Entry to β-alkoxyacrylates via gold-catalyzed intermolecular coupling of alkynoates and allylic ethers

Article abstract of DOI:10.1021/ol4001087

The first gold-catalyzed intermolecular coupling of alkynoates and allylic ethers invoking alkoxy addition and [3,3]-sigmatropic rearrangement as the key mechanism has been developed. Remarkably, the reaction showed complete chemoselectivity toward the pathway initiated by the alkoxy addition to alkynes. This unprecedented reactivity led to a new access to diversely substituted β-alkoxyacrylates in a highly efficient manner.

Full text of DOI:10.1021/ol4001087

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1166–1169
Entry to β‑Alkoxyacrylates via
Gold-Catalyzed Intermolecular Coupling
of Alkynoates and Allylic Ethers
Sae Rom Park,† Cheoljae Kim,† Dong-gil Kim,† Neetipalli Thrimurtulu,†
Hyun-Suk Yeom,‡ Jungho Jun,‡ Seunghoon Shin,*,‡ and Young Ho Rhee*,†
Department of Chemistry, Pohang University of Science and Technology, Hyoja-dong
San 31, Pohang, Kyungbuk 790-784, Republic of Korea, and Department of Chemistry
and Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea
sshin@hanyang.ac.kr; yhrhee@postech.ac.kr
Received November 14, 2012
ABSTRACT
The first gold-catalyzed intermolecular coupling of alkynoates and allylic ethers invoking alkoxy addition and [3,3]-sigmatropic rearrangement as
the key mechanism has been developed. Remarkably, the reaction showed complete chemoselectivity toward the pathway initiated by the alkoxy
addition to alkynes. This unprecedented reactivity led to a new access to diversely substituted β-alkoxyacrylates in a highly efficient manner.
Over the past decades, the use of metal catalysts for
alkyne activation attracted much attention in organic
chemistry.1 In particular, intramolecular alkoxy addition
with the concomitant alkyl shift (formal intramolecular
carboalkoxylation) led to the development of novel cata-
lytic syntheses of various furan heterocycles and carbo-
cycles with excellent chemical efficiency.2 Despite the
notable advances in this area, the more challenging
intermolecular version of this reaction remains underde-
veloped. Recently, a number of Au-catalyzed tandem
processes have been reported which combine the intramole-
cular alkoxy addition with the concomitant allyl shift.3 A key
feature of this transformation is the efficient charge-induced
[3,3]-sigmatropic rearrangement of the oxonium-ion inter-
mediate. We envisioned that the intermolecular variant of
† Pohang University of Science and Technology.
‡ Hanyang University.
(1) For selected reviews of transition-metal-catalyzed reactions of
alkyne, see: (a) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41,
2448. (b) Corma, A.; Leyva-Perez, A.; Sabataer, M. J. Chem. Rev. 2011,
111, 1657. (c) Sohel, S.; Md, A.; Liu, R. Chem. Soc. Rev. 2009, 38, 2269.
€
(d) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208. (e) Michelet, V.;
^
Toullec, P. Y.; Genet, J. Angew. Chem., Int. Ed. 2008, 47, 4268. (f) Li,
Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (g) Arcadi, A. Chem.
ꢀ
ꢀ~
Rev. 2008, 108, 3266. (h) Jimenez-Nunez, E.; Echavarren, A. M. Chem.
Rev. 2008, 108, 3326. (i) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
Rev. 2008, 108, 3351. (j) Gorin, D. J.; Toste, F. D. Nature 2007, 446. (k)
€
Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (l)
Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(3) For selected examples on the intramolecular alkoxy additionꢀ
[3.3]-sigmatropic rearrangement, see: (a) Istrate, F. M.; Gagosz, F. Beilstein
J. Org. Chem 2011, 7, 878. (b) Cheong, J. Y.; Im, D.; Lee, M.; Lim, W.;
Rhee, Y. H. J. Org. Chem. 2011, 76, 324. (c) Bae, H. J.; Baskar, B.; An, S. E.;
Cheong, J. Y.; Thangadurai, D. T.; Hwang, I.-C.; Rhee, Y. H. Angew.
Chem., Int. Ed. 2008, 47, 2263. (d) Baskar, B.; Bae, H. J.; An, S. E.; Cheong,
J. Y.; Rhee, Y. H.; Duschek, A.; Kirsch, S. F. Org. Lett. 2008, 10, 2605. (e)
Hashmi, A. S. K.; Lothschutz, C.; Dopp, R.; Ackermann, M.; Becker,
J. D. B.; Rudolph, M.; Scholz, C.; Rominger, F. Adv. Synth. Catal. 2012,
354, 133. (f) For a related study on the pyrrole formation, see: Istrrate,
F. M.; Gagosz, F. Org. Lett. 2007, 9, 3181.
(2) For selected recent examples on the Pt- or Au-catalyzed carboalk-
oxylation, see: (a) Kim, H.; Rhee, Y. H. J. Am. Chem. Soc. 2012, 134,
4011. (b) Uemura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 3464. (c) Kim, C.; Bae, H. J.; Lee, J. H.;
Jeong, W.; Kim, H.; Sampath, V.; Rhee, Y. H. J. Am. Chem. Soc. 2009,
131, 14460. (d) Nakamura, I.; Chan, C. S.; Araki, T.; Terada, M.;
Yamamoto, Y. Adv. Synth. Catal. 2009, 351, 1089. (e) An, S. E.; Jeong,
J.; Baskar, B.; Lee, J.; Seo, J.; Rhee, Y. H. Chem.;Eur. J. 2009, 15,
€
€
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11837. (f) Dube, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12062. (g)
€
Furstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024. (h)
Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 15022. (i) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2005, 45, 4473. (j) Nakamura, I.; Bjracharya, G. B.; Wu, h.;
Oishi, K.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem.
(4) Compared to allyl ethers, the more nucleophilic allyl alcohols are
known to undergo alkoxylationꢀClaisen rearrangement under Ag(I) or
Au(I) catalysis: (a) Kataoka, Y.; Matsumoto, O.; Tani, K. Chem. Lett. 1996,
727. (b) Ketcham, J. M.; Biannic, B.; Aponick, A. Chem. Commun. 2013,
DOI: 10.1039/c2cc37166a. However, these products need derivatizing steps under
highly basic conditions to obtain the corresponding β-alkoxyacrylates.
€
Soc. 2004, 126, 15423. (k) Furstner, A.; Szillat, H.; Stelzer, F. J. Am.
Chem. Soc. 2000, 122, 6785.
r
10.1021/ol4001087
Published on Web 02/27/2013
2013 American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Basic Scheme of the Coupling Reaction of
Alkynoates and Allylic Ethers
entry 2 (equiv) cat. (mol %) solvent time (h) conv (%) 3b (%)
1
1
5
4 (10)
4 (10)
4 (10)
4 (5)
4 (5)
4 (8)
5 (8)
6 (8)
7 (8)
8 (8)
4 (8)
CH2Cl2
3
3
81
88
95
29
86
99
66
65
59
57
94
56 (70)
63 (72)
74 (78)
18 (62)
70 (82)
86 (87)
36 (55)
34 (52)
26 (44)
35 (61)
92 (98)
2
CH2Cl2
this reaction,4 i.e., coupling of the allylic ethers and alkynes,
would provide a new access to synthetically useful R-allyl-β-
alkoxyacrylates (path A, Scheme 1) with (Z)-geometry that
could not be synthesized via conventional methods.
3
10
10
10
10
10
10
10
10
10
CH2Cl2
3
4
CH2Cl2
10
10
10
10
10
10
10
10
5
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
6
7
This unprecedented reaction raises a number of challeng-
ing issues. In addition to the inherently higher entropic
barrier for the intermolecular alkoxy addition step com-
pared with the intramolecular version, the olefin moiety
can compete with the ether for the attack onto the alkyne
(path B, Scheme 1). In fact, some related intermolecular
coupling reactions of alkyne with various olefins invoking
this mechanism have recently been reported.5 Thus, a key
issue in designing the proposed catalytic cycle shown in
Scheme 1 is the chemoselectivity of the coupling event
that can drive the reaction toward the pathway mediated
by alkoxy-addition step.
We commenced our study with the coupling reaction
of easily available allylic ether 1 and various terminal
alkynes. The reaction of 1 with the unactivated 1-heptyne
or phenylacetylene in the presence of various cationic Au
complexes led to formation of intractable mixture of
compounds.6 We reasoned that the initial alkoxy addition
might be too slow when unactivated alkynes were em-
ployed. Based upon the related studies on the intermole-
cular hydroarylation ofalkynoateesters,7 wesurmisedthat
a cooperative polarization of the alkyne by an acceptor-
substituent and a gold(I)-catalyst might enhance the charge
interaction to facilitate the initial alkoxy addition step.
Indeed, commercially available ethyl propiolate 2
(1 equiv) in the presence of pregenerated cationic Au com-
plex of ligand 4 (10 mol %) showed significant conversion
for the desired tandem process, giving the β-alkoxyacrylate
product 3 in 56% yield with the recovery of the starting
material 1 in ∼20% yield (Table 1, entry 1). In this case,
formation of some side products such as the homodimer
8
9
10
11c
a Typical procedure: A mixture of substrate (0.4 M), pregenerated
gold complexes, and ethyl propiolate was stirred at ꢀ15 °C. b Isolated
yield (yields based on the recovered starting material in parentheses).
c Methyl propiolate was used instead of 2.
of 2 was observed.8 Thus, we used an excess amount of
alkynoate ester 2. Employing5eqof2gave the desired prod-
uct in 63% yield with 88% conversion (Table 1, entry 2).
Further increasing the amount of 2 (to 10 equiv) improved
the yield to 74% with 95% conversion (Table 1, entry 3).
Lowering the catalyst loading to 5 mol % slowed the
reaction significantly, generating the product in only small
yield even after prolonged reaction time (Table 1, entry 4).
Interestingly, using nitromethane as the solvent dramati-
cally improved the conversion. For example, using 5 mol %
catalyst 4 gave the product in satisfactory 70% isolated yield
with 86% conversion (Table 1, entry 5). Simply increasing
the catalyst loading to 8 mol % completed the reaction,
producing the desired product in 86% yield (Table 1, entry 6).
Varying the steric and electronic effects on the phosphine
ligands only slowed the formation of the product (Table 1,
entries 7ꢀ10). Finally, using the smaller methyl propiolate
in place of 2 slightly improved the yield (Table 1, entry 11).
Remarkably, no products derived from the alkyneꢀolefin
coupling (path B, Scheme 1) was observed, which showed
a complete chemoselectivity toward the alkoxy addition-
induced pathway (path A, Scheme 1).9 In addition, only the
less stable (Z)-isomer of the β-alkoxyacrylate was obtained
with no indication of (E)-isomer formation.10,11 It should
also be noted that the linear product 30 was not observed,
supporting a concerted [3,3]-sigmatropic rearrangement in
(5) (a) Yeom, H.-S.; Koo, J.; Park, H.-S.; Wang, Y.; Liang, Y.; Yu,
ꢀ
Z.-X.; Shin, S. J. Am. Chem. Soc. 2012, 134, 208. (b) Lopez-Carrilo, V.;
Echavarren, A. M. J. Am. Chem. Soc. 2010, 132, 9292. (c) Dateer, R. B.;
Shaibu, B. S.; Liu, R. S. Angew. Chem., Int. Ed. 2012, 51, 113. (d)
Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic, E.; Frey, W.; Bats, J. W.
Adv. Synth. Catal. 2006, 348, 709. For intermolecular three-component
coupling: (e) Melhado, A. D.; Brenzovich, W. E., Jr.; Lackner, A. D.;
Toste, F. D. J. Am. Chem. Soc. 2010, 132, 8885.
(8) (a) Chen, C.-K.; Tong, H.-C.; Hsu, C.-Y. C.; Lee, C.-Y.; Fong,
Y. H.; Chuang, Y.-S.; Lo, Y.-H.; Lin, Y.-C.; Wang, Y. Organometallics
2009, 28, 3358. (b) Werner, H.; Schwab, P.; Heinemann, A.; Steinert, P.
J. Organomet. Chem. 1995, 496, 207.
(6) In our case, internal alkynes with or without a CO2R (or SO2Ar)
group did not work.
(7) (a) Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669. (b) Haro, T.;
Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512.
(9) Presumably, the electron-withdrawing alkoxy group slows for-
mation of the intermediate III in path B (Scheme 1).
Org. Lett., Vol. 15, No. 6, 2013
1167

Using the crotonyl alkyl ether 16 uneventfully gave the
product 17 in 76% yield (Table 2, entry 5). Notably, the
reaction showed an excellent compatibility with the func-
tional groups that potentially interfere with the desired
transformation. For example, the phenyl, alkoxy, and
terminal olefin groups were well tolerated, and TBMDS
silyl ether survived the reaction condition (Table 2, entries
6ꢀ9). In addition, the reaction well tolerated base-sensitive
functional groups such as an alkyl ester and a nitrile group
(Table 2, entries 10ꢀ11). These two examples underscore
a unique feature of the current synthesis because these
β-alkoxyacrylate products cannot be easily accessed by
the conventional strongly basic conditions. As is the case
for the previous intramolecular alkoxy additionꢀsigmatropic
processes,2,3 the unsubstituted allyl ether 30 reacted much
slower than the γ-substituted allyl ethers (Table 2, entries
12ꢀ13 vs entries 1ꢀ11). Interestingly, in this case, a change
of ligand to6 in placeof 4 proved more efficient, improving
the yield to52% yield (Table2, entry 13). Also, the reaction
of an R-branched allyl ether 32 was sluggish under the
standardprotocol (Table2, entry 14). Inthiscase, asmaller
ligand 8 proved more effective producing 33 in 55% yield
(Table 2, entries 14 and 15). In all the above examples in
Table 2, the regioselectivity of the products was consistent
with a sigmatropic mechanism in the alkyl shift.
Table 2. Scope of the Reactiona
From a synthetic viewpoint, the current method repre-
sents a highly efficient and stereoselective method for the
synthesis of β-alkoxyacrylates. These types of compounds
are easily found in various bioactive natural products such
as elenolic acid,12a alkaloid mitragynine,12b oudemansin,12c
and secologanin and other derivatives.12d In addition,
β-alkoxyacrylates serve as useful radical acceptors for the
synthesis of oxacyclic natural products.13 Moreover, highly
functionalized 1,4-diene fragments with (Z)-geometry
should find additional use in synthetic organic chemistry.
The conventional multistep syntheses of the β-alkoxyacry-
lates requires reactive reagents and are usually performed
under highly basic conditions.14 As demonstrated by the
examples in Table 2, the current synthesis can be operated
under very mild conditions. Finally, generation of a stereo-
genic center in the product proposes an interesting asym-
metric synthesis of these highly useful compounds.
a Typical procedure: A mixture of substrate (0.4 M in CH3NO2),
pregenerated [Au(L)]SbF6 (8 mol %) and methyl propiolate (10 equiv)
was stirred at ꢀ15 °C. Method A: L = 4. Method B: L = 6. Method C:
L = 8. b Isolated yield (based on recovered starting material in
parentheses). c Mixture of E and Z isomers was obtained.
the allyl shift and no intervention of allyl cation. As control
experiments, we have also screened other catalysts (AgSbF6
(10 mol %), AgNTf2 (10 mol %), or HNTf2 (10 mol %)
in CH3NO2); under these conditions, no reaction was
observed.
Withthe optimized conditions in hand, we thenexplored
an array of the allylic ethers for the formation of
β-alkoxyacrylate products (Table 2). First, we explored
the steric effect of the alkoxy moiety of allyl ethers. Using
n-propryl ether 9 generated the desired product 10 in 71%
yield (Table 2, entry 1). Employing the larger isopropyl
ether 11 gave the product 12 in somewhat lower 59% yield
(Table 2, entry 2). Interestingly, an equimolar mixture of
(Z)- and (E)-isomers of the product was obtained in the
latter case. Then, we investigated the effect of the olefin
structure. As described in entries 3 and 4, the (E)-isomer of
the olefin 13 gave the product 14 in 85% yield, while the
(Z)-isomer 15 generated 14 in somewhat lower 70% yield.
To further investigate the effect of acceptor substituents
on the alkynes in the intermolecular coupling, the more
polarizing p-Ts substituted alkyne 34 was examined
(12) (a) Hatakeyama, S.; Saijo, K.; Takano, S. Tetrahedron Lett.
1985, 26, 865. (b) Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett. 2007,
9, 3491. (c) Wood, K. A.; Kau, D. A.; Wrigley, S. K.; Beneyto, R.;
Renno, D. V.; Ainsworth, A. M.; Penn, J.; Hill, D.; Killaky, J.;
Depledge, P. J. Nat. Prod. 1996, 59, 646. (d) Isoe, S.; Katsumura, S.;
Okada, T.; Yamamoto, K.; Takemoto, T.; Inaba, H.; Han, Q.; Nakatani,
K. Tetrahedron Lett. 1987, 47, 5865.
(13) For a review, see: Lee, E. Pure Appl. Chem. 1996, 68, 631. The
current synthesis of conventionally unavailable (Z)-alkoxyacrylates
might lead to new routes to oxacycles having a complementary
stereochemistry.
(14) For examples on the conventional synthesis of highly substituted
β-alkoxyacrylates, see: (a) Kondo, M.; Tsuzuki, K.; Hamada, H.;
Yamaguchi, Y.; Uchigashima, M.; Saka, M.; Watanabe, E.; Iwasa, S.;
Narita, H.; Miyake, S. J. Agri. Food. Chem. 2012, 60, 904. (b) Kuttruff,
C. A.; Geiger, S.; Cakmak, M.; Mayer, P.; Trauner, D. Org. Lett. 2012,
14, 1070. (c) Akita, H.; Matsukura, H.; Oishi, T. Tetrahedron Lett. 1986,
27, 5397.
(10) The stereochemistry of the product was confirmed by the NOE
study. Moreover, the (Z)-3 (methyl ester) was completely converted into
the thermodynamically more stable (E)-3 by treatment with TsOH
(10%) in CH2Cl2. For details, see the Supporting Information. No
product isomerization into the conjugate 1,3-diene was observed.
(11) This (Z)-stereochemistry is opposite to those observed for
related Pt-catalyzed intramolecular reactions (ref 2d and 2k). Once
trans-addition of ether oxygen to form I occurs, the following allyl
migration and deauration must be faster than CꢀC rotation of II
(Scheme 1).
1168
Org. Lett., Vol. 15, No. 6, 2013

(Scheme 2). The reaction of 34 with allylic ether 35 under
the optimized condition for propiolate esters gave the
desired 1,4-diene 36 in somewhat lower yield (53%).
However, using the allylic ether 35 in excess (3 equiv)
improved the yield to 77% with essentially complete
conversion within 0.5 h at 5 mol % of catalyst loading.
The comparable reactivity of 34 with lower amount of
catalyst and the lower substrates ratio indicated that the
stronger charge-interaction induced by p-Ts substituent is
beneficial for the formation of initial adduct I (Scheme 1)
and/or the [3,3]-sigmatropic rearrangement.
branched product. Most strikingly, 39 having R-substituted
allyl unit delivered a mixture of the [3,3]- and [1,3]-shift
product (40/400 = 1:1.6).16
Even though the reaction of propiolate ester gave no
[1,3]-migration product, the above reaction of alkynyl
sulfone 34 raises a question on the mechanism of the
reaction, particularly with regard to the concerted nature
of the allyl shift process. Thus, we performed a crossover
experiment. As shown in Scheme 3, subjection of a 1:1
mixture of the compounds 16 and 18 under the optimized
condition gave no crossover products. Even in the reaction
of R-branched allyl ether 39 and 41 with alkynyl sulfones
34, where [1,3]-migration is favored, no crossover product
was observed by GCꢀMS or crude NMR spectra. These
experimentsunambiguouslyconfirmedthe concerted[3,3]-
or [1,3]-migration of the allyl group, respectively.
Scheme 2. Reactions of Alkynyl Sulfone 34
Scheme 3. Crossover experiments
In summary, we developed a new and highly efficient
access to substituted (Z)-β-alkoxyacrylates using Au-
catalyzed intermolecular coupling of alkynoates and allylic
ethers. Of particular note is the chemoselectivity of the
reaction. Mechanistic investigation as well as synthetic
application of this catalytic reaction is in progress and will
be reported in due course.
When γ-substituted allyl ether 37 was used, the catalyst
loading could be further reduced to 2 mol % without sig-
nificant loss in the yield of the product 1,4-diene. Interest-
ingly, formation of the branched product 38 was accom-
panied by a small amount of linear product 380 (38/380 =
13:1).15 This stands in sharp contrast to the reaction of
propiolate ester 2 that only showed the formation of the
Acknowledgment. This work was supported by the Na-
tional Research Foundation funded by the Korean gov-
ernment (NRF-2010-0009458, NRF-2012-015662).
Supporting Information Available. Experimental de-
tails and spectral data; 1H and 13C scan of all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) The ratio was determined by the integration of 1H NMR. See ref
2d for a possible Z/E isomerization mechanism.
(16) The R-substituted allyl ethers, such as 39, were generally ineffi-
cient presumably because of premature ionization from the intermediate
I (Scheme 1). In fact, a significant amount of (Z)-2-methoxyvinyl sulfone
was observed from the reaction of 39 with 34.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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