One-pot synthesis of dihydrobenzisoxazoles from hydroxylamines, acetylenedicarboxylates, and arynes via in situ generation of nitrones

Article abstract of DOI:10.1139/cjc-2012-0199

Aryne [3 + 2] cycloaddition with nitrones generated in situ from the addition of hydroxylamines to acetylenedicarboxylates affords moderate to good yields of dihydrobenzisoxazoles. This reaction extends the current scope of aryne cycloaddition to include in situ generated nitrones and produces functionalized dihydrobenzisoxazoles with a quaternary center.

Full text of DOI:10.1139/cjc-2012-0199

43
One-pot synthesis of dihydrobenzisoxazoles from
hydroxylamines, acetylenedicarboxylates, and
arynes via in situ generation of nitrones
Pan Li, Chunrui Wu, Jingjing Zhao, Yang Li, Weichao Xue, and Feng Shi
Abstract: Aryne [3 ϩ 2] cycloaddition with nitrones generated in situ from the addition of hydroxylamines to
acetylenedicarboxylates affords moderate to good yields of dihydrobenzisoxazoles. This reaction extends the current scope
of aryne cycloaddition to include in situ generated nitrones and produces functionalized dihydrobenzisoxazoles with a
quaternary center.
Key words: nitrone, aryne, dipolar cycloaddition, reactive intermediate, dihydrobenzisoxazole.
Résumé : La cycloaddition [3 ϩ 2] d’aryne a des nitrones générées in situ par l’addition d’hydroxylamines a des
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acétylènecarboxylates conduit a la formation avec des rendements allant de modérés a bons de dihydrobenzisoxazoles.
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Cette réaction prolonge la plage d’application des réactions de cycloadditions a des arynes de façon a inclure des nitrones
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générées in situ et a produire des dihydrobenzisoxazoles fonctionnalisés avec un centre quaternaire.
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Mots-clés : nitrone, aryne, cycloaddition dipolaire, intermédiaire réactif, dihydrobenzisoxazole.
[Traduit par la Rédaction]
ever, in most reports, only one or two nitrones were examined.
The substitution pattern and functional group compatibility
have been poorly explored. To the best of our knowledge, to
date, only three reports have focused on the structural modi-
fication of nitrones,12b,15 and regretfully only one has em-
ployed nitrones equipped with functional groups.15a
This deficiency can be partially ascribed to the fact that
nitrones can be hard to work with. Conventional column
chromatography is difficult to use with functionalized nitrones
because of the high polarity they possess. Thus, to expand the
scope of nitrones in the cycloaddition with arynes, alternative
protocols have to be sought. In one attempt, Kivrak and
Larock16 employed oxaziridines in the aryne cycloaddition,
which possibly act as a nitrone precursor. However, this strat-
egy is largely limited to N-tert-butyl oxaziridines. We hypoth-
esized that in situ generation of nitrones would solve the
concerning issue of their isolation and purification, and hence
accommodate complex structures and functional groups. The
same strategy has been used by us and others in the cy-
cloaddition of arynes with other dipoles,17 but not yet with
nitrones.
Introduction
In recent years, the [3 ϩ 2] dipolar cycloaddition of arynes with
various 1,3-dipoles has become resurgent1–7 with the development
of the Kobayashi aryne precursor,8 2-(trimethylsilyl)aryl
triflates. Among the stable and isolable dipoles, diazo com-
pounds2 and azides3 have received heavy investigation. How-
ever, another equally stable and isolable 1,3-dipole, nitrone,
has not been thoroughly studied.
Nitrone cycloaddition with arynes affords dihydroben-
zisoxazole derivatives, which are known synthetic intermedi-
ates and exhibit antimicrobial activities.9 Because of the
limited availability and few synthetic routes, the bioactivity of
dihydrobenzisoxazole derivatives remains underinvestigated.
It is thus not hard to envisage that aryne cycloaddition would
represent a useful synthetic route for dihydrobenzisoxazoles
and potentially allow for the construction of libraries around
this privileged scaffold, given the relatively easy access to
nitrones from readily available starting materials.10
Curiously, the investigation of aryne–nitrone cycloaddition
has paid little attention to the scope of nitrones, but significant
attention to the scope of arynes. In fact, almost every precursor
of aryne has been studied in the context of cycloaddition with
nitrones, including 1-aminobenzotriazoles (with Pb(OAc)4),11
2-halophenyl triflates (with BuLi),12 diazotized anthranilic
acid,13 benzoxadisilole derivatives (with PhI(OAc)2 then fluo-
ride),14 and the Kobayashi precursor (with fluoride).15 How-
Hydroxylamine (2)18 is the usual starting material for the
preparation of nitrones. Although the most widely used route
involves condensation with carbonyl compounds, electron-
poor alkynes19 (1), such as dimethyl acetylenedicarboxylate
(DMAD), and allenes20 have also been used to afford nitrones
(3) via a Michael addition–tautomerization process (Scheme 1).
Received 3 May 2012. Accepted 23 October 2012. Published at www.nrcresearchpress.com/cjc on 18 December 2012.
P. Li, C. Wu, J. Zhao, Y. Li, W. Xue, and F. Shi. Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province,
Henan University, Jinming Campus, Kaifeng, Henan 475004, P.R. China.
Corresponding author: Feng Shi (e-mail: fshi@henu.edu.cn).
This article is part of a Special Issue dedicated to Professor Derrick Clive.
Can. J. Chem. 91: 43–50 (2013)
doi:10.1139/cjc-2012-0199
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Can. J. Chem. Vol. 91, 2013
Scheme 1. Generation of nitrones from hydroxylamines and acetylenedicarboxylates.
Therefore, the treatment of a mixture of hydroxylamines and
electron-poor alkynes with the Kobayashi aryne precursor in the
presence of a fluoride source would lead to the in situ generation
of both nitrones and arynes, and allow for a subsequent cy-
cloaddition in a one-pot, three-component manner.21
Table 1. Reaction optimization.
Results and discussion
We first isolated nitrone 3a from the reaction of DMAD
(1a) with N-(4-methoxybenzyl)hydroxylamine (2a) and sub-
jected it to different reaction conditions with benzyne pre-
cursor 4a (Table 1). Both CsF (Table 1, entry 1) and
tetrabutylammonium fluoride (TBAF; Table 1, entries 4 and 5)
proved effective fluoride sources, and the optimal conditions
involved MeCN as the solvent at a slightly elevated tempera-
ture of 50 °C (Table 1, entry 1). The yield of this reaction was
only moderate, despite a fairly clean thin-layer chromatogra-
phy (TLC). The lost mass is mostly ascribed to some uniden-
tifiable polar side products at the baseline of the TLC, and
charging more benzyne precursor failed to provide a higher
yield. The structure of 5a was characterized by extensive
NMR techniques, including heteronuclear single quantum co-
herence (HSQC) and heteronuclear multiple bond coherence
(HMBC; see the Supplementary data). Note that nitrone 3a
contains an active methylene group, which may tautomerize to
3= (Scheme 1) and react with arynes in a known ␴-bond
cleavage process.22 This side product was not isolated, indi-
cating that 3 reacted largely as the nitrone tautomer.
Next, we moved to the one-pot reaction conditions. We
were pleased to find that the nitrone formation was very fast.
As long as CsF (or TBAF) was added last, by the time we
weighed out CsF (or withdrew TBAF solution from the bottle)
the reaction between 1a and 2a was complete at room tem-
perature (rt). This is an important observation as it may largely
eliminate the potential cycloaddition of 3 with 1 as well as the
N- or O-arylation of 2 with arynes. Under these conditions, 5a
was still isolated in a 58% yield (Table 2, entry 1), indicating
no apparent loss of yield in the one-pot, three-component
protocol. In addition, microwave irradiation afforded a 64%
yield of the desired product.
Entry
Fluoride
Solvent
T (°C)
Time (h)
Yield (%)a
1
2
3
4
5
CsF
CsF
CsF
TBAF
TBAF
MeCN
MeCN
THF
MeCN
THF
50
rt
70
rt
3
16
16
16
16
64
29
9
40
46
rt
Note: All reactions were carried out on a 0.4 mmol scale in 4 mL of
solvent. 3a/4a/fluoride ϭ 1:1.2:2. rt, room temperature; THF, tetrahydrofu-
ran; TBAF, tetrabutylammonium fluoride; PMB, p-methoxybenzyl; TMS,
trimethylsilyl; Tf, trifluoromethanesulfonyl.
aIsolated yields.
the desired product 5b in a moderate 46% yield (Table 2, entry
2), and the unsymmetrical 3-methoxybenzyne gave a single
regioisomer in a 40% yield (Table 2, entry 3). This regiose-
lectivity was similarly observed by Suzuki and co-workers12a
and Larock and co-workers15a in their earlier studies. A range
of hydroxylamines were examined next. As can be seen,
hydroxylamines derived from aromatic aldehydes (Table 2,
entries 4 and 5), an aromatic ketone (Table 2, entry 7), ali-
phatic aldehydes (Table 2, entries 8 and 9), and an aliphatic
ketone (Table 2, entry 10) all afforded moderate to good yields
of the corresponding products. Halogen, ether, and ester func-
tional groups were well-tolerated. However, we noticed that
the hydroxylamine derived from 4-cyanobenzaldehyde (2d)
only afforded a complex mixture (Table 2, entry 6). Detailed
study revealed that this nitrone was unstable under the reaction
conditions and quickly decomposed upon exposure to CsF.
Lastly, the replacement of DMAD with its analogues was
also partly successful, as diethyl acetylenedicarboxylate (1b)
We then started to examine the scope and limitation of this
protocol (Table 2). First, different arynes were tested (Table 2,
entries 2 and 3). The symmetrical dimethoxybenzyne afforded
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Li et al.
45
Table 2. Reaction scope.
Entry
1
R1 (1)
R2 (2)
R3 (4)
H (4a)
Product
Yield (%)a
58b
Me (1a)
PMB (2a)
2
3
Me (1a)
PMB (2a)
4,5-(MeO)2 (4b)
46
Me (1a)
PMB (2a)
3-MeO (4c)
40c
4
5
Me (1a)
Me (1a)
Bn (2b)
(4a)
46
49
H (4a)
6
Me (1a)
H (4a)
Mixture
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Can. J. Chem. Vol. 91, 2013
Table 2 (concluded).
Entry
7
R1 (1)
R2 (2)
R3 (4)
H (4a)
Product
Yield (%)a
74 (1.8:1 dr)d
Me (1a)
8
Me (1a)
Me (2f)
H (4a)
76e
9
10
11
Me (1a)
Me (1a)
Et (1b)
Ph(CH2)3 (2g)
H (4a)
H (4a)
H (4a)
64
90
75
Cy (2h)
PMB (2a)
12
PMB (2a)
H (4a)
36
Note: All reactions were carried out on a 0.4 mmol scale in 4 mL of MeCN for 3 h. PMB, p-methoxybenzyl; Cy, cyclohexyl; Bn, benzyl.
aIsolated yields.
bThe use of microwave irradiation (100 W max, 80 °C, 30 min ϩ 30 min) conditions afforded a 64% yield.
cThe regiochemistry was analogously assigned by comparison with literature results (refs. 12a and 15a) and analysis of the 1H NMR spectroscopy.
dThe diastereomeric ratio (dr) was determined by crude 1H NMR spectroscopy.
eThe hydroxylamine was supplied as an HCl salt, and 1.2 equiv of Cs2CO3 was added to neutralize the acid.
afforded a 75% yield of 5k (Table 2, entry 11). An electron-poor
allene (1c) could also smoothly afford 5l in an unoptimized
36% yield (Table 2, entry 12). Thus, the one-pot three-
component protocol could furnish dihydrobenzisoxazoles with
three different handles for possible manipulation. Regretfully,
the yields and the mass balance of some reactions remained
less than satisfactory.
DMAD reversibly23,24 and thus N-aryldihydrobenzisoxazole
derivatives are not accessible via this approach. Additionally,
some hydroxylamines derived from heteroaromatic aldehydes,
such as 2k and 2l, are unstable and not successfully employed
either. It thus appears that the currently described protocol is
more suitable for nonbenzylic aliphatic hydroxylamines (such as
in Table 2, entries 8–10). Lastly, alkynes with only one electron-
withdrawing group, such as 1d, 1e, and 1f, are not sufficiently
reactive to generate nitrones. To date, all attempts to employ
This protocol poses some limitations (Fig. 1). For exam-
ple, N-arylhydroxylamines, such as 2i and 2j, react with
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Li et al.
47
Fig. 1. Limitation of the protocol. (a) Hydroxylamines that form
nitrones reversibly. (b) Unstable hydroxylamines. (c) Alkynes
with insufficient reactivity.
Experimental section
All reagents purchased from commercial sources were used as
received. THF and MeCN were distilled from Na/benzophenone
and CaH2, respectively. The silica gel for column chromatog-
raphy was supplied as 300–400 mesh from Haiyang Chemi-
cals (Qingdao, China).28 Powdered CsF was used as received
and stored in a dessicator.
All melting points are uncorrected. The H and 13C NMR
1
spectra were referenced to the residual solvent signals (7.26 ppm
for 1H and 77.0 ppm for 13C in CDCl3).
General procedure
To an oven-dried 10 mL round-bottom flask equipped with
a stirrer was added 0.48 mmol of the aryne precursor
(1.2 equiv), followed by 0.4 mmol of the hydroxylamine. Dry
MeCN (2 mL) was added and the mixture was stirred until it
became homogeneous. A solution of dialkyl acetylenedicar-
boxylate (0.4 mmol) in MeCN (2 mL) was added dropwise,
followed by 0.8 mmol of solid CsF (2 equiv) in one portion.
The reaction mixture was stirred at 50 °C and monitored by
TLC. Upon completion, the reaction mixture was poured into
brine and extracted three times with EtOAc. The combined
extracts were dried over MgSO4, filtered, and evaporated. The
residue was purified by column chromatography (petroleum
ether / EtOAc) to afford the dihydrobenzisoxazoles.
Scheme 2. Reduction of the diester.
Compound 5a
Slightly yellow solid; mp 126–127 °C. Rf ϭ 0.43 (petro-
leum ether / EtOAc, 4:1). 1H NMR (300 MHz, CDCl3) ␦: 7.39
(dd, J ϭ 7.6, 1.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.25–7.19
(m, 1H), 6.96 (td, J ϭ 7.5, 0.9 Hz, 1H), 6.92–6.87 (m, 2H), 6.77
(d, J ϭ 8.1 Hz, 1H), 4.18 and 4.10 (ABq, J ϭ 13.8 Hz, 2H),
3.82 (s, 3H), 3.81 (s, 3H), 3.68 (s, 3H), 3.38 and 3.14 (ABq,
J ϭ 16.7 Hz, 2H). 13C NMR (75 MHz, CDCl3) ␦: 170.3, 169.3.
159.0, 156.1, 130.0, 129.6, 128.9, 127.3, 125.0, 121.5, 113.7,
108.2, 74.3, 56.8, 55.2, 52.8, 51.8, 41.2. HR-MS electrospray
ionization (ESI)) calcd for C20H22NO6 (M ϩ H): 372.1442;
found: 372.1440.
hydrazines in place of hydroxylamines to afford azomethine
imine intermediates in situ have not been successful.
The stereochemistry in entry 7 (Table 2) was particularly
worth mentioning. In Larock and co-workers’ report,15a
a
cyclic nitrone with an embedded chiral center provided good
diastereoselectivity. Since previous reports have indicated that
nitrones employed in our chemistry are stereochemically de-
fined (CϭN bond adopting E geometry),25 we were curious about
the level of diastereoselectivity of the reaction involving nitrone 5g in
an open-chain A1,3 strain context. The experiment revealed a very
modest level of stereoseletivity of 1.8:1, indicating that acyclic ste-
reocontrol26 in nitrone–aryne cycloaddition is difficult. A sim-
ilar cycloaddition with alkenes in the literature provided an
agreeable modest level of diastereoselectivity.25
As a useful extension of this protocol, the two ester groups
can be further manipulated. For example, the simple reduction
of 5a using LiBH4 afforded the corresponding diol 6 in an
83% yield (Scheme 2). Unfortunately, reduction with SmI2
only afforded a complex mixture.
In summary, we have developed a one-pot protocol for the
efficient synthesis of functionalized dihydrobenzisoxazoles from
hydroxylamines, acetylenedicarboxylates, and arynes via in situ
generation of nitrones. The protocol not only circumvents the
necessity to isolate nitrones and thus is pot efficient, but also
works with a different scope of nitrones. The stability of the
hydroxylamines and nitrones poses the biggest limitation to the
current method.27
Compound 5b
Slightly yellow oil. Rf ϭ 0.23 (petroleum ether / EtOAc,
2:1). 1H NMR (400 MHz, CDCl3) ␦: 7.32 (d, J ϭ 8.7 Hz, 2H),
6.95 (s, 1H), 6.89 (d, J ϭ 8.7 Hz, 2H), 6.39 (s, 1H), 4.13 and
4.04 (ABq, J ϭ 13.7 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.82
(s, 3H), 3.81 (s, 3H), 3.68 (s, 3H), 3.36 and 3.10 (ABq, J ϭ
16.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) ␦: 170.6, 169.5,
159.0, 150.6, 150.6, 144.1, 130.0, 128.9, 117.0, 113.7, 108.4,
93.1, 74.9, 56.8, 56.7, 56.0, 55.2, 52.8, 51.8, 41.4. HR-MS
(ESI) calcd for C22H26NO8 (M ϩ H): 432.1653; found:
432.1653.
Compound 5c
Colorless oil. Rf ϭ 0.49 (petroleum ether / EtOAc, 4:1).
1H NMR (400 MHz, CDCl3) ␦: 7.37 (m, 2H), 7.15 (t, J ϭ 8.2 Hz,
1H), 6.92–6.83 (m, 2H), 6.43 (d, J ϭ 8.1 Hz, 1H), 6.36 (dd,
J ϭ 8.1, 0.5 Hz, 1H), 4.30 and 4.20 (ABq, J ϭ 13.8 Hz, 2H),
3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.63 (s, 3H), 3.45 and
3.28 (ABq, J ϭ 15.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) ␦:
170.2, 169.3, 159.0, 157.3, 155.6, 130.9, 130.0, 129.3, 114.2,
113.7, 103.4, 100.8, 74.2, 57.5, 55.6, 55.2, 52.6, 51.6, 39.0.
HR-MS (ESI) calcd for C21H24NO7 (M ϩ H): 402.1547;
found: 402.1545.
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Can. J. Chem. Vol. 91, 2013
1H), 7.23–7.17 (m, 1H), 6.90 (td, J ϭ 7.5, 0.9 Hz, 1H), 6.77
(d, J ϭ 8.1 Hz, 1H), 3.78 (s, 3H), 3.61 (s, 3H), 3.36 and 3.03
(ABq, J ϭ 16.2 Hz, 2H), 3.07 (tt, J ϭ 10.7, 3.2 Hz, 1H),
1.91–1.48 (m, 6H), 1.36–1.06 (m, 4H). 13C NMR (75 MHz,
CDCl3) ␦: 170.2, 170.1, 156.7, 129.4, 128.2, 124.3, 121.0,
107.1, 73.7, 62.9, 52.9, 51.7, 41.6, 31.3, 29.8, 25.6, 25.4, 25.1.
HR-MS (ESI) calcd for C18H24NO5 (M ϩ H): 334.1649;
found: 334.1649.
Compound 5d
Colorless oil. Rf ϭ 0.52 (petroleum ether / EtOAc, 4:1).
1H NMR (400 MHz, CDCl3) ␦: 7.46–7.31 (m, 6H), 7.26–7.21
(m, 1H), 6.97 (td, J ϭ 7.5, 0.9 Hz, 1H), 6.78 (d, J ϭ 8.0 Hz, 1H),
4.28 and 4.20 (ABq, J ϭ 14.0 Hz, 2H), 3.83 (s, 3H), 3.69
(s, 3H), 3.41 and 3.18 (ABq, J ϭ 16.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3) ␦: 170.3, 169.3, 156.1, 136.9, 129.6, 128.7,
128.3, 127.5, 127.3, 124.9, 121.5, 108.2, 74.4, 57.3, 52.9, 51.9,
41.2. HR-MS (ESI) calcd for C19H20NO5 (M ϩ H): 342.1336;
found: 342.1332.
Compound 5k
Slightly yellow oil. Rf ϭ 0.49 (petroleum ether/EtOAc, 4:1).
1H NMR (300 MHz, CDCl3) ␦: 7.41 (dd, J ϭ 7.6, 1.0 Hz, 1H),
7.37–7.33 (m, 2H), 7.22 (td, J ϭ 8.0, 1.3 Hz, 1H), 6.98–6.93
(m, 1H), 6.92–6.89 (m, 2H), 6.77 (d, J ϭ 8.0 Hz, 1H),
4.37–4.09 (m, 6H), 3.81 (s, 3H), 3.38 and 3.12 (ABq, J ϭ
16.5 Hz, 2H), 1.31 (t, J ϭ 7.1 Hz, 3H), 1.23 (t, J ϭ 7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3) ␦: 169.8, 168.7, 159.0,
156.1, 130.0, 129.5, 129.1, 127.5, 125.0, 121.3, 113.7, 108.1,
74.3, 61.9, 60.8, 56.7, 55.2, 41.4, 14.0 (overlapped signal).
HR-MS (ESI) calcd for C22H26NO6 (M ϩ H): 400.1755;
found: 400.1750.
Compound 5e
Colorless oil. Rf ϭ 0.30 (petroleum ether / EtOAc, 2:1).
1H NMR (400 MHz, CDCl3) ␦: 7.39 (d, J ϭ 7.1 Hz, 1H), 7.22
(td, J ϭ 7.80, 1.0 Hz, 1H), 6.98–6.92 (m, 3H), 6.85 (d, J ϭ
8.2 Hz, 1H), 6.78 (d, J ϭ 8.1 Hz, 1H), 4.22 and 4.06 (ABq,
J ϭ 13.8 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 3.68
(s, 3H), 3.38 and 3.14 (ABq, J ϭ 16.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3) ␦: 170.3, 169.3, 156.1, 148.8, 148.4, 129.6,
129.3, 127.3, 125.0, 121.5, 121.0, 111.8, 110.9, 108.2, 74.4,
57.1, 55.84, 55.78, 52.9, 51.9, 41.2. HR-MS (ESI) calcd for
C21H24NO7 (M ϩ H): 402.1547; found: 402.1549.
Compound 5l
Colorless oil. Rf ϭ 0.39 (petroleum ether/EtOAc, 4:1).
1H NMR (400 MHz, CDCl3) ␦: 7.36–7.33 (m, 2H), 7.21–7.15
(m, 2H), 6.97–6.89 (m, 3H), 6.79–6.76 (m, 1H), 4.14–4.05
(m, 2H), 4.06 and 3.90 (ABq, J ϭ 13.6 Hz, 2H), 3.81 (s, 3H), 2.80
(s, 2H), 1.73 (s, 3H), 1.19 (t, J ϭ 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) ␦: 170.3, 158.9, 155.6, 132.5, 130.0, 129.6,
128.6, 122.9, 121.2, 113.8, 108.5, 68.3, 60.4, 55.3, 55.2, 44.4,
20.6, 14.1. HR-MS (ESI) calcd for C20H24NO4 (M ϩ H):
342.1700; found: 342.1699.
Compound 5g
Slightly yellow oil. Rf ϭ 0.59 (petroleum ether / EtOAc,
4:1). This compound was obtained as a mixture of diaste-
reomers. A very small quantity of the major isomer could be
purified and characterized as such: 1H NMR (300 MHz,
CDCl3) ␦: 7.34–7.22 (m, 6H), 6.96 (td, J ϭ 7.6, 0.9 Hz, 1H),
6.85 (d, J ϭ 8.0 Hz, 1H), 4.40 (q, J ϭ 6.6 Hz, 1H), 3.57 (s, 3H),
3.48 (s, 3H), 3.27 and 2.81 (ABq, J ϭ 16.7 Hz, 2H), 1.43 (d,
J ϭ 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) ␦: 170.2, 168.8,
156.4, 140.9, 133.2, 129.5, 129.2, 128.4, 128.3, 125.5, 121.5,
107.7, 74.7, 61.6, 52.6, 51.6, 42.4, 22.0. HR-MS (ESI) calcd
for C20H21ClNO5 (M ϩ H): 390.1103; found: 390.1100. The
minor isomer could not be purified.
Compound 6
To an oven-dried 10 mL round-bottom flask equipped with
a stirrer was added 5a (93 mg, 0.25 mmol). Dry THF (3 mL)
was added and the solution was cooled to 0 °C. A LiBH4
solution (2 mol/L in THF, 0.35 mL, 0.7 mmol, 2.5 equiv) was
added dropwise. The reaction mixture was stirred at rt over-
night. Glycerol (1 mL) was added and the mixture was stirred
for 2 h before being poured into brine. It was extracted three
times with EtOAc, and the combined extracts were dried over
MgSO4, filtered, and evaporated. The residue was purified by
column chromatography to afford 6 as a slightly yellow oil.
Compound 5h
The reaction was performed in the presence of 1.2 equiv of
Cs2CO3. The product was as slightly yellow oil. Rf ϭ 0.41
1
(petroleum ether / EtOAc, 4:1). H NMR (300 MHz, CDCl3)
␦: 7.35 (dd, J ϭ 7.6, 0.9 Hz, 1H), 7.25–7.19 (m, 1H), 6.97–
6.91 (m, 1H), 6.80 (d, J ϭ 8.1 Hz, 1H), 3.79 (s, 3H), 3.66
(s, 3H), 3.24 and 3.09 (ABq, J ϭ 16.8 Hz, 2H), 2.86 (s, 3H). 13
C
1
Rf ϭ 0.25 (petroleum ether/EtOAc, 1:1). H NMR (300 MHz,
NMR (75 MHz, CDCl3) ␦: 170.2, 169.4, 156.1, 129.8, 126.8,
125.2, 121.7, 108.2, 74.7, 52.9, 52.0, 40.6, 40.2. HR-MS (ESI)
calcd for C13H16NO5 (M ϩ H): 266.1023; found: 266.1019.
CDCl3) ␦: 7.35–7.32 (m, 2H), 7.23–7.17 (m, 1H), 7.08 (dd, J ϭ
7.5, 0.8 Hz, 1H), 6.98–6.95 (m, 1H), 6.93–6.89 (m, 2H), 6.77
(d, J ϭ 8.0 Hz, 1H), 4.25 and 4.20 (ABq, J ϭ 13.9 Hz, 2H),
3.91–3.69 (m, 4H), 3.80 (s, 3H), 2.26–2.03 (m, 2H), OH
protons show a br at ϳ3.0. 13C NMR (75 MHz, CDCl3) ␦:
150.0, 156.1, 130.1, 129.2 (2C), 128.5, 122.9, 121.4, 113.9,
108.3, 73.9, 65.2, 58.9, 55.2, 54.9, 34.7. HR-MS (ESI) calcd
for C18H22NO4 (M ϩ H): 316.1543; found: 316.1541.
Compound 5i
Slightly yellow oil. Rf ϭ 0.40 (petroleum ether / EtOAc, 4:1).
1H NMR (400 MHz, CDCl3) ␦: 7.37 (dd, J ϭ 7.6, 0.8 Hz, 1H),
7.30–7.25 (m, 2H), 7.21–7.16 (m, 4H), 6.94 (td, J ϭ 7.6, 0.8 Hz,
1H), 6.81 (d, J ϭ 8.0 Hz, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 3.26 and
3.04 (ABq, J ϭ 16.7 Hz, 2H), 3.07–3.01 (m, 1H), 2.93–2.86
(m, 1H), 2.74 (t, J ϭ 7.7 Hz, 2H), 2.11–2.03 (m, 2H). 13C NMR
(75 MHz, CDCl3) ␦: 170.2, 169.3, 156.0, 141.7, 129.6, 128.4,
128.3, 127.4, 125.8, 125.1, 121.5, 108.0, 74.5, 52.8, 52.4, 51.8,
40.5, 32.9, 29.4. HR-MS (ESI) calcd for C21H24NO5 (M ϩ H):
370.1649; found: 370.1646.
Supplementary data
Supplementary data are available with the manuscript through
the journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/cjc-2012-0199.
Acknowledgments
Compound 5j
Slightly yellow oil. Rf ϭ 0.54 (petroleum ether / EtOAc,
This project was financially supported by the National
Natural Science Foundation of China (No. 21002021) and the
4:1). 1H NMR (300 MHz, CDCl3) ␦: 7.29 (dd, J ϭ 7.6, 0.8 Hz,
Published by NRC Research Press

Li et al.
49
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Chinese Ministry of Education (Key Project No. 210127, and
the Scientific Research Foundation for the Returned Overseas
Chinese Scholars). We thank Dr. Jiang Zhou, Professor
Shrong-Shi Lin (both Peking University), Mr. Huaiqiu Wang,
and Professor Zheng Duan (both Zhengzhou University) for
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50
Can. J. Chem. Vol. 91, 2013
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