Transition metal-catalyzed addition reactions of arylboronic acids with alkyl 2-formylbenzoates: Efficient access to chiral 3-substituted phthalides

Article abstract of DOI:10.1039/c001104e

Transition metal-catalyzed addition of arylboronic acids to 2-formylbenzoates afforded 3-substituted phthalides. By using SPINOL-based phosphites as ligands, a Rh(i)-catalyzed asymmetric version of such an addition reaction was achieved. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c001104e

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Transition metal-catalyzed addition reactions of arylboronic acids
with alkyl 2-formylbenzoates: efficient access to chiral
3-substituted phthalideswz
Chun-Hui Xing, Yuan-Xi Liao, Ping He and Qiao-Sheng Hu*
Received (in College Park, MD, USA) 18th January 2010, Accepted 18th February 2010
First published as an Advance Article on the web 25th March 2010
DOI: 10.1039/c001104e
Transition metal-catalyzed addition of arylboronic acids to
2-formylbenzoates afforded 3-substituted phthalides. By using
Table 1 Transition metal-catalyzed addition reactions of phenyl-
boronic acid with methyl 2-formylbenzoate
SPINOL-based phosphites as ligands,
a Rh(I)-catalyzed
asymmetric version of such an addition reaction was achieved.
Chiral 3-substituted phthalides (1(3H)-isobenzofuranones) are
useful molecules as valuable pharmacological compounds and
are important building blocks for the synthesis of biologically
active compounds.1,2 Asymmetric synthesis of chiral
3-substituted phthalides have been explored and several
methods have been developed.1–4 Most successful strategies
are the asymmetric reduction including catalytic and transfer
hydrogenation reduction of the corresponding ketones and
most recently reported Rh(I)-catalyzed asymmetric ketone
hydroacylation.4–6 Very recently, Cheng reported the
Co-catalyzed asymmetric addition reaction of 2-halobenzoates
with aldehydes to access chiral 3-substituted phthalides.7
In recent years, transition metal-catalyzed addition reactions
of arylboronic acids with aldehydes have become useful
tools to access aryl alcohols.8–11 In this context, we have
recently documented Type I palladacycle-, platinacycle- and
Rh(I)/diene-catalyzed addition reactions of arylboronic acids
with carbonyl-containing compounds including aldehydes.12–14
As 2-nitrobenzaldehyde and 2-methoxybenzaldehyde have
been demonstrated to be excellent substrates, we reasoned
that 2-formyl benzoates should also be suitable substrates
for the addition reaction. Based on the consideration that
Entry Catalyst
ArB(OH)2
Solvent Conv.b (%)
1
2
3
1
2
3
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhMe
PhMe
PhMe
100 (81)c,d
100d
100 (86)d
4
5
6
[Rh(C2H4)2Cl]2
[Rh(COD)Cl]2
2
THF
THF
PhMe
o2e
99 (91)
PhB(OH)2
(85)
7
2
PhMe
PhMe
PhMe
THF
(88)
8
3
(92)d
(85)d
(93)
9
3
10
[Rh(COD)Cl]2
11
12
13
14
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
THF
THF
THF
THF
(91)
(90)
(81)
(80)
15
[Rh(COD)Cl]2
THF
(88)
a
Reaction conditions: aldehyde (1.0 equiv.), arylboronic acid
(1.5 equiv.), toluene (2 mL)–K3PO4 (3 equiv.) or THF–K3PO4 (5 M)
room temperature. Conversion based on 1H NMR. In parenthesis:
d
Isolated yields. Reaction temperature: room temperature for 1 or 2,
b
c
e
and 80–90 1C for 3, reaction time: 12 h. 4 : 5 was observed in a ratio
of 1 : 99.
Scheme 1 Mechanistic consideration for transition metal-catalyzed
addition reactions of arylboronic acids with 2-formylbenzoates to
access 3-substituted phthalides.
the addition reactions could be combined with the lactone
formation process (Scheme 1), we envisioned that the addition
of arylboronic acids to 2-formylbenzoates might provide an
efficient way for the preparation of 3-substituted phthalides. In
this communication, we report our results, i. e., transition
metal-catalyzed addition reactions of arylboronic acids with
alkyl 2-formylbenzoates to access 3-substituted phthalides,
including an asymmetric version by using optically active
Rh(I) catalysts.15
Department of Chemistry, College of Staten Island and the Graduate
Center of the City University of New York, 2800 Victory Boulevard,
Staten Island, New York 10314, USA.
E-mail: qiaosheng.hu@csi.cuny.edu; Fax: (+1) 718-982-3910;
Tel: (+1) 718-982-3901
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-themed issue showcasing high quality research in organic chemistry.
Please see our website (http://www.rsc.org/Publishing/Journals/cc/
cc09org_web_issue) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/c001104e
Our study began with a test of the feasibility of the addition
of phenylboronic acid to methyl 2-formylbenzoate by
ꢀc
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Fig. 1 Type I metalacycles.
Table 2 Rh(I)-Catalyzed addition reactions of p-tolyboronic acid to
2-formylbenzoatesa
Fig. 2 Chiral ligands.
and 4). We also tested 1,10-spirodiindane-7,70-diol (SPINOL)-
based monophosphites. Although Rh(I)/10a was not an
effective catalyst when using Zhou’s protocol (KF, toluene–
H2O 1 : 1),19 it efficiently catalyzed the addition reaction with
K3PO4 as base. We have also examined other SPINOL-based
phosphites 10b–d and found 10b exhibited the highest activity
and best enantioselectivity (Table 2, entries 5–9). With 10b as
the ligand, we examined other factors that could influence the
enantioselectivity. We found that decreasing the reaction
temperature from room temperature to 0 1C improved the
enantioselectivity from 68 to 77% (Table 2, entries 6 and 10).
Further decreasing the reaction temperature did not affect the
enantioselectivity, rather it slowed down the reaction (Table 2,
entries 10–12). We have also varied the alkyl groups in the
2-formylbenzoates, finding that methyl formylbenzoate gave
the best enantioselectivity (Table 2, entries 12, 13–15).
Entry Ligand
R
Base
T/1C Conv.b (%) eec (%)
1
6
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
K3PO4
K3PO4-
K3PO4
K3PO4
KF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
0
0
rt
rt
0
rt
rt
rt
rt
59d
99e
21f
40g
5
—
—
—
—
—
56
68
51
6
77
75
72
67
—
65
2
7
3
8
4
9
5
6
7
8
10a
10a
10b
10c
10d
10b
10b
10b
10b
10b
10b
99h
100i
96j
9
100
99j
10
11
12
13
14
15
0
ꢁ5
ꢁ10
rt
rt
rt
84k
24
100l
98m
85n
CH2Ph K3PO4
n-Bu K3PO4
We have examined different arylboronic acids for the
asymmetric addition reaction. We found optically active
3-substituted phthalides were obtained in good yields and
enantioselectivity (Table 3). In addition, we found that the
enantiopurity of the formed products could be improved by
recrystallization. For example, the enantiopurity of 4f can be
improved from 83 to 98% ee after recrystallization.
a
Reaction conditions: aldehyde (1.0 equiv.), p-tolylboronic acid
(1.5 equiv.), toluene (2 mL), K3PO4 (5 M) or KF (1.0–3.0 equiv.).
b
c
Conversion based on 1H NMR. Determined by HPLC (ChiralCel-OD
d
column). 4a :5 in a ratio of 25 : 75. 4a :5 in a ratio of 65 : 35. 4a :5
e
f
g
in a ratio of 1 : 99. 4a :5 in a ratio of 12 : 88. 4a :5 in a ratio of
h
i
77.5 : 22.5. 4a :5 in
j
ratio of 88.5 : 11.5. 4a :5 in
a
a
91 : 9. 4a :5 in a ratio of 88 : 12. 4a :5 in a ratio of 86 : 14. 4a :5
ratio of
m
k
l
n
in a ratio of 17 : 83. 4a :5 in a ratio of 96 : 4.
Table 3 Asymmetric addition reactions of arylboronic acids with
methyl 2-formylbenzoatea
screening a number of transition metal catalysts that were
available to us. Our results are listed in Table 1. We found
Type I palladacycles 1 and 2, platinacycle 3 (Fig. 1) efficiently
catalyzed such addition (Table 1, entries 1–3). While
[Rh(C2H4)2Cl]2 was an inefficient catalyst for the addition
reaction, it catalyzed the formation of 5 in excellent yield
(Table 1, entry 4). On the other hand, [Rh(COD)Cl]2 was
found to catalyze the addition reaction efficiently (Table 1,
entry 5). We have further briefly employed the palladacycle 2,
platinacycle 3 and [Rh(COD)Cl]2 as catalysts for the addition
of different arylboronic acids. We found that high yields
were observed for all arylboronic acids tested (Table 1,
entries 6–15).
Entry
ArB(OH)2
Product
Yieldb (%)
eec (%)
1
2
3
4a
4b
4c
85
94
93
77
71
67
4
5
4d
4e
4f
85
59
69
63
We next turned our attention to the asymmetric version of
the addition reaction. We selected Rh(I) complexes for our
study because the catalytic activity and enantioselectivity of
the catalyst systems could be readily altered by using a number
of readily available ligands. Our results are listed in Table 2 for
the chiral ligands (Fig. 2). We found ligand 616 and chiral
diene 717 gave low yields of the addition products (Table 2,
66.5
83d
6
a
Reaction conditions: aldehyde (1.0 equiv.), arylboronic acid
b
(1.5 equiv.), toluene (2 mL), K3PO4 (1.0–3.0 equiv.), 0 1C. Isolated
yields. Determined by HPLC (Chiralcel-OD column). See Supple-
d
mentary Information for the optical rotation data. CH2Cl2 as the
c
entries
ligands 818 and 9 gave low conversions (Table 2, entries 3
1
and 2). 1,10-Bi-2-naphthyl-based monodentate
solvent.
ꢀc
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In summary, we have demonstrated that the addition
reaction of arylboronic acids with 2-formylbenzoates to
form 3-substituted phthalides can be efficiently catalyzed by
transition-metal catalysts including Type I palladacycles,
platinacycle and Rh(I) catalysts. By using SPINOL-based
phosphites as ligands, a Rh(I)-catalyzed asymmetric version
of such an addition reaction has been realized and up to 83%
ee was achieved. Our study provides an efficient method to
synthesize chiral 3-substituted phthalides. Our future work
will be directed to improve the enantioselectivity20 and to
explore its application for the preparation of biologically
important compounds.
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We gratefully thank the NSF (CHE0719311) for funding.
Partial support from PSC-CUNY Research Award Program is
also gratefully acknowledged. We also thank Frontier
Scientific, Inc. for its generous gifts of arylboronic acids.
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ꢀc
This journal is The Royal Society of Chemistry 2010
3012 | Chem. Commun., 2010, 46, 3010–3012