Gold-catalyzed oxidative rearrangement of homopropargylic ether via oxonium ylide

Article abstract of DOI:10.1021/ol302238t

Synthetically useful α,β-unsaturated carbonyl compounds were obtained from gold-catalyzed oxidative rearrangement of homopropargylic ether under mild reaction conditions. Gold carbenoid and oxonium ylide are proposed as key intermediates.

Full text of DOI:10.1021/ol302238t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Gold-Catalyzed Oxidative Rearrangement
of Homopropargylic Ether via Oxonium Ylide
Mei Xu, Tian-Tian Ren, and Chuan-Ying Li*
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha West Higher Education
District, Hangzhou 310018, China
licy@zstu.edu.cn
Received August 12, 2012
ABSTRACT
Synthetically useful R,β-unsaturated carbonyl compounds were obtained from gold-catalyzed oxidative rearrangement of homopropargylic ether
under mild reaction conditions. Gold carbenoid and oxonium ylide are proposed as key intermediates.
Gold-catalyzed reactions have intensively been investi-
gated in the past decade.1 Numerous new transformations
based on the π-acidity and electron-donor property of gold
catalysts have been developed and applied in multistep
syntheses. In 2007, Toste and co-workers2a and Zhang and
co-workers2b independently reported that alkyne with a
tethered sulfoxide could be used asprecursor of R-oxo gold
carbenoid. This method is promising because it offers a
convenient and benign alternative to generate metal car-
bene, which is tranditionally obtained from the diazo
compound.2,3 Intermolecular oxidation of alkynes was sub-
sequently realizedby using pyridineN-oxide, and the metal
carbenoid or gold-stabilized carbocation can be trapped
€
(1) For selected reviews, see: (a) Furstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410. (b) Hashmi, A. S. K. Chem. Rev. 2007,
107, 3180. (c) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (d)
ꢀ
ꢀ
Arcadi, A. Chem. Rev. 2008, 108, 3266. (e) Jimenez- Nunez, E.;
Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (f) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (g) Hashmi, A. S. K.;
Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766. (h) Michelet, V.; Toullec,
^
€
P. Y.; Genet, J. P. Angew. Chem., Int. Ed. 2008, 47, 4268. (i) Furstner, A.
Chem. Soc. Rev. 2009, 38, 3208. (j) Hashmi, A. S. K. Angew. Chem., Int.
Ed. 2010, 49, 5232. (k) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria,
M.; Simonneau, A. Chem. Rev. 2011, 111, 1954. (l) Krause, N.; Winter,
C. Chem. Rev. 2011, 111, 1994.
(4) Gold-catalyzed intramolecular reactions involving gold carbenes
derived from intermolecular oxidation of alkynes: (a) Ye, L.; Cui, L.;
Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258. (b) Ye, L.; He,
W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550. (c) Lu, B.; Li, C.;
Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070. (d) Ye, L.; He, W.;
Zhang., L. Angew. Chem., Int. Ed. 2011, 50, 3236. (e) Vasu, D.; Hung,
H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-S. Angew. Chem., Int.
Ed. 2011, 50, 6911. (f) Davies, P. W.; Cremonesi, A.; Dumitrescu, L.
Angew. Chem., Int. Ed. 2011, 50, 8931. (g) Davies, P. W.; Cremonesi, A.;
Martin, N. Chem. Commun. 2011, 47, 379. (h) Qian, D.; Zhang, J. Chem.
Commun. 2011, 47, 11152. (i) Li, C.; Zhang, L. Org. Lett. 2011, 13, 1738.
(j) Qian, D.; Zhang, J. Chem. Commun. 2012, 48, 7082. (k) Wang, Y.; Ji,
K.; Lan, S.; Zhang, L. Angew. Chem., Int. Ed. 2012, 51, 1915. (l) Kramer,
S.; Skrydstrup, T. Angew. Chem., Int. Ed. 2012, 51, 4681.
(5) Selected examples of intermolecular redox reactions of alkynes:
(a) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
(b) Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Karad,
S. N.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 15372. (c) He, W.; Xie, L.;
Xu, Y.; Xiang, J.; Zhang, L. Org. Biomol. Chem. 2012, 10, 3168.
(6) (a) Metal Carbenes in Organc Synthesis; Dorwald, F. Z., Ed.;
Wiley-VCH: New York, 1999. (b) Metal Carbenes in Organc Synthesis;
Dotz, K. H., Ed.; Springer-Verlag: Berlin, 2004. (c) Ye, T.; McKervey, M. A.
Chem. Rev. 1994, 94, 1091. (d) Doyle, M. P.; Forbes, D. C. Chem. Rev.
1998, 98, 911. (e) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette,
A. B. Chem. Rev. 2003, 103, 977. (f) Aggarwal, V. K.; Winn, C. L. Acc.
Chem. Res. 2004, 37, 611.
(2) Selected examples of intramolecular redox reactions of alkynes:
(a) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160. (b)
Li, G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156. (c) Yeom, H.-S.;
Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47, 7040. (d) Cui, L.;
Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394. (e) Cui, L.;
Zhang, G.; Peng, Y.; Zhang, L. Org. Lett. 2009, 11, 1225. (f) Yeom, H.-
S.; Lee, Y.; Jeong, J.; So, E.; Hwang, S.; Lee, J.-E.; Lee, S. S.; Shin, S.
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Liao, H.-Y.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 1769. (h) Chen, D.;
Song, G.; Jia, A.; Li, X. J. Org. Chem. 2011, 76, 8488. (i) Yeom, H.-S.;
So, E.; Shin, S. Chem.;Eur. J. 2011, 17, 1764. (j) Patel, P.; Ramana,
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(3) Recent review for R-carbonyl gold carbenoids: (a) Xiao, J.; Li, X.
Angew. Chem., Int. Ed. 2011, 50, 7226. For examples using azide as
nucleophiles, see: (b) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 11260. (c) Wetzel, A.; Gagosz, F. Angew. Chem.,
Int. Ed. 2011, 50, 7354. (d) Lu, B.; Luo, Y.; Liu, L.; Ye, L.; Wang, Y.;
Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 8358. For similar reactions
with different mechanism, see: (e) Cuenca, A. B.; Montserrat, S.;
Hossain, K. M.; Mancha, G.; Lledos, A.; Medio-Simon, M.; Ujaque,
G.; Asensio, G. Org. Lett. 2009, 11, 4906. (f) Li, C.-W.; Pati, K.; Lin,
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Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 2939.
r
10.1021/ol302238t
XXXX American Chemical Society

intramolecularly4 or intermolecularly5 (Scheme 1). Among
all the trapping approaches of metal carbenoids, ylide
formation and the subsequent reaction are attractive be-
cause chemical transformations of ylides have shown great
versatility in the synthesis of natural products.6 Surpris-
ingly, littleworkhas been donein thisarea.7 Exploring new
transformations based on ylide formation that evolve from
alkynes and gold catalyst is of great significance.
Table 1. Optimization of Reaction Conditionsa
entry catalyst (4 mol %) N-oxide (2 equiv) time (h) yield (%)
Scheme 1. Gold-Catalyzed Oxidation of Alkynes
1
2
3
4
5
6
7
Ph3PAuCl/AgSbF6
AuCl/AgSbF6
3a
3a
3a
3a
3a
3b
3c
3a
3a
3a
3a
3.5
6.5
3.5
7.0
4.8
8.0
2.5
40
31
63
48
68
46
trace
34
0
IMesAuCl/AgSbF6
IPrAuCl/AgSbF6
IMesAuCl/AgNTf2
IMesAuCl/AgNTf2
IMesAuCl/AgNTf2
8b,c IMesAuCl/AgNTf2
9b
IMesAuCl
10b AgNTf2
11 HNTf2
11
In 2010, Zhang and co-workers reported that in the
presence of gold catalyst and pyridine N-oxide, homopro-
pargylic alcohol could be converted into dihydrofuran-3-
one 4 via R-oxo gold carbenoid and subsequent OÀH
insertion (Scheme 2).4a We envisioned that if the OH group
was replaced by OMe group, instead of OÀH insertion, an
oxonium ylide may be formed and [1,2]-shift would lead to
cyclobutanone 5. To our surprise, when substrate 1a was
subjected to the gold-catalyzed redox reaction, instead of
cyclobutanone, an R,β-unsaturated carbonyl compound
2a was obtained in moderate yield. Herein, we report an
unprecedented synthesis of R,β-unsaturated carbonyl com-
pound from homopropargylic ether via oxonium ylide route.
24
24
24
0
0
a [1a] = 0.1 M; the reaction was conducted in 2 mL of 1,2-dichlor-
oethane in open flask. b No MsOH was added. c 66% conversion.
obtained in 34% yield (entry 8). IMesAuCl, AgNTf2 or
HNTf2 alone could not catalyze the reaction; the starting
material was recovered unconsumed in each case after 24 h
(entries 9, 10 and 11).
The scope of this reaction was then examined (Scheme 3).
Moderate to high yield could be obtained when methyl
ethers with an electron-poor aromatic unit at the homo-
propargylic position were used (2b, 2c, 2d, 2e, 2f and 2g).
Halogen, trifluoromethyl, ester and cyano groups are well
tolerated in this mild transformation. Aromatic ring at the
homopropargylic position is necessary for high yield since
2h could be obtained only in 28% yield. This method also
worked well with phenyl ether and benzyl ether (2i and 2j).
Additionally, 2-methoxy substituted 1,3-diketone 2k can
be obtained in 52% yield from ynone 1k; compound 6,
which is an sp2 CÀH insertion product, can alsobe isolated
in 16% yield.8 Interestingly, when substrates bearing
electron-rich aryl ring were used, R,β-unsaturated carbonyl
compound 2 and cyclobutanone 5 were obtained (2l, 2m, 5l,
5m and 5n). A general trend can be deduced here: the electron
richer aryl ring the substrates bear, the higher ratio between 5
and 2 we can expect; this is in accordance with the relative
stability of zwitterion (Scheme 4, intermediate I). We also
tried other OH protecting group such as TBS and THP.
Scheme 2. Design for the Trapping of R-Oxo Gold Carbenoid
Using 1a as the model substrate, reaction conditions
such as gold catalysts, silver catalysts, oxygen-delivering
oxidants, acids, solvent and reaction temperature were
screened, representative conditions are summarized in
Table 1. The use of 4 mol % IMesAuCl/AgNTf2 gave
the best result, 68% of 2a could be obtained (entry 5).
Surprisingly, when 8-ethylquinoline N-oxide was used, the
reaction completed in 2.5 h, but the products were complex
and only trace 2a could be isolated (entry 7). In the absence
of MsOH, the reaction proceeded slowly; 34% of the
substrate was recovered after 11 h, and 2a could be
(8) The proposed mechanism for formation of compound 6:
(7) (a) Davies, P. W.; Albrecht, S. J.-C. Chem. Commun. 2008, 238.
(b) Davies, P. W.; Albrecht, S. J.-C. Angew. Chem., Int. Ed. 2009, 48,
8372. (c) Davies, P. W.; Albrecht, S. J.-C. Synlett 2012, 70.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Substrate Scopea
Scheme 4. Proposed Mechanism
final product 2. Alternatively, electrophilic carbene can
be attacked by pendent oxygen atom, which results in
oxonium ylide E. Intramolecular H transfer leads to
intermediate G (path b), subsequent cleavage of CÀAu
and CÀO bond affords 2 and regenerates gold catalyst.
Instead of H transfer, proton at the R-position of
carbonyl can be eliminated, followed by cleavage of
CÀO bond (path c); thus, intermediate H can be ob-
tained. Compound 2 can be formed by subsequent
protodeauration. When aryl ring at homopropargylic
position is electron rich (Scheme 3, 1l, 1m and 1n),
relatively stable intermediate I can be obtained (path d),
a [1] = 0.1 M; the reaction was conducted in 2 mL of 1,2-dichloroethane
in open flask.
Since MsOH was used in the reaction, the OTBS or OTHP
were hydrolyzed, only dihydrofuran-3-one was isolated.
Remarkably, the E/Z selectivity of this reaction is perfect,
all the enone products we obtained are (E)-isomers, and no
(Z)-isomer could be detected from the crude NMR.
To shed light on the reaction mechanism, we synthesized
homopropargylic ester 1o and internal alkyne 1p. Under
the optimized reaction conditions, 1o led to compound 7
(eq 1), which is an sp2 CÀH insertion product. When 1p
was employed, R,β-unsaturated carbonyl compound 8
could be obtained in 82% yield (eq 2). Compared with
compound 2, the regioselectivity here is different. On the
basis of Zhang and co-workers’ report,4c formation of
R-oxo gold carbenoid and subsequent 1,2-CÀH insertion
led to final product 8. These results, together with compound
6 in Scheme 3, indicate that R-oxo gold carbenoid plays a
central role in this reaction.
which undergoes intramolecular nucleophilic attack to
afford cyclobutanone 5.
To gain more information about the mechanism, we did
a crossover experiment (eq 3). When benzyl ether 1j was
used, 1 equiv of MeOH was added to trap the proposed
intermediateF (Scheme 4);only 2j could be isolated in34%
yield, which indicated that path a could not be the actual
mechanism. We also prepared 1a-d, which was deuterated
100% at alkyne terminus, and the gold-catalyzed reaction
led to 2a-d having a >98% deuterium content for the
methylene position (eq 4). This result is in consistent with
path b and path c. Furthermore, when 1a was subjected to
As depicted in Scheme 4, several pathways could
be possible. Nucleophilic attack of pyridine N-oxide
to gold-activated alkyne 1 and subsequent expulsion of
pyridine aided by gold catalyst affords carbenoid C. In
path a, elimination of MeOH leads to intermediate F,
which undergoes intermolecular OÀH insertion to afford
Org. Lett., Vol. XX, No. XX, XXXX
C

the optimized reaction conditions, 2 equiv of D2O was
added simultaneously (eq 5); 42% deuterated product
could be obtained. To rule out the hydrogen exchange
between 2a and D2O under the reaction conditions, 2a was
employed under the same conditions as eq 5; no deuterium
labeled product could be obtained (eq 6). Thus, path c
should be the most possible mechanism.
and trying to figure out the relationship between selectivity
and structure of substrates and catalysts.
Acknowledgment. This work was generously supported
by the National Natural Science Foundation of China
(21002091), Qianjiang Talents Project of the Technology
Office of Zhejiang Province (2011R10019), and the Young
Researchers Foundation of Zhejiang Provincial Top Key
Academic Discipline of Applied Chemistry and Eco-Dye-
ing & Finishing Engineering (ZYG2010010).
In summary, we have described a novel and convenient
approach that converts homopropargylic ethers into R,
β-unsaturated carbonyl compounds. The reaction tolerates
various functional groups and generates a compound
with excellent (E)-selectivity. Oxonium ylide is proposed
as the key intermediate, which is generated from ether
tethered alkynes and pyridine N-oxide for the first time.
When substrates bearing an electron-rich aryl ring at the
homopropargylic position wereused, cyclobutanone could
be obtained. We are working on this interesting reaction
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX