Copper(II)-catalyzed asymmetric henry reaction of o-alkynylbenzaldehydes followed by gold(I)-mediated cycloisomerization: An enantioselective route to chiral 1 H-isochromenes and 1,3-dihydroisobenzofurans

Article abstract of DOI:10.1021/jo201596p

By combining the copper(II)-catalyzed asymmetric Henry reaction of o-alkynylbenzaldehydes with subsequent gold(I)-catalyzed cycloisomerization, optically active 1H-isochromenes and 1,3-dihydroisobenzofurans were successfully synthesized in good overall yields with good to excellent enantioselectivities (up to 98%). Various substrates were investigated, and a correlation between the regioselectivity and electronic nature of the substrates was studied. The substrates with electro-donating groups at the alkynyl moiety preferred a 6-endo-dig manner to generated 1H-isochromenes 3 as main products (up to >30:1) while the ones with electron-withdrawing groups were inclined to undergo 5-exo-dig cyclization to form 1,3-dihydroisobenzofurans 4 (up to 1:5).

Full text of DOI:10.1021/jo201596p

Article
pubs.acs.org/joc
Copper(II)-Catalyzed Asymmetric Henry Reaction of
o-Alkynylbenzaldehydes Followed by Gold(I)-Mediated
Cycloisomerization: An Enantioselective Route to Chiral
1H-Isochromenes and 1,3-Dihydroisobenzofurans
Dengfu Lu, Yirong Zhou, Yajun Li, Shaobai Yan, and Yuefa Gong*
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074,
China
S
* Supporting Information
ABSTRACT: By combining the copper(II)-catalyzed asymmetric Henry reaction of o-alkynylbenzaldehydes with subsequent
gold(I)-catalyzed cycloisomerization, optically active 1H-isochromenes and 1,3-dihydroisobenzofurans were successfully
synthesized in good overall yields with good to excellent enantioselectivities (up to 98%). Various substrates were investigated,
and a correlation between the regioselectivity and electronic nature of the substrates was studied. The substrates with electro-
donating groups at the alkynyl moiety preferred a 6-endo-dig manner to generated 1H-isochromenes 3 as main products (up to
>30:1) while the ones with electron-withdrawing groups were inclined to undergo 5-exo-dig cyclization to form 1,3-dihydro-
isobenzofurans 4 (up to 1:5).
might be a potential nucleophile in the above-mentioned
addition-cycloisomerizaiton sequence. We envisioned that the
chiral β-nitro alcohols obtained in the addition step would
undergo subsequent cycloisomerization without racemization
to give chiral 1H-isochromenes and 1,3-dihydroisobenzofurans.
From the outset of our investigation, we were reminded of
the fact that β-nitro alcohols may suffer from dehydration,
retro-Henry process, and racemization under thermal or basic
conditions. Thus, we initiated our study to identify mild and
base-free conditions to avoid side reactions and racemization
during the cycloisomerization.
In recent decades, great progress has been made on the gold-
catalyzed hydroalkoxylation of alkynes,10 especially the intra-
molecular versions, which provide efficient accesses to oxygen-
containing hetereocycles from alkynylacohols under mild
conditions.11 Therefore, gold catalysis might be an ideal choice
for the cyclization of the Henry products of o-alkynylbenzalde-
hydes. Herein, we present our research results on construct-
ing chiral 1H-isochromenes and 1,3-dihydroisobenzofurans by
combining the asymmetric Henry reaction with gold-catalyzed
cycloisomerization.
INTRODUCTION
■
1H-Isochromenes and 1,3-dihydroisobenzofurans are important
classes of heterocyclic compounds because of their fascinating
biological and pharmacological activities.1 For example,
isochromene carboxamides exhibit excellent activity against
the human ovarian cancer cell line SKOV3,2 and dihydroiso-
benzofuran derivative pestacin displays potent antioxidant
activity and moderate antifungal properties.3 Among the
methods for constructing such types of oxygen-containing
heterocycles, the cycloisomerization of o-alkynylaryl alcohols is
one of the most reliable and atom-economic.4,5 The alkynylaryl
alcohols are usually prepared4 or generated in situ5,6 by
nucleophilic additions of o-alkynylaryl aldehydes. Nucleophiles
such as alcohols,5c,f phosphites,5d terminal alkynes,5b active
methylene compounds5c and organometallic reagents5e have
been successfully utilized on the basis of this strategy. The
cycloisomerization step is usually mediated by bases4a,b,5d or
transition-metal catalysts4c−f,5a−c,g under thermal conditions.
Nevertheless, the enantioselective version of this reaction
sequence has rarely been reported.5e
Since the seminal contribution of Shibasaki in 1992,7
significant progress has been achieved in the implementation
of asymmetric addition of nitroalkanes to carbonyl compounds
(Henry reaction).8,9 Recently, our group has developed a novel
chiral diamine ligand for Cu(II)-catalyzed Henry reaction.9e
Motivated by our previous work, we anticipated that nitromethane
Received: August 3, 2011
Published: October 3, 2011
© 2011 American Chemical Society
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a
RESULTS AND DISCUSSION
Table 2. Optimization of Catalytic Asymmetric Henry Reaction
■
b
At the very beginning, we examined chiral diamine−Cu(II)
complex catalyzed Henry reaction between o-phenylethynyl-
benzaldehyde 1a and nitromethane. A series of chiral diamine
ligands L1−L6 were first screened. The reaction was performed
in nitromethane at 4 °C in the presence of 10 mol % of ligand
and 10 mol % of Cu(OAc)2·H2O. The reaction proceeded
readily, and 1a was consumed after 24 h (Table 1). Among all
enrty
solvent
additive
time (h)
yield (%)
ee (%)
c
1
MeNO2
MeNO2
MeNO2
THF
none
none
48
60
24
24
36
36
24
24
24
24
24
30
91
63
95
95
92
91
95
95
93
91
91
95
94
93
85
96
79
66
97
86
90
86
87
98
2
3
d
TEA
4
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
5
CH2Cl2
CHCl3
Et2O
6
7
8
EtOH
PhCH3
DMF
Table 1. Ligand and Copper Salt Screening of Catalytic
Asymmetric Henry Reaction
9
a
10
11
MeCN
Et2O
e
12
a
Unless otherwise stated, reactions were performed with 0.2 mmol of
1a, 5 mol % of L1-Cu(OAc)2·H2O complex, additive, and 25 equiv of
b
nitromethane in 2 mL of indicated solvent at −20 °C. Determined by
c
chiral HPLC analysis. 10 mol % of Cu(II)−L1 complex was used.
d
e
TEA 50 mol %. Reaction conducted at −40 °C.
was carried out at −20 °C, the starting material 1a could still be
consumed after an extended time; however, the ee value of
the product was hardly improved (Table 2, entry 1). Reduction
of the catalyst loading to 5 mol % did not erode the
enantioselectivity but led to the incomplete reaction (entry 2).
The reaction was accelerated significantly by addition of
50% mol of TEA as additive; in the meantime, a loss of
enantioselectivity was observed (entry 3). Next, a variety
of typical solvents were surveyed in the presence of 25 equiv of
nitromethane. Fortunately, when THF was employed as the
solvent, the ee value was enhanced to 96% and the yield
remained excellent (entry 4). The reaction proceeded slower
and less selectively in dichloromethane and chloroform (entries
5 and 6). Diethyl ether was also an ideal choice, providing
excellent yield and enantioselectivity (97% ee) after 24 h (entry 7).
The reactions in ethanol, toluene, DMF, or acetonitrile all
underwent smoothly but provided 2a with relatively lower
enantioselectivity (entries 8−11). The ee value was further
raised to 98% when the reaction was conducted at −40 °C after
a slightly extended time (Table 2, entry 12).
b
entry
catalyst
time (h)
yield (%)
ee (%)
1
2
L1/Cu(OAc)2·H2O
L2/Cu(OAc)2·H2O
L3/Cu(OAc)2·H2O
L4/Cu(OAc)2·H2O
L5/Cu(OAc)2·H2O
L6/Cu(OAc)2·H2O
L1/CuCl2·2H2O
L1/CuBr2
24
24
24
24
24
24
36
36
24
24
93
92
90
91
92
93
60
54
96
74
93
−40
81
3
4
−67
63
5
6
72
7
94
8
91
9
L1/CuSO4·5H2O
L1/Cu(OTf)2
80
10
86
a
Unless otherwise stated, reactions were carried out on a 0.2 mmol
scale of 1a in 2.0 mL of nitromethane in the presence of 10 mol %
of ligand−Cu(II) complex at 4 °C. Determined by chiral HPLC
b
Next, we turned to investigate the subsequent cyclo-
isomerization of the alkynol 2a. The cyclization reaction of
2a was initially performed in dichloromethane at 4 °C utilizing
5 mol % of the metal catalysts listed in Table 3. To our delight,
gold complex showed high efficiency in this intramolecular
hydroalkoxylation. The reaction mediated by Ph3PAu(OTf)
achieved completion in 1 h, furnishing the 6-endo-dig product
3a and 5-exo-dig product 4a in comparable yields (Table 3,
entry 1). The reaction mediated by palladium(II) chloride
proceeded much slower and afforded 3a and 4a in moderate
yields with poor regioselectivity after 10 h (entry 2). Cyclization
products were not detected when palladium(II) acetate,
bis(triphenylphosphine)palladium(II) chloride, silver triflate,
or copper acetate served as catalyst after 12 h under the same
conditions (entries 3−6). Further study of the gold(I)-
catalyzed reaction revealed that addition of 5 mol % of triflic
acid accelerated the process remarkably, indicating that the
presence of triflic acid could promote protondeauration step
(entry 7). During the reaction, we noticed that the 5-exo-dig
product 4a was not stable enough and inclined to decompose
slowly under the reaction conditions. Fortunately, when the
reaction was performed at −20 °C with 2 mol % of the catalyst,
the isolated yield of 5-exo-dig product 4a increased to 44%,
analysis.
the ligands tested, L1 was identified to be the best one in terms
of both the yield and enantioselectivity of the Henry adduct 2a
(Table 1, entry 1). When the ligand L2 derived from D-proline
was used instead, the configuration-inversed stereomer was
obtained with much lower enantioselectivity (entry 2). The
ligands L3 and L4 derived from (+)-(1S,2S,5R)-menthylamine
showed a similar change in stereoselectivity but failed to offer
better results (entries 3 and 4). L5 and L6, prepared from
camphor amine with L-alanine and L-phenylalanine, respectively,
also showed inferior enantioselectivities (entries 5 and 6).
These results are in agreement with our previous observa-
tions,10 which revealed that the nitronate would attack the
aldehyde from the re face when L1 was used. Therefore, the
absolute configuration of 2a was tentatively assigned as S. Next,
various bivalent copper salts were evaluated in combination with
L1 in nitromethane at 4 °C (entries 7−10). Cu(OAc)2·H2O
was chosen for further studies in consideration of both the yield
and enantioselectivity.
The reaction conditions were then optimized utilizing this
catalyst system. The data is shown in Table 2. When the reaction
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a
1a via the retro-Henry process, and no cyclization products
were detected.
Table 3. Catalysts Screening of the Cycloisomerization Step.
With the optimized conditions in hand, we started to
examine the substrate scope of this reaction sequence. The
Henry reactions of 1a−o were performed following the general
procedure under the established conditions. After simple
treatment,12 the crude products 2a−o were directly subjected
to the Au(I)-catalyzyed cycloisomerization reactions. The
results are summarized in Table 4.
yield of
yield of
entry
catalyst
time (h)
3a (%)
4a (%)
b
Gratifyingly, the stereochemistry of intermediate 2a was well
preserved during cyclization through both 6-endo-dig and 5-exo-
dig ways under the reaction conditions, providing almost equal
amounts of 1H-isochromene 3a and 1,3-dihydroisobenzofurans
4a with excellent enantiopurity (98% ee, Table 4, entry 1).
Another interesting result related to the regioselectivity was
observed during investigation of the cyclization of other
intermediates 2b−o. The regioselectivity between 6-endo-dig
and 5-exo-dig was very poor for 2a, while in the case of 4-Me-
Ph-substituted 2b, the ratio of 3b to 4b was raised to 3:1
(entry 2). 3-Me-Ph and 2-Me-Ph substrates 2c and 2d were
also examined, forming 1H-isochromenes 3c and 3d as main
products versus 4c and 4d, respectively (entries 3 and 4). For
2e, which bears a mesityl group on the alkynyl, the 6-endo-dig
product 3e was generated exclusively in high yield (entry 5).
From these preliminary results, we realized that a direct
dependence on the electronic nature of the alkynyl substituent
may exist in the cycloisomerization step. Thus, further
investigation of alkynylbenzaldehydes with electro-richer
1
2
3
4
5
6
7
Ph3PAu(OTf)
PdCl2
1
10
12
12
12
12
0.3
1
44
41
41
36
Pd(OAc)2
not observed
not observed
not observed
not observed
45
not observed
not observed
not observed
not observed
39
PdCl2(PPh3)2
AgOTf
Cu(OAc)2·H2O
Ph3PAu(OTf)/TfOH
Ph3PAu(OTf)/TfOH
TfOH
cd
,
8
45
44
d
9
12
not observed
not observed
a
Unless otherwise stated, reactions were performed with 0.2 mmol of
2a in the presence of 5 mol % of indicated catalyst at 4 °C. Generated
in situ by Ph3PAuCl and AgOTf. 2 mol % of catalysts were used.
b
c
d
Reaction conducted at −20 °C.
while the yield of 6-endo-dig counterpart 3a remained 45%
(entry 8). The control experiment revealed that triflic acid
alone could not catalyze the cycloisomerization (entry 9). The
addition of base such as DBU or TBAF led to the
decomposition of 2a into the o-phenylethynylbenzaldehyde
a
Table 4. Scope of the Asymmetric Henry Reaction/Gold-Catalyzed Cycloisomerization Sequences
d
T (°C), time
ratio of
yield of 3/4
ee of 3/4
b
c
entry
substrate
(h)
3/4
(%)
(%)
1
2
3
4
1a
1b
1c
1d
1e
1f
−40, 30
−40, 48
−40, 36
−40, 36
−20, 40
−20, 72
−20, 36
−40, 30
−20, 48
−20, 24
−20, 24
−40, 60
−40, 24
−40, 24
−40, 24
−40, 36
1:1
3:1
2:1
6:1
43/42
64/21
58/28
72/11
92/nd
77/nd
85/nd
46/44
38/55
16/68
20/61
15/76
82/nd
87/nd
80/nd
45/43
98/98
97/92
97/94
e
91/nd
f
g
5
>30:1
97/nd
93/nd
92/nd
97/97
96/94
95/92
95/75
nd/90
98/nd
98/nd
98/nd
98/96
f
6
9:1
9:1
f
7
1g
1h
1i
f
8
1:1
f
9
1:1.5
1:4
10
11
1j
1k
1l
1:3
f
12
1:5
13
14
15
1m
1n
1o
1a
24:1
g
>30:1
25:1
1:1
h
16
a
Unless otherwise stated, reactions were performed with 0.2 mmol of 1 and 25 equiv of nitromethane in the presence of 5 mol % of L1−Cu(II)
b
c
complex and 50 mol % of TEA in 2 mL of diethyl ether at the indicated temperature. Parameters of the Henry reaction. Determined by 1H NMR
of the crude product. Determined by chiral HPLC analysis. Not determined. Henry reaction carried out in Et2O/THF (1:1). The other isomer
was not observed on H NMR spectrum. Reaction carried out on 2 mmol scale.
d
e
f
g
h
1
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groups such as 4-MeO-Ph (1f)13 and 3,4-diMeO-Ph (1g)
seemed to be necessary. As expected, the products 3f and 3g
with six-membered ring were predominantly generated (9:1)
(entries 6 and 7). In addition, other functional groups with
different induction ability were also taken into consideration.
The 4-F-Ph-substituted 2h exhibited similar selectivity with 2a
(entry 8), while intermediate 2i with a 4-Cl-Ph preferred 5-exo-
dig cyclization to give product 3i and 4i in the ratio of 1:1.5
(entry 9). When the substituents were changed to m- or o-
chlorophenyl (1j and 1k), the selectivity between the 6-endo-dig
and 5-exo-dig pathways was further improved to 1:4 and 1:3,
respectively (entries 10 and 11). The reaction of 2l with a more
electron-deficient acetyl group furnished the 1,3-dihydroiso-
benzofuran 4l preferentially (entry 12). In some cases, a slight
lose of enantiopurity was observed for 5-exo-dig products 4,
which might be ascribed to the subsequent side reaction of 1,3-
dihydroisobenzofuran.14
Figure 1. Influence of the substituent at Cβ on triple bond polarization.
yield 6-endo-dig product (A). Similarly, the EWGs would
decrease the electron density around Cα, leading to the
formation of a 5-exo-dig propensity (B).
To gain further insight of our assumption, we analyzed the
chemical shifts of the alkyne carbon of Henry products
2a,b,f,h−i,l−o.18 To avoid the influence of steric or anisotropic
effect, the phenyl groups with ortho or meta substituents were
excluded. The alkyne carbon chemical shifts were assigned by
two-dimensional HMBC experiments, and the 13C NMR curves
are drawn in Figure 2. As compared to 2a (R = Ph), the EDG
caused a downfield shift of Cβ and an upfield shift of Cα,
indicating nucleophilic attack at Cβ is favored in the
hydroalkoxylation, and this speculation is in accordance with
our experimental results (Table 4). On the other hand, when
Cβ was substituted by EWG such as chloride and acetyl, the
shift of Cα and Cβ changed conversely and as a consequence
the attack at Cα is favored.
Moreover, alkylethynylbenzaldehydes 1m−o were also
examined. The isomerization of intermediates 2m−o generated
by Henry reaction underwent smoothly under the reaction
conditions, and almost only the 6-endo-dig products 3m−o
were afforded in good yields with excellent enantioselectivities
(entries 13−15). The reaction sequence of 1a can be enlarged
to 2 mmol scale without notable lose of yield and
enantioselectivity (entry 16). The structures of 3m and 3o
1
Additionally, the influence of the substituent on the phenyl at
Cα-end was also surveyed by performing the reaction of
substrates 2r and 2s (Scheme 2). The cycloisomerization of 2r
with a 5-methoxyl group on the phenyl at Cα-end gave 3r
and 4r with poor regioselectivity. This reaction was performed
with 5 mol % of catalyst but without triflic acid because of
the instability of the 5-exo-dig product 4r under the reaction
conditions. The cycloisomerization of 2s with a 5-nitro group
happened under the standard conditions to furnish an inseperable
mixtue of 3s and 4s at a ratio of 4:1 as determined by 1H NMR.
The chemical shifts of the alkyne carbon of 2r and 2s were
also studied and compared with that of 2a (Figure 3). The Cβ
of 2r is slightly upfield shifted after introducing a methoxyl
group and the 5-exo-dig manner would be favored. However,
only a small amount of 4r was isolated by column chro-
matography, which may be ascribed to the decomposition of 4r
during isolation. On the other hand, the 13C NMR spectrum of
2s reveals a downfield shift of Cβ and upfield shift of Cα,
favoring the nucleophilic attack at Cβ to afford the 6-endo-dig
product 3s as the major isomer. From these results, we can
speculate that the influence of substituents on the phenyl at
Cα-end is not as significant as those on the phenyl of Cβ-end.
In conclusion, we have developed a novel asymmetric Henry
reaction/gold catalyzed cycloisomerization sequence for the
synthesis of chiral 1H-isochromenes and 1,3-dihydroisobenzo-
furans frameworks under mild conditions. The chirality was
introduced by the C1-symmetric chiral diamine-Cu(II) complex
catalyzed Henry reaction and preserved in the Au(I) catalyzed
cycloisomerization. A pronounced electronic effect on the
regioselectivity of cycloisomerization was observed. By tuning
the electronic property of the substituents, many substrates
could be selectively transformed to one major product. Further
study on the methodology for constructing chiral heterocycles
is ongoing in our laboratory.
were easily determined by H NMR spectroscopy since the
proton on the olefin was not split by the methylene of R group.
Besides, the structures of 3a and 4l were confirmed
unambiguously by X-ray diffraction.15 Thus, the structural
assignment of other analogues was given by comparison of their
NMR spectra.
Besides o-alkynyl benzaldehydes 1a−o, 2-alkynylcycloalkene
aldehydes were also prepared and tested under the optimized
conditions to expand the scope of this reaction sequence. The
intermediates 2p and 2q were smoothly produced by the Henry
reaction. However, during the gold(I)-catalyzed cycloisomeri-
zation, achiral tetrasubstituted furans 5p or 5q, rather that the
expected chiral cyclized products, were produced as the major
products, possibly due to the rapid 1,5-hydride shift driven by
the formation of aromatic system (Scheme 1).
Scheme 1. Reactions of 2-Alkynylcycloalkene Aldehydes
From the results obtained with 1a−o, it is evident that the
regioselectivity of cycloisomerization is dependent on the
electronic property of alkyne. The alkyne substrate with an
electron-donating group (EDG) has a tendency to react in a
6-endo-dig way to form 1-H-isochromene, while that bearing
an electron-withdrawing (EWG) favors the 5-exo-dig manner
to offer 1,3-dihydroisobenzofuran. These observations are in
accordance with some previous reports about the cyclo-
isomerizaiton of alkynols16 or alkynylimines.17 As depicted in
Figure 1, the EDGs would push the electron atmosphere of the
triple bond toward Cα and decrease the electronic density
around Cβ, which favors Cβ toward a nucleophilic attack to
EXPERIMENTAL SECTION
■
General Information. Solvents were purified according to the
standard procedures and distilled before use. Reagents and starting
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Figure 2. Experimental 13C NMR spectra of the Henry products.
Scheme 2. Reactions of nitroalcohols 2r and 2s
materials purchased from commercial suppliers were used without
further purification unless otherwise stated. For thin-layer chromatog-
raphy (TLC), silica gel plates GF254 were used, and compounds were
visualized by irradiation with UV light, I2, or by treatment with basic
KMnO4. NMR spectra were measured on a 400 MHz spectrometer.
1H NMR chemical shifts were reported in ppm with tetramethylsilane
(TMS, δ 0 ppm) as the internal standard. Data for 1H NMR are
reported as follows: chemical shift (ppm), and multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). Data
for 13C NMR are reported as ppm. High resolution mass spectral
analyses (HRMS) were measured using APCI ionization. High
performance liquid chromatography (HPLC) analysis was per-
formed on chiral columns. Optical rotations were measured in the
solvent indicated. Flash chromatography was carried out on silica gel
200−300 mesh.
Preparation of Substrates 1a−s. The 2-alkynylbezaldehydes
1a−o,r−s were prepared by Pd/Cu catalyzed Sonogashira coulping
between the corresponding 2-bromobenzaldehyde and terminal
acetylenes or between 2-ethynylbenzaldehyde and corresponding
1
iodobenzene according to refs 17 and 19, and the H and 13C NMR
of the products are in agree with published data. 2-Alkynylcycloalkene
aldehydes 1p and 1q were also prepared according to the literature.20
Typical Procedure for the Asymmetric Henry Reaction and
Gold-Catalyzed Cycloisomerization Sequence. Ligand L1 (2.4
mg, 0.01 mmol, 5 mol %) and Cu(OAc)2·H2O (2 mg, 0.01 mmol,
5 mol %) were added to 2 mL of indicated solvent, and the mixture
was stirred for 2 h at room temperature to afford a blue solution.
To the mixture the o-phenylethynylbenzylaldehyde 1a (41 mg,
0.2 mmol) was added, and the solution was then cooled to −40 °C,
stirred, and followed by the addition of nitromethane (270 μL,
5 mmol) and TEA (14 μL, 0.1 mmol). The stirring was continued
until the aldehyde was fully consumed as indicated by TLC, and
then 200 μL of 2 M HCl and 2 mL of water were added to quench
the reaction. The mixture was extracted with ether for three times,
and the combined organic layer was dried over anhydrous Na2SO4.
After concentrated under vacuo, the crude product was dissolved in
3 mL of dichloromethane and cooled to −20 °C. To the solution,
2 mol % of TfOH, Ph3PAuCl, and AgOTf was added successively
and the mixture was stirred for additional 0.5−2 h until 2a was
completely consumed as indicated by TLC.21 At this point,
saturated brine (1 mL) was added under stirring. After the organic
layer was separated, the aqueous phase was extracted with ether.
The combined organic phase was dried over anhydrous MgSO4,
concentrated and purified by flash chromatography to afford the
cycloisomerization products 3a and 4a.
Figure 3. Experimental 13C NMR spectra of the Henry products 2r
and 2s.
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Preparation of Racemic Products. All the racemic compounds
were prepared by the cycloisomerization of the corresponding racemic
nitrolalcohols 2a−s which were obtained by the Henry reaction
catalyzed by 30 mol % of triethylamine with 20 equiv of nitromethane
in dichloromethane at room temperature.
1-(Nitromethyl)-3-m-tolyl-1H-isochromene (3c): [α]25
=
D
1
−142.79 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.52−7.42
(m, 2H), 7.32 (td, J = 7.5, 1.2 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.22
(td, J = 7.5, 1.3 Hz, 1H), 7.19−7.09 (m, 3H), 6.47 (s, 1H), 6.13 (dd,
J = 10.2, 3.2 Hz, 1H), 4.95 (dd, J = 12.4, 10.2 Hz, 1H), 4.35 (dd, J =
12.4, 3.3 Hz, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
150.5, 138.1, 133.3, 130.8, 130.3, 129.6, 128.4, 127.2, 125.9, 125.3,
124.7, 124.4, 122.5, 100.2, 76.5, 74.9, 21.5; HRMS (APCI, m/z) calcd
for C17H16NO3 (M + H+), 282.1125, found 282.1131; HPLC
(Chiralpak AS-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min,
λ = 254 nm), tmajor = 26.5, tminor = 23.0, 97% ee.
2-Nitro-1-(2-(phenylethynyl)phenyl)ethanol (2a): [α]25
=
D
1
+28.64 (c 2.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.64 (d, J =
7.7 Hz, 1H), 7.58−7.51 (m, 3H), 7.44−7.29 (m, 5H), 6.00 (d, J = 9.4
Hz, 1H), 4.80 (dd, J = 13.1, 2.4 Hz, 1H), 4.52 (dd, J = 13.1, 9.8 Hz,
1H), 3.00 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 139.6, 132.3,
131.6, 129.1, 129.0, 128.6, 128.5, 125.7, 122.3, 120.6, 96.4, 85.6, 80.4,
69.6; HPLC (Chiralpak AS-H, hexane/i-PrOH = 90:10, flow rate: 0.5
mL/min, λ = 254 nm), tmajor = 28.2, tminor = 31.2, 98% ee.
(Z)-1-(3-Methylbenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
1
benzofuran (4c): [α]25 = −69.00 (c 0.7, CHCl3); H NMR (400
D
1-(Nitromethyl)-3-phenyl-1H-isochromene (3a): [α]25
=
MHz, CDCl3) δ 7.60 (d, J = 7.7 Hz, 1H), 7.53−7.42 (m, 3H), 7.39
(td, J = 7.4, 0.9 Hz, 1H), 7.34−7.28 (m, 1H), 7.28−7.20 (m, 1H), 7.01
(d, J = 7.5 Hz, 1H), 6.33 (dd, J = 8.4, 3.8 Hz, 1H), 5.99 (s, 1H), 4.76
(dd, J = 13.2, 3.9 Hz, 1H), 4.67 (dd, J = 13.2, 8.4 Hz, 1H), 2.36 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 153.4, 137.9, 136.5, 135.2,
135.1, 129.8, 129.2, 129.0, 128.4, 127.0, 125.4, 121.5, 120.4, 98.7, 81.3,
78.6, 21.6; HRMS (APCI, m/z) calcd for C17H16NO3 (M + H+),
282.1125, found 282.1119; HPLC (Chiralpak AS-H, hexane/i-PrOH =
90:10, flow rate: 0.5 mL/min, λ = 210 nm), tmajor = 24.7, tminor = 23.5,
94% ee.
D
1
−191.91 (c 1.3, CHCl3); H NMR (400 MHz, CDCl3) δ 7.69−7.61
(m, 2H), 7.44−7.29 (m, 4H), 7.24 (td, J = 7.5, 1.2 Hz, 1H), 7.20−7.08
(m, 2H), 6.50 (s, 1H), 6.15 (dd, J = 10.3, 3.2 Hz, 1H), 4.96 (dd, J =
12.4, 10.3 Hz, 1H), 4.37 (dd, J = 12.4, 3.2 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 150.4, 133.4, 130.8, 129.6, 129.4, 128.5, 127.3, 125.3,
125.2, 124.7, 124.4, 100.2, 76.6, 74.9; HRMS (APCI, m/z) calcd for
C16H14NO3 (M + H+) 268.0968, found 268.0967; HPLC (Chiralpak
AD-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min, λ = 210 nm),
tmajor = 17.2, tminor = 22.0, 98% ee.
2-Nitro-1-(2-(o-tolylethynyl)phenyl)ethanol (2d): 1H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 7.7 Hz, 1H), 7.60−7.49 (m, 2H),
7.41 (td, J = 7.6, 1.3 Hz, 1H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.30−7.15
(m, 3H), 6.01 (dd, J = 9.7, 1.7 Hz, 1H), 4.79 (dd, J = 13.4, 2.5 Hz,
1H), 4.53 (dd, J = 13.3, 9.8 Hz, 1H), 3.01 (br, 1H), 2.51 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 140.0, 139.2, 132.6, 132.2, 129.7, 129.1,
129.0, 128.5, 125.9, 125.8, 122.2, 121.0, 95.1, 89.4, 80.2, 69.4, 20.8.
(Z)-1-Benzylidene-3-(nitromethyl)-1,3-dihydroisobenzofur-
1
an (4a): [α]25 = −101.35 (c 1.2, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.67 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.7 Hz, 1H), 7.44 (t,
J = 7.4 Hz, 1H), 7.41−7.27 (m, 4H), 7.17 (t, J = 7.4 Hz, 1H), 6.31 (dd,
J = 8.3, 3.7 Hz, 1H), 6.00 (s, 1H), 4.74 (dd, J = 13.3, 3.8 Hz, 1H), 4.65
(dd, J = 13.2, 8.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 153.6,
136.6, 135.3, 135.2, 129.8, 129.2, 128.5, 128.2, 126.1, 121.5, 120.4,
98.6, 81.3, 78.5; HRMS (APCI, m/z) calcd for C16H14NO3 (M + H+)
268.0968, found 268.0964; HPLC (Chiralpak AD-H, hexane/i-PrOH =
85:15, flow rate: 0.5 mL/min, λ = 210 nm), tmajor = 18.6, tminor = 22.7,
98% ee.
1-(Nitromethyl)-3-o-tolyl-1H-isochromene (3d): [α]25
=
D
1
−56.62 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.44−7.39
(m, 1H), 7.32 (td, J = 7.5, 1.3 Hz, 1H), 7.29−7.17 (m, 4H), 7.10 (ddd,
J = 10.3, 7.6, 0.7 Hz, 2H), 6.14 (dd, J = 9.8, 3.4 Hz, 1H), 6.04 (s, 1H),
5.06 (dd, J = 12.7, 9.8 Hz, 1H), 4.51 (dd, J = 12.7, 3.4 Hz, 1H), 2.42
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.3, 136.5, 134.1, 130.9,
130.8, 129.5, 129.1, 129.0, 127.3, 125.9, 124.7, 124.5, 124.1, 104.5,
76.8, 74.8, 20.9; HRMS (APCI, m/z) calcd for C17H16NO3 (M + H+),
282.1125, found 282.1129; HPLC (Chiralpak AD-H, hexane/i-PrOH
= 95:5, flow rate: 0.5 mL/min, λ = 254 nm), tmajor = 18.0, tminor = 20.4,
91% ee.
2-Nitro-1-(2-(p-tolylethynyl)phenyl)ethanol (2b): 1H NMR
(400 MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 7.6,
1.1 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.35 (td, J = 7.6, 1.3 Hz, 1H),
7.28 (td, J = 7.5, 1.2 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 5.94 (dd, J =
9.8, 2.2 Hz, 1H), 4.74 (dd, J = 13.1, 2.4 Hz, 1H), 4.45 (dd, J = 13.1,
9.9 Hz, 1H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 139.5,
139.3, 132.2, 131.5, 129.4, 128.9, 128.5, 125.6, 120.8, 119.2, 96.7, 85.0,
80.4, 69.7, 21.6.
(Z)-1-(2-Methylbenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
benzofuran (4d). Compound 4d was generated as a minor product,
typical peaks: 1H NMR (101 MHz, CDCl3) δ 6.31 (dd, J = 8.0, 4.0 Hz,
1H), 6.16 (s, 1H), 4.76 (dd, J = 13.2, 4.1 Hz, 1H), 4.69 (dd, J = 13.2,
8.1 Hz, 1H).
1-(Nitromethyl)-3-p-tolyl-1H-isochromene (3b): [α]25
=
D
1
−191.90 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.55 (d,
J = 7.9 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.27−7.04 (m, 5H), 6.45 (s,
1H), 6.13 (dd, J = 10.2, 2.7 Hz, 1H), 4.95 (dd, J = 12.3, 7.2 Hz, 1H),
4.36 (dd, J = 12.3, 3.0 Hz, 1H), 2.37 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 150.5, 139.6, 130.9, 130.6, 129.6, 129.2, 127.0, 125.2, 124.6,
124.4, 99.5, 76.5, 74.9, 21.4; HRMS (APCI, m/z): calcd for
C17H16NO3 (M + H+), 282.1125, found 282.1135; HPLC (Chiralpak
AS-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min, λ = 210 nm),
tmajor = 21.0, tminor = 22.5, 97% ee.
1-(2-(Mesitylethynyl)phenyl)-2-nitroethanol (2e): 1H NMR
(400 MHz, CDCl3) δ 7.62 (d, J = 7.3 Hz, 1H), 7.55 (dd, J = 7.6,
1.1 Hz, 1H), 7.39 (td, J = 7.6, 1.3 Hz, 1H), 7.33 (td, J = 7.5, 1.3 Hz,
1H), 6.89 (s, 2H), 5.99 (d, J = 9.9 Hz, 1H), 4.74 (dd, J = 13.6, 2.5 Hz,
1H), 4.51 (dd, J = 13.6, 9.9 Hz, 1H), 2.46 (s, 6H), 2.29 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 140.3, 138.7, 132.7, 128.8, 128.5, 128.0,
127.9, 125.8, 121.5, 119.2, 94.0, 93.4, 80.0, 69.2, 21.4, 21.1.
(Z)-1-(4-Methylbenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
1
benzofuran (4b): [α]25 = −77.05 (c 0.4, CHCl3); H NMR (400
3-Mesityl-1-(nitromethyl)-1H-isochromene (3e): [α]25
=
D
D
1
MHz, CDCl3) δ 7.61−7.54 (m, 3H), 7.44 (t, J = 7.5 Hz, 1H), 7.37 (t,
J = 7.3 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.8 Hz, 2H),
6.32 (dd, J = 8.3, 3.4 Hz, 1H), 5.99 (s, 1H), 4.75 (dd, J = 13.2, 3.7 Hz,
1H), 4.66 (dd, J = 13.1, 8.4 Hz, 1H), 2.34 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 152.9, 136.5, 135.9, 135.3, 132.4, 129.7, 129.2, 129.0,
128.2, 121.4, 120.3, 98.6, 81.2, 78.6, 21.3; HRMS (APCI, m/z): calcd
for C17H16NO3 (M + H+), 282.1125, found 282.1133; HPLC
(Chiralpak AS-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min,
λ = 210 nm), tmajor = 28.4, tminor = 26.0, 92% ee.
42.72 (c 1.3, CHCl3); H NMR (400 MHz, CDCl3) δ 7.30 (t, J =
7.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 6.8 Hz, 2H), 6.87 (s,
2H), 6.13 (dd, J = 9.6, 3.1 Hz, 1H), 5.79 (s, 1H), 5.06 (dd, J = 12.6,
9.9 Hz, 1H), 4.54 (dd, J = 12.8, 3.3 Hz, 1H), 2.31 (s, 6H), 2.28 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 151.8, 138.6, 137.1, 131.6,
130.7, 129.5, 128.3, 127.1, 124.4, 124.2, 124.1, 104.7, 77.4, 74.7, 21.1,
19.9; HRMS (APCI, m/z) calcd for C19H20NO3 (M + H+), 310.1443,
found 310.1448; HPLC (Chiralpak AD-H, hexane/i-PrOH = 90: 10,
flow rate: 0.5 mL/min, λ = 210 nm), tmajor = 12.5, tminor = 14.6, 97% ee.
1-(2-((4-Methoxyphenyl)ethynyl)phenyl)-2-nitroethanol
(2f): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.7 Hz, 1H), 7.55−
7.44 (m, 3H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.31 (td, J = 7.5, 1.3 Hz,
1H), 6.88 (d, J = 8.9 Hz, 2H), 5.98 (dd, J = 9.8, 1.8 Hz, 1H), 4.79 (dd,
J = 13.0, 2.4 Hz, 1H), 4.50 (dd, J = 13.0, 9.9 Hz, 1H), 3.81 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 160.1, 139.3, 133.2, 132.0, 128.7,
2-Nitro-1-(2-(m-tolylethynyl)phenyl)ethanol (2c): 1H NMR
(400 MHz, CDCl3) δ 7.63 (d, J = 7.7 Hz, 1H), 7.52 (dd, J = 7.6,
1.1 Hz, 1H), 7.45−7.28 (m, 4H), 7.24 (t, J = 7.6 Hz, 1H), 7.16 (d, J =
7.6 Hz, 1H), 5.98 (dd, J = 9.6, 1.6 Hz, 1H), 4.79 (dd, J = 13.1, 2.4 Hz,
1H), 4.51 (dd, J = 13.1, 9.8 Hz, 1H), 3.01 (br, 1H), 2.35 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 139.6, 138.3, 132.3, 132.2, 129.9, 129.0,
128.7, 128.5, 128.4, 125.7, 122.1, 120.7, 96.6, 85.3, 80.4, 69.7, 21.2.
128.4, 125.6, 121.0, 114.4, 114.3, 96.6, 84.4, 80.4, 69.7, 55.4.
8874
dx.doi.org/10.1021/jo201596p|J. Org. Chem. 2011, 76, 8869−8878

The Journal of Organic Chemistry
Article
3-(4-Methoxyphenyl)-1-(nitromethyl)-1H-isochromene (3f):
D
(376 MHz, CDCl3) δ −115.56; HRMS (APCI, m/z) calcd for
C16H13FNO3 (M + H+), 286.0874, found 286.0885; HPLC (Chiralpak
AD-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min, λ = 210 nm),
tmajor = 21.5, tminor = 23.5, 97% ee.
1-(2-((4-Chlorophenyl)ethynyl)phenyl)-2-nitroethanol
(2i): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.52
(dd, J = 7.6, 0.9 Hz, 1H), 7.50−7.44 (m, 2H), 7.41 (td, J = 7.6, 1.1 Hz,
1H), 7.37−7.29 (m, 3H), 5.97 (d, J = 9.8 Hz, 1H), 4.76 (dd, J = 13.0,
2.3 Hz, 1H), 4.50 (dd, J = 13.0, 9.9 Hz, 1H), 3.06 (d, J = 3.2 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 139.7, 135.1, 132.8, 132.3, 129.4,
1
[α]25 = −138.11 (c 1.5, CHCl3); H NMR (400 MHz, CDCl3) δ
7.62−7.55 (m, 2H), 7.31 (td, J = 7.5, 1.1 Hz, 1H), 7.20 (td, J = 7.5, 1.1
Hz, 1H), 7.12 (dd, J = 11.4, 7.6 Hz, 2H), 6.93−6.86 (m, 2H), 6.37 (s,
1H), 6.11 (dd, J = 10.3, 3.2 Hz, 1H), 4.95 (dd, J = 12.3, 10.3 Hz, 1H),
4.35 (dd, J = 12.3, 3.2 Hz, 1H), 3.82 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 160.7, 150.3, 131.1, 129.6, 126.9, 126.8, 126.0, 125.0, 124.4,
124.3, 113.9, 98.6, 76.50, 74.9, 55.4; HRMS (APCI, m/z) calcd for
C17H16NO4 (M + H+), 298.1074, found 298.1056; HPLC (Chiralpak
AS-H, hexane/i-PrOH = 70:30, flow rate: 0.5 mL/min, λ = 210 nm),
tmajor = 37.4, tminor = 30.3, 93% ee.
129.0, 128.5, 125.7, 120.8, 120.3, 95.2, 86.5, 80.5, 69.7.
(Z)-1-(4-Methoxybenzylidene)-3-(nitromethyl)-1,3-dihydro-
3-(4-Chlorophenyl)-1-(nitromethyl)-1H-isochromene (3i):
D
1
[α]25 = −93.39 (c 0.7, CHCl3); H NMR (400 MHz, CDCl3) δ
isobenzofuran (4f). Compound 4f was generated as a minor
1
product, typical peaks: H NMR (400 MHz, CDCl3) δ 6.27 (dd, J =
7.58 (d, J = 8.6 Hz, 2H), 7.38−7.30 (m, 3H), 7.25 (t, J = 7.5 Hz, 1H),
7.15 (dd, J = 13.6, 7.5 Hz, 2H), 6.47 (s, 1H), 6.13 (dd, J = 10.3, 3.1
Hz, 1H), 4.93 (dd, J = 12.2, 10.5 Hz, 1H), 4.37 (dd, J = 12.3, 3.2 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 149.3, 135.3, 131.8, 130.4,
129.7, 128.7, 127.5, 126.5, 125.2, 124.9, 124.4, 100.6, 76.5, 75.0;
HRMS (APCI, m/z) calcd for C16H13ClNO3 (M + H+), 302.0578,
found 302.0572; HPLC (Chiralpak AD-H, hexane/i-PrOH = 90:10,
flow rate: 0.5 mL/min, λ = 210 nm), tmajor = 24.2, tminor = 21.0, 96% ee.
8.5, 3.3 Hz, 1H), 5.95 (s, 1H), 4.73 (dd, J = 13.2, 3.5 Hz, 1H), 4.60
(dd, J = 13.2, 8.6 Hz, 1H).
1-(2-((3,4-Dimethoxyphenyl)ethynyl)phenyl)-2-nitroethanol
(2g): 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.6 Hz, 1H), 7.53
(d, J = 7.5 Hz, 1H), 7.44−7.37 (m, 1H), 7.37−7.31 (m, 1H), 7.16 (dd,
J = 8.2, 1.8 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H),
6.03 (d, J = 9.6 Hz, 1H), 4.84 (dd, J = 13.0, 2.3 Hz, 1H), 4.54 (dd, J =
13.0, 10.0 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 150.1, 148.9, 139.4, 131.9, 128.8, 128.5, 125.6, 125.0, 120.9,
114.5, 114.2, 111.2, 96.8, 84.3, 80.5, 69.8, 56.0, 55.9.
3-(3,4-Dimethoxyphenyl)-1-(nitromethyl)-1H-isochromene
(3g): [α]25D = −154.88 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.33 (td, J = 7.5, 1.2 Hz, 1H), 7.29−7.10 (m, 5H), 6.88 (d, J = 8.5
Hz, 1H), 6.38 (s, 1H), 6.13 (dd, J = 10.4, 3.0 Hz, 1H), 4.98 (dd, J =
12.2, 10.4 Hz, 1H), 4.37 (dd, J = 12.3, 3.1 Hz, 1H), 3.94 (s, 3H), 3.91
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 150.3, 150.2, 148.9, 131.0,
129.6, 126.9, 126.3, 125.1, 124.5, 124.4, 118.4, 110.9, 108.6, 99.0, 76.6,
75.1, 56.0, 55.9. HRMS (APCI, m/z) calcd for C18H18NO5 (M + H+),
328.1179, found 328.1198; HPLC (Chiralpak AS-H, hexane/i-PrOH =
70: 30, flow rate: 0.5 mL/min, λ = 210 nm), tmajor = 30.6, tminor = 24.1,
92% ee.
(Z)-1-(4-Chlorobenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
1
benzofuran (4i): [α]25 = −99.84 (c 1.0, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.62−7.56 (m, 3H), 7.49−7.38 (m, 2H), 7.34−7.25
(m, 3H), 6.32 (dd, J = 8.5, 3.6 Hz, 1H), 5.96 (s, 1H), 4.77 (dd, J =
13.2, 3.6 Hz, 1H), 4.65 (dd, J = 13.2, 8.5 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 154.0, 136.6, 134.9, 133.8, 131.4, 129.9, 129.5, 129.4,
128.6, 121.5, 120.5, 97.5, 81.5, 78.4; HRMS (APCI, m/z) calcd for
C16H13ClNO3 (M + H+), 302.0578, found 302.0589; HPLC
(Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min,
λ = 210 nm), tmajor = 23.3, tminor = 25.1, 93% ee.
1-(2-((3-Chlorophenyl)ethynyl)phenyl)-2-nitroethanol
(2j): 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.8 Hz, 1H), 7.58−
7.51 (m, 2H), 7.47−7.39 (m, 2H), 7.38−7.27 (m, 3H), 5.99 (dd, J =
9.8, 2.0 Hz, 1H), 4.77 (dd, J = 13.0, 2.4 Hz, 1H), 4.52 (dd, J = 13.0,
9.8 Hz, 1H), 3.04 (br, 1H); 13C NMR (101 MHz, CDCl3) δ 139.8,
134.4, 132.4, 131.4, 129.9, 129.8, 129.5, 129.2, 128.6, 125.7, 124.0,
120.1, 94.7, 86.6, 80.4, 69.6.
(Z)-1-(3,4-Dimethoxybenzylidene)-3-(nitromethyl)-1,3-dihy-
droisobenzofuran (4g). Compound 4g was generated as a minor
1
product, typical peaks: H NMR (400 MHz, CDCl3) δ 6.32 (dd, J =
9.3, 3.0 Hz, 1H), 5.98 (s, 1H), 4.79 (dd, J = 13.0, 3.1 Hz, 1H), 4.60
(dd, J = 13.0, 9.4 Hz, 1H).
3-(3-Chlorophenyl)-1-(nitromethyl)-1H-isochromene (3j):
1
[α]25 = −110.29 (c 0.8, CHCl3); H NMR (400 MHz, CDCl3) δ
D
1-(2-((4-Fluorophenyl)ethynyl)phenyl)-2-nitroethanol
(2h): 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 1H), 7.59−
7.49 (m, 3H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.11−
7.02 (m, 2H), 6.00 (d, J = 9.6 Hz, 1H), 4.79 (dd, J = 13.1, 2.3 Hz, 1H),
4.52 (dd, J = 13.1, 9.9 Hz, 1H), 2.94 (br, 1H); 13C NMR (101 MHz,
7.65 (s, 1H), 7.56−7.51 (m, 1H), 7.39−7.28 (m, 3H), 7.28−7.24 (m,
1H), 7.17 (dd, J = 14.3, 7.5 Hz, 2H), 6.51 (s, 1H), 6.15 (dd, J = 10.2,
3.2 Hz, 1H), 4.95 (dd, J = 12.3, 10.3 Hz, 1H), 4.39 (dd, J = 12.4, 3.3
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.9, 135.2, 134.6, 130.2,
129.8, 129.7, 129.3, 127.7, 125.3, 125.2, 125.0, 124.4, 123.3, 101.2,
76.5, 75.0.; HRMS (APCI, m/z) calcd for C16H13ClNO3 (M + H+),
302.0578, found 302.0573; HPLC (Chiralpak AD-H, hexane/i-PrOH =
90:10, flow rate: 0.5 mL/min, λ = 254 nm), tmajor = 19.3, tminor = 23.0,
95% ee.
1
3
CDCl3) δ162.9 (d, JC,F = 250.7 Hz), 139.5, 133.6 (d, JC,F = 8.5 Hz),
4
132.3, 129.2, 128.5, 125.7, 120.5, 118.4 (d, JC,F = 3.5 Hz), 116.0 (d,
2JC,F = 22.2 Hz), 95.3, 85.3, 80.5, 69.7; 19F NMR (376 MHz, CDCl3) δ
−109.38.
3-(4-Fluorophenyl)-1-(nitromethyl)-1H-isochromene
(3h): [α]25D = −197.13 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.67−7.59 (m, 2H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.24 (td, J = 7.5,
1.2 Hz, 1H), 7.19−7.11 (m, 2H), 7.11−7.03 (m, 2H), 6.42 (s, 1H),
6.14 (dd, J = 10.3, 3.1 Hz, 1H), 4.95 (dd, J = 12.3, 10.4 Hz, 1H), 4.38
(dd, J = 12.3, 3.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ163.5 (d,
(Z)-1-(3-Chlorobenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
1
benzofuran (4j): [α]25 = −122.80 (c 1.0, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.64 (t, J = 1.8 Hz, 1H), 7.58 (dd, J = 13.9, 7.6 Hz,
2H), 7.47 (t, J = 7.3 Hz, 1H), 7.42 (td, J = 7.4, 1.0 Hz, 1H), 7.36−7.30
(m, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.14 (ddd, J = 8.0, 1.9, 0.9 Hz, 1H),
6.32 (dd, J = 8.2, 3.9 Hz, 1H), 5.94 (s, 1H), 4.78 (dd, J = 13.3, 3.9 Hz,
1H), 4.68 (dd, J = 13.3, 8.2 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ 154.6, 137.1, 136.8, 134.7, 134.2, 129.9, 129.6, 127.9, 126.2, 125.9,
121.5, 120.6, 97.3, 81.5, 78.3; HRMS (APCI, m/z) calcd for
C16H13ClNO3 (M + H+), 302.0578, found 302.0587; HPLC
(Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min,
λ = 254 nm), tmajor = 25.7, tminor = 30.1, 92% ee.
4
1JC,F = 249.6), 149.5, 130.6, 129.7, 129.5 (d, JC,F = 3.2), 127.3 (d,
3JC,F = 4.2), 127.2, 125.1, 124.7, 124.4, 115.6 (d, 2JC,F = 21.9), 100.0 (d,
6JC,F = 1.7), 76.5, 75.0; 19F NMR (376 MHz, CDCl3) δ −111.34;
HRMS (APCI, m/z) calcd for C16H13FNO3 (M + H+), 286.0874,
found 286.0858; HPLC (Chiralpak AD-H, hexane/i-PrOH = 95:5,
flow rate: 0.5 mL/min, λ = 210 nm), tmajor = 27.8, tminor = 26.5, 97% ee.
(Z)-1-(4-Fluorobenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
1-(2-((2-Chlorophenyl)ethynyl)phenyl)-2-nitroethanol
(2k): 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 1H), 7.61−
7.55 (m, 2H), 7.46−7.39 (m, 2H), 7.34 (td, J = 7.5, 1.0 Hz, 1H),
7.32−7.23 (m, 2H), 6.03 (dd, J = 9.7, 2.3 Hz, 1H), 4.83 (dd, J = 13.6,
2.5 Hz, 1H), 4.54 (dd, J = 13.6, 9.7 Hz, 1H), 3.25 (br, 1H); 13C NMR
(101 MHz, CDCl3) δ 139.7, 135.8, 133.4, 132.7, 129.9, 129.6, 129.4,
128.5, 126.7, 125.9, 122.4, 120.2, 92.6, 90.7, 80.1, 69.1.
1
benzofuran (4h): [α]25 = −82.84 (c 0.9, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.68−7.60 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.45 (t,
J = 7.4 Hz, 1H), 7.42−7.36 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.07−
6.97 (m, 2H), 6.31 (dd, J = 8.6, 3.5 Hz, 1H), 5.97 (s, 1H), 4.77 (dd,
J = 13.2, 3.6 Hz, 1H), 4.64 (dd, J = 13.2, 8.6 Hz, 1H); 13C NMR (101
1
6
MHz, CDCl3) δ 161.1 (d, JC,F = 246.2), 153.14 (d, JC,F = 2.5 Hz),
136.4, 135.0, 131.5 (d, 4JC2,F = 3.3), 129.8 (d, 3JC,F = 4.8), 129.7, 129.3,
121.5, 120.3, 115.4 (d, JC,F = 21.4), 97.5, 81.3, 78.5; 19F NMR
3-(2-Chlorophenyl)-1-(nitromethyl)-1H-isochromene (3k):
[α]25 = −67.99 (c, CHCl3); 1H NMR (400 MHz, CDCl3) δ;
D
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The Journal of Organic Chemistry
Article
1H NMR (101 MHz, CDCl3) δ 7.53 (dd, J = 5.9, 3.5 Hz, 1H), 7.43
(dd, J = 5.8, 3.5 Hz, 1H), 7.34 (dt, J = 7.5, 3.8 Hz, 1H), 7.30 (dd, J =
6.0, 3.5 Hz, 2H), 7.28−7.26 (m, 1H), 7.14 (dd, J = 17.0, 7.5 Hz, 2H),
6.42 (s, 1H), 6.18 (dd, J = 9.7, 3.5 Hz, 1H), 5.12 (dd, J = 12.8, 9.7 Hz,
1H), 4.49 (dd, J = 12.9, 3.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
148.8, 132.9, 132.7, 130.5, 130.4, 130.2, 130.1, 129.6, 127.8, 126.9,
125.0, 124.9, 124.3, 106.2, 77.2, 75.0; HRMS (APCI, m/z) calcd for
C16H13ClNO3 (M + H+), 302.0578, found 302.0584; HPLC
(Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min,
λ = 254 nm), tmajor = 16.9, tminor = 18.6, 95% ee.
13C NMR (101 MHz, CDCl3) δ 139.4, 132.2, 128.4, 128.2, 125.5,
121.2, 106.0, 80.2, 75.8, 69.6, 30.9, 28.3.
3-tert-Butyl-1-(nitromethyl)-1H-isochromene (3n): [α]25
=
D
−23.86 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 (t, J = 7.5
Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.01 (t, J = 7.3 Hz, 2H), 6.02 (dd,
J = 10.0, 3.2 Hz, 1H), 5.73 (s, 1H), 4.88 (dd, J = 13.0, 10.0 Hz, 1H),
4.26 (dd, J = 13.0, 3.3 Hz, 1H), 1.14 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 162.2, 131.0, 129.4, 126.6, 124.4, 124.2, 124.1, 97.1, 76.4,
74.3, 35.1, 27.7; HRMS (APCI, m/z) calcd for C14H18NO3 (M + H+),
248.1281, found 248.1298; HPLC (Chiralpak AD-H, hexane/i-PrOH
= 95:5, flow rate: 0.5 mL/min, λ = 210 nm), tmajor = 14.1, tminor = 16.5,
98% ee.
(Z)-1-(2-Chlorobenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
1
benzofuran (4k). [α]25 = −64.21 (c 1.0, CHCl3); H NMR (400
D
1-(2-(Hept-1-ynyl)phenyl)-2-nitroethanol (2o): 1H NMR (400
MHz, CDCl3) δ 7.57 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H),
7.35 (t, J = 7.5 Hz, 1H), 7.30−7.26 (m, 1H), 5.85 (dd, J = 9.7, 2.1 Hz,
1H), 4.73 (dd, J = 13.2, 2.4 Hz, 1H), 4.48 (dd, J = 13.2, 9.8 Hz, 1H),
3.03 (br, 1H), 2.46 (t, J = 7.1 Hz, 2H), 1.75−1.56 (m, 2H), 1.50−1.30
(m, 4H), 0.92 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
139.4, 132.4, 128.3, 128.2, 125.5, 121.4, 98.0, 80.2, 77.2, 69.6, 31.2,
28.3, 22.2, 19.5, 13.9.
MHz, CDCl3) δ 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.69 (d, J = 7.7 Hz,
1H), 7.48 (t, J = 7.3 Hz, 1H), 7.45−7.39 (m, 1H), 7.39−7.29 (m, 2H),
7.28−7.22 (m, 1H), 7.09 (td, J = 7.9, 1.6 Hz, 1H), 6.47 (s, 1H), 6.32
(dd, J = 8.5, 3.6 Hz, 1H), 4.78 (dd, J = 13.3, 3.6 Hz, 1H), 4.65 (dd, J =
13.3, 8.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 154.9, 136.6, 135.0,
132.9, 132.1, 129.9, 129.7, 129.6, 129.3, 127.0, 126.9, 121.4, 120.9,
93.9, 81.5, 78.4; HRMS (APCI, m/z) calcd for C16H13ClNO3 (M +
H+), 302.0578, found 302.0583; HPLC (Chiralpak AS-H, hexane/
i-PrOH = 90:10, flow rate: 0.5 mL/min, λ = 254 nm), tmajor = 32.7,
tminor = 28.6, 75% ee.
1-(4-((2-(1-Hydroxy-2-nitroethyl)phenyl)ethynyl)phenyl)-
ethanone (2l): 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.3 Hz,
2H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 7.6
Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 6.04 (d, J =
9.7 Hz, 1H), 4.80 (dd, J = 13.1, 2.2 Hz, 1H), 4.55 (dd, J = 13.1, 9.9
Hz, 1H), 3.05 (br, 1H), 2.61 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
197.4, 139.9, 136.7, 132.5, 131.8, 129.7, 128.6, 128.5, 127.1, 125.8,
120.0, 95.3, 88.6, 80.5, 69.6, 26.7.
1-(Nitromethyl)-3-pentyl-1H-isochromene (3o): [α]25
=
D
1
−22.84 (c 0.7, CHCl3); H NMR (400 MHz, CDCl3) δ 7.25 (td,
J = 7.5, 1.2 Hz, 1H), 7.15 (td, J = 7.5, 1.1 Hz, 1H), 7.03 (d, J = 7.5 Hz,
1H), 6.98 (d, J = 7.5 Hz, 1H), 5.94 (dd, J = 10.2, 3.3 Hz, 1H), 5.68 (s,
1H), 4.88 (dd, J = 12.3, 10.3 Hz, 1H), 4.26 (dd, J = 12.3, 3.3 Hz, 1H),
2.24−2.10 (m, 2H), 1.62−1.41 (m, 2H), 1.41−1.20 (m, 4H), 0.90 (t,
J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.3, 130.8, 129.4,
126.5, 124.4, 123.6, 100.3, 76.7, 74.5, 33.6, 31.4, 26.1, 22.4, 14.0;
HRMS (APCI, m/z) calcd for C15H20NO3 (M + H+), 262.1438, found
262.1454; HPLC (Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate:
0.5 mL/min, λ = 210 nm), tmajor = 13.1, tminor = 11.5, 98% ee.
2-Nitro-1-(2-(phenylethynyl)cyclopent-1-enyl)ethanol
(2p): 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 6.5, 2.9 Hz, 2H),
7.39−7.28 (m, 3H), 5.52−5.39 (m, 1H), 4.61 (dd, J = 12.9, 9.3 Hz,
1H), 4.52 (dd, J = 12.9, 3.3 Hz, 1H), 2.83 (d, J = 3.8 Hz, 1H), 2.71−
2.53 (m, 3H), 2.53−2.35 (m, 1H), 1.96 (p, J = 7.5 Hz, 2H); 13C NMR
(101 MHz, CDCl3) δ 146.2, 131.5, 128.7, 128.5, 122.7, 122.6, 96.8,
83.8, 78.6, 67.6, 37.0, 32.0, 22.4.
1-(4-(1-(Nitromethyl)-1H-isochromen-3-yl)phenyl)ethanone
(3l). Compound 3l was generated as a minor product, typical peaks:
1H NMR (400 MHz, CDCl3) δ 6.64 (s, 1H), 6.18 (dd, J = 10.4, 3.2 Hz,
1H), 4.96 (dd, J = 12.3, 10.4 Hz, 1H), 4.41 (dd, J = 12.4, 3.2 Hz, 1H).
(Z)-1-(4-Acetylbenzylidene)-3-(nitromethyl)-1,3-dihydroiso-
1
benzofuran (4l): [α]25 = −129.42 (c 1.0, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.91 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H),
7.62 (d, J = 7.3 Hz, 1H), 7.51−7.40 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H),
6.34 (dd, J = 8.6, 3.5 Hz, 1H), 6.04 (s, 1H), 4.82 (dd, J = 13.3, 3.6 Hz,
1H), 4.66 (dd, J = 13.3, 8.6 Hz, 1H), 2.58 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 197.6, 155.8, 140.4, 136.9, 134.6, 134.3, 130.0, 128.7,
128.0, 121.6, 120.8, 97.7, 81.8, 78.3, 26.5. HRMS (APCI, m/z) calcd
for C18H16NO4 (M + H+), 310.1074, found 310.1103; HPLC
(Chiralpak AS-H, hexane/i-PrOH = 60:40, flow rate: 0.5 mL/min,
λ = 210 nm), tmajor = 52.9, tminor = 29.6, 90% ee.
1-Benzyl-3-(nitromethyl)-5,6-dihydro-4H-cyclopenta[c]furan
(5p): 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.2 Hz, 2H), 7.26−
7.17 (m, 3H), 5.31 (s, 2H), 3.90 (s, 2H), 2.57 (dd, J = 9.3, 4.8 Hz,
2H), 2.37−2.18 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 146.1,
137.5, 137.4, 131.7, 130.3, 128.9, 128.5, 126.6, 71.3, 34.0, 31.9, 23.5, 23.4.
2-Nitro-1-(2-(phenylethynyl)cyclohex-1-enyl)ethanol
(2q): 1H NMR (400 MHz, CDCl3) δ 7.51−7.41 (m, 2H), 7.38−7.29
(m, 3H), 5.71−5.58 (m, 1H), 4.62−4.45 (m, 2H), 2.56 (d, J = 4.4 Hz,
1H), 2.47−2.24 (m, 3H), 2.03 (d, J = 18.4 Hz, 1H), 1.75−1.59 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 141.2, 131.4, 128.5, 128.4,
122.8, 119.1, 95.6, 87.0, 78.8, 70.9, 30.0, 24.0, 22.0, 21.9.
1-Benzyl-3-(nitromethyl)-4,5,6,7-tetrahydroisobenzofuran
(5q): 1H NMR (400 MHz, CDCl3) δ 7.31−7.26 (m, 2H), 7.24−7.14
(m, 3H), 5.31 (s, 2H), 3.89 (s, 2H), 2.57−2.47 (m, 2H), 2.44−2.33
(m, 2H), 1.76−1.62 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 149.7,
137.9, 135.7, 128.6, 128.5, 126.5, 126.1, 118.5, 70.5, 32.8, 22.9, 22.7,
20.2, 20.1.
1-(2-(Hex-1-ynyl)phenyl)-2-nitroethanol (2m): 1H NMR (400
MHz, CDCl3) δ 7.56 (d, J = 7.7 Hz, 1H), 7.40 (dd, J = 7.6, 1.1 Hz,
1H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H),
5.89−5.78 (m, 1H), 4.71 (dd, J = 13.2, 2.4 Hz, 1H), 4.46 (dd, J = 13.2,
9.8 Hz, 1H), 3.17 (d, J = 4.4 Hz, 1H), 2.46 (t, J = 7.1 Hz, 2H), 1.67−
1.56 (m, 2H), 1.54−1.40 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 139.5, 132.3, 128.3, 128.2, 125.5, 121.4, 97.9,
80.2, 77.2, 69.5, 30.7, 22.1, 19.2, 13.6.
3-Butyl-1-(nitromethyl)-1H-isochromene (3m): [α]25
=
D
1
−29.20 (c 0.7, CHCl3); H NMR (400 MHz, CDCl3) δ 7.25 (dt,
J = 7.5, 3.8 Hz, 1H), 7.20−7.12 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.98
(d, J = 7.5 Hz, 1H), 5.95 (dd, J = 10.3, 3.3 Hz, 1H), 5.69 (s, 1H), 4.88
(dd, J = 12.2, 10.3 Hz, 1H), 4.26 (dd, J = 12.3, 3.3 Hz, 1H), 2.25−2.11
(m, 2H), 1.60−1.45 (m, 2H), 1.44−1.28 (m, 2H), 0.92 (t, J = 7.3 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 155.3, 130.8, 129.4, 126.5,
124.4, 124.3, 123.6, 100.3, 76.7, 74.5, 33.3, 28.5, 22.3, 13.8; HRMS
(APCI, m/z) calcd for C14H18NO3 (M + H+), 248.1281, found
248.1292; HPLC (Chiralpak AS-H, hexane/i-PrOH = 95:5, flow rate:
0.5 mL/min, λ = 210 nm), tmajor = 15.5, tminor = 17.4, 98% ee.
1-(2-(3,3-Dimethylbut-1-ynyl)phenyl)-2-nitroethanol
(2n): 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.7 Hz, 1H), 7.39
(dd, J = 7.5, 1.2 Hz, 1H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 7.29−7.22 (m,
1H), 5.82 (ddd, J = 9.8, 4.2, 2.4 Hz, 1H), 4.71 (dd, J = 13.1, 2.4 Hz,
1H), 4.45 (dd, J = 13.1, 9.9 Hz, 1H), 3.12 (br, 1H), 1.34 (s, 9H);
2-Nitro-1-(5-nitro-2-(phenylethynyl)phenyl)ethanol (2s): 1H
NMR (400 MHz, CDCl3) δ 8.57 (d, J = 2.3 Hz, 1H), 8.19 (dd, J = 8.5,
2.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.61−7.55 (m, 2H), 7.47−7.37
(m, 3H), 6.07 (d, J = 9.7 Hz, 1H), 4.86 (dd, J = 13.3, 2.2 Hz, 1H), 4.53
(dd, J = 13.3, 9.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 147.6,
141.5, 133.0, 132.0, 130.0, 128.8, 127.1, 123.4, 121.4, 121.2, 101.5,
84.2, 79.8, 68.9.
1H-Isochromene 3r and 1,3-dihydroisobenzofurans 4r were generated
as a mixture which could not be separated by chromatography on silica
gel, and the typical peaks are described below.
7-Nitro-1-(nitromethyl)-3-phenyl-1H-isochromene (3s): 1H
NMR (400 MHz, CDCl3) δ 6.58 (s, 1H), 6.28 (dd, J = 10.2, 3.2
Hz, 1H), 5.03 (dd, J = 12.7, 10.2 Hz, 1H), 4.51 (dd, J = 12.7, 3.3 Hz,
1H).
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Article
(Z)-1-Benzylidene-5-nitro-3-(nitromethyl)-1,3-dihydroiso-
benzofuran (4s): 1H NMR (400 MHz, CDCl3) δ 6.40 (dd, J = 7.7,
3.8 Hz, 1H), 6.20 (s, 1H), 4.87 (dd, J = 13.5, 3.9 Hz, 1H), 4.77 (dd,
J = 13.5, 7.9 Hz, 1H).
2-Nitro-1-(5-methoxyl-2-(phenylethynyl)phenyl)ethanol
(2r): 1H NMR (400 MHz, CDCl3) δ 7.56−7.49 (m, 2H), 7.47 (d, J =
8.5 Hz, 1H), 7.39−7.31 (m, 3H), 7.20 (d, J = 2.6 Hz, 1H), 6.86 (dd,
J = 8.5, 2.7 Hz, 1H), 5.97 (d, J = 9.8 Hz, 1H), 4.82 (dd, J = 13.1, 2.3
Hz, 1H), 4.50 (dd, J = 13.1, 9.9 Hz, 1H), 3.84 (s, 3H), 3.04 (br, J = 3.2
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 160.3, 141.5, 133.8, 131.4,
128.6, 128.5, 122.7, 114.3, 112.5, 111.2, 95.0, 85.6, 80.3, 69.6, 55.5.
(4) Selected examples for cycloisomerization of alkynylbenzyl
alcohols: (a) Padwa, A.; Krumpe, K. E.; Weingarten, M. D. J. Org.
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Org. Lett. 2005, 7, 5437−5440. (e) Messerle, B. A.; Vuong, K. Q.
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, C. Org. Lett.
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C.-J. Org. Lett. 2006, 8, 1953−1955. (c) Obika, S.; Kono, H.; Yasui, Y.;
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Wang, J.-D. J. Org. Chem. 2008, 73, 2947−2950. (f) Dell’Acqua, M.;
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7-Methoxy-1-(nitromethyl)-3-phenyl-1H-isochromene (3r):
1
[α]25 = −119.11 (c 1.4, CHCl3); H NMR (400 MHz, CDCl3) δ
D
7.67−7.58 (m, 2H), 7.42−7.29 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.88
(dd, J = 8.4, 2.5 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 6.46 (s, 1H), 6.09
(dd, J = 10.2, 3.2 Hz, 1H), 4.94 (dd, J = 12.4, 10.3 Hz, 1H), 4.37 (dd,
J = 12.4, 3.2 Hz, 1H), 3.82 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
159.1, 148.2, 133.5, 129.0, 128.5, 126.9, 126.1, 124.9, 123.5, 114.9,
110.3, 100.0, 74.9, 55.5; HRMS (APCI, m/z) calcd for C17H16NO4 (M
+ H+) 298.1074, found 298.1065; HPLC (Chiralpak AD-H, hexane/
i-PrOH = 90: 10, flow rate: 0.5 mL/min, λ = 254 nm), tmajor = 27.4,
tminor = 30.0, 98% ee.
(6) For selected examples for one-pot cyclization including a
(Z)-1-Benzylidene-5-methoxy-3-(nitromethyl)-1,3-dihydro-
isobenzofuran (4r): [α]25D = −53.45 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.66 (d, J = 7.3 Hz, 2H), 7.52 (d, J = 8.5 Hz, 1H),
7.35 (t, J = 7.8 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.02 (dd, J = 8.5, 2.1
Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.29 (dd, J = 8.3, 3.9 Hz, 1H), 5.89
(s, 1H), 4.77 (dd, J = 13.2, 3.9 Hz, 1H), 4.69 (dd, J = 13.2, 8.3 Hz,
1H), 3.88 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.0, 153.6,
138.4, 135.6, 128.4, 127.9, 127.6, 125.7, 121.6, 116.7, 106.1, 96.8, 80.9,
78.5, 55.8; HRMS (APCI, m/z) C17H16NO4 (M + H+) 298.1074,
found 298.1080; HPLC (Chiralpak AD-H, hexane/i-PrOH = 90:10,
flow rate: 0.5 mL/min, λ = 254 nm), tmajor = 31.9, tminor = 40.9, 83% ee.
benzopyrylium intermediate, see: (a) Barluenga, J.; Vaz
́
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Ballesteros, A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028−9029.
́
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Tetrahedron Lett. 2008, 49, 4390−4393. (d) Ouyang, B.; Yuan, J.; Yang,
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(8) For recent reviews on the catalytic asymmetric Henry reaction,
see: (a) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron:
Asymmetry 2006, 17, 3315−3326. (b) Palomo, C.; Oiarbide, M.; Laso,
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ASSOCIATED CONTENT
* Supporting Information
(9) For recent examples of asymmetric Henry reactions, see: (a) Xin,
D.; Ma, Y.; He, F. Tetrahedron: Asymmetry 2010, 21, 333−338.
(b) Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org.
Chem. 2010, 75, 1313−1316. (c) Steurer, M.; Bolm, C. J. Org. Chem.
2010, 75, 3301−3310. (d) Yang, W.; Liu, H.; Du, D.-M. Org. Biomol.
Chem. 2010, 8, 2956−2960. (e) Zhou, Y.; Dong, J.; Zhang, F.; Gong,
Y. J. Org. Chem. 2011, 76, 588−600. (f) Gualandi, A.; Cerisoli, L.;
Stoeckli-Evans, H.; Savoia, D. J. Org. Chem. 2011, 76, 3399−3408.
(g) Guo, Z.-L.; Zhong, S.; Li, Y.-B.; Lu, G. Tetrahedron: Asymmetry
2011, 22, 238−245. (h) Reddy, B. V. S.; Reddy, S. M.; Manisha, S.;
Madan, C. Tetrahedron: Asymmetry 2011, 22, 530−535. (i) Dhahagani,
K.; Rajesh, J.; Kannan, R.; Rajagopal, G. Tetrahedron: Asymmetry 2011,
22, 857−865. (j) Wei, Y.; Yao, L.; Zhang, B.; He, W.; Zhang, S.
Tetrahedron 2011, 67, 8552−8558.
■
S
X-ray structural data (CIF), NMR spectra, and HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +86 027 87543232. Fax: +86 027 87543632. E-mail:
gongyf@mail.hust.edu.cn.
■
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (20872041). The Analysis and Testing
Centre of Huazhong University of Science and Technology is
acknowledged for the characterization of new compounds.
(10) For reviews on homogeneous gold catalysis, see: (a) Hashimi,
A. S. K. Chem. Rev. 2007, 107, 3180−3211. (b) Li, Z.; Brouwer, C.;
He, C. Chem. Rev. 2008, 108, 3239−3265. (c) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351−3378. (d) Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766−1775.
(e) Sengupta, S.; Shi, X. ChemCatChem 2010, 2, 609−619. (f) Hashimi,
A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232−5241. (g) Nolan, S. P.
Acc. Chem. Res. 2011, 44, 91−100. (h) Wegner, H. A.; Auzias, M.
Angew. Chem., Int. Ed. 2011, 50, 8236−8247.
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The Journal of Organic Chemistry
Article
(12) See the Experimental Section for the details.
(13) Substrate 1f could not be completely consumed even after an
extended period. Thus, the Henry product 2f was isolated by flash
chromatography and then subjected to the cyclization step.
(14) The decreasing of the ee values of 1,3-dihydroisobenzofurans
seemed to have a relationship with the rate of cyclization step. The
nitro alcohols 2k and 2r endured a slower cycloisomerization and the
1,3-dihydroisobenzofurans 4k and 4r suffered significant racemization.
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longer reaction time.
8878
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