Efficient synthesis of e -α-haloenones through chemoselective alkyne activation over allene with triazole-Au catalysts

Article abstract of DOI:10.1021/ol100576m

Figure presented The E-α-haloenones were prepared through a triazole-Au complex (TriA-Au) catalyzed propargyl acetate rearrangement and sequential allene halogenation. The reactions proceeded with only 1% catalyst loading, giving the challenging kinetic p

Full text of DOI:10.1021/ol100576m

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2088-2091
Efficient Synthesis of E-r-Haloenones
Through Chemoselective Alkyne
Activation Over Allene with Triazole-Au
Catalysts
Dawei Wang, Xiaohan Ye, and Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506
xiaodong.shi@mail.wVu.edu
Received March 10, 2010
ABSTRACT
The E-r-haloenones were prepared through a triazole-Au complex (TriA-Au) catalyzed propargyl acetate rearrangement and sequential
allene halogenation. The reactions proceeded with only 1% catalyst loading, giving the challenging kinetic products in excellent yields and
good to excellent stereoselectivity. These results not only provided the first example for the synthesis of challenging kinetic E-haloenones,
but also revealed triazole-Au complexes as effective catalysts in promoting chemoselective activation of alkynes over allenes.
The motivation for chemists to develop new synthetic
methodologies is to find effective solutions for challenging
functional group transformations, especially those with
good chemo-, regio-, and stereoselectivities.1 Within this
context, selective synthesis of kinetic products from their
thermodynamically stable partners is challenging and
attractive. Herein, we report the efficient synthesis of E-R-
haloenones from triazole-gold (TriA-Au)2 catalyzed
propargyl acetate rearrangement in the presence of NXS.
It is important to notice that by simply using the triazole
as the “X-factor”3 in Au coordination, good chemoselec-
tivity was achieved, where cationic Au catalyst activated
alkynes without influencing the reactivity of electron-
enriched allenes.
The first decade of the 21st century evidenced the
extremely fast growth of homogeneous Au catalysis.4 Both
Au(I) and Au(III) cations indicated great reactivity toward
C-C multiple bonds, especially for alkynes and allenes. On
the basis of this unique property, numerous new reactions
have been developed in the last several years to facilitate
complex functional group transformations.
(4) For selected recent reviews on homogeneous Au catalysis, see: (a)
Hashmi, A. S. K.; Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766–1775. (b)
Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351–
3378. (c) Arcadi, A. Chem. ReV. 2008, 108, 3266–3325. (d) Jimenez-Nunez,
E.; Echavarren, A. M. Chem. ReV. 2008, 108, 3326–3350. (e) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180–3211. (f) Fu¨rstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410–3449. (g) Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem. Commun. 2007, 333–346. (h) Zhang, L.; Sun, J.;
Kozmin, S. A. AdV. Synth. Catal. 2006, 348, 2271–2296. (i) Hashmi,
A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896–7936. (j)
Diez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. ReV. 2009, 109, 3612–
3676.
(1) For some recent reviews, see: (a) Doyle, M. P.; Duffy, R.; Ratnikov,
M.; Zhou, L. Chem. ReV. 2010, 110, 704–724. (b) Lyons, T.; Sanford, M. S.
Chem. ReV. 2010, 110, 1147–1169. (c) Do¨tz, K. H.; Stendel, J. Chem. ReV.
2009, 109, 3227–3274. (d) D´ıez-Gonza´lez, S.; Nolan, S. P. Acc. Chem.
Res. 2008, 41, 349–358. (e) Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem.
ReV. 2008, 108, 2916–2927.
(2) Duan, H.; Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X.
J. Am. Chem. Soc. 2009, 131, 12100–12102.
(3) Chen, Y.; Yan, W.; Akhmedov, N. G.; Shi, X. Org. Lett. 2010, 12,
344–347.
10.1021/ol100576m  2010 American Chemical Society
Published on Web 04/12/2010

One interesting gold-mediated transformation was the
propargyl acetate arrangement as shown in Scheme 1A. As
importance of vinyl halide products in organic synthesis, we
were interested in pursuing the possibility to achieve the
challenging E-isomers.
While the hypothesis for the observed Z-selectivity was
associated with Au activation of allenes, we first evaluated
the stereoselectivity in the iodination of allenes. The allene
ester 1a was prepared by using a literature reported method6
to react with NIS (Scheme 2A). As expected, the kinetically
Scheme 1. Au-Catalyzed Propargyl Acetate Arrangements
Scheme 2. Formation of Kinetically Favored E-Isomers
readily available starting materials, the propargyl acetate
could undergo 1,3-migration with the presence of Au
catalysts,5 giving the corresponding allene ester A.
Although this migration was widely accepted as the key
step in the Au-catalyzed propargyl acetate activation, allene
A has not been successfully isolated with good yields under
the reaction conditions.6 This is due to the fact that cationic
Au catalysts can also activate allene to give active intermedi-
ate, which may undergo different reaction paths. Using this
strategy, different cascade-type reactions have been devel-
oped by introducing proper reactants to react with gold-
activated allene. One example is the synthesis of Z-R-
iodoenones recently reported by Zhang and co-workers
(Scheme 1B).7
Through condition screening, the authors revealed that the
reactions gave good to excellent yields in mixed solvents
(acetone:H2O ) 800:1) with the thermodynamically stable
Z-isomer as the dominant products. Notably, the composition
of solvents appeared crucial for good reaction performance,
where mixed solvents such as acetone/H2O ) 40:1 gave only
35% yields. This cascade reaction is attractive since it gives
the R-iodoenones, which are important synthetic intermedi-
ates and can be readily converted into many different vinyl
compounds through metal-mediated cross coupling.8
However, there was one mechanistic concern regarding
the product stereochemistry: while the R1 group blocks one
side of the allene, the iodination should occur from the
opposite site of R1, giving the kinetically favored E-isomers.
The authors later proposed the Au activation of allene esters
to explain the observed dominant Z-selectivity.7c Giving the
favored E-isomer was obtained as the major product, which
supported the hypothesis that Au activation of allene 1a was
likely the reason for the formation of Z-isomer when
(PPh3)AuNTf2 was used as the catalyst.
Recently, we reported the synthesis and characterization
of triazole-coordinated cationic Au(I) complexes as new
catalysts in the alkyne activation.2,9 The key feature of these
new catalysts was to provide effective dynamic binding between
1,2,3-triazole and gold cations, which helped the stability of
the gold catalysts without significantly decreasing their
reactivity.3 We wondered whether triazole-Au (TriA-Au)
could be an effective catalyst in promoting this cascade vinyl-
iodination reaction. The propargyl acetate 3b was then used
to react with NIS in the presence of triazole-Au catalyst.
To our delight, the TriA-Au promoted this reaction with
high efficiency and an excellent yield of vinyl-iodide 2b was
received with only 1% catalyst loading. Notably, compared
with the previously reported Ph3PAuNTf2 catalyst, no special
solvent mixture was required when triazole-Au catalyst was
used and excellent yields of the desired products 2b were
received in various solvents (Scheme 2B). Encouraged by
this result, we then investigated the Z/E selectivity of this
cascade process. The propargyl acetate 3a was prepared to
(5) For 1,3-shifts, see: (a) Zhang, L. J. Am. Chem. Soc. 2005, 127,
16804–16805. (b) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442–
1443. (c) Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957–1959.
(d) Wang, S.; Zhang, L. Org. Lett. 2006, 8, 4585–4587. (e) Wang, S.; Zhang,
L. J. Am. Chem. Soc. 2006, 128, 8414–8415. (f) Buzas, A.; Gagosz, F.
J. Am. Chem. Soc. 2006, 128, 12614–12615. (g) Wang, S.; Zhang, L. J. Am.
Chem. Soc. 2006, 128, 14274–14275.
(9) See recent examples in triazole bound metal complexes see: (a) Liao,
W.; Chen, Y.; Duan, H.; Liu, Y.; Petersen, J. L.; Shi, X. Chem. Commun.
2009, 6436–6438. (b) Duan, H.; Sengupta, S.; Petersen, J. L.; Shi, X.
Organomatellic 2009, 28, 2352–2355. See the following for recent
developments for the preparation of substituted triazoles: (c) Sengupta, S.;
Duan, H.; Lu, W.; Petersen, J. L.; Shi, X. Org. Lett. 2008, 10, 1493–1496.
(d) Chen, Y.; Liu, Y.; Petersen, J. L.; Shi, X. Chem. Commun. 2008, 3254–
3256. (e) Liu, Y.; Yan, W.; Chen, Y.; Petersen, J. L.; Shi, X. Org. Lett.
2008, 10, 5389–5392. (f) Duan, H.; Yan, W.; Sengupta, S.; Shi, X. Bioorg.
(6) Marion, N.; Carlqvist, P.; Gealageas, R.; Fremont, P.; Maseras, F.;
Nolan, S. P. Chem.sEur. J. 2007, 13, 6437–6451.
(7) (a) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147–2150.
(b) Ye, L.; Zhang, L. Org. Lett. 2009, 11, 3646–3649. (c) Yu, M.; Zhang,
G.; Zhang, L. Tetrahedron 2009, 65, 1846–1855.
(8) For a review, see: Negishi, E. J. Organomet. Chem. 1999, 576, 179–
194.
Med. Chem. Lett. 2009, 19, 3899–3902
.
Org. Lett., Vol. 12, No. 9, 2010
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react with NIS in the presence of TriA-Au 4 catalysts. The
results are summarized in Table 1.
Lowering the reaction temperature to 0 °C provided the
optimal reaction conditions, where the E-isomer was pro-
duced in excellent yields (entry 10). Considering the high
E-selectivity for the allene iodination shown in Scheme 2A,
these results indicated that triazole-Au complexes were
effective precatalysts with outstanding chemoselectivity:
effectiVe actiVation of alkynes without influencing the
reactiVity of the allenes. With this new method in hand,
representative propargyl acetates were prepared to investigate
the reaction substrate scope. The results are summarized in
Figure 1.
Table 1. Screening of Reaction Conditionsa e
,
loading
(%)
temp time yield
catalyst
solvents
(°C)
(h)
(%)b E/Zc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
wet CH2Cl2
wet CH2Cl2
wet CH2Cl2
wet CH2Cl2
wet CH2Cl2
wet MeNO2
wet acetone
wet CH3CN
wet EtOAc
wet MeNO2
wet EtOAc
wet acetone
wet CH2Cl2
wet CH3CN
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
1
1
1
1
2
2
2
2
2
>98
95
96
7.0:1
5.0:1
5.7:1
6.3:1
7.0:1
12:1
11:1
9.0:1
10:1
89
>98
>98
94
90
>98
10
10 >98
10
10
10
93d >20:1
0
0
0
0
15:1
17:1
15:1
10:1
89
88
86
a General reaction conditions: 3a (0.25 mmol, 1.0 equiv) and NIS (1.2
equiv), monitored by TLC. b Yields determined by NMR with 1,3,5-
trimethoxybenzene as internal standard. c ratio determined by NMR of
crude reaction mixtures. d Isolated yield. e Various amounts of water have
been investigated and results are shown in ref 10.
It has been reported by Nolan and co-worker that 3a could
undergo the intramolecular hydroarylation in the presence
of 2% Ph3PAuCl/AgBF4 in DCM, giving substituted indenes
in modest yields (51%, 5 min).11 This was confirmed by the
experimental observation where the reaction of 3a and NIS
gave complex mixtures along with Au(I) catalyst decomposi-
tion in 30 min when 2% Ph3PAuCl/AgOTf was used as the
catalyst.
Impressively, similar to the alkyl-substituted propargyl
acetate 3b, reactions of 3a and triazole-Au 4 gave very clean
reactions and, more importantly, the kinetically favored
E-isomer was obtained as the major product. These precata-
lysts were very efficient and near-quantitative yields were
obtained with only 1% catalyst loading. Moreover, the
counteranions and the acidic proton on the triazole showed
little influence regarding the performance and selectivity
(entries 1-4). Screening of solvents revealed that nitro
methane gave the best stereoselectivity (entries 6-9).
Figure 1. Reaction substrate scope. (a) General reaction conditions:
3 (0.25 mmol, 1.0 equiv), NXS (1.2 equiv), 4a (1.0 mol %), and
MeNO2 (2.5 mL), monitored by TLC. (b) E:Z ratio determined by
NMR of crude reaction mixtures. (c) Reactions proceeded at room
temperature.
As shown in Figure 1, both aliphatic-substituted alkynes
and aromatic-substituted alkynes were suitable for this
transformation. Notably, this reaction did not work for the
terminal alkyne since the 1,2-rearrangement was usually
preferred for terminal alkyne propargyl acetate.12 The
reaction could also tolerate both alkyl- and aryl-substituted
groups on the acetate side, giving excellent yields in all cases.
NBS was suitable for this transformation, giving the corre-
(10) Reagents and conditions: 1.0 equiv of H2O in dry DCM gave 89%
yield in 2 h; 2.0 equiv of H2O in dry DCM gave 94% yield in 2 h; 10
equiv of H2O in dry DCM gave 91% yield in 2 h. A 7:1 E:Z ratio was
observed in all cases.
(11) Marion, N.; D´ıez-Gonzalez, S.; Fremont, P.; Noble, A. R.; Nolan,
S. P. Angew. Chem., Int. Ed. 2006, 45, 3647–3650.
(12) The triazole-Au promoted terminal alkyne propargyl acetate
rearrangement is currently under investigation. The result will be reported
in due course.
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Org. Lett., Vol. 12, No. 9, 2010

sponding vinyl bromide, which further extended the reaction
substrate scope. NCS did not work in this reaction, which
was likely caused by the decreased reactivity of the elec-
trophile. Compared with previously reported Au catalysts,
the triazole-Au complexes promoted this transformation
with much improved efficiency, broader substrate scope, and
more practical reaction conditions (no need for careful
solvents control).
Different substitution groups showed great influences on
the double bond stereoselectivity. For substrates with phenyl
and electron withdrawing group substituted benzenes, excel-
lent E-selectivity was received. To the best of our knowledge,
this is the first example for the synthesis of kinetically
favored R-haloenones. However, the E-isomer selectivity
decreased significantly in the alkyl-substituted substrates,
which was likely caused by the poor stereoselectivity
between electron-enriched allenes and NIS electrophile. This
hypothesis was supported by the observation in o-nitro-
substituted benzene 2p, where low E-selectivity was received,
which was likely caused by the nitro-directing effect for the
cis-iodination. To test our hypothesis, a reaction between
toluene-substituted allene and NIS was performed (Scheme
3). As expected, similar poor E/Z selectivity was obtained.
could be caused by the competition between the triazole
ligands and the vinyl-Au intermediates (note: addition of
excess 1,2,3-triazoles gave a slower reaction rate due to the
low concentration of active Ph3PAu+). More mechanistic
studies regarding triazole-Au promoted propargyl acetate
rearrangement are currently underway.
While the reported method gave the challenging E-isomers
in good yields, these kinetic products could be readily
transferred into thermodynamically stable Z-isomers by
treating with acids (Scheme 5A,B). This stereochemistry
Scheme 5
Scheme 3. Lack of E/Z Selectivity of Electron-Enriched Allene
conversion could be avoided through enone reduction to the
corresponding allylic alcohol (Scheme 5C). Excellent ster-
eochemistry retention was achieved, giving the corresponding
vinyl iodide and vinyl bromide in good yields.13
This result provided strong support for our hypothesis that
the triazole-Au complexes, unlike other cationic Au(I)
catalysts, provided a unique class of precatalysts that
selectively activated alkyne without influencing the reactivity
of the allene acetate intermediates (Scheme 4).
In summary, the triazole-Au complexes were revealed
as effective precatalysts in promoting propargyl acetate
rearrangement in the presence of NXS. The catalysts were
efficient to give >90% yields with only 1% loading. Unlike
other gold catalysts, the triazole-Au complexes effectively
promoted the formation of challenging kinetic E-isomers with
good to excellent selectivity. These results indicated the
excellent chemoselectivity of these triazole-Au catalysts.
It is expected that this unique property from triazole-Au
complexes could lead to the discoveries of other attractive
transformations by producing stable, in situ formed highly
reactive allenes.
Scheme 4. Proposed Reaction Mechanism
Acknowledgment. We thank the NSF (CHE-0844602),
DOE (DE-FC26-04NT42136), and ACS-PRF-47843-G1 for
financial support.
Supporting Information Available: Experimental details
and spectrographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
As reported in our previous studies, the key function of
1,2,3-triazole ligands was to provide effective dynamic
coordination with the Au(I) cation. Through this coordina-
tion, the actual Au catalyst (Ph3PAu+ in this case) was
stabilized from decomposition. The observed excellent
chemoselectivity of triazole-Au in this cascade reaction
OL100576M
(13) The proposed vinyl-gold intermediateds have been suggested in
literature (ref 7) and not been proved yet.
Org. Lett., Vol. 12, No. 9, 2010
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