In situ generation of nucleophilic allenes by the gold-catalyzed rearrangement of propargylic esters for the highly diastereoselective formation of intermolecular C(sp3)-C(sp2) bonds

Article abstract of DOI:10.1002/anie.201302402

New perspectives, in particular for the synthesis of isochromane derivatives (see scheme), are provided by the title reaction. Excellent diastereoselectivites are achieved in this reaction which proceeds through a gold-catalyzed 1,3-acyloxy migration. In some cases exclusively the Z isomer is detected. Copyright

Full text of DOI:10.1002/anie.201302402

Angewandte
Chemie
Communications
Gold Catalysis
Y. Yu, W. Yang, F. Rominger,
A. S. K. Hashmi*
&&&& — &&&&
In Situ Generation of Nucleophilic
Allenes by the Gold-Catalyzed
New perspectives, in particular for the
synthesis of isochromane derivatives (see
scheme), are provided by the title reac-
tion. Excellent diastereoselectivites are
achieved in this reaction which proceeds
through a gold-catalyzed 1,3-acyloxy
migration. In some cases exclusively the
Z isomer is detected.
Rearrangement of Propargylic Esters for
the Highly Diastereoselective Formation
3
2
À
of Intermolecular C(sp ) C(sp ) Bonds
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DOI: 10.1002/anie.201302402
Gold Catalysis
In Situ Generation of Nucleophilic Allenes by the Gold-Catalyzed
Rearrangement of Propargylic Esters for the Highly Diastereoselective
3
2
À
Formation of Intermolecular C(sp ) C(sp ) Bonds**
Yang Yu, Weibo Yang, Frank Rominger, and A. Stephen K. Hashmi*
À
In the last few years, in the field of homogeneous gold
catalysis[1] rearrangement reactions involving propargylic
esters have received considerable attention owing to the
synthetic utility of these easily accessible compounds in
a wide variety of intriguing, fascinating transformations.[2] It is
established that in gold catalysis these propargylic esters can
undergo 1,2- or 1,3-acyloxy migration leading to a gold vinyl
carbenoid species or a gold allenic intermediate (Scheme 1),[3]
lecular reaction involving C X bond formation (X = iodine,
bromide as electrophiles) has been reported by Zhang et al.[7]
However, to the best of our knowledge, there are no examples
in which nucleophilic allenes are generated in situ by gold-
catalyzed acyloxy migration in propargylic esters for inter-
3
2
À
molecular C(sp ) C(sp ) bond formation. This reactivity
mode would considerably extend the potential of gold-
catalyzed 1,3-acyloxy migration.
We were interested in developing this new type of gold-
catalyzed intermolecular reaction. Here the gold catalyst
should serve two purposes simultaneously: treatment of
a propargylic ester of an internal alkyne with the gold catalyst
would generate a nucleophilic allene in situ through the gold-
catalyzed 1,3-acyloxy migration; at the same time the gold
catalyst would serve as an Lewis acid, promoting the
formation of electrophilic oxocarbenium ions[8] from isochro-
mane acetals. Electrophilic attack of these oxocarbenium
À
intermediates at the allene would lead to the desired C C
Table 1: Optimization studies on the gold-catalyzed reaction of 1a with
2a.[a]
Scheme 1. Gold vinyl carbenoid and gold allenic intermediates.
which can be further trapped by other functional groups to
allow the synthesis of diverse organic products. The gold vinyl
carbenoid species can undergo prototypical reactions, for
example the cyclopropanation of alkenes and dienes, as well
[4]
À
as insertion into C H bonds. For the gold allenic inter-
Entry Catalyst
Solvent
t
Yield [%][b]
mediate, most studies cover intramolecular electrophilic
addition reactions.[5]
(Z)-3a (E)-3a
In contrast, the few examples of the catalytic generation
of nucleophilic gold allenic intermediate have been limited to
the study of intramolecular reactions.[6] Only one intermo-
1
SPhosAuCl/AgNTf2 DCE
SPhosAuCl/AgNTf2 DCE
10 min 68
23 min 58
10 min 61
10 min 52
trace
–
–
–
2[c]
3
Ph3PAuNTf2
DCE
DCE
DCE
DCE
4
IPrAuCl/AgNTf2
5[d]
6
[Au3+
]
24 h
8 h
trace
–
–
[*] M. Sc. Y. Yu, M. Sc. W. Yang, F. Rominger, Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
p-TsOH
trace
–
–
–
–
–
–
trace
trace
trace
7
8
9
10
11
12
13[e]
14[f]
15[g]
SPhosAuCl/AgSbF6 DCE
10 min 63
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
SPhosAuCl/AgOTs
AgNTf2
DCE
DCE
24 h
24 h
8 h
n.r.
16
32
SPhosAuCl/AgNTf2 Toluene
SPhosAuCl/AgNTf2 CH3CN
SPhosAuCl/AgNTf2 1,4-Dioxane 8 h
SPhosAuCl/AgNTf2 DCE
SPhosAuCl/AgNTf2 DCE
SPhosAuCl/AgNTf2 DCE
Homepage: http://www.hashmi.de
8 h
22
trace
62
60
Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University
2.5 h
7 h
10 min 85
Jeddah 21589, Saudi Arabia
[**] Y.Y. and W.Y. are grateful to the CSC for a fellowship; they
contributed equally to this work. Gold salts were generously
donated by Umicore AG & Co. KG.
[a] Reaction conditions: substrate (100 mmol), [Au] (2 mol%), [Ag]
(2 mol%), solvent (2 mL), in air, 808C. The reaction was monitored by
TLC. [b] Yield of isolated product. [c] [Au] 1 mol%, [Ag] 1 mol%.
[d] Dichloro(2-picolinato)gold(III). [e] Reaction at 408C. [f] Reaction at
room temperature. [g] Pivaloyl ester. n.r.=no reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302402.
2
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Chemie
bond formation. We expected that this
new type of transformation could be used
for the efficient synthesis of various useful
isochromane derivatives,[9] important
building blocks for the total synthesis of
natural products.
Based on these considerations, we
chose 1a and 2a as model substrates for
an initial optimization of the reaction
conditions. The results obtained with
various catalysts and solvents are sum-
marized in Table 1. Among the catalysts
tested, SPhosAuCl/AgNTf2 was found to
be the most effective one for this trans-
formation (Table 1, entries 1–4). The
desired product (Z)-3a (68%) was
obtained in the presence of 2 mol% of
this catalyst at 808C after 10 min in air.
Gratifying, 58% yield was still achieved
when 1 mol% of catalyst was used
(Table 1, entry 2). When the reaction
was
conducted
with
dichloro(2-
picolinato)gold(III)[10] and p-TsOH, only
a trace conversion was visible by TLC
(Table 1, entries 5 and 6). Subsequently,
in order to investigate the effects of the
counterions, various silver salts were
examined (Table 1, entries 7 and 8). Sur-
prisingly, when SPhosAuCl/AgOTs was
employed, no reaction was observed,
even when we prolonged the reaction
time to 24 h (Table 1, entry 8). The con-
trol experiment with AgNTf2 gave (Z)-3a
in only 16% yield (Table 1, entry 9).
Changing to solvents such as toluene,
CH3CN, or 1,4-dioxane failed to improve
the yield (Table 1, entries 10–12).
Decreasing the temperature to 408C or
room temperature resulted in moderate
yields of 62% and 60% (Table 1,
entries 13 and 14). To our delight, when
Scheme 2. Scope and limitation of the AuI-catalyzed synthesis of 3.[a]
the acetate 2a was replaced by the corresponding propargylic
pivalate, the yield of (Z)-3a reached 85% together with (E)-
3a as minor side product (Table 1, entry 15).
We applied the optimized reaction conditions (Table 1,
entry 15) to explore the generality of this intermolecular
reaction. A variety of propargylic pivalates were investigated
in combination with isochromane acetal 1a. As presented in
Scheme 2, all of these substrates delivered good to excellent
yields. For substrates with aromatic substituents R2, except for
the thienyl group (2h), very good to excellent stereoselectiv-
ities favoring the Z isomer were observed. Under the standard
conditions, substrates 2b, 2d, and 2i deliver the Z isomer as
a single stereoisomer. The structure of 3d was proven
unambiguously by an X-ray single-crystal structure analysis[11]
and NOE spectra of (Z)-3a (Figure 1). In the case of
substrates 2 f and 2h, although the Z/E selectivities were
diminished, good yields could still be obtained. Next, two
different isochromane acetal substrates in combination with
Figure 1. Left: Solid-state molecular structure of (Z)-3d (thermal
ellipsoids at 50% probability); right: NOE observed in (Z)-3a.
diverse propargylic pivalates were examined. Both the fluoro-
and the naphthyl-substituted isochromane acetals were con-
verted to the corresponding products in excellent yields with
good to excellent selectivities. In particular, the reaction of
substrate 2n provides the product solely as the Z isomer in
quantitative yield.
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Two supplementary experiments
strongly support path A and clearly
exclude path B (Scheme 4). Initially,
we attempted to isolate the nucleo-
philic allene intermediate B with the
novel and efficient catalyst triazole-
Au (TA-Au), which was synthesized
by Shi et al.[12] To our delight, the
nucleophilic allene intermediate F
was obtained in 85% yield. This
allene intermediate was treated
with 1a under the standard gold-
catalyzed reaction conditions; the
transformation proceeded smoothly
and the desired product 3 f was
indeed formed in 78% yield. To
Scheme 3. Two possible mechanisms for the formation of 3 from 1 and 2.
exclude path B, we conducted an
18O-labeling experiment with 2k.
Two possible mechanistic pathways have to be considered
(Scheme 3). In path A, the activation of the propargyl
pivalate 2 by the gold catalyst would induce a 1,3-pivalate
migration to generate the nucleophilic allene B. B then reacts
with the oxocarbenium ion C, the latter generated from the
isochromane acetal 1 by gold acting as a Lewis acid. The
observed diastereoselectivity could then easily be explained
by the preferred electrophilic attack at the p face of the enol
ether substructure of the allene which is anti to the substituent
R3 (repulsion between R3 and the incoming C). In path B, first
MeOÀ would be transferred from 1 to the alkyne, which is p-
coordinated to gold. The reaction of C with the vinyl gold
species D delivers intermediate E. Finally, elimination of
methyl pivaloate delivers the product 3.
The 18O label was still present in the product 3s (as detected
by MS), and the fragmentation clearly shows its location in
the carbonyl group (PhC18O+ with m/z 107.0385 is detected as
the only location of 18O).
In summary, we have developed a new stereocontrolled
3
2
À
gold-catalyzed intermolecular C(sp ) C(sp ) bond-forming
reaction involving the in situ generation of a nucleophilic
allene and an electrophilic oxocarbenium ion. This new
reactivity mode represents a considerable extension of the
synthetic potential of gold-catalyzed 1,3-acyloxy migration as
À
it not only allows a highly valuable C C bond formation but
also opens new perspectives for synthetic applications espe-
cially for the synthesis of isochromane derivatives. Good to
excellent diastereoselectivities are achieved, in some cases
only the Z isomer could be detected.
Received: March 21, 2013
Published online: && &&, &&&&
Keywords: chromanes · gold · homogeneous catalysis ·
.
propargyl esters · rearrangement
[1] a) G. Dyker, Angew. Chem. 2000, 112, 4407 – 4409; Angew.
Chem. Int. Ed. 2000, 39, 4237 – 4239; b) A. S. K. Hashmi, G. J.
Hutchings, Angew. Chem. 2006, 118, 8064 – 8105; Angew. Chem.
Int. Ed. 2006, 45, 7896 – 7936; c) A. S. K. Hashmi, Chem. Rev.
2007, 107, 3180 – 3211; d) A. Fꢀrstner, P. W. Davis, Angew.
Chem. 2007, 119, 3478 – 3519; Angew. Chem. Int. Ed. 2007, 46,
3410 – 3449; e) A. Arcadi, Chem. Rev. 2008, 108, 3266 – 3325;
f) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108,
3351 – 3378; g) A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev.
2008, 37, 1766 – 1775; h) A. Corma, A. Leyva-Pꢁrez, M. J.
Sabater, Chem. Rev. 2011, 111, 1657 – 1712; i) M. Rudolph,
A. S. K. Hashmi, Chem. Soc. Rev. 2012, 41, 2448 – 2462.
[2] a) D. H. Zhang, L. F. Yao, Y. Wei, M. Shi, Angew. Chem. 2011,
123, 2631 – 2635; Angew. Chem. Int. Ed. 2011, 50, 2583 – 2587;
b) D. Garayalde, K. Krꢀger, C. Nevado, Angew. Chem. 2011,
123, 941 – 945; Angew. Chem. Int. Ed. 2011, 50, 911 – 915;
c) I. D. G. Watson, S. Ritter, F. D. Toste, J. Am. Chem. Soc.
2009, 131, 2056 – 2057; d) M. Uemura, I. D. G. Watson, M.
Katsukawa, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 3464 –
3465; e) P. Mauleꢂn, J. L. Krinsky, F. D. Toste, J. Am. Chem.
Soc. 2009, 131, 4513 – 4520; f) N. Marion, Chem. Eur. J. 2009, 15,
Scheme 4. Mechanistic control experiments provide evidence for
path A.
4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
3243 – 3260; g) A. S. Dudnik, T. Schwier, V. Gevorgyan, Org.
Lett. 2008, 10, 1465 – 1468; h) A. Correa, N. Marion, L.
Fensterbank, M. Malacria, S. P. Nolan, L. Cavallo, Angew.
Chem. 2008, 120, 730 – 733; Angew. Chem. Int. Ed. 2008, 47,
718 – 721; i) G. Lemiꢃre, V. Gandon, K. Cariou, T. Fukuyama,
A.-L. Dhimane, L. Fensterbank, M. Malacria, Org. Lett. 2007, 9,
2207 – 2209; j) L. Zhang, S. Z. Wang, J. Am. Chem. Soc. 2006,
128, 1442 – 1443; k) N. Marion, P. de Frꢁmont, E. D. Stevens, L.
Fensterbank, M. Malacria, S. P. Nolan, Chem. Commun. 2006,
2048 – 2050; l) N. D. Shapiro, F. D. Toste, J. Am. Chem. Soc. 2008,
130, 9244 – 9245; m) P. W. Davies, S. J.-C. Albrecht, Chem.
Commun. 2008, 238 – 240; n) Y. Zou, D. Garayalde, Q. Wang,
C. Nevado, A. Goeke, Angew. Chem. 2008, 120, 10264 – 10267;
Angew. Chem. Int. Ed. 2008, 47, 10110 – 10113; o) X. Moreau, J.-
P. Goddard, M. Bernard, G. Lemiꢃre, J. M. Lꢂpez-Romero, E.
Mainetti, N. Marion, V. Mouriꢃs, S. Thorimbert, L. Fensterbank,
M. Malacria, Adv. Synth. Catal. 2008, 350, 43 – 48; p) C. H. M.
Amijs, V. Lꢂpez-Carrillo, A. M. Echavarren, Org. Lett. 2007, 9,
4021 – 4024; q) D. J. Gorin, P. Dubꢁ, F. D. Toste, J. Am. Chem.
Soc. 2006, 128, 14480 – 14481; r) M. J. Johansson, D. J. Gorin,
S. T. Staben, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 18002 –
18003; s) X. Shi, D. J. Gorin, F. D. Toste, J. Am. Chem. Soc. 2005,
127, 5802 – 5803; t) S. Z. Wang, L. Zhang, J. Am. Chem. Soc.
2006, 128, 14274 – 14275; u) V. Rautenstrauch, J. Org. Chem.
1984, 49, 950 – 952.
Garayalde, E. Gꢂmez-Bengoa, X. Huang, A. Goeke, C.
Nevado, J. Am. Chem. Soc. 2010, 132, 4720 – 4730; g) A. S. K.
Hashmi, W. Yang, Y. Yu, M. M. Hansmann, M. Rudolph, F.
Rominger, Angew. Chem. 2013, 125, 1368 – 1371; Angew. Chem.
Int. Ed. 2013, 52, 1329 – 1332; first description: h) A. S. K.
Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew. Chem.
2000, 112, 2382 – 2385; Angew. Chem. Int. Ed. 2000, 39, 2285 –
2288.
[6] For examples of the allene moiety acting as a nucleophilic
reagent, see: a) T. Luo, S. L. Schreiber, J. Am. Chem. Soc. 2009,
131, 5667 – 5674; b) T. Luo, S. L. Schreiber, Angew. Chem. 2007,
119, 8398 – 8401; Angew. Chem. Int. Ed. 2007, 46, 8250 – 8253;
c) J. Zhao, C. O. Hughes, F. D. Toste, J. Am. Chem. Soc. 2006,
128, 7436 – 7437; d) S. Z. Wang, L. Zhang, J. Am. Chem. Soc.
2006, 128, 8414 – 8415; e) W. Rao, D. Susanti, P. W. H. Chan, J.
Am. Chem. Soc. 2011, 133, 15248 – 15251; f) D. Lebœuf, A.
Simonneau, C. Aubert, M. Malacria, V. Gandon, L. Fensterbank,
Angew. Chem. 2011, 123, 7000 – 7003; Angew. Chem. Int. Ed.
2011, 50, 6868 – 6871; g) J. W. Cran, M. E. Krafft, Angew. Chem.
2012, 124, 9532 – 9536; Angew. Chem. Int. Ed. 2012, 51, 9398 –
9402.
[7] a) M. Yu, G. Zhang, L. Zhang, Org. Lett. 2007, 9, 2147 – 2150;
b) M. Yu, S. Wang, G. Zhang, L. Zhang, Tetrahedron 2009, 65,
1846 – 1855.
[8] Such oxocarbenium ions have been used as electrophiles in the
reaction with vinyl gold intermediates, but there the ionization
step was initiated by the gold-activated substrate and not directly
by the gold catalyst: a) M. Zhang, Y. Wang, Y. Yang, X. Hua,
Adv. Synth. Catal. 2012, 354, 981 – 985; b) A. S. K. Hashmi, T.
Hꢆffner, W. Yang, S. Pankajakshan, S. Schꢆfer, L. Schultes, F.
Rominger, W. Frey, Chem. Eur. J. 2012, 18, 10480 – 10486.
[9] P. Maity, H. D. Srinivas, M. P. Watson, J. Am. Chem. Soc. 2011,
133, 17142 – 17145.
[10] A. S. K. Hashmi, J. P. Weyrauch, M. Rudolph, E. Kurpejovic,
Angew. Chem. 2004, 116, 6707 – 6709; Angew. Chem. Int. Ed.
2004, 43, 6545 – 6547.
[11] CCDC 926852 ((Z)-3d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[3] For reviews, see: a) A. S. Dudnik, N. Chernyak, V. Gevorgyan,
Aldrichimica Acta 2010, 43, 37 – 46; b) S. Z. Wang, G. Z. Zhang,
L. Zhang, Synlett 2010, 692 – 706; c) for highlights, see: N.
Marion, S. P. Nolan, Angew. Chem. 2007, 119, 2806 – 2809;
Angew. Chem. Int. Ed. 2007, 46, 2750 – 2752.
[4] a) N. D. Shapiro, Y. Shi, F. D. Toste, J. Am. Chem. Soc. 2009, 131,
11654 – 11655; b) C. Fehr, J. Galindo, Angew. Chem. 2006, 118,
2967 – 2970; Angew. Chem. Int. Ed. 2006, 45, 2901 – 2904; c) A.
Fꢀrstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006 – 3019.
[5] For examples of the allene moiety acting as an electrophilic
reagent, see: a) T. M. Teng, R.-S. Liu, J. Am. Chem. Soc. 2010,
132, 9298 – 9300; b) A. Buzas, F. Istrate, F. Gagosz, Org. Lett.
2006, 8, 1957 – 1959; c) A. Buzas, F. Gagosz, J. Am. Chem. Soc.
2006, 128, 12614 – 12615; d) N. Marion, S. Dꢄez-Gonzꢅlez, P.
de Frꢁmont, A. R. Noble, S. P. Nolan, Angew. Chem. 2006, 118,
3729 – 3732; Angew. Chem. Int. Ed. 2006, 45, 3647 – 3650; e) L.
Zhang, J. Am. Chem. Soc. 2005, 127, 16804 – 16805; f) D.
[12] D. Wang, Y. Zhang, R. Cai, X. Shi, Beilstein J. Org. Chem. 2011,
7, 1014 – 1020.
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