative synthetic procedure of skeleton 5 is as
follows
C
12H13NO4Na 258.0742, found 258.0736; 1H NMR (400 MHz,
CDCl3):
J¼8.0 Hz, 1H), 7.14 (d, J¼8.0 Hz, 1H), 7.00 (d, J¼8.0 Hz, 1H), 3.92 (s,
2H), 3.83 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3):
205.12,
d
8.12 (d, J¼13.6 Hz, 1H), 7.46 (d, 13.6 Hz, 1H), 7.30 (t,
PdCl2 (13 mg, 6.5 mol %) and CuCl2 (200 mg, 1.5 mmol) were
added to a solution of skeleton 4 (1.0 mmol) in co-solvent of THF and
d
Please cite this article in press as: Chan, C.-K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.021

6
C.-K. Chan et al. / Tetrahedron xxx (2015) 1e8
157.79, 138.72, 136.36, 130.78, 128.62, 124.87, 119.40, 113.20, 55.77,
40.80, 29.80.
reaction mixture was stirred at reflux for 3 h. The reaction mixture
was cooled to 25 ꢀC. Water (5 mL) was added to the reaction
mixture and extracted with EtOAc (3ꢁ20 mL). The combined or-
ganic layers were washed with brine, dried, filtered and evaporated
to afford crude product. Purification on silica gel (hexanes/
EtOAc¼10/1e6/1) afforded skeleton 6.
4.3.7. (E)-1-(2-Butoxy-6-(2-nitrovinyl)phenyl)propan-2-one
(5g). Yield¼81% (224 mg); Colorless solid; mp¼81e82 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for
C
15H19NO4Na 300.1212, found 300.1208; 1H NMR (400 MHz,
CDCl3):
d
8.13 (d, J¼13.6 Hz, 1H), 7.49 (d, J¼13.6 Hz, 1H), 7.27 (t,
4.4.1. 5,6-Dimethoxy-3-methyl-1-(nitromethyl)-1H-isochromene
(6a). Yield¼88% (253 mg); Colorless oil; HRMS (ESI, MþþNa) calcd
for C13H15NO5Na 288.0848, found 288.0845; 1H NMR (400 MHz,
J¼8.0 Hz, 1H), 7.12 (d, J¼8.0 Hz, 1H), 6.97 (d, J¼8.0 Hz, 1H), 3.97 (t,
J¼6.4 Hz, 2H), 3.91 (s, 2H), 2.23 (s, 3H), 1.80e1.73 (m, 2H), 1.52e1.43
(m, 2H), 0.97 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
205.15,
CDCl3):
d
6.78 (d, J¼8.4 Hz, 1H), 6.71 (d, J¼8.4 Hz, 1H), 6.00 (s, 1H),
157.20, 138.59, 136.43, 130.69, 128.51, 124.94, 119.08, 113.89, 68.10,
40.83, 31.09, 29.74, 19.16, 13.68.
5.84 (dd, J¼3.6, 10.4 Hz, 1H), 4.84 (dd, J¼10.4, 12.0 Hz, 1H), 4.24 (dd,
J¼3.6, 12.0 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 1.95 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 153.27, 151.82, 142.35, 124.76, 120.16, 109.85,
4.3.8. (E)-1-(2-(Cyclopentyloxy)-6-(2-nitrovinyl)phenyl)propan-2-
one (5h). Yield¼84% (243 mg); Colorless solid; mp¼91e92 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd
for C16H19NO4Na 312.1212, found 312.1209; 1H NMR (400 MHz,
95.56, 76.74, 74.17, 62.16, 60.91, 55.78, 19.91.
4.4.2. 5-Butoxy-6-methoxy-3-methyl-1-(nitromethyl)-1H-iso-
chromene (6b). Yield¼86% (264 mg); Colorless oil; HRMS (ESI,
MþþNa) calcd for C16H21NO5Na 330.1317, found 330.1314; 1H NMR
CDCl3):
d
8.15 (d, J¼13.6 Hz, 1H), 7.45 (d, J¼13.6 Hz, 1H), 7.25 (t,
J¼8.0 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 6.97 (d, J¼8.0 Hz, 1H),
4.81e4.77 (m, 1H), 3.86 (s, 2H), 2.22 (s, 3H), 1.95e1.80 (m, 4H),
1.79e1.70 (m, 2H), 1.69e1.60 (m, 2H); 13C NMR (100 MHz, CDCl3):
(400 MHz, CDCl3):
d
6.76 (d, J¼8.0 Hz, 1H), 6.70 (d, J¼8.0 Hz, 1H),
5.99 (s, 1H), 5.84 (dd, J¼3.2, 10.4 Hz, 1H), 4.84 (dd, J¼10.4, 11.6 Hz,
1H), 4.24 (dd, J¼3.6, 11.6 Hz, 1H), 3.96e3.88 (m, 2H), 3.83 (s, 3H),
1.95 (s, 3H), 1.79e1.72 (m, 2H), 1.56e1.46 (m, 2H), 0.98 (t, J¼7.6 Hz,
d
205.21, 156.14, 138.55, 136.55, 130.81, 128.35, 125.45, 118.81,
115.01, 79.74, 41.02, 32.70 (2ꢁ), 29.73, 23.90 (2ꢁ).
3H); 13C NMR (100 MHz, CDCl3):
d 153.39, 151.58, 141.71, 124.95,
119.90, 117.71, 109.92, 95.86, 76.78, 74.23, 73.29, 55.83, 32.28, 19.97,
19.17, 13.88.
4.3.9. (E)-1-(2-(Benzyloxy)-6-(2-nitrovinyl)phenyl)propan-2-one
(5i). Yield¼78% (243 mg); Colorless solid; mp¼86e87 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for
4.4.3. 5-(Cyclopentyloxy)-6-methoxy-3-methyl-1-(nitromethyl)-1H-
isochromene (6c). Yield¼85% (271 mg); Colorless oil; HRMS (ESI,
MþþNa) calcd for C17H21NO5Na 342.1317, found 342.1313; 1H NMR
C
18H17NO4Na 334.1055, found 334.1051; 1H NMR (400 MHz, CDCl3):
d
8.15 (d, J¼13.2 Hz, 1H), 7.46 (d, J¼13.2 Hz, 1H), 7.43e7.34 (m, 5H),
7.29 (t, J¼8.0 Hz, 1H), 7.16 (d, J¼8.0 Hz, 1H), 7.06 (d, J¼8.0 Hz, 1H),
(400 MHz, CDCl3):
d
6.75 (d, J¼8.0 Hz, 1H), 6.70 (d, J¼8.0 Hz, 1H),
5.07 (s, 2H), 3.96 (s, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3):
5.96 (s, 1H), 5.84 (dd, J¼3.6, 10.4 Hz, 1H), 4.83 (dd, J¼10.4, 11.6 Hz,
1H), 4.83e4.81 (m, 1H), 4.24 (dd, J¼3.6, 11.6 Hz, 1H), 3.83 (s, 3H),
1.95 (s, 3H), 1.88e1.81 (m, 4H), 1.74e1.68 (m, 2H), 1.66e1.57 (m,
d
205.09, 156.89, 138.71, 136.29, 136.14, 130.87, 128.59 (2ꢁ), 128.54,
128.15, 127.35 (2ꢁ), 125.26, 119.59, 114.44, 70.53, 40.89, 29.93.
2H); 13C NMR (100 MHz, CDCl3):
d 153.40, 151.27, 140.54, 125.57,
4.3.10. (E)-1-(2-Isopropoxy-6-(2-nitrovinyl)phenyl)propan-2-one
(5j). Yield¼83% (218 mg); Colorless solid; mp¼67e68 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, MþþNa) calcd for
119.60, 117.74, 109.99, 96.29, 84.72, 76.77, 74.29, 55.81, 32.83, 32.68,
23.67, 23.63, 20.00.
C
14H17NO4Na 286.1055, found 286.1051; 1H NMR (400 MHz, CDCl3):
4.4.4. 5-(Benzyloxy)-6-methoxy-3-methyl-1-(nitromethyl)-1H-iso-
chromene (6d). Yield¼78% (266 mg); Colorless oil; HRMS (ESI,
MþþNa) calcd for C19H19NO5Na 364.1161, found 364.1157; 1H NMR
d
8.16 (d, J¼13.2 Hz, 1H), 7.47 (d, J¼13.2 Hz, 1H), 7.28 (t, J¼8.4 Hz,
1H), 7.12 (d, J¼8.4 Hz, 1H), 6.99 (d, J¼8.4 Hz, 1H), 4.62e4.56 (m, 1H),
3.89 (s, 2H), 2.25 (s, 3H), 1.33 (d, J¼6.0 Hz, 6H); 13C NMR (100 MHz,
(400 MHz, CDCl3):
d 7.46e7.45 (m, 2H), 7.40e7.33 (m, 3H), 6.79 (d,
CDCl3):
d
205.31, 156.12, 138.69, 136.65, 131.08, 128.49, 125.81,
J¼8.4 Hz, 1H), 6.73 (d, J¼8.4 Hz, 1H), 5.90 (s, 1H), 5.83 (dd, J¼3.2,
10.4 Hz, 1H), 5.01 (d, J¼11.2, 1H), 4.95 (d, J¼11.2 Hz, 1H), 4.80 (dd,
J¼10.4, 12.0 Hz, 1H), 4.22 (dd, J¼3.2, 12.0 Hz, 1H), 3.86 (s, 3H), 1.89
119.07, 115.16, 70.54, 41.12, 29.93, 22.01, 21.94.
4.3.11. (E)-1-(2,3-Dimethoxy-6-(2-nitroprop-1-en-1-yl)phenyl)
propan-2-one (5k). Yield¼88% (246 mg); Colorless solid;
mp¼67e68 ꢀC (recrystallized from hexanes and EtOAc); HRMS (ESI,
MþþNa) calcd for C14H17NO5Na 302.1004, found 302.1000; 1H NMR
(s, 3H); 13C NMR (100 MHz, CDCl3):
d 153.39, 151.67, 141.12, 137.43,
128.36, 128.30 (2ꢁ), 128.07, 125.23, 120.28, 117.68, 109.86, 95.89,
76.67 (2ꢁ), 75.08, 74.18, 55.86, 19.88.
(400 MHz, CDCl3):
d
7.92 (s, 1H), 6.99 (d, J¼8.4 Hz, 1H), 6.89 (d,
4.4.5. 5-Isopropoxy-6-methoxy-3-methyl-1-(nitromethyl)-1H-iso-
chromene (6e). Yield¼81% (237 mg); Colorless gum; HRMS (ESI,
MþþNa) calcd for C15H19NO5Na 316.1161, found 316.1157; 1H
J¼8.4 Hz,1H), 3.88 (s, 3H), 3.81 (s, 2H), 3.77 (s, 3H), 2.28 (s, 3H), 2.22
(s, 3H); 13C NMR (100 MHz, CDCl3):
d
205.02, 153.43, 148.23, 147.48,
131.67 (2ꢁ), 129.22, 125.01 (2ꢁ), 60.48, 55.63, 41.92, 29.78, 13.72.
Single-crystal X-ray diagram: crystal of 5k was grown by slow
diffusion of EtOAc into a solution of 5k in CH2Cl2 to yield colorless
prisms. The compound crystallizes in the monoclinic crystal sys-
NMR (400 MHz, CDCl3):
d
6.76 (d, J¼8.4 Hz, 1H), 6.70 (d, J¼8.4 Hz,
1H), 6.00 (br s, 1H), 5.83 (dd, J¼3.6, 10.4 Hz, 1H), 4.83 (dd, J¼10.4,
12.0 Hz, 1H), 4.41 (m, 1H), 4.24 (dd, J¼3.6, 12.0 Hz, 1H), 3.82 (s,
3H), 1.95 (s, 3H), 1.29 (d, J¼6.4 Hz, 3H), 1.27 (d, J¼6.4 Hz, 3H); 13C
ꢀ
ꢀ
tem, space group P 21/c, a¼12.9058(14) A, b¼13.0754(14) A,
NMR (100 MHz, CDCl3): d 153.54, 151.27, 140.39, 125.65, 119.69,
c¼8.2832(9) A, V¼1379.5(3) A , Z¼4, dcalcd¼1.345 g/cm3, F(000)¼
117.71, 109.81, 96.47, 76.77, 75.26, 74.26, 55.77, 22.56, 22.50,
19.96.
3
ꢀ
ꢀ
592,
2
q
range 1.60e26.40ꢀ,
R
indices (all data) R1¼0.0653,
wR2¼0.1116.
4.4.6. 5-Methoxy-3-methyl-1-(nitromethyl)-1H-isochromene
(6f). Yield¼78% (201 mg); Colorless oil; HRMS (ESI, MþþNa) calcd
for C12H13NO4Na 258.0742, found 258.0734; 1H NMR (400 MHz,
4.4. A representative synthetic procedure of skeleton 6 is as
follows
CDCl3):
d
7.13 (dd, J¼7.6, 8.0 Hz, 1H), 6.81 (d, J¼8.0 Hz, 1H), 6.68 (d,
Potassium carbonate (K2CO3, 276 mg, 2.0 mmol) was added to
J¼7.6 Hz, 1H), 6.03e6.02 (m, 1H), 5.89 (dd, J¼3.2, 10.4 Hz, 1H), 4.89
(dd, J¼10.4, 11.6 Hz, 1H), 4.27 (dd, J¼3.2, 11.6 Hz, 1H), 3.84 (s, 3H),
a solution of skeleton 5 (1.0 mmol) in THF (10 mL) at 25 ꢀC. The
Please cite this article in press as: Chan, C.-K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.021

C.-K. Chan et al. / Tetrahedron xxx (2015) 1e8
7
1.95 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
152.87, 150.83, 127.15,
3H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
151.51,151.45,151.43,
125.26, 119.94, 116.67, 110.96, 95.42, 76.33, 74.42, 55.53, 19.83.
140.88, 132.35, 124.36, 123.01, 114.64, 111.95, 61.03, 56.44, 24.31.
4.4.7. 5-Butoxy-3-methyl-1-(nitromethyl)-1H-isochromene
(6g). Yield¼76% (228 mg); Colorless oil; HRMS (ESI, MþþNa) calcd
for C15H19NO4Na 300.1212, found 300.1204; 1H NMR (400 MHz,
Acknowledgements
We thank for the Ministry of Science and Technology of the
Republic of China for financial support (MOST 104-2113-M-037-
012).
CDCl3):
d
7.11 (dd, J¼7.6, 8.4 Hz, 1H), 6.79 (d, J¼8.4 Hz, 1H), 6.66 (d,
J¼7.6 Hz, 1H), 6.04 (s, 1H), 5.88 (dd, J¼3.6, 10.4 Hz, 1H), 4.89 (dd,
J¼10.4, 12.0 Hz, 1H), 4.26 (dd, J¼3.6, 12.0 Hz, 1H), 3.97 (t, J¼6.4 Hz,
2H), 1.95 (s, 3H), 1.84e1.77 (m, 2H), 1.57e1.47 (m, 2H), 1.00 (t,
Supplementary data
J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 152.41, 150.64, 127.10,
125.27, 120.04, 116.44, 111.88, 95.55, 76.39, 74.45, 68.00, 31.30,
19.84, 19.30, 13.85.
Supplementary data related to this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2015.12.021.
4.4.8. 5-(Cyclopentyloxy)-3-methyl-1-(nitromethyl)-1H-iso-
chromene (6h). Yield¼75% (234 mg); Colorless gum; HRMS (ESI,
MþþNa) calcd for C16H19NO4Na 312.1212, found 312.1207; 1H NMR
References and notes
1. (a) Hari, L.; De Buyck, L. F.; De Pootert, H. L. Photochemistry 1991, 30, 1726; (b)
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Org. Chem. 2011, 5195.
(400 MHz, CDCl3):
d
7.09 (t, J¼8.0 Hz, 1H), 6.80 (d, J¼8.0 Hz, 1H),
6.64 (d, J¼8.0 Hz, 1H), 5.99 (s, 1H), 5.87 (dd, J¼3.2, 10.4 Hz, 1H), 4.88
(dd, J¼10.4, 12.0 Hz, 1H), 4.78e4.74 (m, 1H), 4.26 (dd, J¼3.2, 12.0 Hz,
1H), 1.95 (s, 3H), 1.90e1.74 (m, 4H), 1.69e1.59 (m, 4H); 13C NMR
(100 MHz, CDCl3):
d 151.38, 150.48, 126.95, 120.53, 116.19, 113.26,
112.71, 95.73, 79.65, 76.93, 74.47, 32.88, 32.86, 24.06, 24.04, 19.85.
4.4.9. 5-(Benzyloxy)-3-methyl-1-(nitromethyl)-1H-isochromene
(6i). Yield¼75% (251 mg); Colorless gum; HRMS (ESI, MþþNa)
calcd for
C
18H17NO4Na 334.1055, found 334.1052; 1H NMR
(400 MHz, CDCl3):
d
7.45e7.35 (m, 5H), 7.11 (t, J¼8.0 Hz,1H), 6.87 (d,
J¼8.0 Hz, 1H), 6.69 (d, J¼8.0 Hz, 1H), 6.09 (s, 1H), 5.90 (dd, J¼3.6,
10.4 Hz, 1H), 5.08 (s, 2H), 4.90 (dd, J¼10.4, 12.0 Hz, 1H), 4.27 (dd,
J¼3.6, 12.0 Hz, 1H), 1.95 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
152.05, 150.91, 136.77, 128.62 (2ꢁ), 128.04, 127.34 (2ꢁ), 127.10,
125.42, 120.37, 116.98, 112.44, 95.58, 74.43, 70.28, 29.69, 19.85.
3. (a) Davis, C. S. J. Pharm. Sci. 1962, 51, 1111; (b) Feng, Y.; Jiang, X.; Brabander, J. K.
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Williams, N.; Floreancig, P. E.; Brabander, J. K. D.; Roth, M. J. J. Am. Chem. Soc.
2012, 134, 18998; (d) Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, L. R.;
Baran, P. S. J. Am. Chem. Soc. 2015, 137, 10160.
4.4.10. 5-Isopropoxy-3-methyl-1-(nitromethyl)-1H-isochromene
(6j). Yield¼79% (226 mg); Colorless oil; HRMS (ESI, MþþNa) calcd
for C14H17NO4Na 286.1055, found 286.1049; 1H NMR (400 MHz,
4. (a) Mutter, R.; Campbell, I. B.; Martin de la Nava, E. M.; Merritt, A. T.; Wills, M. J.
Org. Chem. 2001, 66, 3284; (b) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y. J.
Org. Chem. 2003, 68, 9496; (c) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y.
J. Am. Chem. Soc. 2002, 124, 764; (d) Giles, R. G. F.; Green, I. R.; Taylor, C. P.
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Chem. 2011, 76, 8869; (f) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahe-
dron 2003, 59, 6251; (g) Kobayashi, K.; Nagaoka, T.; Fukamachi, S.; Shirai, Y.;
Morikawa, O.; Konishi, H. Synthesis 2007, 3032; (h) Butin, A. V.; Abaev, V. T.;
Melchin, V. V.; Dmitriev, A. S.; Pilipenko, A. S.; Shashkov, A. S. Synthesis 2008,
1798; (i) Arigela, R. K.; Samala, S.; Mahar, R.; Shukla, S. K.; Kundu, B. J. Org.
Chem. 2013, 78, 10476; (j) Bian, J.; Qian, X.; Wang, N.; Mu, T.; Li, X.; Sun, H.;
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B.; Qian, M. Org. Lett. 2008, 10, 2533.
CDCl3):
d
7.09 (dd, J¼7.6, 8.4 Hz, 1H), 6.81 (d, J¼8.4 Hz, 1H), 6.65 (d,
J¼7.6 Hz, 1H), 6.03 (br s, 1H), 5.87 (dd, J¼3.6, 10.4 Hz, 1H), 4.88 (dd,
J¼10.4,12.0 Hz,1H), 4.56e4.50 (m,1H), 4.26 (dd, J¼3.6,12.0 Hz,1H),
1.95 (s, 3H), 1.36 (d, J¼6.0 Hz, 3H), 1.34 (d, J¼6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
d 151.26, 150.28, 126.99, 125.26, 121.03, 116.49,
113.77, 95.81, 76.42, 74.47, 70.60, 22.12, 22.06, 19.85.
4.4.11. 5,6-Dimethoxy-3-methyl-1-(1-nitroethyl)-1H-isochromene
(6k). Four isomers; Yield¼79% (221 mg); Colorless oil; HRMS (ESI,
MþþNa) calcd for C14H17NO5Na 302.1004, found 302.0997; 1H NMR
5. Gharpure, S. J.; Shelke, Y. G.; Reddy, S. R. B. RSC Adv. 2014, 4, 46962.
6. Varela-Fernandez, A.; Garcia-Yebra, C.; Varela, J. A.; Ester, M. A.; Saa, C. Angew.
Chem., Int. Ed. 2010, 49, 4278.
7. Varela-Fernandez, A.; Gonzalez-Rodriguez, C.; Varela, J. A.; Castedo, L.; Saa, C.
Org. Lett. 2009, 11, 5350.
(400 MHz, CDCl3):
d
6.77 (d, J¼8.4 Hz, 1H), 6.71 (d, J¼8.4 Hz, 1H),
5.99 (s, 1H), 5.32 (d, J¼9.6 Hz, 1H), 4.92e4.94 (m, 1H), 3.85 (s, 3H),
3.80 (s, 3H), 1.92 (s, 3H), 1.33 (d, J¼6.8 Hz, 3H).
8. Liu, P. N.; Su, F. H.; Wen, T. B.; Sung, H. H.-Y.; Williams, I. D.; Jia, G. Chem.dEur. J.
2010, 16, 7889.
4.5. 5,6-Dimethoxy-3-methylisoquinoline (7)
9. Yao, W.; Zhang, Y.; Jia, X.; Huang, Z. Angew. Chem., Int. Ed. 2014, 53, 1390.
10. Zhang, M.; Zhang, H.-J.; Han, T.; Ruan, W.; Wen, T.-B. J. Org. Chem. 2015, 80, 620.
11. Hassam, M.; Taher, A.; Arnott, G. E.; Green, I. R.; van Otterlo, W. A. L. Chem. Rev.
2015, 115, 5462.
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(b) Chang, M.-Y.; Chan, C.-K.; Lin, S.-Y. Tetrahedron 2013, 69, 1532.
13. (a) Chang, M.-Y.; Chan, C.-K.; Chen, Y.-C. Tetrahedron 2014, 70, 2529; (b) Wen, L.;
Yin, L.; Shen, Q.; Lu, L. ACS Catal. 2013, 3, 502; (c) Wang, Z.-C.; Xu, X.-D.; Chen,
C.-S.; Yun, L.; Song, J.-C.; Zhang, X.-Z.; Zhuo, R.-X. ACS Appl. Mat. Interfaces 2010,
2, 1009; (d) Li, H.; Zu, L.; Xie, H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9,
1833; (e) Gaggero, N.; Albanese, D. C. M.; Nava, D. Tetrahedron 2014, 70, 8744;
(f) Deredas, D.; Huben, K.; Maniukiewicz, W.; Krawczyk, H. Tetrahedron 2014,
70, 8925.
Ammonium acetate (NH4OAc, 115 mg, 1.5 mmol) was added to
a solution of skeleton 5 (1.0 mmol) in MeOH (10 mL) at 25 ꢀC. The
reaction mixture was stirred at reflux for 4 h. The reaction mixture
was cooled to 25 ꢀC. The reaction mixture was concentrated, di-
luted with water (10 mL), and extracted with EtOAc (3ꢁ20 mL). The
combined organic layers were washed with brine, dried, filtered
and evaporated to afford crude product. Purification on silica gel
(hexanes/EtOAc¼10/1e6/1) afforded compound 7. Yield¼78%
(158 mg); Colorless solid; mp¼83e84 ꢀC (recrystallized from hex-
anes and EtOAc); HRMS (ESI, MþþH) calcd for C12H14NO2 204.1025,
14. Zhao, J.; Zhao, Y.; Fu, H. Org. Lett. 2012, 14, 2710.
15. CCDC 1062569 (5k) contains the supplementary crystallographic data for this
paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
found 204.1017; 1H NMR (400 MHz, CDCl3):
d
9.04 (s, 1H), 7.67 (d,
J¼9.2 Hz, 1H), 7.66 (s, 1H), 7.27 (d, J¼9.2 Hz,1H), 3.99 (s, 3H), 3.95 (s,
Please cite this article in press as: Chan, C.-K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.021

8
C.-K. Chan et al. / Tetrahedron xxx (2015) 1e8
16. (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257; (b)
Chen, L.; Conda-Sheridan, M.; Reddy, P. V. N.; Morrell, A.; Park, E.-J.; Kon-
dratyuk, T. P.; Pezzuto, J. M.; van Breemen, R. B.; Cushman, M. J. Med. Chem.
2012, 55, 5965.
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2015, 17, 3374; (d) Pilgrim, B. S.; Gatland, A. E.; McTernan, C. T.; Procopiou, P. A.;
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Please cite this article in press as: Chan, C.-K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.021