Gallium trihalide catalyzed sequential addition of two different carbon nucleophiles to esters by using silyl cyanide and ketene silyl acetals

Article abstract of DOI:10.1002/chem.201403734

A sequential addition of silyl cyanide and ketene silyl acetals to esters was achieved by a gallium trihalide catalyst to produce β-cyano-β- siloxy esters. This is the first example of the sequential addition of two different carbon nucleophiles to esters. The employment of lactones provided α,α-disubstituted cyclic ethers with a cyano group and an ester moiety. A variety of esters and lactones are applicable to this reaction system.

Full text of DOI:10.1002/chem.201403734

DOI: 10.1002/chem.201403734
Communication
&
Synthetic Methods
Gallium Trihalide Catalyzed Sequential Addition of Two Different
Carbon Nucleophiles to Esters by Using Silyl Cyanide and Ketene
Silyl Acetals
Yoshihiro Inamoto, Yuta Kaga, Yoshihiro Nishimoto, Makoto Yasuda,* and Akio Baba*[a]
cyanide 2 and dimethylketene methyl trimethylsilyl acetal 3a
Abstract: A sequential addition of silyl cyanide and
ketene silyl acetals to esters was achieved by a gallium tri-
halide catalyst to produce b-cyano-b-siloxy esters. This is
the first example of the sequential addition of two differ-
ent carbon nucleophiles to esters. The employment of lac-
tones provided a,a-disubstituted cyclic ethers with
a cyano group and an ester moiety. A variety of esters and
lactones are applicable to this reaction system.
(Table 1). As to indium(III) trihalides, even the use of InI3, which
showed efficient transformation in the reductive functionaliza-
tion of esters, gave a low yield of b-cyano-b-siloxy ester 4aa
(Table 1, entries 1–3). A variety of Lewis acid catalysts such as
BF3·OEt2, AlCl3, TiCl4, FeBr3, CuBr2, and ZnBr2 were also found to
be ineffective (Table 1, entries 4–9). To our delight, the applica-
tion of GaBr3 and GaI3 successfully gave 4aa in high yields
along with a small amount of b-keto ester 5aa, in which the
successive reaction of 1a with 2 and 3a proceeded via single-
stage treatment (Table 1, entries 11 and 12).[7] It is noteworthy
that a double addition of the same nucleophiles would not
proceed—neither 2 nor 3a to 1a. The employment of either
Ga(OTf)3 or GaCl3 resulted in the recovery of 1a (Table 1, en-
tries 10 and 13). The solvent-free conditions led to an excellent
yield of 4aa (Table 1, entry 14).[8] Finally, the treatment in
entry 15 using GaI3 was determined to be the best conditions.
To discuss the reaction path, we investigated the reactions
between ester 1a with either silyl cyanide 2 or ketene silyl
The addition of nucleophiles to carbonyl compounds is one of
the most important tools in organic chemistry.[1] In this con-
text, esters have a potential advantage because they can re-
ceive two nucleophiles to produce multi-functionalized alco-
hols, while ketones or aldehydes can receive only one carbon
nucleophile. However, the introduction of two different carbon
nucleophiles into esters is difficult, because the intermediate
produced by the first addition is more reactive than the start-
ing ester to give undesired products that possess the same
substituents (Scheme 1). Therefore, a multi-step process is gen-
erally required for such a transformation.[2] In this regard, the
sequential addition of two different carbon nucleophiles to
esters via a single-stage treatment has been rare, though a hy-
dride and carbon nucleophiles have been introduced by using
DIBALH,[3] LiBH4,[4] and hydrosilane.[5] Herein, we report the gal-
lium trihalide-catalyzed sequential addition of two different
carbon nucleophiles to esters using ketene silyl acetals and
silyl cyanide.
Scheme 1. Double nucleophilic addition to esters.
We recently reported that the indium(III)-catalyzed reductive
functionalization of esters, amides, and carboxylic acids has
been achieved via the single-stage treatment of hydrosilanes
and organosilicon nucleophiles such as ketene silyl acetals and
silyl cyanide.[5,6] On the basis of these previous studies, we ex-
amined the successive introduction of two different carbon nu-
cleophiles into methyl benzoate 1a by employing trimethylsilyl
acetal 3a. No cyanation took place, perhaps because of its low
nucleophilicity, and 1a was recovered [Eq. (1)]. On the other
hand, the reaction of ester 1a with ketene silyl acetal 3a gave
b-keto ester 5aa in 94% yield [Eq. (2)]. This is the first case of
a Lewis acid catalyzed cross-Claisen condensation between an
ester and a ketene silyl acetal, which is an important factor in
the present reaction.[9] It is noteworthy that no further reaction
of the obtained 5aa with 3a was observed even though an
excess amount of 3a was used. The use of InI3 in the same re-
action resulted in low yields.[10] A Lewis acidity of GaX3 that is
higher than that of InX3 effectively accelerated the cross-Clais-
en condensation. b-Keto ester 5aa reacted with silyl cyanide 2
in the presence of GaI3 catalyst to produce the corresponding
product 4aa quantitatively [Eq. (3)]. In the absence of GaI3, nei-
ther the reaction of Equation (2) nor that of Equation (3) pro-
ceeded.
[a] Dr. Y. Inamoto, Y. Kaga, Dr. Y. Nishimoto, Prof. Dr. M. Yasuda,
Prof. Dr. A. Baba
Department of Applied Chemistry
Graduate School of Engineering, Osaka University
2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)
E-mail: yasuda@chem.eng.osaka-u.ac.jp
baba@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403734.
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The scope and limitations of ester 1 and ketene silyl acetal 3
are shown in Table 2. Aromatic esters 1b and 1c bearing an
electron-donating group gave high yields of 4ba and 4ca, re-
spectively, whereas an electron-withdrawing group slightly de-
creased the yield of desired product 4da (Table 2, entries 1–3).
Ethyl ester 1e was also applicable to afford product 4eb in
65% yield along with a small amount of ethyl ether product
(Table 2, entry 4).[11] Disubstituted ketene silyl acetal 3c also
gave product 4ac in 80% yield (Table 2, entry 5). When mono-
substituted ketene silyl acetal 3d was used, 12% yield of 7ad
accepting two equivalents of 3d was detected along with
66% yield of the desired product 4ad (Table 2, entry 6). The
generation of 7ad could be explained by the low steric hin-
drance of b-keto ester intermediate 5ad produced by the reac-
tion of 1a with 3d.[12] Aliphatic ester 1 f and methyl acetate
1g were also applicable to this reaction system to provide 4 fa
and 4ga in moderate to good yields (Table 2, entries 7 and 8).
Moreover, methyl fluoroacetate 1h produced fluorinated
product 4ha in 82% yield (Table 2, entry 9). Methyl cyclohexa-
necarboxylate 1i barely gave product 4ia because of its steric
hindrance (Table 2, entry 10). Fortunately, the sequential addi-
tion reaction of formic acid ester 1j smoothly proceeded to
afford the corresponding product 4ja in high yield despite the
very low steric hindrance of 1j (Table 2, entry 11). It is noted
that b-cyano-b-siloxy ester 4ja could not be synthesized by
a stepwise approach selectively.[13] Industrial material was also
applied to this system. For example, dimethyl terephthalate 1k
afforded the corresponding product 4ka [Eq. (4)].
Table 1. Screening of catalysts.[a]
Entry
Catalyst
Yield of 4aa [%][b]
Yield of 5aa [%][b]
1
InCl3
0
0
8
9
5
0
2
0
0
0
1
1
1
0
3
2
2
InBr3
6
3
InI3
15
4
5
BF3·OEt2
AlCl3
2
0
6
TiCl4
0
7
8
9
10
11
12
13
14[c]
15[c]
FeBr3
CuBr2
ZnBr2
GaCl3
GaBr3
GaI3
Ga(OTf)3
GaBr3
GaI3
0
0
0
2
85
69
0
92
95 (94)[d]
[a] 1a (1 equiv), 2 (2 equiv), 3a (2 equiv), catalyst (20 mol%), CH2Cl2 (1m),
rt, 0.5 mmol scale. [b] GC yield. [c] No solvent was used. [d] Isolated yield.
Next, we applied lactones to this reaction system (Table 3).
Mukaiyama et al. previously reported the catalytic reaction of
lactones with a ketene silyl acetal and other organosilicon nu-
A proposed reaction mechanism that is based on
the results of Equations (1)–(3) is illustrated in
Scheme 2. First, the carbonyl group of the ester coor-
dinates to GaI3 to increase its positive charge. The
nucleophilic addition of ketene silyl acetal 3 to ester
1 predominantly takes place to afford acetal inter-
mediate 8. An alkoxy (R2O) group of acetal 8 selec-
tively coordinates to GaI3, affording Me3SiOR2 and b-
keto ester intermediate 5. Next, GaI3 accelerates the
nucleophilic addition of Me3SiCN 2 to b-keto ester 5,
giving product 4 selectively. In the first addition reac-
tion, ketene silyl acetal 3 exclusively reacts with
esters due to the high nucleophilicity. And, in the
second addition reaction, b-keto ester 5 does not
react with 3 because of the steric repulsion between
the substituents of 5 and 3. Therefore, the addition
of 2 to 5 takes place selectively.
Scheme 2. Proposed reaction mechanism for esters.
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Communication
Table 2. Scope and limitation of esters and ketene silyl acetals.[a]
Table 3. Scope and limitation of esters and ketene silyl acetals.[a]
Ent. Ester 1
3
Time (h)
4
Yield [%][b]
1
2
3
R=Me; 1b
R=OMe; 1c 3a
R=Cl; 1d
3a
5
5
4ba 97
4ca 93
4da 73
3a 12
4[c]
5
6[d]
R2 =Et; 1e
3b
9
4eb 65
4ac 80
4ad 66[e]
R2 =Me; 1a 3c 12
R2 =Me; 1a 3d
5
7
1 f
3a 12
4 fa 76
4ga 53
4ha 82
8[f]
9[f]
1g
1h
3a
3a
5
5
[a] 9 (1 equiv), 2 (1.5 equiv), 3 (1.5 equiv), GaBr3 (5 mol%), CH2Cl2 (1m), RT, 2-
12 h. Isolated yield. [b] GaBr3 (20 mol%), 608C. [c] Cyclic ether 10ja was ob-
tained in 8% yield. [d] 1:1 d.r. was determined by H NMR spectroscopy.
10
1i
1j
3a 24
4ia
5
1
11[g]
3a
2
4ja 90
10ae in 61% yield. Monosubstituted ketene silyl acetal 3d was
also applicable to this reaction system to afford cyclic ether
10ed. An unsubstituted ketene silyl acetal gave no product,
because it is unstable and tends to decompose under these re-
action conditions.
[a] 1 (1 equiv),
2 (2 equiv), 3a (2 equiv), GaI3 (20 mol%), neat, RT,
0.5 mmol scale. [b] Isolated yield. [c] GaBr3 (20 mol%). [d] 2 (3 equiv).
[e] 1:1 d.r. was determined by 1H NMR spectroscopy. [f] CH2Cl2 (2m),
2 mmol scale. [g] 2 (1.5 equiv), 3a (1.5 equiv), GaI3 (5 mol%), CH2Cl2 (1m).
Reaction was carried out from 08C to RT. 2 mmol scale.
The reaction mechanism of lactone 9 with silyl cyanide 2
and ketene silyl acetal 3 is illustrated in Scheme 3. First, GaBr3
accelerates the reaction of 3 with 9 to give cyclic acetal 13.
Next, a siloxy group in advance of the alkoxy group is eliminat-
ed by GaBr3 due to the entropy gain, affording oxocarbenium
ion 14. Then, the nucleophilic attack of silyl cyanide 2 to 14
produces cyclic ether 10. An electron-withdrawing group of
phthalide derivatives destabilizes oxocarbenium ion 14 to de-
crease the yield of 10 (Table 3). The use of g-butyrolactone 9j
gave acyclic product 12ja because the corresponding acetal
intermediate 13ja has a large ring strain (Table 3).[17]
cleophiles to provide a,a-disubstituted cyclic ethers.[14] In the
reported reaction, however, only one type of unsubstituted
ketene silyl acetal was utilized, and temperature-controlled
conditions were required. The reaction among phthalide 9a,
silyl cyanide 2, and ketene silyl acetal 3a in the presence of
5 mol% of GaBr3 provided a,a-disubstituted cyclic ether 10aa
in 95% yield, in which bulky disubstituted ketene silyl acetal
was applicable in contrast to Mukaiyama’s system.[15] The use
of phthalide derivatives 9b–d also gave the corresponding
products 10ba–10da, respectively, although 9c and 9d had
an electron-withdrawing group and required a longer reaction
time. It was noteworthy that the chemoselective transforma-
tion of the lactone moiety of 9d took place prior to the con-
version of an intramolecular aromatic ester group.[16] Six-mem-
bered cyclic aromatic lactones were converted to 10ea and
10 fa, respectively. Benzocoumarin also gave product 10ga in
73% yield under heating conditions. The use of d-valero- and
e-caprolactones afforded cyclic ethers 10ha and 10ia, respec-
tively. On the other hand, when the reaction of g-butyrolac-
tone was carried out, acyclic product 12ja was predominantly
obtained. Dialkylketene silyl acetals 3e produced product
Scheme 3. Ring-maintained and ring-opening mechanism for cyclic acetals.
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Ishihara, A. Takahashi, H. Hayashi, H. Yamanaka, T. Kubota, Tetrahedron
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[5] We reported reductive functionalization of esters by indium-silicon
system, please see the following: a) Y. Nishimoto, Y. Inamoto, T. Saito,
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[6] We reported reductive functionalization of amides and carboxylic acids,
please see following: a) Y. Inamoto, Y. Kaga, Y. Nishimoto, M. Yasuda, A.
Baba, Org. Lett. 2013, 15, 3452–3455; b) Y. Inamoto, Y. Nishimoto, M.
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The preparation of a spirocyclic compound, which is a useful
building block in biological chemistry,[18] from a cyclic ether
was carried out (Scheme 4). The selective reduction of a cyano
group in 10aa by the combination of a Raney nickel and KBH4
gave spiro oxacyclic g-lactam 16 in 71% yield.[19,20]
[7] For review, see the following: a) M. K. Gupta, T. P. O’Sullivan, RSC Adv.
2013, 3, 25498–25522; b) M. Yamaguchi, Y. Nishimura, Chem. Commun.
2008, 35–48.
Scheme 4. Synthesis of spiro oxacyclic g-lactam 16.
[8] See the Supporting Information for the further optimization of the reac-
tion conditions.
[9] To the best of our knowledge, Lewis acid-catalyzed cross-Claisen con-
densations between simple esters and ketene silyl acetals were not de-
veloped so far. The reactions of esters or lactones with ketene silyl ace-
tals in the presence of catalytic amount of acid were reported, but
these reactions did not give cross-Claisen condensation product. See
the following: a) M. Onaka, T. Mimura, R. Ohno, Y. Izumi, Tetrahedron
Lett. 1989, 30, 6341–6344; b) S. Iwata, T. Hamura, T. Matsumoto, K.
Suzuki, Chem. Lett. 2007, 36, 538–539; For the reaction of lactone with
ketene silyl acetal, see the following: c) K. Homma, T. Mukaiyama, Chem.
Lett. 1990, 19, 161–164; d) R. Csuk, M. Shaade, Tetrahedron Lett. 1993,
34, 7907–7910; e) H. Yanai, T. Taguchi, Chem. Commun. 2012, 48, 8967–
8969; f) H. Yanai, N. Ishii, T. Matsumoto, T. Taguchi, Asian J. Org. Chem.
2013, 2, 989–996; We developed a Lewis acid-catalyzed cross-Claisen
condensation from carboxylic acid, see: g) Y. Nishimoto, A. Okita, M.
Yasuda, A. Baba, Angew. Chem. 2011, 123, 8782–8784; Angew. Chem.
Int. Ed. 2011, 50, 8623–8625.
In summary, we have accomplished a gallium trihalide-cata-
lyzed sequential addition of two different carbon nucleophiles
to esters using silyl cyanide and ketene silyl acetals. The reac-
tion of methyl esters predominantly gave b-cyano-b-siloxy
esters. Aromatic, aliphatic, and formic acid esters gave the cor-
responding products. The transformation of lactones produced
a,a-disubstituted cyclic ethers containing a cyano group and
an ester moiety. The functional group transformation of the
obtained cyclic ether gave spiro oxacyclic g-lactam. Further ex-
pansion of this system is now ongoing.
Experimental Section
[10] Indium triiodide catalyzed cross-Claisen condensation between ester
1a and ketene silyl acetal gave b-keto ester 5aa in 41%.
[11] Following compound 6eb was ob-
served in 6% yield.
[12] Illustrated compound 7ad was de-
Typical procedure (Table 2): Ketene silyl acetal (1 mmol) was
added to a suspension of catalyst (0.1 mmol), ester (0.5 mmol), and
trimethylsilyl cyanide (1 mmol). The mixture was stirred at room
temperature for 5 h. And then, the resulting mixture was quenched
by aqueous NaOH solution. The mixture was extracted with Et2O
(3ꢁ10 mL). The collected organic layer was dried (MgSO4). The sol-
vent was evaporated and the residue was purified by column chro-
matography to give the product.
tected in 12% yield by monosubstiut-
ed ketene silyl acetal 3d, which was
afforded by the reaction of ester 1a
with two equivalent of 3d. And, inter-
mediate 5ad was represented below.
[13] In the reaction of formic acid ester 1j with ketene silyl acetal 3a, the
product, which was afforded by the addition of two equivalent of 3a
to 1j, was obtained mainly.
Acknowledgements
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology (Japan). Y.I. thanks the JSPS Re-
search Fellowships for Young Scientists. SANUKI CHEMICAL IN-
DUSTRY co., LTD. provided trimethylsilyl cyanide.
Keywords: esters · gallium · lactones · silicon · synthetic
methods
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[16] Aromatic ester group of 9d was converted in 7% yield.
[17] Please see the Supporting Information for investigation of reaction
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Received: May 29, 2014
Published online on August 5, 2014
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