Skeletal rearrangement of cyano-substituted iminoisobenzofurans into alkyl 2-cyanobenzoates catalyzed by B(C6F5)3

Article abstract of DOI:10.1021/ol5026519

An efficient method for the direct conversion of cyano-substituted iminoisobenzofurans into their corresponding alkyl 2-cyanobenzoates has been developed. This transformation proceeds via cleavage of C-C, C-O, and C-N bonds in starting iminoisobenzofurans. DFT study revealed that intermediate α-iminonitriles are produced in situ via C-C bond formation between 2-iminium benzoates and a cyanide ion. Generation of isocyanide as the byproduct in a more thermodynamic manner in DFT calculations also supports the experimental results.

Full text of DOI:10.1021/ol5026519

Letter
pubs.acs.org/OrgLett
Skeletal Rearrangement of Cyano-Substituted Iminoisobenzofurans
into Alkyl 2‑Cyanobenzoates Catalyzed by B(C6F5)3
Jing Li,† Yasuhiro Okuda,† Jiaji Zhao,† Seiji Mori,‡ and Yasushi Nishihara*,†,§
†Division of Earth, Life, and Molecular Sciences, Graduate School of Natural Science and Technology, Okayama University, 3-1-1
Tsushimanaka, Okayama 700-8530, Japan
‡Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512, Japan
§ACT-C, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: An efficient method for the direct conversion of
cyano-substituted iminoisobenzofurans into their corresponding
alkyl 2-cyanobenzoates has been developed. This transformation
proceeds via cleavage of C−C, C−O, and C−N bonds in starting
iminoisobenzofurans. DFT study revealed that intermediate α-
iminonitriles are produced in situ via C−C bond formation between
2-iminium benzoates and a cyanide ion. Generation of isocyanide as the byproduct in a more thermodynamic manner in DFT
calculations also supports the experimental results.
Scheme 1. B(C6F5)3-Catalyzed Transformation of Cyano-
Substituted Iminoisobenzofurans 1 into 2-Cyanobenzoates 2
yano and ester groups are recognized as one of the most
Cfundamental functional groups and are found in various
bioactive molecules and functionalized materials.1,2 In particular,
nitriles can serve as versatile synthetic precursors such as
amides,3 carboxylic acids,4 aldehydes,5 and amines.6 Because of
broad transformations of a cyano group, the development of
novel and efficient synthetic methods for the preparation of
nitriles is of long-standing interest to organic chemists.7
Over the past few years, continuous efforts have been devoted
to carbonylation or cyanation of aromatic rings.8 Although there
have been several synthetic methods of alkyl 2-cyanobenzoate,
which bear both cyano and ester groups in the o-position, to the
best our knowledge, the reported procedures for these variants to
date have been rather routine.
To our surprise, with the aid of several Lewis acids, we found
that N-[3-cyano-3-ethoxy-1(3H)-isobenzofuranylidene]-2,4,4-
trimethyl-2-pentanamine (1a), derived from the palladium-
catalyzed three-component coupling reaction of benzyne,
1,1,3,3-tetramethylbutyl isocyanide, and ethyl cyanoformate,
accidentally produced ethyl 2-cyanobenzoate (2a). A series of
Lewis acids were investigated and the results are summarized in
Table 1. The reaction did not proceed at all with 20 mol % of CuI
in THF at 70 °C (entry 1). When other copper compounds such
as CuBr, CuCl, or Cu(OTf)2 were employed as the catalyst, 2a
was formed in moderate yields (entries 2−4). Although we
further investigated employing other metal-containing Lewis
acids such as Sc(OTf)3, InCl3, Hf(OTf)4, and AlCl3, lower yields
of 2a were obtained (entries 5−8). The reaction did not proceed
with a stoichiometric amount of DIBAL-H (entry 9), which is
quite different from the result of the formation of α-
iminonitriles.19 Subsequently, aluminum reagents such as AlF3,
AlBr3, AlCl3, and AlPh3 at room temperature were also screened,
but the substrate was recovered in all cases. Delightfully, when 1a
was treated with 20 mol % of B(C6F5)3, the yield of 2a was
significantly improved to 93% (entry 10). Reducing the amount
of B(C6F5)3 to 5 mol % gave rise to the comparable yield (90%)
Recently, our group has reported a versatile synthetic route to
iminoisobenzofurans by the palladium-catalyzed three-compo-
nent coupling of arynes, isocyanides, and cyanoformates.9 On the
other hand, transition-metal-catalyzed carbocyanation reactions
of unsaturated organic compounds have been developed to
synthesize highly functionalized nitriles, which allowed a
simultaneous introduction of both a cyano group and other
organic functionalities in highly regio-, stereo-, and chemo-
selective manners.10 In this regard, we and other research groups
have proved that acyl,11,12 aryl,13,14 allyl,15 alkyl,14,16 alkenyl,14
and alkynyl17 cyanides can participate in carbocyanation
reactions. Although arynes are synthetically valuable intermedi-
ates and have been widely used in the preparation of 1,2-
disubstituted arenes,18 carbocyanation across arynes has not
been reported. Herein, we report B(C6F5)3-catalyzed reaction of
a series of iminoisobenzofurans into the corresponding 2-
cyanobenzoates as the exclusive products. Formally, an initial
isocyanide moiety in the three-component coupling reaction is
installed to the products as the CN source (Scheme 1).
Received: September 6, 2014
© XXXX American Chemical Society
A
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Letter
1,1,3,3-tetramethylbutyl isocyanide, and benzoyl cyanide (entry
7). Other iminoisobenzofurans 1h and 1i bearing the different R1
substituents could also participate in the reaction to afford 2a in
88% and 50% yields, respectively (entries 8 and 9).
Table 1. Transformation of 1a to 2a Catalyzed by a Lewis
Acid
a
Iminoisobenzofurans bearing substituents on the phenyl ring
can also be transformed (Scheme 2). Treatment of 1j, derived
Scheme 2. Substrate Scope
b
entry
Lewis acid
yield (%)
1
2
3
4
5
6
7
8
CuI
0
CuBr
34
CuCl
57
Cu(OTf)2
Sc(OTf)3
InCl3
45
>1
5
Hf(OTf)4
AlCl3
>1
7
c
9
DIBAL-H
B(C6F5)3
B(C6F5)3
B(C6F5)3
BF3·Et2O
BPh3
0
10
93
d
11
91 (90)
from 4,5-dimethylbenzyne, tert-butyl isocyanide, and ethyl
cyanoformate with a catalytic amount of B(C6F5)3, gave 2j in
89% yield. Iminoisobenzofuran 1k could also be applied to the
present transformation, leading to product 2k in 83% yield.
To gain insight into the reaction mechanism of this novel
transformation, the time-course experiments were performed.20
An NMR monitoring experiment was conducted using 1a as a
model substrate at 70 °C. Interestingly, iminoisobenzofuran 1a
was immediately transformed to the corresponding cyanoben-
zoate 2a and α-iminonitrile 3a in 31 and 41% yields, respectively.
After 0.5 h, 1a was completely consumed, while 3a was increased
to 47% yield, accompanied by 2a in 34% yield. Later, 2a was
gradually generated along with 3a. In contrast, the NMR-
monitoring experiment performed at room temperature led to 2a
in less than 20% yield after 1 h, and 3a was also formed slowly.
After 14 h, the substrate 1a was completely consumed and
cyanobenzoate 2a and α-iminonitrile 3a were formed in 49 and
39% yields, respectively. Consequently, 3a was gradually
diminished until the reaction time was prolonged to 24 h,
affording 2a as the exclusive product.
d,e
12
13
14
84
0
0
a
The reactions were carried out using 1a (0.1 mmol) and Lewis acid
b
(20 mol %) in THF (0.5 mL) at 70 °C for 8 h. Determined by the 1H
NMR spectra using CH2Br2 as an internal standard. An isolated yield is
shown in parenthesis. 1 equiv of DIBAL-H was used. 5 mol % of
B(C6F5)3 was used. The reaction was carried out at room temperature
c
d
e
for 24 h.
of 2a (entry 11). The transformation was also proceeded with 5
mol % of B(C6F5)3 at room temperature to afford 2a in 84% yield
(entry 12). However, other boron reagents such as BF3·Et2O or
BPh3 did not produce 2a (entries 13 and 14).
The scope of this transformation of a variety of cyano-
substituted iminoisobenzofurans 1 into the corresponding alkyl
2-cyanobenzoates 2 is shown in Table 2. A series of
iminoisobenzofurans 1a−f bearing Et, Me, nPr, iPr, nBu, and Bn
substituents were transformed efficiently to afford the corre-
sponding products 2a−f in high to excellent yields (entries 1−6).
Under identical reaction conditions, this reaction was not
applicable to the formation of iminoisobenzofuran 1g, prepared
from a three-component coupling of the benzyne precursor,
Additional experiments were also performed, as shown in
Scheme 3. When 3a was treated with 5 mol % of B(C6F5)3, 2a was
Scheme 3. Effect of R1 Group on B(C6F5)3-Catalyzed
Transformation of 3 to 2a
a
Table 2. Scope of B(C6F5)3-Catalyzed Synthesis of 2
b
entry
1
R1 =
R2 =
product
yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
CMe2CH2CMe3
OEt
OMe
OnPr
OiPr
OnBu
OBn
Ph
2a
2b
2c
2d
2e
2f
90
99
89
94
88
82
0
formed in 97% yield, whereas 3b bearing the cyclohexyl imine
substituent could not afford 2a and the substrate was recovered
completely, indicating that the substituent of imine strongly
affects the success of this transformation.
It has been reported that Lewis acid induced reductive cleavage
of furans, leading to the acyclic products,21 and that a C−N bond
of isocyanides can be cleaved.22 On the basis of previous works
reported, we carried out density functional theory (DFT)
calculations for a plausible mechanism, as shown in Figure 1.
Although this skeletal transformation includes two bond
cleavages (C−C and C−O) and one bond formation (CO),
the activation barrier (INT1 to TS1) is moderate (∼50 kJ/mol),
1g
1h
1i
2g
2a
2a
tBu
OEt
OEt
88
50
c
9
1-adamantanyl
a
The reactions were carried out using 1 (0.1 mmol) and B(C6F5)3 (5
mol %) in THF (0.5 mL) at 70 °C for 8 h. Isolated yields. 10 mol %
of B(C6F5)3 was used for 24 h.
b
c
B
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Figure 1. Computed Gibbs free energies (kJ/mol) at 70 °C and 1 atm for B(C6F5)3-catalyzed transformation pathway from iminoisobenzofurans 1 to
cyanobenzoates 2. Gibbs energies in kJ/mol are shown, relative to 1 + B(C6F5)3.
presumably owing to high stability of generated a tertiary
carbocation as well as a strong Lewis acidity of B(C6F5)3.
Subsequently, we found that both INT2 and cyanide-inverted
INT2′ possess electrostatic interactions (C−CN = 3.07 Å for
INT2; C−NC = 2.90 Å for INT2′) but that inverted INT2′ is
more preferable (ΔΔG = 39.4 kJ/mol). It is noteworthy that the
direct C−CN bond formation in INT2 generates α-iminonitriles
palladium-catalyzed cyanoesterification of arynes are currently
underway.
Computational Methodology
All calculations in the present study were performed with the
Gaussian 09 program24 using the Becke three parameter plus
Lee−Yang−Parr (B3LYP) density functional theory (DFT)
method.25 For all geometry optimizations and normal coordinate
analyses at stationary points, we used the 6-31G(d) basis set for
all atoms.26 We also employed a larger basis set for single-point
energy calculations, 6-311+G(d) for all atoms.27,28 In the single-
point energy calculations, the polarized continuum method
(PCM),29,30 with a dielectric constant of 7.58 (THF), was also
used. Corrections for Gibbs energy were calculated from the
normal coordinate analyses of the stationary points at the
thermal state (70 °C, 1 atm).
3.19 The H NMR time-course experiments indicate that α-
1
iminonitrile 3 is formed as the intermediate during this
transformation. The activation barrier of C−N bond cleavage
from INT2′ is also moderate (∼50 kJ/mol) with a release of a
tertiary carbocation. Given that the secondary α-iminonitrile 3b
could not afford the corresponding 2-cyanobenzoate (Scheme
3), INT3′ is reasonable from the viewpoint of the stable tertiary
carbocation.23 Finally, C−N bond formation affords tBuNC, not
tBuCN, which is consistent with the experimental result, as
shown in Scheme 4. When iminoisobenzofuran 1i was treated
with 5 mol % of B(C6F5)3 at 70 °C for 8 h, 2a was formed in 28%
yield, accompanied by 1-adamantanyl isocyanide in 34% yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full characterizations for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 4. B(C6F5)3-Catalyzed Transformation of 1i to 2a
with the Formation of Isocyanide
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ynishiha@okayama-u.ac.jp.
Notes
The authors declare no competing financial interest.
In summary, we have disclosed the B(C6F5)3-catalyzed
transformation of cyano-substituted iminoisobenzofurans into
the corresponding alkyl 2-cyanobenzoates in good yields. In this
transformation, the original isocyanide moiety acts as the CN
source via the C−N bond cleavage of the tertiary imine
substituents. This novel synthetic method may open a new
window for the synthesis of alkyl 2-cyanobenzoates. Further
studies on a direct synthesis of alkyl 2-cyanobenzoates by the
ACKNOWLEDGMENTS
■
This work was partly supported by a Grant-in-Aid for Scientific
Research (KAKENHI) (No. 24550119) from JSPS and the
Program for Promoting the Enhancement of Research
Universities from MEXT and a Special Project of Okayama
University. We gratefully thank Ms. Megumi Kosaka and Mr.
Motonari Kobayashi at the Department of Instrumental Analysis,
C
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Letter
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measurements of elemental analyses and the SC-NMR
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measurements. The generous allotment of computation time
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the National Institutes of Natural Sciences, Japan, is also
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