Zn(ii) chloride-catalyzed direct coupling of various alkynes with acetals: Facile and inexpensive access to functionalized propargyl ethers

Article abstract of DOI:10.1039/c3cc46570e

The coupling of acetals with various alkynes was achieved using only 1 mol% of inexpensive and mild Lewis acid ZnCl₂, which furnished propargyl ethers. The coupling was catalyzed by Zn(OMe)Cl, which was generated in situ to form an alkynylzinc species. This protocol was allowed to expand to a one-pot subsequent reaction with allylchlorosilane to obtain a 1,4-enyne product.

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ARTICLE TYPE
Zn(II) Chloride-Catalyzed Direct Coupling of Various Alkynes with
Acetals: Facile and Inexpensive Access to Functionalized Propargyl
Ethers
a
a*
a*
Itaru Suzuki, Makoto Yasuda, Akio Baba
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The coupling of acetals with various alkynes was attained using
only 1 mol% of inexpensive and mild Lewis acid ZnCl , which
Fortunately, direct coupling could be promoted by using only a
catalytic amount of inexpensive ZnBr or ZnCl to furnish
propargyl ethers, and it was a surprise that a weak Lewis acid
such as ZnCl worked with no additives.
An investigation into the reaction conditions was
commenced. Benzaldehyde dimethyl acetal (1a) did not react
with 1-decyne (2a) without a catalyst under toluene refluxing
2
2
2
furnished propargyl ethers. The coupling was catalyzed by
Zn(OMe)Cl, which was generated in situ to form an alkynyl
zinc species. This protocol was allowed to expand to a one-pot
subsequent reaction with allylchlorosilane to obtain a 1,4-
enyne product.
1
0
2
45
conditions (Table 1, entry 1). The addition of 10 mol% of ZnBr
provided the coupling product 3aa in an 81% yield (entry 2). A
higher yield was realized when ZnCl was utilized (entry 3).
The reaction was completed in 12 h using only 1 mol% loading
of ZnCl /Et O, furnishing 3aa quantitatively (entry 4). ZnI and
Zn(OTf) gave moderate yields, while Zn(OAc) showed no
effect (entries 5-7). Employment of mild Lewis acids like InCl
CuCl , and BiCl gave moderate yields (entries 8-10). In
contrast, strong Lewis acids such as AlCl , TiCl , BF ·OEt, or
SnCl did not promote the reaction at all (entries 11-14). The
2
1
Alkynylation is a fundamental and valuable method for the
2
1
5
preparation of bioactive compounds and charge transport
materials. The employment of alkynyl metal agents such as
5
5
6
0
5
0
2
3
4
5
6
7
alkynyllithiums, -silanes, -stannanes, and -boranes make for
versatile methods, but these cannot avoid the annoying
preparation of, and the incompatibility that results from,
various functional groups. To overcome these issues, the direct
use of terminal alkynes has been the focus from an
2
2
2
2
2
3
,
2
0
2
3
3
4
3
8
environmental point of view.
4
Our group has reported the direct synthesis of
alkynylstannanes from various terminal alkynes and
combined Lewis acid, which was reported as an effective
catalyst for the coupling using alkynylsilanes,13 gave no
product (entry 15).
2
5
Bu
3
SnOMe as catalyzed by ZnBr
2
, in which Zn(OMe)Br is
generated by transmetalation between Bu
3
SnOMe and ZnBr
and plays a key role in producing an active alkynylzinc species
in situ (Scheme 1a).9 We expected the reaction between
2
a
Table 1. Screening of Catalysts
2
dimethyl acetals and ZnBr to generate oxonium cations along
3
0
with Zn(OMe)Br,10 which may be an alternative formation of
Zn(OMe)Br. This idea prompted us to develop the reaction
between terminal alkynes and acetals in the presence of ZnBr
wherein the generated alkynyl zinc from Zn(OMe)Br was
expected to promote the coupling (Scheme
2
3
5
Scheme 1. Comparison of Previous Work with This Work
1
b). Some examples of coupling between acetals and alkynes
a
Reaction conditions: 1a (2.0 mmol), 2a (1.0 mmol), and a catalyst (0.10
have been recently reported, but these generated a cation of
metals like Au for the acivation of alkynes or more than one
equimolar amoumt of base for alkynyl metal generation.12
b 1
+
11
mmol) were refluxed in toluene (1 mL) for 24 h. H NMR yield. The
c
6
5
value in parenthesis indicates an isolated yield. Catalyst (0.01 mmol),
2 h.
4
0
1
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The optimized reaction conditions (Table 1, entry 4) were 40 importance of removing the produced alcohol from the reaction
media, because the alcohol would hamper the interaction
between an acetal and ZnCl
applicable to the series of terminal alkynes listed in Table 2.
Aryl alkynes 2b-d also afforded the corresponding adducts
2
.
3
ab-3ad, but the electron-rich alkyne 2d was not as effective
owing to a low pK of the terminal proton. Ester and silicon
moieties did not disturb the reaction (entries 4 and 5). Alkynes
g and 2h bearing active propargyl positions were also
5
0
5
a
2
effectively coupled with an acetal (entries 6 and 7). Chloro and
cyano groups were intact after the reaction (entries 8 and 9).
Cyclohexylacetylene (2k) gave the desired product 3ak in a
high yield. It is noteworthy that a variety of alkynes, including
functionalized alkyls, were applicable in contrast with previous
Scheme 2. Disturbing Effect of an Alcohol By-Product
1
a
4
5
Table 3. Scope of Acetals
1
1,12
methods that were limited to aromatic alkynes.
The
mildness of our method could be the reason for the wide
application.
1
a
Table 2. Coupling with Various Terminal Alkynes
OMe
OMe
ZnCl2/Et2O (1 mol%)
+
RFG toluene, reflux, 12 h
Ph
Ph
OMe
1a
2
3
RFG
entry
alkyne
R =
product
yield (%)b
1c
2d
3
93(86)
69(43)
99(98)
H
2b
3ab
3ac
3ad
Me 2c
Br
2d
2e
R
4c
91(80)
3ae
OMe
O
5c
6
2f
3af
97(86)
94(94)
SiEt3
Ph
2g
3ag
7c
8
2h
2i
3ah
3ai
3aj
99(77)
99(78)
99(82)
O
Ph
Cl
9c
2j
CN
a
Reaction Conditions: 1 (2.0 mmol), 2a (1.0 mmol), and catalyst (0.01
1
0
2k
3ak
91(81)
b 1
mmol) were refluxed in toluene (1 mL) for 12 h. H NMR yield. Values
in parentheses indicate isolated yields. Catalyst (0.05 mmol). Catalyst
(0.03 mmol).
c
d
5
0
a
Reaction conditions: 1a (2.0 mmol), alkyne (1.0 mmol), and a catalyst
To confirm the incorporation of an alkynylzinc species,
which was proposed in our previous report, the alkynylzinc
prepared by alkynylbromide 4 and zinc metal was treated with
acetal 1a.14 To our delight, the desired coupling product was
obtained in a 59% yield (Scheme 3). This result strongly
indicates that the reaction contained an alkynyzinc species.
b 1
(
0.01 mmol) were refluxed in toluene (1 mL) for 12 h. H NMR yield.
9
c
2
0
The values in parentheses indicate isolated yields. Catalyst (0.03 mmol).
d
Catalyst (0.05 mmol).
Next, the effect of acetals was investigated (Table 3). Diethyl
acetal 1b gave a high yield by increasing the amount of catalyst
to 0.05 mmol (entry 1). However, no reaction took place when
using dihexyl acetal 1c even with a 5 mol% loading of catalyst
5
5
2
3
3
5
0
5
(
entry 2). An electron-withdrawing group on an aromatic ring
in an acetal decreased the yield of 3 plausibly due to an
unstabilization of the oxonium cation intermediate (entry 5).
Isochroman derivative 1g gave an excellent yield (entry 6). An
alkynylation of cynnamyl aldehyde dimethyl acetal (1h) was
also attained (entry 7) to give the mixture of regioisomers 3ha,
which also suggested the reaction proceeded via an oxonium
cation species. Unfortunately, no product was obtained from
aliphatic actal 1i (entry 8).
To explain the results in entries 1 and 2 and in Table 3, the
effect of an alcohol that was generated in situ, plausibly as a
by-product, was investigated. No reaction proceeded in a sealed
vessel (Scheme 2). Moreover, the addition of 0.1 mL of
methanol decreased the yield to 29%. These results indicate the
Scheme 3. Reaction of Alkynylzinc 5 with Acetal 1a
We investigated whether this protocol would allow the
alkynylation of aldehydes, because the catalytic alkynylation of
aldehydes with terminal alkynes has been reported.15 The fact
that there was no reaction of alkyne 2c with benzaldehyde (6)
(Scheme 4) implies that the active species, Zn(OMe)Cl,
generated from dimethyl acetals is essential for the catalytic
6
0
2
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coupling reaction.
product, propargy ether, was funcionallized without isolation,
which shows that this reaction is clean enough to effectively
undergo further transformation.
3
5
This work was supported by the Ministry of Education,
Culture, Sports, Science and Technology (Japan) and the Shorai
Foundation for Science and Technology.
Scheme 4. Reaction of Aldehyde 6 with Alkyne 2c
A plausible reaction mechanism is shown in Scheme 5.
ZnCl acivates the acetal to give zinc species 7, which interacts
Notes and references
5
0
5
2
a
Department of Applied Chemistry, Graduate School of Engineering,
with an alkyne and leads to the formation of alkynylzinc 8. The
alkynylzinc 8 reacts with acetal 1 via an oxonium cation and
zincate complex to afford the desired product 3 along with the
regeneration of 7. The kinetic study of the coupling was carried
out by GC (See Supporting Information) and showed that the
reaction was dependent on the first order of each component (v
4
4
5
5
6
6
7
7
8
8
9
0
5
0
5
0
5
0
5
0
5
0
Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
E-mail: yasuda@chem.eng.osaka-u.ac.jp; Fax: +81-6-6879-7387;
Tel: +81-6-6879-7386
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
1
‡
Footnotes should appear here. These might include comments relevant
-
2
-2 2 -1
=
k[1a][2a][catalyst], k; 4.06 x 10 mol L s , T = 130 °C). The
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
result and implication of containing an alkynylzinc as shown in
Scheme 3 might indicate that the interaction between an acetal
and alkynylzinc 8 is a rate-limiting step.
1
For recent reviews of alkynylation of carbonyl compounds, see; (a) S.
Guillarme, K. Plé, A. Banchet, A. Liard, A. Haudrechy, Chem. Rev.,
1
2
3
006, 106, 2355. (b) B. M. Trast, A. H. Weiss, Adv. Synth. Catal., 2009,
51, 963. For a transition metal catalyzed cross coupling, see; (c) K,
Sonogashira, J. Organomet. Chem., 2002, 653, 46. (d) E.-i. Negishi, L.
Anastasia, Chem. Rev., 2003, 103, 1979. (e) H. Doucet, J.-C. Hierso,
Angew. Chem. Int. Ed., 2007, 46, 834. For a review of electrophilic
alkynylation, see; (f) J. P. Brand, J. Waser, Chem. Soc. Rev., 2012, 41,
4
165.
2
3
(a) K. C. Nicolau, W.-M. Dai, Angew. Chem., 1991, 103, 1453; Angew.
Chem. Int. Ed., 1991, 30, 1387. (b) M. E. Maier, Synlett, 1995, 13. (c)
A. L. K. Shi Shu, R. R. Tykwinski, Angew. Chem. Int. Ed., 2006, 45,
1
034. (d) R. E. Minto, B. J. Blacklock, Prog. Lipid. Res., 2008, 47, 233.
(e) B. W. Gung, C. R. Chimie, 2009, 12, 489.
(a) A. Harriman, R. Ziessel, Chem. Commun., 1996, 1707. (b) N. J.
Long, C. K. Williams, Angew. Chem. Int. Ed., 2003, 42, 2586. (c) K.
A. Green, M. P. Cifuentes, M. Samoc, M. G. Humphrey, Cood. Chem.
Rev., 2011, 255, 2530. (d) K. A. Green, M. P. Cifuentes, M. Samoc,
M. G. Humphrey, Cood. Chem. Rev., 2011, 255, 2025. (e) G. Bottari,
D. D. Díaz, T. Torres, J. Porphyrins Phthalocyanines, 2006, 10, 1083.
(f) F. Silvestri, A. Marrocchi, Int. J. Mol. Sci., 2010, 11, 1471.
4
5
6
G. Wu, M. Huang, Chem. Rev., 2006, 106, 2596.
Scheme 5. Plausible Reaction Mechanism
S. E. Denmark, M. H. Ober, Aldrichimica Acta, 2003, 36, 75.
S. Pascual, A. M. Echavarren, In Tin Chemistry; A. G. Davies, Ed.;
John Wiley & Sons Ltd.: Chichester, 2008; pp 579-606.
J. Jiao, Y. Nishihara, J. Organomet. Chem., 2012, 721-722, 3.
(a) N. K. Anand, E. M. Carreira, J. Am. Chem. Soc., 2001, 123, 9687.
The produced propargyl ether 3aa was found to subsequently
react with allylchlorosilane 10 in a one-pot treatment, where
the allylation was completed in 30 min at room tempelature,
yielding 1,5-enyne 11 (Scheme 6). The isolated 3aa did not
7
8
2
0
(b) R. Takita, Y. Fukuta, R. Tsuji, T. Ohshima, M. Shibasaki, Org.
Lett., 2005, 7, 1363. (c) R. Takita, K. Yakura, T. Ohshima, M.
Shibasaki, J. Am. Chem. Soc., 2005, 127, 13760.
K. Kiyokawa, N. Tachikake, M. Yasuda, A. Baba, Angew. Chem. Int.
Ed., 2011, 50, 10393.
ZnBr catalyzed reaction of acetals with acetyl chloride was reported.
2
See: M. A. Berliner, K. Belecki, J. Org. Chem., 2005, 70, 9618.
(a) C. Li, F. Mo, W. Li, J. Wang, Tetrahedron Lett., 2009, 50, 6053.
react with 10 in the absence of ZnCl
2
, which apparently
9
1
1
suggested the catalyst role of ZnCl
OMe moiety to allyl one.
2
in the substitution of the
2
5
0
1
(b) M. Zhang, Y. Wang, Y. Yang, X. Hu, Adv. Synth. Catal., 2012, 354,
981.
1
1
2
3
P. Maity, H. D. Srinivas, M. P. Watson, J. Am. Chem. Soc. 2011, 133,
1
7142.
M. Hayashi, A. Inubushi, T. Mukaiyama, Bull. Chem. Soc. Jpn., 1988,
1, 4037.
14 G. M. R. Tombo, E. Didier, B. Loubinoux, Synlett, 1990, 547.
6
1
5
(a) J.-i. Ito, R. Asai, H. Nishiyama, Org. Lett., 2010, 12, 3862. (a) P.
K. Dhondi, J. D. Chisholm, Org. Lett., 2006, 8, 67. (b) Y. Asano, K.
Hara, H. Ito, M. Sawamura, Org. Lett., 2007, 9, 3901. (c) T. Ishikawa,
T. Mizuta, K. Hagiwara, T. Aikawa, T. Kudo, S. Saito, J. Org. Chem.,
2001, 68, 3702. (e) M. Yamashita, K.-i. Yamada, K. Tomioka, Adv.
Synth. Catal., 2005, 347, 1649. (f) T. Weil, P. R. Schreiner, Eur. J. Org.
Chem., 2005, 2213. Also see; ref 8.
Scheme 5. One-pot Allylation of the Product 3aa
In conclusion, we developed an alkynylation of acetals with
various alkynes including alkyls that can be catalyzed by
95
3
0
2
inexpensive ZnCl . This reaction needs no expensive metal
catalyst, such as gold, nor does it need additives. The
1
1
12
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