Relay-Heck Cross-Coupling Between Alkenyl Halides and Unsaturated Alcohols in the Synthesis of Open-Chain Analogues of Musk Odorant Vulcanolide

Article abstract of DOI:10.1002/chem.202101080

Unactivated alkenyl iodides and bromides underwent an unprecedented palladium-catalyzed relay-Heck cross-coupling with a whole range of alkenols of different chain lengths linking the alkene and the alcohol, affording unsaturated aldehydes and ketones in moderate to good yields. In contrast, alkenyl triflates were not suitable partners for this reaction. This method allowed the preparation of open-chain analogues of the musk odorant Vulcanolide, several of which retained key olfactory properties of the parent molecule.

Full text of DOI:10.1002/chem.202101080

Accepted Article
Accepted Article
Title: A Relay-Heck Cross-Coupling Between Alkenyl Halides and
Unsaturated Alcohols in the Synthesis of Open-Chain Analogues
of Musk Odorant Vulcanolide
Authors: Julien Coulomb, Anthony Lenormand, and Lucía Reyes
Méndez
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202101080
Link to VoR: https://doi.org/10.1002/chem.202101080
01/2020

10.1002/chem.202101080
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A Relay-Heck Cross-Coupling Between Alkenyl Halides and
Unsaturated Alcohols in the Synthesis of Open-Chain Analogues
of Musk Odorant Vulcanolide
Anthony Lenormand,[a] Lucía Reyes Méndez,[a] and Julien Coulomb*[a]
Dedicated to Charles Fehr on the occasion of his 75th birthday
[a]
A. Lenormand, L. Reyes Méndez, Dr. J. Coulomb
Firmenich SA, Corporate R&D Division
Rue de la Bergère 7, 1242 Satigny, Switzerland
E-mail: julien.coulomb@firmenich.com
http://www.firmenich.com/
Abstract: Unactivated alkenyl iodides and bromides underwent an
unprecedented palladium-catalyzed relay-Heck cross-coupling with a
whole range of alkenols of different chain lengths linking the alkene
and the alcohol, affording unsaturated aldehydes and ketones in
moderate to good yields. In contrast, alkenyl triflates were not
suitable partners for this reaction. This methodology allowed for the
preparation of open-chain analogues of the musk odorant
Vulcanolide, several of which retained key olfactory properties of the
parent molecule.
Cashmeran (4) (IFF), Moxalone (5) (Givaudan) and Nebulone
(6) (IFF) (Figure 2), all share the same olfactophore based on a
double bond at the ring junction. We surmised that this was a
structural requirement for a musky smell, and designed target
open-chain analogues of the type 7, where R stands for an alkyl
substituent.
O
O
O
O
H
O
R
The importance of musk odorants in perfumery is directly related
to their distinctive scent, which is commonly depicted as soft,
warm, sweet, animal, combined with their tenacity and
longlastingness.[1,2] Among the different families of musks known
to date, polycyclic aromatic musks (PCMs), and particularly
Galaxolide (1) (International Flavors and Fragrances Inc. (IFF))
and Tonalide (2) (Polak’s Frutal Works) (Figure 1), are still
predominant in terms of tonnage.[3] Vulcanolide (3), discovered
at Firmenich by Charles Fehr in the late 1980s,[4,5] turned out to
exhibit additional earthy and powdery facets, while being more
tenacious than Tonalide and at least 10 times stronger. Further
investigation revealed that its odor was almost entirely due to
the (–)-enantiomer,[6] and two efficient enantioselective
syntheses involving the enantioselective protonation of a ketone
enolate as a key step were developed.[7]
Cashmeran
Moxalone
Nebulone
4
5
6
7
Figure 2. Polycyclic non-aromatic musks.
Our retrosynthetic analysis suggested that the cyclohexene-
propanal moiety of 7 could arise from the corresponding
cyclohexanone 8, as already well-documented in the perfumery
chemistry field (Figure 3).[12] The trans-configuration of 8 would
be installed during the reductive cycloisomerization of 1,7-diene
9 which, in turn, would be prepared by the addition of a prenylic
organometallic reagent onto aldehyde 10.
O
O
OH
H
O
H
R
O
O
7
10
8
9
H
Figure 3. Retrosynthetic approach towards 7.
O
Aldehyde 10 was easily prepared in multi-decagram scale in a
known two-step sequence starting from prenol 11[13] (Scheme 1).
A Barbier-type addition of prenyl bromide in the presence of zinc
provided alcohol 9. The zirconocene-promoted reductive
cycloisomerization of 1,6 or 1,7-dienes is known to provide
mixtures of cis and trans isomers, with a ratio strongly
depending on the substitution pattern.[14] To our delight, multi-
substituted dienol 9 afforded 12 on several decagram-scale as
the sole trans diastereomer, without the need for alcohol
protection. Its oxidation with PCC proceeded smoothly to
provide heptamethyl-cyclohexanone 8.
1
2
3
Galaxolide
Tonalide
Vulcanolide
Figure 1. Polycyclic aromatic musks.
These unique features make Vulcanolide an attractive target for
the design of new musk odorants; however, the use of PCMs in
fragrances is regulated due to their low biodegradabilities and
tendencies to bioaccumulate.[8] We hypothesized that the
synthesis of open-chain analogues could, at least partially,
overcome these challenges, while maintaining good olfactory
properties. This strategy has already been used extensively by
Kraft, in particular for the preparation of new rose,[9] musk[10] and
cassis[11] odorants.
The design of acyclic analogues implies the breaking of alicyclic
carbon-carbon bonds. Non-aromatic polycyclic musks, such as
1
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the branched isomer was not observed, probably owing to the
steric bias around the alkenyl Pd(II) intermediate.
H
O
2 steps
OH
Br, Zn
13)
Encouraged by these promising results, we sought to extend our
methodology to more challenging substrates. The Heck cross-
coupling of unactivated alkenyl halides and allylic alcohols is
known,[22] and it can be the result of a simple addition/elimination,
without proceeding via a relay process (Scheme 2a). However,
in the case of homoallylic and longer chain unsaturated alcohols,
a relay must occur. This reaction has only been exploited with α-
oxo alkenyl iodides (Scheme 2b)(i).[23] Sigman demonstrated
that alkenyl triflates were eligible coupling partners for the
enantioselective relay-Heck alkenylation of various alkenols
(Scheme 2b)(ii),[24] but introducing an electron-withdrawing
group was again necessary, as a preliminary experiment with 1-
NH
10
96
4Cl/THF
min
%
(ref.
aq.
r.t.,
11
10
n
1. -BuLi
equiv.)
equiv.)
(3.8
ZrCl
Cp2
THF, -78°C to
2 (1.5
OH
OH
r.t.
PCC
CH2Cl2
2.
NH Cl
aq.
53
4
%
98
%
9
12
1. N2H
equiv.)
equiv.)
-BuOH/(CH2OH)2
4 (20
4 (1
H
2SO
I
O
n
∆
,
2. I2 NEt toluene, 0°C
,
,
3
37
%
cyclohexen-1-yl triflate gave a disappointing 15% yield.[24a]
A
8
13
single efficient reaction involving unactivated alkenyl triflates
was reported,[25] but it did not proceed with substrates derived
from cyclic ketones, and was only exploited in the specific case
of trisubstituted alkenol partners (Scheme 2b)(iii). In this work
(Scheme 2c), we will show that unactivated alkenyl halides,
mainly cyclic ones, are effective substrates for relay-Heck cross-
Scheme 1. Synthesis of alkenyl iodide 13.
As a consequence of the seemingly small steric change induced
by additional methyl groups, ketone 8 turned out to be
unexpectedly more challenging to functionalize than other
α,α,α’-trisubstituted cyclohexanones reported in the literature.
Grignard additions were difficult, and conditions known to afford
the corresponding alkenyl triflate[15] or alkenyl iodide[16] gave only
marginal conversions. A specific optimization was necessary:
refluxing the ketone in the presence of stoichiometric sulfuric
acid and a large excess of hydrazine in a mixture of n-butanol
and ethylene glycol finally gave a full conversion to the
corresponding hydrazone after 3 weeks. Its oxidation with iodine
according to a modification of Barton’s procedure[17] afforded
alkenyl iodide 13 in 37% overall yield.
couplings with
a
whole range of unsaturated alcohols
possessing diverse substitution patterns and chain lengths.
a.
work
:
Heck
cross-coupling
alcohols
Previous
alkenyl halides
non-activated
between
and
examples)
allylic
(many
Pd
R3
R1
X
R1
R2
R3
O
OH
+
R2
=
X
Br
I,
The relay-Heck cross-coupling of alkenyl precursors with allylic
alcohols would be a straightforward manner of preparing a
series of cyclohexene-propanal derivatives with different
substitution patterns from a common intermediate. Among
different conditions already published in the aromatic series,[18]
our attention was drawn to Xiao’s catalytic system[19] involving
electron-rich phosphine ligand L. It has already been used for
the synthesis of odorant aldehydes from aryl bromides by us[20]
and our competitors,[21] but its extension to alkenyl halides has
remained unexplored.
work:
cross-coupling
b. Previous
between alkenyl halides
relay-Heck
or
and
or
homoallylic
longer
triflates
(i) Dyker's
O
chain unsaturated alcohols
α
-oxo
with
alkenyl iodides
couplings
R4
O
Pd
O
I
+
R1
R1
OH
R4
R2 R3
R2 R3
with activated alkenyl triflates
couplings
(ii) Sigman's
OTf
R2
R1
n
O
R3
Pd
(
)
R2
+
X
R3
X
n
)
OH
2
R1
=
(
Table 1. Heck cross-coupling between 13 and allylic alcohols.
n =
O
O
X
CH2
O
,
1,
O
equiv.)
equiv.)
Pd(dba)2 (0.04
R1
I
with unactivated,
R4
alkenyl triflates
acyclic
L
couplings
(iii) Sigman's
R2
R2
(0.12
OH
+
R2
R1
R3
( )
NMe
Cy2
Pd
equiv.)
45 min
(1.1
R2
n
O
OTf
R1
+
R1
DMF,
100°C,
n
)
OH
R3
(
R3
1.1
equiv.
13
7
≠
n =
R4
H
1, 2;
c.
work:
This
cross-coupling
or
between unactivated,
chain unsaturated alcohols
relay-Heck
and
cyclic
Entry
R1
R2
Yield
[a]
7
[%]
alkenyl halides
homoallylic
longer
R2
n
P
R2
Pd
7a
7b
7c
7d
O
1
2
3
4
H
H
H
H
Me
78
82
87
85
N
X
(
)
R1
R1
Me
Et
H
+
L
n
OH
(
n =
)
m
)
m
(
(
Br;
)
=
m =
0,
X
1
1 to 4
I,
[a] Yield of isolated material.
Scheme 2. Heck and relay-Heck cross-couplings involving alkenyl substrates.
The application of Xiao’s conditions to alkenyl iodide 13 and
various allylic alcohols proceeded remarkably well, with yields
ranking in the upper range of those reported from aryl
bromides,[19] albeit with a higher catalyst loading (Table 1).
Notably, 7a and 7d were isolated as single linear regioisomers;
Gratifyingly, the cross-coupling of 13 with homoallylic alcohols
15a and 15b using the previously described conditions afforded
desired adducts in excellent yields (Table 2, entries 1-2),
prompting us to examine the reactivity of more accessible
alkenyl halides. 14a was prepared from commercially available
2,2,6-trimethylcyclohexanone and reacted with homoallylic
2
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alcohols 15b-e to give aldehydes 16c-d and ketones 16e-f in 57-
69% yield (entries 3-6).[26] In particular, 16d is an isomer of
fragrance ingredient Cetonal (Givaudan) and a key synthetic
intermediate in the preparation of Ambrox.[27] Elongating the
tether between the olefin and the alcohol affected only modestly
the reaction efficiency (entries 7-10). Decreasing the steric bulk
around the halide was found to be detrimental, with
decomposition processes often taking the lead (entries 11-14);
in spite of this limitation, the range of readily accessible
unsaturated aldehyde and ketone products considerably
broadened. In particular, odorant molecule 16m was previously
patented by Kelkar as the result of a five-step synthesis.[28] Our
approach rendered this preparation expeditious, in a single
operation from two commercially available materials (entry 14).
O
I
52
d.r. 1.2:1
11
15c
16k
14b
14c
I
O
40
15e
15e
15c
15e
12
13
14
15
16l
Br
16l
42
30
63
14d
14e
14f
O
Br
16m
16n
I
Table 2. Relay-Heck cross-couplings involving unactivated alkenyl substrates.
O
equiv.)
equiv.)
Pd(dba)2 (0.04
L
(0.12
Alkenyl halide
+
Unsaturated alcohol
equiv.)
Product
O
or
triflate
Br
54[b]
15e
15e
15e
15c
15c
15e
NMe
Cy2
16
17
18
19
20
21
equiv.)
1-4 h
(1.1
(1.1
DMF,
100°C,
16o
16p
14g
14h
Alkenyl halide
Unsaturated
alcohol
[a]
Entry
1
Product
Yield
[%]
or
triflate
Br
O
32
O
O
I
84
OH
15a
Br
38
d.r. 1.2:1
O
16a
13
13
16q
14i
14j
87
2
OH
OTf
OTf
15b
15c
16b
16m
trace
trace
O
I
3
4
57
57
OH
OH
16c
16c
14a
14a
O
O
14k
14k
OH
15d
15b
51
d.r. 2:1
16d
16e
16r
5
6
14a
14a
14a
14a
14a
14a
69
67
60
57
48
[a] Yield of isolated material. [b] 0.08 equiv. of Pd(dba)2 and 0.24 equiv. of
ligand L were used.
Alkenyl iodides or bromides derived from substituted
cyclopentanones also reacted well under these conditions
(entries 15-16). The process was not limited to cycloalkanone
derivatives, as alkenyl bromides 14h-i also participated (entries
17-18), albeit in slightly lower yield.
Finally, we checked that alkenyl triflates 14j and 14k did not
provide isolatable amounts of expected adducts with isoprenol
15c (entries 19 and 20 vs. 14 and 3). More interestingly, triflate
14k reacted with cyclopentenol 15e to afford allylic alcohol 16r in
51% yield (entry 21), with a regioselectivity consistent with
Correia’s results.[29] We surmised that weakly coordinating anion
TfO- favored the formation of vacant coordination sites on
palladium, inducing an easier β-hydride elimination.[30] This
divergent reactivity, as compared to entry 6, highlighted the
crucial role played by the halide, as well as the possibility to
obtain ketones or allylic alcohols by selecting the adequate
alkenyl partner.
O
OH
16f
15e
15f
OH
7
O
16g
16h
16i
O
8
OH
15g
15h
OH
O
9
O
OH
50
d.r. 1:1
10
16j
15i
Compounds 7a-d were studied for their olfactory properties
(Figure 4). 7b exhibited the most distinct, pleasant, musky smell,
although much weaker than Vulcanolide. This illustrates a good
3
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[3]
[4]
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olfactory correlation between a PCM and one of its non-aromatic,
monocyclic analogues possessing a cyclohexenyl-propanal core
structure. It is all the more remarkable given that all the odorant
cyclohexenyl-propanal derivatives patented so far, and in
particular Tillenal 17 (Firmenich SA)[31] and Lilybelle 18
(Symrise)[32] have a lily of the valley smell with no musky facet.
In this series, incorporating additional methyl substituents not
only enhanced the lipophilicity of the molecule, but also induced
an olfactory shift from the floral to the musky family. In contrast,
lower homologue 7a and higher homologue 7c lost most of their
musky character, whereas ketone 7d was not musky at all.
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O
O
O
7a
weak,
7b
7c
weak,
Very
earthy,
Musky,
metallic,
hot iron,
weaker
Very
dry,
much
than Vulcanolide
slightly
musky
vaguely
fruity-pear,
musky
vaguely
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O
O
O
7d
Almost odorless,
metallic
17
18
)
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13, 1273–1290.
Tillenal
(
)
Lilybelle (
Lily of the valley,
sweet,
Lily of the valley,
linden blossom
aldehydic,
watery
slightly
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Figure 4. Olfactory evaluation of acyclic Vulcanolide analogues.
.
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27, 158–174.
In conclusion, we have shown that acyclic analogues of PCM
Vulcanolide, prepared in 8 synthetic steps, could still retain its
key olfactory note. The syntheses undertaken involve a relay-
Heck cross-coupling between an alkenyl iodide and a series of
allylic alcohols as a key step. While attempting to broaden the
scope of this reaction, we successfully performed a cross-
coupling of unactivated alkenyl halides with homoallylic and
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longer chain unsaturated alcohols. This process gives
a
straightforward access to a whole range of unsaturated carbonyl
compounds, including patented odorant molecules. All the
reactions described in this manuscript were performed using
commercially available reagents on at least a gram-scale, and
we hope to provide organic chemists with a versatile, robust and
convenient synthetic tool likely to find practical applications. Its
use for the discovery of novel odorant molecules is underway in
our laboratory and will be reported in due course.
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Acknowledgements
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The authors thank Maud Reiter, Gilles Oddon, Lionel Saudan
and Elodie Brun for helpful discussions and proofreading of this
manuscript, Emilie Belhassen for the mass-spectrometric data,
and François-Raphaël Balestra for the olfactory evaluations.
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[26] The yield erosion was attributed to incomplete isomerization side-
products.
Keywords: alkenyl halides • Heck reaction • palladium • relay •
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4
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C. Braga, A. Aponick, C. R. D. Correia, J. Org. Chem. 2016, 81, 2010–
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10.1002/chem.202101080
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
R2
n
equiv.)
Ligand (0.12 equiv.)
Pd(dba)2 (0.04
R2
O
X
(
)
R1
=
R1
+
1
n
OH
(
)
NMe
Cy2
m
equiv.)
1-4 h
m
(1.1
(
Br;
)
(
)
m =
n =
DMF,
X
1 to 4
100°C,
I,
0,
Unactivated alkenyl iodides and bromides underwent an unprecedented palladium-catalyzed relay-Heck cross-coupling with a wide
range of alkenols. This methodology allowed for the preparation of open-chain analogues of the musk odorant Vulcanolide.
6
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