Gold-mediated synthesis of α-ionone

Article abstract of DOI:10.1016/j.tetlet.2011.01.010

A simple and convenient synthesis of α-ionone, an important component of flowers and fragrances, is reported. The key step in the formation of the α,β-unsaturated ketone moiety involves an NHC-Au^I catalyzed Meyer-Schuster-like rearrangement of readily prepared propargylic esters. The complex [{Au(IPr)}₂(μ-OH)][BF₄] proved to be the most efficient catalyst leading to α-ionone in 70% yield from a propargylic benzoate. This optimized procedure represents a valuable and attractive alternative to classical methods leading to α,β- unsaturated ketones, such as the Wittig or aldol reactions.

Full text of DOI:10.1016/j.tetlet.2011.01.010

Tetrahedron Letters 52 (2011) 1124–1127
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-mediated synthesis of a-ionone
Valentina Merlini a, Sylvain Gaillard b, Alessio Porta a, Giuseppe Zanoni a, Giovanni Vidari a,
,
⇑
Steven P. Nolan b,
⇑
a Università degli Studi di Pavia, Dipartimento di Chimica Organica, viale Taramelli 10, 27100 Pavia, Italy
b EaStCHEM School of Chemistry, University of Saint Andrews, North Haugh, KY16 9ST St Andrews, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and convenient synthesis of
a
-ionone, an important component of flowers and fragrances, is
reported. The key step in the formation of the
alyzed Meyer–Schuster-like rearrangement of readily prepared propargylic esters. The complex
[{Au(IPr)}2( -OH)][BF4] proved to be the most efficient catalyst leading to -ionone in 70% yield from
a propargylic benzoate. This optimized procedure represents a valuable and attractive alternative to clas-
sical methods leading to ,b-unsaturated ketones, such as the Wittig or aldol reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
a
,b-unsaturated ketone moiety involves an NHC-AuI cat-
Received 12 November 2010
Revised 23 December 2010
Accepted 4 January 2011
Available online 13 January 2011
l
a
a
Keywords:
Ionone
Gold catalysis
Meyer–Schuster rearrangement
Propargylic esters
NHC
1. Introduction
a,b-Unsaturated carbonyl compounds are usually obtained by
aldol or Knoevenagel-type condensation reactions7 or by Wittig
or Horner–Wadsworth–Emmons olefinations.8 These reactions
usually require strong basic conditions, which are often incompat-
ible with various functional groups as well as with the integrity of
stereogenic centers. Moreover, steric hindrance around the car-
bonyl group may severely jeopardize the addition of voluminous
phosphor derivatives. For example, in our previous synthesis of 1,
the Horner–Wadsworth–Emmons olefination of aldehyde 5 affor-
a
-Ionone (1) is a C13 norterpenoïd a,b-unsaturated ketone with
remarkable olfactory properties.1 It occurs in the headspace of dif-
ferent blooming flowers along with the other two regioisomers (2)
and (3) (Fig. 1). a-Ionone (1) represents one of the most important
fragrances used in the perfume industry for their distinctive fine
violet and rose scents. In fact, it is of great economical value in
the creation of violet and many other olfactory notes,2 in addition
to being an important building block in the synthesis of several
natural products.3
ded
a-ionone very sluggishly, resulting in only 13% conversion
after 17 h.6 To circumvent the problem, we resourced to
a
In 1992, Fehr and Guntern4 reported a synthesis of
starting from
this synthesis, the tetrasubstituted cyclohexene ring and the
a
-ionone
-damascone in six-steps and 48% overall yield. In
,b-
Julia–Lythgoe olefination strategy which, however, lengthened
a
the synthetic sequence significantly.6 Therefore, a short and effi-
a
cient synthesis of
a-ionone 1 remained to be explored.
unsaturated ketone are already present in the starting material.
In 2002, Fuganti, Serra et al. summarized the main synthetic routes
An alternative method to obtain
a
,b-unsaturated ketones,
which is attracting increasing interest in the synthetic community,
is the Meyer–Schuster (M.S.) rearrangement9 of propargylic alco-
hols, and related propargylic esters. Strong protic or Lewis acids
have mostly been used as promoters in the earliest versions of
the M.S. reaction. The most recent procedures are based on a
to
a-ionone (as well as to a number of derivatives), including
routes to single enantiomers and their corresponding olfactory
properties.5 All aforementioned syntheses were quite elaborate.
In 2004, Vidari and co-workers reported a highly enantioselective
synthesis of a-ionone 1, which proceeded in 12-steps from a chiral
building block prepared using the asymmetric Sharpless dihydr-
oxylation reaction.6
O
O
O
⇑
Corresponding authors. Tel.: +39 0382 987 322; fax: +39 0382 987 323 (G.V.);
tel.: +44 01334 463763; fax: +44 01334 463808 (S.P.N.).
E-mail addresses: vidari@unipv.it (G. Vidari), snolan@st-andrews.ac.uk (S.P.
Nolan).
α-ionone 1
β-ionone 2
γ-ionone 3
Figure 1. Ionone regioisomers
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.010

V. Merlini et al. / Tetrahedron Letters 52 (2011) 1124–1127
1125
variety of catalytic organometallic species, to which AuI or AuIII
Table 1
complexes have recently been added.10
Optimization of the catalytic system for the synthesis of
a
-ionone 1
In fact, gold derivatives often show high catalytic activity, im-
proved selectivity compared to other methods, and are performed
under mild reaction conditions.11 Therefore, gold catalysis is
receiving considerable attention in the field of natural product syn-
thesis, where functional group compatibility and stereochemistry
integrity are of paramount importance.12
cat.
A, B or C, time, rt
OAc
O
4b
1
A = acetone
B = MeOH/H2O 10:1
C = 2-butanone/H2O 100:1
In 2009, Vidari and co-workers reported a M.S. rearrangement
involving propargylic alcohols mediated by a rhenium(V)-oxo
complex, initially applied to the synthesis of several
a,b-unsatu-
Entry
Cat. (mol %)
HBF4 (6)
Solvent
Time (h)
Yielda (%)
rated ketones, including
a
-ionone 1.10 In addition to its intrinsic
1
2
3
A
B
C
96b
96b
96b
96b
96b
96b
0
0
0
importance, this substrate was selected for its particular electronic
and steric hindrance features, and for the absence of any aromatic
system conjugated to the
a,b-unsaturated moiety, which could
4
5
6
A
B
C
0
40
0
function as the driving force behind the M.S. rearrangement. How-
ever, when we repeated the same reaction of 4a to 1 with other
batches of the rhenium catalyst, prepared from rhenium sources differ-
ent from the original one, we were unable to reproduce the high yields
of the Meyer–Schuster rearrangement previously observed with 4a.10
At present, we do not have any rationale for these contradictory re-
sults, which need further investigation. Thus, we believe that 1 still
represents an ideal substrate to evaluate the efficiency of catalytic
methods leading to the construction of the enone system. Zhang
and co-workers first observed the formation of enones from the
rearrangement of propargylic acetates catalyzed by phosphine
AuI complexes.13 Later, Nolan and co-workers reported a study
on the same reaction with several model substrates, efficiently cat-
alyzed by different NHC-AuI (NHC = N-heterocyclic carbene) com-
plexes in an aqueous medium.14 The course of the reaction was
affected by different factors that include in particular the nature
of the substrate and of the ligand. The reaction mechanism in-
volved the formation of an intermediate gold-allenolate, eventu-
[Au(IPr)(OH)] (4)
7
8
9
A
B
C
0.75
18
30
31
52
33
[{Au(IPr)}2(l-OH)][BF4] (2)
10
11
12
A
B
C
0.75
24
30
30
49
36
[{Au(IPr)}2(l-OH)][NTf2] (2)
13
14
15
A
B
C
0.75
24
30
31
38
44
[Au(IPr)(CH3CN)][BF4] (4)
[Au(IPr)][NTf2] (4)
16
17
18
A
B
C
0.75
24
30
29
44
44
19
20
21
[Au(IPr)(OH)] (4)
+ aq. HBF4 (6)
A
B
C
0.75
1
5
40
51
51
22
23
24
[Au(IPr)(OH)] (4)
+ HNTf2 (6)
A
B
C
5
5
5
37
48
45
ally collapsing to an
Therefore, we envisaged the NHC-AuI catalyzed route to enones
from propargylic esters as a simple alternative approach to
a
,b-unsaturated ketone.15
a
Isolated yield.
24 h at rt and 72 h at 60 °C.
a
-
b
ionone 1 (Scheme 1). Moreover, we were attracted by a few
remarkable features of the present method that nicely agree with
the principles of Green chemistry, such as the non-toxicity of the
solvent and metal ligands and the small amount of the catalyst
employed.
to [Au(OH)(IPr)] (Table 1). All experiments were carried out at room
temperature and monitored by GC until complete consumption of
the starting material 4b. Results are summarized in Table 1.
In control experiments, Brønsted acid alone did not lead to any
conversion of 4b, which was recovered unchanged (Table 1, entries
1–3). Noteworthy, in good agreement with previous work by No-
lan,18b a catalytic amount of [Au(IPr)(OH)] promoted the conver-
sion of 4b to 1 only if the solvent was a mixture of MeOH/H2O
(10/1) (Table 1, entry 5), where [Au(OH)(IPr)] was observed to be
Propargylic ester 4b16 was easily obtained from aldehyde 5,
which was prepared in only three steps from acyclic geranic acid
6, as reported in the literature.3g,10
Initial AuI catalyst optimization experiments (Table 1) made use
of propargylic acetate 4b (R0 = Me), which is the ester-type sub-
strate most frequently encountered in this transformation. The
reactions were performed in three different solvents (A = acetone;
B = MeOH/H2O 10:1; C = 2-butanone/H2O 100:1) in which AuI cata-
lysts have shown the highest efficacy in previous studies.13,14,17As
for the NHC-AuI catalysts, our attention focused on a selection of
(IPr)AuI complexes,18 (IPr = 1,3-bis(2,6-diisopropylphenyl)imida-
zol-2-ylidene) both of mononuclear and dinuclear types18b (Table
1). The digold complexes are generated by Brønsted acid activation
of [Au(OH)(IPr)]. Thus, several well-defined (IPr)AuI complexes or
catalytic systems containing different cationic gold(I) species were
readily prepared by adding 0, 0.5, 1, and 1.5 equiv of a Brønsted acid
in equilibrium with a dinuclear species of type [{Au(IPr)}2(l-OH)]
[X].18b All cationic AuI complexes showed good catalytic activity
for the conversion of porpargylic acetate 4b, affording the expected
a-ionone 1 in 29–52% isolated yield (Table 1, entries 7–24). In ace-
tone (Table 1, entries 7, 10, 13, 16, and 19) the reaction of 4b took
place in only 45 min, while in the other two solvents B and C the
conversion was much slower. On the other hand, in all the three
solvents, especially in acetone, considerable amounts of unidenti-
fied by-products were formed. On the contrary, in MeOH/H2O
(10:1) or 2-butanone/H2O (100:1), in spite of longer reaction times
OH
H
O
4
OR
1
O
O
5
6
4a: R = -H
4b: R = -(CO)R'
Scheme 1. Retrosynthesis of a-ionone.

1126
V. Merlini et al. / Tetrahedron Letters 52 (2011) 1124–1127
(1–30 h), yields of
a-ionone 1 were constantly higher (33–52%)
than in acetone. The use of NTf2 as a counter anion,19, which is
an inner sphere counter anion and well-known to improve selec-
O
Ph
O
tivity, gave results comparable to BF4. Finally, the best yield of
a-
4c
1
ionone 1 was obtained with [{Au(IPr)}2( -OH)][BF4] (2 mol %) as
l
[Au]+
O
the catalyst, in a mixture of MeOH/H2O (10:1) as the solvent (Table
1, entry 8).
H2O
Ph
O
[Au]+
Subsequently, to improve the chemoselectivity of the reaction,
we turned our attention to the R substituent of the propargylic es-
ter 4 (Scheme 1). Propargylic benzoate 4c, p-methoxybenzoate 4d,
and p-chlorobenzoate 4e were investigated in order to evaluate the
electronic effects of the acyl R group on the nucleophilicity of the
carbonyl group that was anticipated to play a key role in the reac-
tion mechanism (see below). The reactions were conducted in the
three different solvents A–C at 60 °C and monitored by GC until
O+
[Au]
O
O
I
III
Ph
Ph
consumption of the starting material. [{Au(IPr)}2(
selected as the best catalyst on the basis of the optimization results
discussed above. In all reactions, a mixture of (Z)- and (E)- -ionone
l-OH)][BF4] was
O
O
[Au]+
II
a
1 was obtained which, after solvent exchange to CH2Cl2, was equil-
ibrated with I2 to the sole (E)-diastereomer.20 Results are presented
in Table 2.
Scheme 2. Proposed mechanism for the formation of
ester 4c.
a-ionone 1 from propargylic
Interestingly, independently from the starting benzoate, the
Based on our recent work on Au-catalyzed allene synthesis,21
and the previous work of Zhang on -iodo- ,b-unsaturated ketone
synthesis,17 we propose the mechanism shown in Scheme 2 for the
conversion of 4c into 1. Initially, activation of the acetylenic -sys-
tem by coordinated AuI induces migration of the benzoate group to
give the allenic ester II. The latter, after activation of the -system
highest yields of
a-ionone 1 were obtained in the 2-butanone/
a
a
H2O (100/1) solvent mixture (Table 2, entries 3, 6, and 9). In stark
contrast, the reaction led to the formation of a large quantity of by-
products in acetone. This was expected on the basis of the results
observed for the rearrangement of acetate 4b (Table 2, entries 1,
4, and 7). Either an-electron donating (Table 2, entries 4–6) or an
electron-withdrawing substituent (Table 2, entries 7–9) at the para
position of the benzoate ring caused no improvement of the reac-
tion chemoselectivity. Finally, the best reaction conditions were
obtained with the unsubstituted propargylic benzoate 4c in the
p
p
of the allenyl framework by the gold center, evolves to the metal-
lated intermediate III, which then collapses to the enone moiety of
a-ionone 1 by proton-Au exchange and hydrolysis of the ester.
In conclusion, we have developed a convenient and efficient
synthesis of the valuable (E)-a
-ionone 1 through a NHC-AuI cata-
presence of [{Au(IPr)}2(l-OH)][BF4] (2 mol %), in a mixture of 2-
lyzed Meyer–Schuster-like rearrangement of readily prepared
propargylic esters. Under optimized conditions, only 2 mol % of
the dimeric species [{Au(IPr)}2(l-OH)][BF4] were required to pro-
butanone/H2O (100:1) at 60 °C for 12 h, affording (E)-
a
-ionone 1
in reproducible 70% isolated yield (Table 2, entry 3).
mote the smooth conversion of the unsubstituted benzoate 4c to
1 in 2-butanone/H2O (100/1). This synthesis of enone 1 represents
the most straightforward approach to the important perfume
Table 2
Optimization of the ester for the
a-ionone 1 synthesis
ingredient
a-ionone, readily proceeding in only seven-steps from
1) [{Au(IPr)}2(µ-OH)][BF4] 2 mol %
A, B or C, time, T (°C)
cyclogeranic acid 6, which is available on multigram scale.
We anticipate that this NHC-AuI catalyzed variant of the
Meyer–Schuster-like rearrangement will find audience among or-
ganic chemists devoted to the synthesis of complex natural prod-
O
O
R
2) I2, CH2Cl2, rt
1
O
ucts or synthetic molecules, where the
a,b-unsaturated ketone
moiety frequently occurs. In fact, we believe that our optimized
procedure is a valuable and attractive alternative to classical meth-
ods leading to enone systems, such as the Wittig or aldol reactions.
R = Ph 4c, p-methoxyphenyl 4d, p-chlorophenyl 4e
A = acetone
B = MeOH/H2O 10:1
C = 2-butanone/H2O 100:1
2. Experimental section
2.1. Benzoate 4c
Entry
Ester
Solvent
Time (h)
T (°C)
Yielda (%)
1
2
3
4c
4c
4c
A
B
C
14b
14b
14b
60
60
60
22
43
70
Pyridine (0.18 ml, 2.23 mmol) was added to a solution of alco-
hol 4a (75 mg, 0.39 mmol) in dry CH2Cl2 (4 ml). Subsequently, ben-
zoyl chloride (0.085 ml, 0.73 mmol), followed by catalytic amount
of DMAP, were slowly added at 0 °C. After 1 h of stirring at rt, the
reaction mixture was quenched by the addition of saturated aque-
ous solution of NaHCO3. The aqueous layer was extracted with
CH2Cl2 (3 ꢀ 25 ml). The combined organic layers were washed
with H2O, saturated aqueous solution of CuSO4, dried over Na2SO4,
and concentrated at reduced pressure. The crude product was puri-
fied by column chromatography (pentane/Et2O 97:3) to give the
pure benzoate 4c (77.2 mg, 73%). 1H NMR (300 MHz, CDCl3): d
0.96 (s, 3H), 1.12 (s, 3H), 1.74–1.82 (m, 2H), 1.85 (s, 3H), 1.86 (s,
3H), 2.01 (m, 1H), 2.01–2.07 (m, 2H), 5.64 (m, 1H), 5.70 (t, 1H),
4
5
6
4d
4d
4d
A
B
C
14b
14b
14b
48c
24
48
60
60
60
38
43
52
7
8
9
4e
4e
4e
A
B
C
60
rt
60
30d
25
42e
a
Isolated yield.
b
Reaction afforded a mixture of (E)- and (Z)-a-ionone at 60 °C in 12 h. Subse-
quently, the solvent was removed; CH2Cl2 and two crystals of I2 were added, to
isomerize the entire mixture to (E)-
a
-ionone.
c
24 h at rt + 24 h at 60 °C.
Only 70% starting material was converted.
Only 85% starting material was converted.
d
e

V. Merlini et al. / Tetrahedron Letters 52 (2011) 1124–1127
1127
7.47 (m, 2H), 7.57–7.60 (m, 1H), 8.05–8.07 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d 3.8 (q), 22.9 (t), 24.2 (q), 27.3 (q), 28.5 (q), 32.1
(t), 32.5 (s), 53.7 (d), 63.6 (d), 77.6 (s), 82.8 (s), 124.5 (d), 128.4 (d),
129.8 (d), 130.4 (s), 131.1 (s), 133.0 (d), 165.5 (s) ppm. HRMS (ES+):
calcd for C20H24O2Na: 319.1674. Found: 319.1677.
3. (a) Frater, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633–7703; (b)
Buchecker, R.; Egli, R.; Regel-Wild, H.; Tscharner, C.; Eugster, C. H.; Uhde, G.;
Ohloff, G. Helv. Chim. Acta 1973, 56, 2548–2563; (c) Baraldi, P. G.; Barco, A.;
Benetti, S.; Pollini, G. P.; Polo, E.; Simoni, D. J. Chem. Soc., Chem. Commun. 1986,
86, 757–758; (d) Ubelhart, P.; Baumeler, A.; Haag, A.; Prewo, R.; Bieri, J. H.;
Eugster, C. H. Helv. Chim. Acta 1986, 69, 816–834; (e) Colombo, M. I.; Zinczuk, J.;
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A.; Zanoni, G.; Vidari, G. Chem. Biodivers. 2008, 5, 1045–1057.
2.2. AuI-catalyzed rearrangement of 4c:
a-ionone (1)
4. Fehr, C.; Guntern, O. Helv. Chim. Acta 1992, 75, 1023–1028.
5. Brenna, E.; Fuganti, C.; Serra, S.; Kraft, P. Eur. J. Org. Chem. 2002, 967–978.
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2004, 69, 8959–8962.
In a screw cap vial, [{Au(IPr)}2(
mmol) was added to a solution of propargylic benzoate 4c
l
-OH)][BF4] (6.3 mg, 4.9 ꢀ 10ꢁ3
7. (a) Jones, G. Org. React. 1967, 15, 204–599; (b) Smith, M. B.; March, J. Advanced
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(73 mg, 0.25 mmol) in a mixture of butanone/water (2.5 ml +
25 ll), then the reaction mixture was stirred at 60 °C for 12 h.
The solvent was removed at reduced pressure and CH2Cl2
(2.5 ml), followed by two crystals of I2 were added. After 2 h of stir-
ring at rt, the reaction mixture was quenched by the addition of a
saturated aqueous solution of Na2S2O3, then the aqueous layer was
extracted with CH2Cl2 (3 ꢀ 20 ml), and the combined organic lay-
ers were washed with brine, dried over Na2SO4, and concentrated
at reduced pressure. The crude product was purified by column
chromatography (pentane/Et2O 98:2) to give pure (E)-a-ionone 1,
identical with a commercial authentic sample (33 mg, 70%). 1H
NMR (300 MHz, CDCl3) d 0.87 (s, 3H), 0.94 (s, 3H), 1.19–1.29 (m,
1H), 1.47 (ddd, J = 13.3, 8.3, 8.1 Hz, 1H), 1.58 (q, J = 1.7 Hz, 3H),
2.0–2.10 (m, 2H), 2.26 (s, 3H), 2.30 (d, J = 9.2 Hz, 1H), 5.48–5.55
(m, 1H), 6.06 (d, J = 16.0 Hz, 1H), 6.63 (dd, J = 16.0, 9.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 22.8 (q), 23.0 (t), 26.7 (q), 26.9 (q),
27.8 (q), 31.1 (t), 32.5 (s), 54.2 (d), 122.6 (d), 131.9 (s), 132.3 (d),
149.1 (d), 198.6 (s); HRMS calcd for C13H20O: 192.15142. Found:
192.15145.
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3940–3944. and references cited therein.
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Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896–7936; (c) Hashmi, A. S. K.
Chem. Rev. 2007, 107, 3180–3211.
13. (a) Yu, M.; Li, G.; Wang, S.; Zhang, L. Adv. Synth. Catal. 2007, 349, 871–875; For a
review on propargylic esters in gold catalysis, see: (b) Marion, N.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 2750–2752.
14. Marion, N.; Carlqvist, P.; Gealageas, R.; de Frémont, P.; Maseras, F.; Nolan, S. P.
Chem. Eur. J. 2007, 13, 6437–6451.
Acknowledgments
15. (a) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L.
Angew. Chem., Int. Ed. 2008, 47, 718–721; (b) Marion, N.; Nolan, S. P. Chem. Soc.
Rev. 2008, 37, 1776–1782.
16. We are well aware that, in principle, the direct Meyer–Schuster rearrangement
of propargylic alcohol 4a could yield the expected enone 1; however, under our
conditions, a complex mixture was obtained, containing also an unidentified
The ERC (FUNCAT-Advanced Researcher grant to S.P.N.), the
EPSRC, and the MIUR (PRIN funds) are gratefully acknowledged
for the support of this work. S.P.N. is a Royal Society-Wolfson Re-
search Merit Award holder.
product, which is under investigation in our laboratories. For
a recent
application of the Meyer–Schuster rearrangement to the synthesis of natural
products, see: Ramón, R. S.; Gaillard, S.; Slawin, A. M. Z.; Porta, A.; D’Alfonso, A.;
Zanoni, G.; Nolan, S. P. Organometallics 2010, 29, 3665–3668.
17. Yu, M.; Zhang, G.; Zhang, L. Tetrahedron 2009, 65, 1846–1855.
18. For the synthesis of well-defined gold(I) complexes, see Ref. 15 and: (a)
Gaillard, S.; Slawin, A. M. Z.; Nolan, S. P. Chem. Commun. 2010, 46, 2742–2744;
(b) Gaillard, S.; Bosson, J.; Ramón, R. S.; Nun, P.; Slawin, A. M. Z.; Nolan, S. P.
Chem. Eur. J. 2010, 16, 13729–13740.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.010.
References and notes
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