Incorporation of carbon dioxide into phthalides: Via ligand-free copper-catalyzed direct carboxylation of benzoxasiloles

Article abstract of DOI:10.1039/c7gc00917h

The direct carboxylation of benzoxasiloles with carbon dioxide proceeded smoothly under mild conditions using copper iodide as a catalyst to afford phthalides after an acid work-up. Broad substrate scope and application of this methodology for the synthesis of natural products highlight the synthetic utility of this protocol.

Full text of DOI:10.1039/c7gc00917h

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ARTICLE
Incorporation of Carbon Dioxide into Phthalides via Ligand-Free
Copper-Catalyzed Direct Carboxylation of Benzoxasiloles†
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
Thanh V. Q. Nguyen, José A. Rodríguez-Santamaría, Woo-Jin Yoo and Shū Kobayashi*
DOI: 10.1039/x0xx00000x
The direct carboxylation of benzoxasiloles with carbon dioxide proceeded smoothly under mild conditions using copper
iodide as a catalyst to afford phthalides after an acid work-up. Broad substrate scope and the application of this
methodology for the synthesis of natural products highlight the synthetic utility of this protocol.
www.rsc.org/
6
silylation and borylation
7
Introduction
(a) Reaction of CO2 with dilithiated benzyl alcohols
O
X
OH Li OLi
Phthalides, a class of bicyclic heterocycles containing a γ-
lactone fused with an aromatic ring, are common structural
motifs found in numerous natural products, and are versatile
synthetic intermediates for the preparation of other heterocy-
n-BuLi (2 eq)
CO
2
O
R
R
(heating)
then HCl
X = H or Br
R
1
cles, such as phthalans, isoindolinones, and carbazoles. Due to
(b) Synthesis of aromatic carboxylic acids from CO
or aryl boronic esters
2
and arylsilanes
their importance in medicinal and natural product chemistry,
phthalides have been the targets of many synthetic methodol-
ogies.
Ar SiR
3
C-H activation
R = alkyl
(cat.)
HCl
Ar
H
Ar-CO
2
H
or
Ar B(OR)2 CO
2
On the other hand, the organic transformation of carbon diox-
(c) This work: Synthesis of phthalides from CO
2
and benzoxasiloles
ide (CO
2
) is an attractive topic in modern organic chemistry
O
H
OH
[M]
since it represents a low-cost, abundant, safe, and renewable
2
C1 carbon feedstock. This naturally occurring gas has been
C-H activation
O
cat., CO
2
O
R
[M] = Si or B
then HCl
typically used to prepare carboxylic acids via addition reactions
with carbon-based nucleophiles. For instance, CO2 has been
reported to react with dilithiated benzyl alcohols to afford
R
R
2
Scheme 1. Incorporation of CO into phthalides
3
phthalides after an acidic work-up (Scheme 1a). While this
synthetic method leads to the expedient synthesis of phthal-
ides from either benzyl or ortho-bromobenzyl alcohols, the use
of n-BuLi limits the functional group compatibility of this car-
boxylation process. As such, new synthetic protocols that
avoid this strongly basic and pyrophoric reagent would expand
the available phthalides derived from benzyl alcohols and
make the overall process safer and more convenient.
chemistry, in principle, the formal C–H carboxylation of aro-
matic moieties could be achieved in the absence of highly re-
active and strongly basic organo-lithium and magnesium rea-
gents.
In order to develop a new synthetic method that allows access
to phthalides using CO2 as a building block, we hypothesized
that the carboxylation of benzoxaboroles and benzoxasiloles,
in place of dilithiated benzyl alcohols, would provide a general
entry into a wide range of phthalides bearing sensitive func-
tional groups (Scheme 1c). Both starting materials are report-
ed to be stable and have been involved in several transition
Recently, the carboxylation of bench-stable organometallic
4
5
reagents, such as arylsilanes and arylboronic esters, has
garnered much attention (Scheme 1b). In particular, the
transition metal-catalyzed carboxylation of arylboronic esters
has been demonstrated to occur under mild reaction
conditions to provide benzoic acids bearing halides and other
sensitive functional groups. Since these bench-stable
organometallic reagents are accessible through catalytic C–H
8
,9
metal-catalyzed cross-coupling reactions. After careful con-
sideration, we decided to investigate the carboxylation of ben-
zoxasiloles since these bench-stable reagents are readily avail-
able through C–H silylation reactions with a convenient purifi-
cation process. In contrast, the synthesis of benzoxaboroles
mainly relies on the borylation of dilithiated benzyl alcohols
and thus limits the substrates available for the carboxylation
reaction.
However, the main challenge with this approach is the
2
underexplored reactivity of organosilanes with CO . The most
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common strategy involves the generation of stabilized In addition to the broader substrate scope achieved through
carbanions via fluoride-mediated desilylation, and in the the carboxylation of benzoxasiloles derived from the C–H si-
presence of an appropriate fluoride activator, electron- lylation of benzyl alcohols, a sharp contrast in the regioselec-
4
a-c
deficient arylsilanes
neutral or electron-rich arylsilanes hardly reacted.
overcome this limitation, we postulated that transmetallation uniquely accessed through our current strategy due to the
could undergo carboxylation while tivity between dilithiated benzyl alcohols and benzoxasiloles is
4
d
To highlighted in Scheme 3. Phthalides 2f, 2h, and 2k were
1
0
8b
of arylsilanes with a transition metal catalyst, such as copper,
sterically controlled C–H silylation step. In contrast, different
would generate a more reactive aryl organometallic regioisomers were selectively generated using the traditional
intermediate that would undergo addition to CO
2
.
method due to the directing effect of the methoxy group or
3
the high acidity of the benzylic proton.
a,b,12
a
Table 1. Optimization of the carboxylation of 1a.
Result and discussion
iPr
O
We began our investigation by studying the carboxylation of
benzoxazole 1a to produce phthalide 2a (Table 1). An encour-
aging result was obtained when the reaction was performed in
the presence of CuI (10 mol%) and CsF (3 equiv) in DMF at 60
iPr
MeO
MeO
Si
CuI
HCl
O
O
r.t., 2 h
CO
2
(balloon)
1a
CsF, Solvent
2a
°
C to provide the desired product 2a in 71% yield (entry 1). The
reaction also proceeded well in other polar aprotic solvents
entries 2-3), and DMSO was chosen as the best solvent (entry
). In a control experiment (entry 4), 2a was not detected in
6
0 °C, 20 h
(
b
Entry
Solvent
CuI (mol%)
CsF (eq)
Yield (%)
3
1
2
3
4
DMF
10
10
10
-
3
71
the absence of CuI, indicating the crucial role of aryl copper
species as the intermediate for the desired carboxylation reac-
tion. Gratifyingly, the carboxylation of 1a occurred with equal
efficiency in a larger scale with lower loading of both CuI and
CsF (entry 5). It is noteworthy that such remarkable reactivity
could be achieved without the aid of any ligands, highlighting
the efficiency and simplicity of the carboxylation reaction.
MeCN
DMSO
DMSO
DMSO
3
72
c
3
86 (79)
3
n.d.
d
c
5
1
1.5
88 (82)
a
Reaction condition: 1a (0.4 mmol), CuI (0.04 mmol), CsF (1.2 mmol), solvent (1.6
b
1
mL). Yields were determined by H NMR analysis using 1,3,5-trimethoxybenzene
c
d
as an internal standard. Isolated yield. 1a (1 mmol), CuI (0.01 mmol), CsF (1.5
More interestingly, under the conditions described in entry 3, mmol), DMSO (4 mL), 24 h. n.d. = not detected.
the carboxylation of PhSi(OMe) only provided benzoic acid in
a modest yield of 45%, whereas PhSiMe did not undergo the
3
iPr
Si
O
3
iPr
1
1
carboxylation reaction. These results indicate a subtle struc-
ture-reactivity relationship for carboxylation of arylsilanes.
Furthermore, the conversion of benzoxaboroles to phthalides
using our optimized conditions or the one reported for the
CuI (1 mol%)
HCl
R1
R1
Cl
O
O
CO2 (balloon)
CsF (1.5 equiv), DMSO
60 °C, 24 h
r.t., 12 h
R2
R2
1
b-l
2b-l
5
b
carboxylation of arylboronic esters did not yield the expected
phthalide.
O
O
O
O
Me
Me2N
F
O
O
O
O
The carboxylation of benzoxasiloles containing diisopropylsilyl
moiety 1b-l is described in Scheme 2. In contrast to previous
[4]
2b, 77%
2c, 72%
2d, 77%
2e, 80%
reports on arylsilane carboxylations, both electron-rich (1b-c
)
O
O
O
O
and electron-deficient substrates (1d-e) smoothly underwent
carboxylation to afford phthalides 2b-e in good yields. Moreo-
ver, substrates with different substitution patterns on the ar-
omatic ring (1f-h) were also applicable. Similarly, the reaction
of napthoxasilole 1i provided tricyclic phthalide 2i in moderate
yield. While introducing a methyl group at the benzylic posi-
tion (1j-l) somewhat decreased the reactivity, high yields could
be achieved with higher catalyst loading (2j-l). In addition, the
current method was found to be suitable for the synthesis of
chiral phthalide, as the enantioenriched substrate (R)-1k, pre-
pared from the corresponding chiral alcohol with 94% ee, was
O
O
O
O
MeO
Me
OMe
Me
2h, 77%
2
f, 68%
2g, 76%
2i: 64%b
O
O
O
O
O
O
O
O
MeO
Me
Me
OMe Me
Me
OH
j, 82%b
2k, 83%b
2l, 79%
2m, 68%b,d
2
b
(R)-2k, 80%, 94% ee
converted into (R)-2k without any loss of enantiopurity. Thus, Scheme 2. Substrate scope for the carboxylation of diisopropyl benzoxasiloles. Reaction
condition: 1b-m (1 mmol), CuI (0.01 mmol), CsF (1.5 mmol), DMSO (4 mL), 24 h. Isolat-
both the preparation of benzoxasiloles and the subsequent
a
b
ed yields of 2b-m were reported. CuI (0.1 mmol) was used. The starting material was
c
carboxylation reaction did not degrade the chirality at the ben- prepared from the (R)-alcohol with 94% ee. The starting material is a cyclic silyl acetal
2
with R = -OMe.
zylic position. Furthermore, the carboxylation of cyclic silyl
acetal 1m, which could be conveniently prepared from a se-
quential hydrosilylation/C–H activation of the corresponding
8
esters, afforded phthalaldehydic acid 2m in 68% yield.
c
2
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Pleas Ge rd eo e nn o Ct ah de j mu si ts mt r ya rgins
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DOI: 10.1039/C7GC00917H
Journal Name
ARTICLE
OMe
iPr
O
O
1. n-BuLi
lithiation
1. silylation
O
iPr
R1
OH
MeO
MeO
2. CO
2
2. CO2
Si
CuI (1 mol%)
O
MeO
O
O
O
(a)
3. HCl
3. HCl
CO2 (balloon)
R1
MeO
6
2% (ref. 3b)
CsF (1.5 equiv), DMSO
R1
4
6%
OMe
lithiation silylation
1. silylation
2. CO
60 °C, 24 h, then HCl
1x
2
x: R1 = OMe, 58%
, R1 = OH, quant.
O
1
. n-BuLi
BBr
3
, DCM, -78 °C to r.t.
Me
OH
4
O
2
. CO
2
2
iPr
O
iPr
O
THPO
HO
O
3. HCl
3. HCl
silylation
Si
CuI (1 mol%)
O
O
(b)
Me
60% (ref. 12)
46%
CO2 (balloon)
CsF (1.5 equiv), DMSO
60 °C, 24 h, then HCl
O
OMe
1y
OMe
Scheme 3. Difference in the regioselectivity between traditional method and current
2y, 65%
method.
RO
R =
R-X (3 equiv)
O
5 (Antifungal), quant.
O
K
2
CO
KI (3 equiv)
acetone, 60 °C, 12 h
3
(5 equiv)
Si
CuI (1 mol%)
HCl
R1
R =
O
R1
O
OMe
CO
R2 CsF (1.5 equiv), DMSO
0 °C, 24 h
2
(balloon)
r.t., 12 h
6
(Marilone C), 78%
R2
6
1
n-w
2n-w
2
Scheme 5. Incorporation of CO into natural products possessing the phthalide core
O
O
O
structure.
MeO
Cl
O
O
O
2
scalability of the CO incorporating process was demonstrated
Me
n, 76%
Me
Me
2p, 84%, 77%c
by a gram scale carboxylation of 1p to provide phthalide 2p in
77% yield.
2
o, 75%
2
R)-2n, 76%, 94% eeb
(
O
O
O
Next, the synthetic utility of the carboxylation of benzox-
asiloles was demonstrated by the preparation of several natu-
ral products. We found that the carboxylation of trimethoxy-
substituted benzoxasilole 1x provided phthalide 2x, which
I
Br
O
O
O
Br
Me
Me
Me
2
q, 72%
2r, 75%
2s, 70%
could be converted in quantitative yield to 4, which is known
13
to possess in vitro growth inhibitory activities (Scheme 5a). In
addition, highly substituted benzoxasiloles 1y, conveniently
O
O
O
O
O
O
O
O
prepared by
a
synthetic sequence starting from 2-
to provide Silva-
14
iPr
Me
Ph
2u, 70%
Bu
2v, 85%
Me
methylresorcinol, was found to react with CO
2
2
t, 74%
2
w, 57%d
ticol (2y), an antifungal agent, in 65% yield (Scheme 5b).
Moreover, 2x could also be used for the synthesis of other
14,15
natural products such as phthalide 5 and Marilone C (6).
Scheme 4. Substrate scope for the carboxylation of dimethyl benzoxasiloles. Reaction
condition: 1n-w (1 mmol), CuI (0.01 mmol), CsF (1.5 mmol), DMSO (4 mL), 24 h. Isolat-
a
ed yields of 2n-w were reported. The starting material was prepared from (R)-alcohol Based on several previous reports on the transformation of
b
c
with 94% ee. Gram scale reaction (4.8 mmol of 1p). CuI (0.1 mmol).
oxasiloles and copper-catalyzed carboxylation reactions, a
plausible mechanism for the carboxylation of benzoxasiloles is
shown in Figure 1. Initially, benzoxasilole 1a were activated by
Next, the direct carboxylation of benzoxasiloles 1n-w, which
contains the dimethylsilyl moiety, was investigated (Scheme
fluoride to generate the pentavalent silicate intermediate
which then underwent transmetallation with the copper cata-
lyst to provide aryl copper intermediate . The transmetalla-
A,
4). Although these substrates are generally less stable, they
can be prepared from low-cost, commercially available silylat-
ing reagents. Our investigations revealed that the structural
changes on the silicon center did not prevent the effective
carboxylation of these substrates. It was found that 1n could
be converted to the corresponding phthalide 2n in high yield.
Substrates with different substituents on the benzene ring (1o-
B
tion of pentavalent silicates with in situ generated CuF has
been proposed in copper-catalyzed Hiyama coupling reac-
[10b]
tions.
In addition, the combination of CuI and a fluoride
source (TBAF or KF) have been reported to mediate the cou-
[
10c]
pling reaction of oxasiloles with allyl chloride
or aryl io-
affords copper car-
, which can undergo salt metathesis with CsF to pro-
and regenerate the copper catalyst. The reaction of
stoichiometric arylcopper species with CO has been previous-
and catalytically generated arylcopper inter-
mediates, derived from transmetallation with arylboronic es-
s) were efficiently carboxylated, providing 2o-s in good to ex-
[10d]
dides . Next, the insertion of CO
boxylate
vide
2
into B
cellent yields. It should be noted that bromo and iodo substit-
uents were tolerated under the reaction conditions (2q-s),
indicating a clear advantage over the traditional method. In
addition, the carboxylation of substrates bearing different sub-
stituents at the benzylic position (1t-v) afforded the corre-
C
D
2
[16]
ly described
sponding phthalides (2t-v) in good yields. Benzoxasilole 1w
,
[5a,b]
ters, have been reported for carboxylation reactions.
Since
derived from a tertiary alcohol, underwent carboxylation to
copper-catalyzed carboxylation reactions generally require the
provide phthalide 2w in a moderate yield. In addition, the
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[
2e,f]
use of external ligands,
we speculated that the oxygen at-
3
4
Selected examples: (a) K. Orito, M. Miyazawa and H.
Suginome, Tetrahedron, 1995, 51, 2489; (b) F. Kaiser, L.
Schwink, J. Velder and H.-G. Schmalz, J. Org. Chem., 2002,
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Yonemoto-Kobayashi, K. Inamoto and Y. Kondo, Chem. Lett.,
om in benzoxasiloles may undergo an intramolecular coordina-
tion with the copper center in intermediate , to facilitate ei-
ther the transmetallation or carboxylation steps. Finally, ce-
sium salt can undergo an acid mediated esterification to
provide phthalide 2a
B
D
.
Cs
O
iPr
CuI
CsF
iPr
MeO
MeO
CsF
F
Si
O
2
014, 43, 477.
O
1a
O[Si]
5
(a) J. Takaya, S. Tadami, K. Ukai and N. Iwasawa, Org. Lett.,
2008, 10, 2697; (b) T. Ohishi, M. Nishiura and Z. Hou, Angew.
Chem. Int. Ed., 2008, 47, 5792; (c) K. Ukai, M. Aoki, J. Takaya
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I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and
J. F. Hartwig, Chem. Rev., 2010, 110, 890.
"
Cu-F"
D
A
HCl
CsF
2a
Cu
O
6
7
MeO
Cu
MeO
O[Si]
O
O[Si]
8
(a) E. M. Simmons and J. F. Hartwig, J. Am. Chem. Soc., 2010,
132, 17092; (b) Y. Hua, S. Jung, J. Roh and J. Jeon, J. Org.
Chem., 2015, 80, 4661; (c) Y. Hua, P. Asgari, U. S. Dakarapu
and J. Jeon, Chem. Commun., 2015, 51, 3778.
B
2 2
Si] = -SiMe F
C
[
CO
2
9
(a) J. Zhu, Y. Wei, D. Lin, C. Ou, L. Xie, Y. Zhao and W. Huang,
Org. Biomol. Chem., 2015, 13, 11362; (b) D. S. Gunasekera,
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Kiprof, V. V. Zhdankin and M. V. R. Reddy, Tetrahedron,
Figure 1. Proposed mechanism for the carboxylation of benzoxasilole 1a
.
2
007, 63, 9401.
0 A review on metal-catalyzed coupling of organosilicons: (a) T.
Komiyama, Y. Minami and T. Hiyama, ACS Catal., 2017, 7,
Conclusions
1
In conclusion, we demonstrated that CO
2
could be incorpo-
rated into phthalides via a copper-catalyzed carboxylation re-
action with benzoxasiloles. Several advantages of this meth-
odology are: the use of a simple copper salt as a catalyst, the
ease of substrate preparation, and convenient reaction setup.
631; Coupling of aryl and alkenylsilanes involving the
transmetallation to copper: (b) S. K. Gurung, S. Thapa, A. S.
Vangala and R. Giri, Org. Lett., 2013, 15, 5378; (c) S. V.
Maifeld and D. Lee, Org. Lett., 2005, 7, 4995; (d) S. E. Den-
mark and T. Kobayashi, J. Org. Chem., 2003, 68, 5153.
Since this method avoids the use of n-BuLi as a reagent, a wide 11 See Supporting Information for details
range of phthalides could be prepared from readily available 12 N. Philippe, V. Levacher, G. Dupas, J. Duflos, G. Quéguiner
and J. Bourguignon, Tetrahedron: Asymmetry, 1996, 7, 417.
benzyl alcohols as precursors, including those containing halo-
gens and chiral centers. Finally, the synthetic utility of this
method was demonstrated through the synthesis of some nat-
ural products containing the phthalide framework.
1
3 E. L. Mullady, W. P. Millett, H.-D. Yoo, A. S. Weiskopf, J. Chen,
D. DiTullio, V. Knight-Connoni, D. E. Hughes and W. E.
Pierceall, J. Nat. Prod., 2004, 67, 2086.
14 X.-L. Yang, S. Zhang, Q.-B. Hu, D.-Q. Luo and Y. Zhang, J Anti-
biot, 2011, 64, 723.
1
5 C. Almeida, S. Kehraus, M. Prudêncio and G. M. König,
Beilstein J. Org. Chem., 2011, , 1636.
7
Acknowledgements
1
6 G. W. Ebert, W. L. Juda, R. H. Kosakowski, B. Ma, L. Dong, K. E.
Cummings, M. V. B. Phelps, A. E. Mostafa and J. Luo, J. Org.
Chem., 2005, 70, 4314.
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Japan Society for the Promotion of Sci-
ence (JSPS) and, the Japan Science and Technology Agency
(JST). J.A.R.-S. would like to thank the Moritani Scholarship
Foundation for financial support.
Notes and references
1
A comprehensive review on phthalides: R. Karmakar, P. Pa-
hari and D. Mal, Chem. Rev., 2014, 114, 6213.
2
Several recent reviews on the organic transformation of car-
bon dioxide: (a) T. Sakakura, J.-C. Choi and H. Yasuda, Chem.
Rev., 2007, 107, 2365. (b) M. Cokoja, C. Bruckmeier, B. Rieg-
er, W. A. Herrmann and F. E. Kühn, Angew. Chem. Int. Ed.,
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011, 50, 8510; (c) K. Huang, C.-L. Sun and Z.-J. Shi, Chem.
Soc. Rev., 2011, 40, 2435; (d) Q. Liu, L. Wu, R. Jackstell and
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4
Org. Biomol. Chem., 2016, 14, 3666.
4
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Green Chemistry
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HO
R2
R'
O
R'
Si
C-H silylation R1
CO
R1
2
O
O
R1
R2
R2
•
•
Formal C-H carboxylation!
• "Green" carbon source!
• Natural product synthesis!
Easily accessed intermediates!
The synthesis of a wide range of phthalides was achieved through a copper-catalyzed
carboxylation reaction of benzoxasiloles.