The tandem intermolecular hydroalkoxylation/claisen rearrangement

Article abstract of DOI:10.1039/c2cc37166a

The Au(i)-catalyzed intermolecular hydroalkoxylation of alkynes with allylic alcohols to provide allyl vinyl ethers that subsequently undergo Claisen rearrangement is reported. This new cascade reaction strategy facilitates the direct formation of γ,δ-unsaturated ketones from simple starting materials in a single step.

Full text of DOI:10.1039/c2cc37166a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
The tandem intermolecular hydroalkoxylation/claisen
rearrangement†‡
Cite this: Chem. Commun., 2013,
49, 4157
John M. Ketcham, Berenger Biannic and Aaron Aponick*
Received 1st October 2012,
Accepted 5th November 2012
DOI: 10.1039/c2cc37166a
www.rsc.org/chemcomm
The Au(I)-catalyzed intermolecular hydroalkoxylation of alkynes simple substrates in an atom-economical reaction to selectively
with allylic alcohols to provide allyl vinyl ethers that subsequently produce enol ethers and subsequently g,d-unsaturated ketones.
undergo Claisen rearrangement is reported. This new cascade
Although a variety of catalytic methods for the formation of allyl
reaction strategy facilitates the direct formation of c,d-unsaturated vinyl ethers from an array of different precursors have previously
ketones from simple starting materials in a single step.
been disclosed,3e–g,4 the possibility of using a hydroalkoxylation
was intriguing because the enol ether olefin geometry would be set
The Claisen rearrangement stands as one of the most powerful in a stereospecific manner according to the mechanism of alcohol
sigmatropic rearrangements utilized by the synthetic community, addition.5 Intermolecular hydroalkoxylation reactions of alkynes
producing g,d-unsaturated carbonyl compounds in a highly stereo- are well-known using a variety of catalysts,5a,6 but to the best of our
defined manner.1 Despite the development of many successful knowledge this reaction cascade has not been explored. At the
variants1 since Claisen’s original report2 (1 - 2, Scheme 1), the outset, it seemed logical to study the use of Au-catalysts because
preparation of classical acyclic allyl vinyl ethers with defined olefin excellent selectivities for anti-alkoxyauration reactions are observed
geometry can be quite challenging, especially when a cis-enol ether and Au-complexes also catalyze Claisen rearrangement reactions
is required.1,3 A simple strategy to access these classical substrates such as the propargyl Claisen rearrangement.7 In these
would be highly advantageous. Herein, we report a tandem one-pot instances, the substrates are typically preformed, highly activated,
hydroalkoxylation/Claisen rearrangement (Scheme 1) that employs or embedded in substrates predisposed towards intramolecular
reactions.
Initial experiments focused on using crotyl alcohol 4a and
alkyne 3a (eqn (1)). Unfortunately, exposure of the substrates to
the complex generated from I/AgOTf at 90 1C (sealed tube) in
THF did not produce the desired product 6a. Instead, a mixture
of alkyne hydration products 7 and 8, in addition to the some-
what volatile ether 9 resulting from self-condensation of 4a,
were observed. Despite the promising literature precedent for
each step, sequencing them in tandem proved to be an
arduous task.
(1)
Scheme 1 Claisen rearrangement.
Department of Chemistry, University of Florida, P. O. Box 117200, Gainesville,
Previous work from our laboratory has focused on using
FL 32611, USA. E-mail: aponick@chem.ufl.edu
allylic and propargylic alcohols as electrophiles in Au-catalyzed
† This article is part of the ChemComm ‘Emerging Investigators 2013’ themed issue.
reactions that proceed with loss of water.8 In contrast, for them
‡ Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data. See DOI: 10.1039/c2cc37166a
to serve instead as nucleophiles, condensation reactions of the
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 4157--4159 4157

View Article Online
Communication
ChemComm
Table 1 Preliminary studies
Table 3 Substrate scopea
Entry
R
Catalyst system Solvent
Temp (1C) Yielda (%)
1b
2
Me (3a)
Me (3a)
Ph (3b) II
Ph (3b) II
Ph (3b) II
I
I
THF
THF
Dioxane 100
Dioxane 120
90
65
0c (6b)
0c (6b)
25 (6c)
34 (6c)
50 (6c)
3
4b
5
THF
65
a
b
c
Isolated yield. Reaction run in sealed tube. A complex mixture of
hydration and self-condensation products was observed. I = (o-biphenyl-
di-tert-butylphosphine)gold(I) chloride/AgOTf; II = (IPr)AuCl/AgBF4.
allylic alcohol component must be avoided8h and Claisen
rearrangement would need to occur more rapidly than ketalization9
(further reaction of enol 5 with an additional equivalent of alcohol).
These ostensibly facile but undesirable side-reactions posed a
significant challenge. After extensive screening of catalysts, condi-
tions, etc., to our delight, exposure of prenyl alcohol and tolane to
the cationic Au(I)-complex formed in situ from 5 mol% (IPr)AuCl/
AgBF4 did indeed form the product resulting from tandem hydro-
alkoxylation/Claisen rearrangement, albeit in only 25% yield
(Table 1, entry 3). Increasing the temperature to 120 1C made a
modest enhancement 34% (entry 4), which interestingly was
improved to 50% with the use of THF at 65 1C (entry 5). This
reactivity was unanticipated, as much higher temperatures are
typically required for thermal rearrangements.10
These experiments demonstrated that the desired sequence
could indeed function, but the yield would need to be significantly
improved. The methyl groups in 4b may reduce undesired SN20
reactions,8 but likely also reduce the rate of rearrangement. E- and Z-
substrates 4c and 4d were studied to determine if disubstitution at
C3 was required. Gratifyingly, exposure of 4c to the conditions
resulted in a smooth reaction to provide 6d in 73% yield as a 5 : 1
mixture of diastereomers (entry 1, Table 2). Control experiments
(entries 2, 3) verified that neither Ag+ or H+ catalyze the reaction.
Surprisingly, when the conditions from entry 1 were used with cis-
olefin 4d, none of the desired product was observed (entry 4).
Fortunately, slow addition of 4d led to isolation of the ketone
product in 33% yield in 1 : 11 dr along with 37% of the intermediate
allyl vinyl ether adduct of 4d and 3b (entry 5). Since the
a
b
Isolated yields. Yield obtained using conditions from Table 1, entry
9. Diastereoselectivity determined by 1H NMR (500 MHz). Slow
c
d
e
f
addition of alcohol not required. Substrates: 4c, 3-hexyne. Ratio
(arylketone : alkylketone) determined by 1H NMR (500 MHz). Only a
g
single diastereomer of each regioisomer was observed. Ar = p-OMe-Ph.
rearrangement had not gone to completion, the same conditions
were repeated followed by heating to 120 1C for 6 h (entry 6). The
ketone 6e was produced in 75% yield and 1 : 11 dr and these
conditions were adopted as the standard.
With the optimal conditions established, the substrate scope
was then explored. As can be seen in Table 3, the yield of 6c was
increased to 83% with the optimized conditions (cf. 50%, Table 1).
Allyl alcohol also functioned well, producing 6f in 95% yield
(unoptimized conditions; 15%) and demonstrating that substitu-
ents at C3 of the alcohol are not required. Having two C3
substituents is also tolerated, and the use of geraniol and nerol
provided diastereomers 6j and 6k respectively. Differentially sub-
stituted alkynes were also explored under the optimized conditions.
When one of the phenyl groups in 3b was replaced by methyl (3a), a
4 : 1 mixture of regioisomers 6s was obtained in 78% yield with only
a single diastereomer of each regioisomer detectable.
Table 2 Optimization studies
The electronic and steric nature of the alkyne substituents
were modulated and it was found that when electron-
withdrawing groups are included, the a-aryl ketone is the major
product (e.g. 6m). This regioselectivity is reversed when elec-
tron-donating groups are included, instead favoring aryl
ketones (e.g. 6o). Both a-arylation products and electron rich
aryl ketones are versatile synthons.11 A variety of functional
groups were also tolerated and high selectivity was observed,
e.g. 6i, 6q–6t.
Entry Alcohol Additional conditions
Yielda (%) 6d : 6eb
1
2
3
4
5
6
4c
4c
4c
4d
4d
4d
—
73
0
0
5 : 1
—
—
AgBF4 only
HBF4 OEt2 only
—
Slow addition of 4d
Slow addition of 4d then 120 1C, 6 h 75
.
0
—
1 : 11
1 : 11
33c
a
b
c
Isolated yields. Determined by 1H NMR (500 MHz). Enol ether
adduct of 4d + 3b was also isolated in 37%, see ESI.
4158 Chem. Commun., 2013, 49, 4157--4159
c
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
Notes and references
´
1 For reviews see: (a) A. M. Martın Castro, Chem. Rev., 2004, 104, 2939;
(b) The Claisen Rearrangement: Methods and Applications, ed.
M. Hiersemann and U. Nubbemeyer, Wiley-VCH, 1st edn, 2007, p. 591.
2 L. Claisen, Ber., 1912, 45, 3157.
3 (a) S. E. Denmark and M. A. Harmata, J. Am. Chem. Soc., 1982,
104, 4972; (b) S. E. Denmark and M. A. Harmata, J. Org. Chem., 1983,
48, 3369; (c) M. Koreeda and J. I. Luego, J. Am. Chem. Soc., 1985,
107, 5572; (d) H. Ito, A. Sato, T. Kobayashi and T. Taguchi, Chem.
Commun., 1998, 2441; (e) J. A. May and B. M. Stoltz, J. Am. Chem. Soc.,
2002, 124, 12426; ( f ) G. Nordmann and S. L. Buchwald, J. Am. Chem.
Soc., 2003, 125, 4978; (g) C. Nevado and A. M. Echavarren, Tetra-
hedron, 2004, 60, 9735.
Scheme 2 Transition state analysis.
4 (a) A. Wille, S. Tomm and H. Frauenrath, Synthesis, 1998, 305;
(b) Y. Yamamoto, R. Fujikawa and N. Miyuara, Synth. Commun.,
2000, 30, 2383; (c) T. Higashino, S. Sakaguchi and Y. Ishii, Org. Lett.,
2000, 2, 4193; (d) J. L. Notre, L. Brissieux, D. Semeril, C. Bruneau and
P. H. Dixneuf, Chem. Commun., 2002, 1772; (e) S. C. Nelson,
C. J. Bungard and K. Wang, J. Am. Chem. Soc., 2003, 125, 13000;
( f ) B. Schmidt, Synlett, 2004, 1541; (g) S. G. Nelson and K. Wang,
J. Am. Chem. Soc., 2006, 128, 4232; (h) B. D. Stevens, C. J. Bungard
and S. G. Nelson, J. Org. Chem., 2006, 71, 6397; (i) K. Wang,
C. J. Bungard and S. G. Nelson, Org. Lett., 2007, 9, 2325;
( j) N. T. Patil and A. Konala, Eur. J. Org. Chem., 2010, 6813;
(k) Y. Wang, L. Ye and L. Zhang, Chem. Commun., 2011, 47, 7815.
5 For reviews see: (a) F. Alonso, I. P. Beletskaya and M. Yus, Chem.
Rev., 2004, 104, 3079; (b) H. C. Shen, Tetrahedron, 2008, 64, 3885;
(c) L. Hintermann, Top. Organomet. Chem., 2010, 31, 123.
The origin of the diastereoselectivity was also of interest as
data on alkyl substrates with this enol ether substitution pattern
is sparse. It was found that the products do not equilibrate under
the reaction conditions (eqn (2)), which is in agreement with the
fact that reactions employing isomeric allyl alcohols (4c/4d) do
not provide the same ratio of diastereomeric products.
optimized
ꢀ!
6d or 6e
6d or 6e
(2)
no epimerization
single diastereomer conditions
The observation that cis-allylic alcohols consistently yield pro-
ducts in higher dr than the corresponding trans-allylic alcohols
provides key insight into the relevant reaction pathways. Analysis
of the possible chair and boat transition states (cis-allylic alcohol: C1/
B1; trans-allylic alcohol: C2/B2) for thermal rearrangement reactions
reveals that both of the enol ether substituents are oriented in the
pseudoaxial positions in (Scheme 2). This is inherent to Claisen
substrates with the R1,R2-trans-enol substitution pattern. The chair
transition states (C1/2) would be predicted to be lower in energy than
the competing boat transition states (B1/2),12 and hence cis- and
trans-allylic alcohols lead to the syn and anti diastereomers, respec-
tively. The diastereoselectivity is likely higher for the cis-allylic alcohol
due to specific steric interactions between the alkene and enol ether
substituents. The 1,2-eclipsing interaction in B1 between R2 and R3
likely increases the TS‡ energy more substantially than the corres-
ponding 1,3-diaxial interaction between R1 and R3 in C1. This effect
is diminished in C2/B2 because R3 is equatorial and thus avoids
eclipsing interactions, leading to a smaller DDG‡ with trans-allylic
alcohol substrates. The boat-like transition state therefore becomes
more competitive, leading to the observed erosion in diastereoselec-
tivity. Although the allyl vinyl ether isolated above (Table 2, entry 5)
does undergo thermal rearrangement in the absence of catalyst,13
studies on the extent to which the cascade process is also catalyzed
are underway and will be reported in due course.
6 For reviews see: (a) M. Beller, J. Seayad, A. Tillack and H. Jiao, Angew.
Chem., Int. Ed., 2004, 43, 3368; (b) C. Bruneau and P. Dixneuf, Angew.
Chem., Int. Ed., 2006, 45, 2176. See also: (c) T. Fjermestad, J. H.
H. Ho, S. A. Macgregor, B. A. Messerle and D. Tuna, Organometallics,
2011, 30, 618 and references cited therein.
7 (a) B. D. Sherry and F. D. Toste, J. Am. Chem. Soc., 2004, 126, 15978;
(b) M. H. Suhre, M. Reif and S. F. Kirsch, Org. Lett., 2005, 7, 3925;
(c) B. D. Sherry, L. Maus, B. N. Laforteza and F. D. Toste, J. Am. Chem.
Soc., 2006, 128, 8132; (d) N. W. Reich, C.-G. Yang, Z. Shi and C. He,
Synlett, 2006, 1278; (e) H. J. Bae, B. Baskar, S. E. An, J. Y. Cheong,
D. T. Thangadurai, I. C. Hwang and Y. H. Rhee, Angew. Chem., Int. Ed.,
2008, 47, 2263; ( f ) B. Baskar, H. J. Bae, S. E. An, J. Y. Cheong, Y. H. Rhee,
A. Duschek and S. F. Kirsch, Org. Lett., 2008, 10, 2605; (g) M.-C. P. Yeh,
H.-F. Pai, C.-Y. Hsiow and Y.-R. Wang, Organometallics, 2010, 29, 160;
(h) A. Saito, T. Konishi and Y. Hanzawa, Org. Lett., 2010, 12, 372;
(i) T. Harschneck and S. F. Kirsch, J. Org. Chem., 2011, 76, 2145.
8 (a) A. Aponick, C.-Y. Li and B. Biannic, Org. Lett., 2008, 10, 669;
(b) A. Aponick and B. Biannic, Synthesis, 2008, 3356; (c) A. Aponick,
C.-Y. Li and J. A. Palmes, Org. Lett., 2009, 11, 121; (d) A. Aponick, C.-Y. Li,
J. Malinge and E. F. Marques, Org. Lett., 2009, 11, 4624; (e) A. Aponick,
B. Biannic and M. R. Jong, Chem. Commun., 2010, 46, 6849;
( f ) A. Aponick and B. Biannic, Org. Lett., 2011, 13, 1330; (g) B. Biannic,
T. Ghebreghiorgis and A. Aponick, Beilstein J. Org. Chem., 2011, 7, 802;
(h) B. Biannic and A. Aponick, Eur. J. Org. Chem., 2011, 6605.
9 See: (a) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180; (b) J. Muzart,
Tetrahedron, 2008, 64, 5815; (c) Y. Fukuda and K. Utimoto, J. Org.
Chem., 1991, 56, 3729; (d) J. H. Teles, S. Brode and M. Chabanas,
Angew. Chem., Int. Ed., 1998, 37, 1415; (e) A. Corma, V. R. Ruiz,
´
A. Leyva-Perez and M. J. Sabater, Adv. Synth. Catal., 2010, 352, 1701;
¨
( f ) A. S. K. Hashmi, M. Bu¨hrle, M. Wolfle, M. Rudolph, M. Wieteck,
F. Rominger and W. Frey, Chem.–Eur. J., 2010, 16, 9846; (g) P. Nun,
´
R. S. Ramon, S. Gaillard and S. P. Nolan, J. Organomet. Chem., 2011,
In summary, we have reported an efficient new cascade
696, 7 and references therein.
reaction approach to the synthesis and rearrangement of allyl 10 Reactions often require temperatures in the range of 150–300 1C: see
ref. 1.
vinyl ethers that proceeds from simple compounds to form
ketone products in high yield and diastereoselectivity. The
11 For a-arylation: (a) D. A. Culkin and J. F. Hartwig, Acc. Chem. Res.,
2003, 36, 234; (b) C. C. C. Johansson and T. J. Colacot, Angew. Chem.,
concept of tandem intermolecular alkyne addition/[3,3]-sigma-
tropic rearrangement should be applicable in a variety of
different reaction constructs further enabling the rapid intro-
duction of complexity to simple substrates.
We thank the Herman Frasch Foundation (647-HF07) and
the James and Ester King Biomedical Research Program (09KN-
01) for their generous support of our programs.
Int. Ed., 2010, 49, 676. For oxidation of aryl ketones: (c) R. Gottlich,
K. Yamakoshi, H. Sasai and M. Shibasaki, Synlett, 1997, 971;
(d) P. A. Evans and M. J. Lawler, J. Am. Chem. Soc., 2004, 126, 8642.
12 For relevant reports that include computational analyses of the
transition states see: (a) R. L. Vance, N. G. Rondan, K. N. Houk,
F. Jensen, W. T. Borden, A. Komornicki and E. Wimmer, J. Am.
Chem. Soc., 1988, 110, 2314; (b) C. Uyeda and E. N. Jacobsen, J. Am.
Chem. Soc., 2011, 133, 5062.
13 See Scheme S1 in the ESI‡ for further details.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 4157--4159 4159