A general procedure for the synthesis of enones via gold-catalyzed Meyer-Schuster rearrangement of propargylic alcohols at room temperature

Article abstract of DOI:10.1021/jo102263t

Meyer-Schuster rearrangements of propargylic alcohols take place readily at room temperature in toluene with 1-2 mol % PPh₃AuNTf₂, in the presence of 0.2 equiv of 4-methoxyphenylboronic acid or 1 equiv of methanol. Good to excellent yields of enones can be obtained from secondary and tertiary alcohols, with high selectivity for the E-alkene in most cases. A one-pot procedure for the conversion of primary propargylic alcohols into β-arylketones was also developed, via Meyer-Schuster rearrangement followed by Pd-catalayzed addition of a boronic acid.(Figure Presented)

Full text of DOI:10.1021/jo102263t

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developed using Au(I) catalysis.4 The first reports required
A General Procedure for the Synthesis of Enones via
Gold-Catalyzed Meyer-Schuster Rearrangement of
Propargylic Alcohols at Room Temperature
conversion of the alcohol to the corresponding acetate,5 but
more recently procedures have been developed for the direct
rearrangement of the alcohols themselves.6-10
During the course of an ongoing research project on the
gold-catalyzed generation of boron enolates from alkynes,11
we explored the reaction of propargylic alcohols with boronic
acids in the presence of the commercially available gold
catalyst, PPh3AuNTf2.12 We had envisioned that rapid con-
densation of the alcohol 1 with the boronic acid would lead
to an intermediate 2, which would form the boron enolate 3
after Au(I)-catalyzed cyclization (Scheme 1). We hoped to be
able to trap the enolate 3 with an aldehyde but the only
products observed were the β-hydroxyketone 4 and the
enone 5. Previous literature reports of gold-catalyzed rear-
rangements of this type require prolonged heating in
methanol,6 the addition of additives which can hinder
purification,7 or moderately high catalyst loadings and/or
noncommercial catalysts.8,9 In some cases, the procedures
are limited to highly activated alkynyl ethers.9 We therefore
reasoned that our boronic acid mediated approach might
provide a superior method, especially as it employed a simple
and readily available catalyst and appeared to take place
rapidly at room temperature.
Matthew N. Pennell,† Matthew G. Unthank,‡ Peter Turner,‡
and Tom D. Sheppard*,†
†Department of Chemistry, University College London,
Christopher Ingold Laboratories, 20, Gordon Street, London
WC1H 0AJ, U.K., and ‡GlaxoSmithKline R & D Limited,
Medicines Research Centre, Gunnels Wood Road, Stevenage,
Herts, SG1 2NY, U.K.
tom.sheppard@ucl.ac.uk
Received November 18, 2010
SCHEME 1. Proposed Gold-Catalyzed Boron Enolate Forma-
tion from a Propargylic Alcohol
Meyer-Schuster rearrangements of propargylic alcohols
take place readily at room temperature in toluene with
1-2 mol % PPh3AuNTf2, in the presence of 0.2 equiv of
4-methoxyphenylboronic acid or 1 equiv of methanol.
Good to excellent yields of enones can be obtained from
secondary and tertiary alcohols, with high selectivity
for the E-alkene in most cases. A one-pot procedure
for the conversion of primary propargylic alcohols into
β-arylketones was also developed, via Meyer-Schuster
rearrangement followed by Pd-catalayzed addition of a
boronic acid.
Propargylic alcohol 6a was used as a test substrate to
optimize the reaction conditions (Scheme 2 and Table 1).
A brief examination of solvents (entries 1-5) indicated that
The synthesis of R,β-unsaturated carbonyl compounds is
traditionally achieved via aldol condensation or via a Wittig,
Horner-Wadsworth-Emmons or Petersen olefination
reaction.1 A potentially useful alternative strategy is the
addition of a metalated alkyne to an aldehyde or ketone,
followed by a Meyer-Schuster rearrangement2,3 of the
resulting propargylic alcohol. The classical Meyer-Schuster
rearrangement3 involves heating the alcohol with strong acid
which is incompatible with many functional groups. More
recently, milder conditions for this reaction have been
(4) For recent reviews on gold catalysis, see: (a) Shapiro, N. D.; Toste,
F. D. Synlett 2010, 675–691. (b) Hashmi, A. S. K. Angew. Chem., Int. Ed.
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Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351–3378. (f)
Li, Z; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265. (g) Arcadi, A.
Chem. Rev. 2008, 108, 3266–3325. (h) Hashmi, A. S. K. Chem. Rev. 2007, 107,
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DOI: 10.1021/jo102263t
r
Published on Web 01/25/2011
J. Org. Chem. 2011, 76, 1479–1482 1479
2011 American Chemical Society

Pennell et al.
JOCNote
SCHEME 2. Optimization of the Gold-Catalyzed Meyer-
Schuster Rearrangement
SCHEME 3. Gold-Catalyzed Meyer-Schuster Rearrangement
of Secondary Propargylic Alcohols
TABLE 1. Optimization of the Gold-Catalyzed Meyer-Schuster
Rearrangement in the Presence of Hydroxyl-Containing Additives
entry
solvent
additive
conversion
9a:8a
E:Z
1
2
3
4
5
6
7
8
CH2Cl2
MeOH
THF
0.1 equiv 7a
0.1 equiv 7a
0.1 equiv 7a
43%
58%
46%
28%
76%
99%
99%
54%
64%
43%
98%
100%
1.2:1
4.3:1
1.6:1
3.0:1
1.8:1
2.0:1
1.8:1
1.8:1
1.1:1
>36:1
2.6:1
10.5:1
>30:1
27:1
20:1
20:1
Acetone 0.1 equiv 7a
aReaction performed on a 1 g scale with 1 mol % Au catalyst.
bSixteen hours reaction time.
PhMe
PhMe
PhMe
PhMe
PhMe
MeOH
PhMe
PhMe
0.1 equiv 7a
0.2 equiv 7a
1 equiv 7a
0.2 equiv 7b
-
27:1
>30:1
7.8:1
5.6:1
5.1:1
5.1:1
SCHEME 4. Gold-Catalyzed Meyer-Schuster Rearrangement
of Tertiary Propargylic Alcohols
9
10
11
12
-
0.1 equiv MeOH
1 equiv MeOH
9a only 17:1
more polar solvents were unsuitable and that toluene was
optimal, giving a much higher conversion. Increasing the
quantity of boronic acid 7a to 0.2 equiv led to higher
conversion and gave the enone 9a with a higher E:Z selec-
tivity (entry 6). However, there was no real benefit in using a
stoichiometric quantity of 7a (entry 7). Phenylboronic acid
7b was much less effective (entry 8).13
In the absence of boronic acid, a lower conversion was
observed, suggesting that the boronic acid accelerates
the rearrangement reaction (entry 9). Curiously, the use
of methanol as solvent, either in the presence (entry 2)
or absence of 7a (entry 10), suppressed the formation of
β-hydroxyketone 8a, with 9a being obtained as the sole
product in the latter case. This led us to examine the use
of small quantities of methanol as an additive (Entries 11
and 12). Pleasingly, the use of 1 equiv of methanol, with
toluene as the solvent, led to clean rearrangement of 6a to
9a with excellent conversion and very high selectivity in
favor of the E isomer (entry 12).
aWith 1 equiv MeOH. bWith 0.2 equiv 7a.
In combination with the straightforward addition of an
alkynyl anion to an aldehyde, this reaction offers a conve-
nient alternative to the Horner-Wadsworth-Emmons ole-
fination or the Wittig reaction of a ketone-stabilized ylide,1
and avoids the generation of phosphorus waste products.
The rearrangement of alcohol 6a was also performed on a 1 g
scale to give the enone 9a in 83% yield using only 1 mol % Au
catalyst.
Under the optimized reaction conditions, a number of
secondary propargylic alcohols underwent Meyer-Schuster
rearrangement to give the corresponding E-enones in good
to excellent yield and with high E:Z selectivity (Scheme 3).
Tertiary propargylic alcohols also underwent rearrange-
ment in the presence of 1 equiv of methanol to give the
corresponding β,β-disubstituted enones (Scheme 4). Higher
yields and greater E:Z selectivities were obtained in the
presence of catalytic quantities of boronic acid 7a, though
longer reaction times were required. This method provides
access to highly substituted enones in good to excellent yield,
and with moderate to excellent E:Z selectivity. Notably, the
sterically crowded enone 11d was obtained in good yield and
ꢀ
(8) (a) Ramon, R. S.; Gaillard, S.; Slawin, A. M. Z.; Porta, A.; D’Alfonso,
A.; Zanoni, G.; Nolan, S. P. Organometallics 2010, 29, 3665–3668. (b) Lee,
S. I.; Baek, J. Y.; Sim, S. H.; Chung, Y. K. Synthesis 2007, 2107–2114. (c)
Georgy, M.; Boucard, V.; Debleds, O.; Dal Zotto, C.; Campagne, J.-M.
Tetrahedron 2009, 65, 1758–1766.
(9) (a) Engel, D. A.; Lopez, S. S.; Dudley, G. B. Tetrahedron 2008, 64,
6988–6996. (b) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027–4029. (c)
Lopez, S. S.; Engel, D. A.; Dudley, G. B. Synlett 2007, 949–953.
(10) For examples of other metal catalysts for the Meyer-Schuster
rearrangement, see: (a) Tanaka, K.; Shoji, T.; Hirano, M. Eur. J. Org.
Chem. 2007, 2687–2699. (b) Stefanoni, M.; Luparia, M.; Porta, A.; Zanoni,
G.; Vidari, G. Chem. - Eur. J. 2009, 15, 3940–3944. (c) Cadierno, V.;
Francos, J.; Gimeno, J. Tetrahedron Lett. 2009, 50, 4773–4776.
€
(11) Korner, C. K.; Starkov, P.; Sheppard, T. D. J. Am. Chem. Soc. 2010,
132, 5968–5969.
(14) (a) Castelani, P.; Comasseto, J. V. Tetrahedron 2005, 61, 2319–2326.
(b) Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008, 10, 1291–
1294. (c) Bunnelle, W. H.; Rafferty, M. A.; Hodges, S. L. J. Org. Chem. 1987,
52, 1603–1605. See also ref 7a for a synthesis of this compound via a gold-
catalyzed Meyer-Schuster rearrangement that proceeds with much lower
E:Z selectivity.
ꢀ
(12) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–4136.
(13) We have observed that commercially available samples of phenyl-
boronic acid often contain large quantities of the trimeric boroxine and this
may account for its poor reactivity in this reaction.
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Pennell et al.
JOCNote
SCHEME 5. One-Pot Meyer-Schuster Rearrangement and
Boronic Acid Addition Reactions of Primary Propargylic
Alcohols
SCHEME 6. Possible Mechanisms for the Gold-Catalyzed
Meyer-Schuster Rearrangement
of the vinyl gold intermediate 20 might help to prevent
elimination to form an allenyl boranate analogous to 18.
The possibility that enone 5 may result from boronic acid
assisted addition of adventitious water to the alkyne cannot
be excluded at this stage however. We have observed that an
isolated sample of β-hydroxyketone 8a was not converted to
enone 9a (and vice versa) under the reaction conditions, so
the two products must be produced via divergent reaction
pathways, possibly from an intermediate such as 3. However,
we are still not certain exactly what role the protic nucleo-
phile (MeOH or 7a) plays in the reaction. Further work is
underway to obtain a detailed understanding of the mechan-
ism of these rearrangement reactions and to determine the
precise role of these additives.
In summary, we have developed convenient and general
protocols for gold-catalyzed room temperature Meyer-
Schuster rearrangement of secondary and tertiary pro-
pargylic alcohols in the presence of small quantities of
methanol or 4-methoxyphenylboronic acid. Coupled with
the straightforward addition of metalated alkynes to carbo-
nyl compounds, this provides a convenient enone synthesis
that is competitive with traditional phosphorus-mediated
olefination approaches and proceeds in good to excellent
overall yield. Highly reactive terminal enones can also be
generated from primary propargylic alcohols, and used directly
in one-pot transformations to give β-arylketones via Pd-cata-
lyzed addition of a boronic acid to the resulting enone.
with excellent selectivity for the E-isomer.14 Even the enone
11c in which the two alkyl groups are very similar in size was
obtained with moderate E:Z selectivity. These highly hin-
dered enones would be very difficult to access via traditional
olefination chemistry.
Meyer-Schuster rearrangement of primary propargylic
alcohols leads to the formation of highly reactive unsubsti-
tuted enones and, even in the presence of the small quantities
of methanol used in our reactions, conjugate addition of
methanol to the enone was observed.15 However, in the
presence of the boronic-acid additive 7a, clean rearrange-
ment to the unsubstituted enones could be achieved (Scheme 5).
These enone systems are difficult to handle, so we therefore
sought to develop practical one-pot procedures for their
generation and reaction in situ. As an example, gold/boronic
acid catalyzed rearrangement could readily be combined
with Pd-catalyzed addition of the boronic acid to the enone
1316 to give access to β-arylketones 14a-14d in moderate to
good yields. The lower yield of 14b can be attributed to the
fact that boronic acid 7b is less effective in the rearrangement
step and this is also likely to be the case for the hindered
boronic acid used in the preparation of 14c.13
In the presence of alcohols, the Meyer-Schuster rearran-
gement has been proposed to proceed via the formation of an
allenyl ether (Scheme 6).2,7-9 This can be generated by
addition of methanol (16) to the activated alkyne (15),
followed by proton transfer (17) and elimination of water
to give the allenyl ether 18.5 This then undergoes hydrolysis,
possibly via further activation by the gold catalyst, to give the
enone 5. The formation of the enone in the boronic-acid
mediated reaction could also proceed via a similar pathway.
However, the β-hydroxyketone 4 is also obtained from these
reactions and one plausible explanation is that 4 and 5 are
produced via a common intermediate such as 3. This inter-
mediate 3 could be generated via initial formation of the
boronate half ester 19, followed by cyclization (20) and
protodeauration. The β-hydroxyketone 4 could then be
produced via direct hydrolysis of this intermediate and the
enone 5 via a concerted (potentially Au-catalyzed) rearran-
gement. It seems reasonable to assume that the cyclic nature
Experimental Section
Dec-6-en-5-one 9a5c. [Ph3PAuNTf2]2PhMe (8 mg, 1 mol %)
and MeOH (0.02 mL, 0.53 mmol) were added to a solution of
Dec-5-yn-4-ol 6a (95 mg, 0.53 mmol) in toluene (0.5 mL) and the
solution was stirred at room temperature until the starting
material had disappeared (TLC). The solvent was removed
in vacuo and the crude product was purified by column chro-
matography to afford Dec-6-en-5-one 9a as a pale yellow oil:
(77 mg, 91%); νmax (film/cm-1) 2933, 2873 (C-H), 1712 (CdO);
δH (500 MHz, CDCl3) 0.91 (3H, t, J 7.5), 0.93 (3H, t, J 7.4),
1.29-1.37 (2H, sx, J 7.5), 1.45-1.53 (2H, sx, J 7.4), 1.55-1.61
(2H, qn, J 7.5), 2.16-2.20 (2H, qd, J 7.4, 1.4), 2.52 (2H, t, J 7.5),
6.08 (1H, dt, J 15.8, 1.4), 7.09 (1H, dt, J 15.8, 7.0); δC (500 MHz,
CDCl3) 13.8, 14.0, 21.5, 22.5, 26.4, 34.3, 39.8, 130.7, 147.1,
201.1.
(15) The addition of methanol to unsubstituted enones during Au(I)-
catalyzed Meyer-Schuster rearrangements has been previously observed,
see ref 6.
(16) Yamamoto, T.; Iizuka, M.; Takenaka, H.; Ohta, T.; Ito, Y.
J. Organomet. Chem. 2009, 694, 1325–1332.
3-Ethyl-non-3-en-5-one 11a. [Ph3PAuNTf2]2PhMe (10 mg,
1 mol %) and MeOH (0.03 mL, 0.65 mmol) or 4-methoxyboronic
acid 7a (21 mg, 0.13 mmol) were added to a solution of 3-ethyl-
non-4-yn-3-ol 10a (100 mg, 0.65 mmol) in toluene (0.5 mL) and
J. Org. Chem. Vol. 76, No. 5, 2011 1481

Pennell et al.
JOCNote
the solution was stirred at room temperature until the starting
material had disappeared (TLC). The solvent was removed in
vacuo and the crude product was purified by column chroma-
tography to afford 3-ethyl-non-3-en-5-one 11a (75 mg, 75%);
for 24 h. After cooling to room temperature, the reaction was
quenched with sat. NaHCO3 solution (5 mL). The organic
layer was then extracted with diethyl ether (2 Â 10 mL). The
combined organic layers were washed with brine (10 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by
column chromatography (ethyl acetate-petrol 1:30) to give 14a as
a colorlessoil(170 mg, 81%); νmax (film/cm-1) 2960, 2835 (C-H),
1710 (CdO), 1511 (Ar-OMe); δH (500 MHz, CDCl3) 0.89 (3H, t,
J 7.4), 1.58 (2H, sx, J 7.4), 2.35 (2H, t, J 7.4), 2.68 (2H, t, J 7.6), 2.83
(2H, t, J 7.6), 3.77 (3H, s), 6.81 (2H, d, J 8.5) 7.09 (2H, d, J 8.5); δC
(500 MHz, CDCl3) 13.8, 17.3, 29.1, 44.4, 44.7, 55.4, 114.3, 129.5,
133.4, 158.0, 210.5; Found (EI): [M] 206.13054, C13H18O2 requires
206.13012.
ν
max (film/cm-1) 2962, 2934, 2875 (C-H), 1686 (CdO); δH (500
MHz, CDCl3) 0.89 (3H, t, J 7.4), 1.03 (3H, t, J 7.5), 1.05 (3H, t, J
7.5), 1.27-1.34 (2H, sx, J 7.4), 1.52-1.57 (2H, qn, J 7.5),
2.12-2.17 (2H, qd, J 7.4, 1.3), 2.40 (2H, t, J 7.4), 2.54 (2H,
qd, J 7.5, 1.3), 5.97 (1H, s); δC (500 MHz, CDCl3) 12.2, 13.1,
14.0, 22.5, 25.9, 26.6, 31.1, 44.3, 121.2, 165.5, 201.4; Found (EI):
[M] 168.15087, C11H20O requires 168.15043.
1-(4-Methoxyphenyl)-hexan-3-one 14a17. [Ph3PAuNTf2]2PhMe
(16 mg, 1 mol %) and 4-methoxyphenylboronic acid 7a (33 mg,
0.20 mmol) were added to a solution of 2-hexyn-1-ol 12a (100 mg,
1.02 mmol) in toluene (2 mL) under argon and the solution was
stirred at room temperature until the starting material had
Acknowledgment. We would like to thank the EPSRC
(EP/E052789/1: Advanced Research Fellowship to T.D.S.,
and EP/G040680/1: Organic Synthesis Studentship to M.N.P.),
and GlaxoSmithKline for supporting this work.
disappeared (TLC). The reaction was then charged with Pd2(dba)3
3
CHCl3 (27 mg, 2.5 mol %), PPh3(13 mg, 5 mol %), 4-methoxy-
phenylboronic acid 7a (297 mg 1.84 mmol), and cesium carbonate
(332 mg 1.02 mmol). The resulting solution was stirred at 60 °C
Supporting Information Available: Experimental procedures,
1
spectral data and copies of H and 13C NMR. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Berthiol, F.; Doucet, H.; Santelli, M. Appl. Organomet. Chem. 2006,
20, 855–868.
1482 J. Org. Chem. Vol. 76, No. 5, 2011