Exploring Site Selectivity of Iridium Hydride Insertion into Allylic Alcohols: Serendipitous Discovery and Comparative Study of Organic and Organometallic Catalysts for the Vinylogous Peterson Elimination

Article abstract of DOI:10.1021/acscatal.6b03376

The vinylogous Peterson elimination of a broad range of primary, secondary, and tertiary silylated allylic alcohols by two distinct and complementary catalytic systems - a cationic iridium complex and a Br?nsted acid - is reported. These results are unexpected. Nonsilylated substrates are typically isomerized into aldehydes and silylated allylic alcohols into homoallylic alcohols with structurally related iridium complexes. Although several organic acids and bases are known to promote the vinylogous Peterson elimination, the practicality, mildness, functional group tolerance, and generality of both catalysts are simply unprecedented. Highly substituted C=C bonds, stereochemically complex scaffolds, and vicinal tertiary and quaternary (stereo)centers are also compatible with the two methods. Both systems are stereospecific and enantiospecific. After optimization, a vast number of dienes with substitution patterns that would be difficult to generate by established strategies are readily accessible. Importantly, control experiments secured that traces of acid that may be generated upon decomposition of the in situ generated iridium hydride are not responsible for the activity observed with the organometallic species. Upon inspection of the reaction scope and on the basis of preliminary investigations, a mechanism involving iridium-hydride and iridium-allyl intermediates is proposed to account for the elimination reaction. Overall, this study confirms that site selectivity for [Ir-H] insertion across the C=C bond of allylic alcohols is a key parameter for the reaction outcome.

Full text of DOI:10.1021/acscatal.6b03376

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Article
Exploring Site Selectivity of Iridium Hydride Insertion into Allylic Alcohols:
Serendipitous Discovery and Comparative Study of an Organic and
an Organometallic Catalysts for the Vinylogous Peterson Elimination
Houhua Li, Daniele Fiorito, and Clément Mazet
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03376 • Publication Date (Web): 17 Jan 2017
Downloaded from http://pubs.acs.org on January 17, 2017
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Exploring Site Selectivity of Iridium Hydride Insertion into Allylic Al-
cohols: Serendipitous Discovery and Comparative Study of an Or-
ganic and an Organometallic Catalysts for the Vinylogous Peterson
Elimination
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Houhua Li‡, Daniele Fiorito‡, Clément Mazet*
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland.
ABSTRACT: The vinylogous Peterson elimination of a broad range of primary, secondary and tertiary silylated allylic al-
cohols by two distinct and complementary catalytic systems - a cationic iridium complex and a Brønsted acid - is report-
ed. These results are unexpected. Non-silylated substrates are typically isomerized into aldehydes and silylated allylic al-
cohols into homoallylic alcohols with structurally related iridium complexes. Although several organic acids and bases are
known to promote the vinylogous Peterson elimination, the practicality, mildness, functional group tolerance and gener-
ality of both catalysts are simply unprecedented. Highly substituted C=C bonds, stereochemically complex scaffolds, vici-
nal tertiary and quaternary (stereo)centers are also compatible with the two methods. Both systems are stereospecific and
enantiospecific. After optimization, a vast number of dienes with substitution patterns that would be difficult to generate
by established strategies are readily accessible. Importantly, control experiments secured that traces of acid that may be
generated upon decomposition of the in situ generated iridium hydride are not responsible for the activity observed with
the organometallic species. Upon inspection of the reaction scope and on the basis of preliminary investigations, a mech-
anism involving iridium-hydride and iridium-allyl intermediates is proposed to account for the elimination reaction.
Overall, this study confirms that site selectivity for [Ir−H] insertion across the C=C bond of allylic alcohols is a key param-
eter for the reaction outcome. KEYWORDS: iridium catalysis, Bronsted acid catalysis, vinylogous Peterson elimination,
dienes, selective catalysis.
[(P,N)Ir(cod)]BArF were competent candidates for the
isomerization of primary allylic alcohols. Once activated
■ INTRODUCTION
The 1,2-insertion of an olefin into a transition metal
hydride (i.e. migratory insertion) is a fundamental ele-
mentary step in organometallic chemistry that constitutes
the basis of a plethora of catalytic processes.1 Site-
selectivity of insertion is primarily dictated by the nature
and the size of the substituents of the C=C bond. Modifi-
cation of the catalyst structure allows to either alter or
best override the inherent electronic and steric biases
imposed by the olefin substituents and, consequently, to
change the outcome of the transformation. Therefore,
gaining understanding on the parameters that control site
selectivity of [M−H] insertion across a C=C bond provides
a means to elaborate improved catalyst structures (more
reactive, more selective) or to access unconventional reac-
tivity patterns by deviating transient intermediates to-
wards novel catalytic manifolds.
by molecular hydrogen and after degassing of the solu-
tion, these typical hydrogenation catalysts can be diverted
from their initial task and favor exclusive isomerization
into aldehydes instead.5 The Pfaltz modified version of
Crabtree’s catalyst 1 was first established as a very general
catalyst for the non-asymmetric version of the reaction,
operating under unusually mild reaction conditions.5a,6,7
Subsequently, highly enantioselective variants of this re-
action using prochiral 3,3-disubstituted allylic alcohols
and catalyst-controlled diastereoselective isomerizations
of stereochemically complex steroid derivatives have been
developed using chiral catalysts such as 2 (Figure 1).5
Isotopic labeling experiments have shed light on an
unconventional intermolecular hydride-type mechanism
involving migratory insertion of the in situ generated
[Ir−H] intermediates across the C=C bond of the sub-
strate. Productive isomerization proceeds via insertion of
iridium at C2, followed by β-hydride elimination and tau-
tomerization to deliver the carbonyl compound. The col-
lective results gathered over several years of investigation
indicate that substrate polarity clearly influences site se-
In recent years, we and others have pursued the de-
velopment of late transition metal catalysts for the selec-
tive isomerization of allylic and alkenyl alcohols into the
corresponding carbonyl derivatives.2-4 Specifically, we
have shown that iridium complexes of general formula
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Figure 1. (A) Prototypical iridium precatalysts for the selective isomerization of primary allylic alcohols. (B) Influence
of site-selectivity of [Ir−H] insertion in allylic alcohols isomerizations. (C) Vinylogous Peterson elimination.
lectivity of migratory insertion.2g,5 Formation of homoal-
lylic alcohols – which implies iridium insertion at C3 – has
been observed only with alkyl/alkyl 3,3-disubstituted al-
lylic alcohols and not with aryl/alkyl3,3-disubstituted sub-
strates. Adventitious traces of water were also found to
potentially influence site selectivity of migratory insertion
and lead to the formation of homoallylic alcohols. Finally,
competing E/Z isomerization – which also operates by
insertion at C3 – has been observed in several occasions
(Figure 1, B).
thesis.10,11 At the outset of our investigations, we were in-
trigued by the potential influence a β-silyl group may ex-
ert on site-selectivity of [Ir−H] insertion in the C=C bond
of allylic alcohols. Therefore, the representative silylated
substrates 4a and 4b (which possess an aryl and an alkyl
group at C3 respectively) were subjected to the typical
reaction conditions for isomerization of allylic alcohols
using achiral complexes 1 and 3.5a,12,13 While isomerization
of 4a with 1 produced aldehyde 5a exclusively (32% yield),
isomerization of (Z)-3-cyclopentyl-4-(trimethylsilyl)but-2-
enol 4b afforded homoallylic alcohol 7b as the sole prod-
uct of the reaction (eqs (1) and (3), Figure 2). Unexpected-
ly, when subjecting 4a and 4b to the same experimental
protocol using 3, exclusive formation of 1,3-dienes 6a and
6b by a formal 1,4 Peterson elimination was observed
(>99% conv., 91% and 82% yield respectively) (eqs (2) and
(4), Figure 2). Consistent with our previous investigations,
isomerization of 4c and 4d − two closely related allylic
alcohols devoid of a β-silyl group − furnished quasi-
quantitatively aldehydes 5c and 5d − both with complex 1
and 3 (eqs (5) and (6), Figure 2). Collectively, these results
indicate that if indeed the presence of a silyl group in the
vicinity of the C=C bond of the substrate strongly influ-
ences site selectivity of [Ir−H] insertion; the outcome of
the reaction is also heavily depending on the structure of
the catalyst employed. This latter observation is more
surprising as both 1 and 3 behave similarly for non-
silylated 3,3-disubstituted alkyl/alkyl and alkyl/aryl pri-
mary allylic alcohols.
In this report, we describe how attempts to tune site-
selectivity of migratory insertion by introduction of a silyl
substituent in the vicinity of the C=C bond of the allylic
alcohol led to the serendipitous discovery of a cationic
iridium catalyst for a vinylogous Peterson elimination
(Figure 1, C). In addition, control experiments also
showed that [H(OEt2)2]BArF (noted HBArF), a Brønsted
acid, effects this transformation in a complementary
manner.8 Optimization of this rather underdeveloped
reaction was pursued with both catalytic systems to fur-
nish a variety of 1,3-dienes in excellent yields under par-
ticularly mild reaction conditions.9 Overall, olefinic sub-
stitution patterns that would be otherwise difficult to
prepare and compatibility with functional groups that
would not be tolerated by the more conventional reagents
used for this transformation are important assets of these
methods. Finally, preliminary investigations suggest that
the iridium catalyst operates via an unorthodox mecha-
nism, distinct from those previously reported for Peterson
1,4-elimination, while HBArF likely functions via a more
traditional carbocationic pathway.9b,e,10
Interrogating the specificity of 3 for the vinylogous
Peterson elimination. Intrigued by the mildness of the
reaction conditions and the selectivity with which 3 con-
verted 4a-b into 6a-b, we set out to test the potential of
this precatalyst with a substrate that in principle should
not be compatible with the typical Brønsted and Lewis
acid catalysts/reagents known to effect Peterson 1,4-
eliminations. Therefore, both geometrical isomers of an
N-Boc-protected phenylalanine derived silylated primary
allylic alcohol (E)-4e and (Z)-4e were evaluated with a set
■ RESULTS AND DISCUSSION
Exploring site selectivity of [Ir−H] insertion in the
isomerization of allylic alcohols. The β-silicon effect
refers to the ability of a silyl group to stabilize a develop-
ing positive charge at a carbon atom in the beta position
by hyperconjugation; a property that has been judiciously
employed in a variety of transformations in organic syn-
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Figure 2. Comparative reactivity of achiral catalysts 1 and 3 for the isomerization of aryl and alkyl containing silylated
primary allylic alcohols (eqs. (1)-(4)). Comparison between 1 and 3 for the isomerization of model aryl and alkyl-
containing primary allylic alcohols (eqs. (5) and (6)).
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Table 1. Reaction optimizationa
mixture of side-products. A commercially available cati-
onic iridium source ([Ir(cod)2]BArF) was also tested.
Product formation was observed with (E)-4e (ca. 40%
along with degradation products), and only decomposi-
tion of the substrate was noted with (Z)-4e (entry 6-7).
Much to our satisfaction, with complex 3, both geomet-
rical isomers of allylic alcohol 4e were quantitatively con-
verted into 6e, thus underlying the unique character of
this catalyst to effect a 1,4 Peterson elimination on a sensi-
tive substrate. Noticeably, while the use of only 5 mol% of
3 afforded 6e in 92% yield, 10 mol% were required to ob-
serve a similar outcome (81% yield). This different reactiv-
ity between (E)-4e and (Z)-4e highlights the stereospecif-
ic nature of the elimination reaction when catalyzed by
complex 3 (entry 8-12).
entry catalyst
substrate
mol
%
conv. (%)b
1
ZnCl2
rac-(E)-4e
5
nr
dec.c
2
ZnCl2
rac-(E)-4e 100
3
HCl
rac-(E)-4e
rac-(E)-4e
5
5
nr
4
5
HOTs
nr
~35d
~40d
dec.c
>99 (92)
nre
HCl
rac-(E)-4e 100
The decomposition of the catalytically competent irid-
ium hydrides [(P,N)Ir(H)2(solv)2]BArF generated upon
activation of 1 (or related structures) by molecular hydro-
gen has been studied in details over the last 40 years.14,15
Typically, di-, tri- and tetranuclear polyhydrido-iridium
clusters are generated upon aggregation of the coordina-
tively unsaturated cationic dihydride intermediates. As
this process is formally accompanied by the liberation of
one equivalent of HBArF, the behavior of a catalytic
amount (5 mol%) of this peculiar Brønsted acid was also
evaluated using allylic alcohol 4e (Table 1, entry 12-13).16
6
7
[Ir(cod)2]BArF
rac-(E)-4e
rac-(Z)-4e
rac-(E)-4e
rac-(E)-4e
rac-(Z)-4e
5
5
5
5
5
[Ir(cod)2]BArF
8
9
10
11
12
13
3
3
3
3
12
rac-(Z)-4e 10
>99 (81)
>99 (82)f
>99 (82)f
[H(OEt2)2BArF] rac-(E)-4e
[H(OEt2)2BArF] rac-(Z)-4e
5
5
In contrast to HCl or HOTs but also to 3, after only 4 h
quantitative conversion into 6e was observed starting
indifferently from (E)-4e or (Z)-4e (82% yield in both cas-
es).
a Reaction conditions: 4e (0.1 mmol). Catalyst 3 was activated
b
by molecular hydrogen unless otherwise noted. Conversion
1
into 6e determined by H NMR of the crude reaction mix-
ture. In parenthesis, yield of isolated product after purifica-
c
tion by column chromatography. Decomposition of the
substrate. d Along with an intractable mixture of degradation
products. e Without activation by molecular hydrogen. f After
4 h.
of representative catalysts and reagents (Table 1). When
used in catalytic amount ZnCl2, HCl and HOTs did not
display any reactivity (entry 1-5). A stoichiometric amount
of ZnCl2 only led to decomposition of (E)-4e, while a 100
mol% of HCl gave ca. 35% of 6e along with an intractable
Figure 3. Isomerization of silylated allylic alcohol 4e cata-
lyzed by 1.
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Me3Si
(A) General route to geometrically pure silylated 1° allylic alcohols 4a-r
OTs
O
i. Me3SiCH2ZnCl,
[Pd], THF
1
2
3
4
5
6
Et3N/NMI/TsCl
CH2Cl2
R
R
ii. DIBAL/Et2O
MgCl2, KO2CCH2CO2R'
then CDI, THF
O
O
O
OR'
OH
4ꢀaꢀb,eꢀf, kꢀo
10aꢀb,eꢀf, kꢀo
(E)-
(E)-
Me3Si
R
OR'
R
OH
i. Me3SiCH2ZnCl,
[Pd], THF
Et3N/NMI/
TsCl/LiCl
OTs
O
8
9aꢀr
R' = Me, Et
NaH, MeI
R
OR'
10aꢀe, jꢀg, lꢀm, oꢀr
(Z)-
R
OH
CH2Cl2
ii. DIBAL/Et2O
4aꢀe, jꢀg, lꢀm, oꢀr
(Z)-
7
8
THF
Catalysts for Negishi cross-couplings:
i. Me3SiCH2ZnCl,
[Pd(OAc)2] / CPhos
THF
O
O
OTs
O
Me3Si
Ar
Et3N/NMI/
TsCl/LiCl/CH2Cl2
9
[Pd]: [(PPh3)4Pd]
or [(PPh3)2PdCl2]
Ar
OEt
Ar
OEt
PCy2
NMe2
10
11
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OH
or [Pd(OAc)2] / CPhos
Me2N
Me
9s
Ar = 4-MeO-C6H4
Me
Z)-10s
76% (2 steps)
ii. DIBAL/Et2O
Me
4s
(Z)-
(1 5 mol%)
CPhos
(
69% (2 steps)
(B) Substrate diversity (yields are given over 3 steps from -keto ester 9a-r; products were typically obtained on a 3.0 mmol scale)
Me
MeS
NHBoc
NHBoc
R
N
MeO
Me
rac-(E)-4k 50%b
Z)-4a 84%a
(Z)-
(E)-
4b 48%a
4b 61%b
rac-(Z)-4e 24%a
rac-(E)-4e 28%b
(S)-(E)-4f 25%a,c
R = -OMe
R = -CF3
Z
Z
4g 34%a
4h 49%a
4i 55%d
(Z)-4j 46%d
(
(
(
(
)-
)-
(S)-(E)-4k 65% (85% ee)b
E)-4a 15%b
(S)-(E)-4e 24% (26% ee)b
R = -NO2 (Z)-
Me
H
Me
O
Me
Me Me
O
Me
H
Me
H
Me
O
O
Me
H
H
O
Me
Me
Me
Me
Me
OTBS
Me
Me
HO
Me
(
(
Me
Z)-4l 48%d
E)-4l 60%b
(Z,Z)-
(E,Z)-
4m 40%a
rac-(E)-4n 55%b
Z
( )-
4o 64%a,e
4o 35%b
(Z)-4p 14%a,e
(E/Z)-4q (38/62) 76%d
4r 49%a
(S)-(Z)-
4m 71%b
(E)-
(C) Synthesis of 2° and 3° allylic alcohols
Me3Si
Me3Si
Me3Si
Me3Si
Me
OH
Me
Me
i. MnO2/CH2Cl2
ii. MeMgBr/Et2O
i. MnO2/CH2Cl2
ii. MeLi/Et2O
OH
Me
OH
OH
Me
Me
66% (2 steps)
MeO
MeO
11m 31% (2 steps)
11m 29% (2 steps)
(Z,Z)-
(E,Z)-
4m
(Z,Z)-
4m
(E,Z)-
11s
13s
(Z)-
4s
(Z)-
Me3Si
Me3Si
Me3Si
Me3Si
O
MeMe
MeLi/Et2O
MeLi/Et2O
OMe
OH
71%
86%
Me
Z)-12s
Me
Me
Me
Me
MeO
MeO
O
OMe
Me
OH
13m
(E,Z)-
(
E,Z)-12m
(
(Z)-
Figure 4. Substrates syntheses. (A) General route to geometrically pure silylated primary allylic alcohols. (B) Substrate
a
b
diversity for primary allylic alcohols. Catalyst used for the Negishi cross-coupling: [(PPh3)4Pd] (1-5 mol%). Catalyst
c
d
used for the Negishi cross-coupling: [(PPh3)2PdCl2] (1-5 mol%). Enantiopurity not determined. Catalytic system used
for the Negishi cross-coupling: [Pd(OAc)2] (5 mol%)/CPhos (10 mol%). e Prepared via the corresponding enol triflate ac-
cording to Frantz’s protocol (see ref 19). (C) Synthesis of silylated secondary and tertiary allylic alcohols.
Of important note, at this stage of our studies, the dis-
tinct behaviors of 3 and HBArF toward both geometrical
isomers of substrate 4e already point to potential mecha-
nistic differences between the two catalytic systems. It
also suggests that liberated HBArF upon catalyst decom-
position is not responsible for the catalytic activity ob-
served with 3 (vide infra), and clearly eliminates the pos-
sibility of hidden Brønsted acid catalysis.16 In line with the
isomerization of 4b (Figure 2 eq. (3)), when rac-(E)-4e
was subjected to catalysis with 1 after activation by mo-
lecular hydrogen, homoallylic alcohol (Z)-7e was isolated
as the sole product of the reaction. No reaction was ob-
served with rac-(Z)-4e (Figure 3). These results further
underscore the distinct reactivity profile of both iridium
catalysts with silylated allylic alcohols despite their seem-
ingly related structures.
Modular synthesis of silylated allylic alcohols. Having
established the ability of 3 and HBArF in effecting vinylo-
gous Peterson elimination on a particularly sensitive sub-
strate, we sought to explore and delineate the scope and
limitations of both catalysts in a systematic comparative
study. To ensure maximum efficiency and modularity for
substrates synthesis, we adopted a strategy similar to the
one recently followed in our laboratories for the prepara-
tion of steroidal allylic alcohols and which takes inspira-
tion from protocols developed by Tanabe and co-workers
on simple precursors (Figure 4).5h,17 The pivotal 1,3-
ketoesters 9a-r were either commercially available or
prepared in one step from the corresponding carboxylic
acid.18 The (E)-configured enol tosylates (E)-10a-b,e-f,k-o
were obtained after treatment with triethylamine, N-
methylimidazole and tosyl chloride (1.5 equiv. each). Ke-
toesters 9a-e, j-g,l-m,o-r were stereoselectively converted
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Conditions A
Conditions A
or
Conditions B
1
2
3
4
t-Bu
t-Bu
Me3Si
R1
R3
R3 R3
OH
BArF
Conditions B
P
Ir
R1
R3
N
HBAr
F (5 mol%)
R2
R2
THF, 23 C, [0.1], 4 h
3
(5 mol%), H2 activation
THF, 23 C, [0.1], 24 h
4aꢀs, 11m,s, 13m,s
6aꢀs, 14m, 15s, 17m, 18s
5
6
2-substituted dienes
7
8
MeS
9
NHBoc
6e
92% (>99% es)
from (S)-(E)-4e
NHBoc
F3C
MeO
10
11
12
13
14
15
16
17
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6a
6b
S
S
6f
6g
6h
(
)-
(
)-
Z)-4a
E)-4a
4a
4a
82% from (Z)-
87% from (E)-
4b
44%b,d from (S)-(E)-4f
87% from (Z)-4g
59% from (Z)-4hb
91% from (
81% from (
4ba
4b
Z
E
82% (>
99% es)
fr )-(E -4e
om (S )
91% from
Me
(S)- E 4f
(
)-
94% from ( )-
Z
4g
88% from ( )-
Z
4h
85% from (Z)-
85% from (E)-
84% from ( )-
82% from ( )-
4b
Me Me
Me
Me
MeO
N
O2N
Me
Me
Me
Me
Me
rac-6l
6i
6j
R
6k
rac-6n
(
)-
( )-
Z
6m
nr from (Z)-4ib
81% from (Z)-
4jb
4j
95%
(>99% es)
45% from ( )-
95% from ( )-
Z
4l
4l
4l
4l
92% from ( )-
Z,Z 4m
85% from (
90% from (
90% from (
83%
4kc
E
rac- E 4na,c
from (S)-(E)-
)-
E,Z 4ma,c
Z,Z 4m
E,Z 4m
from
(
)-
89% from (
Z)-4i
85% from (Z)-
84%
(>99% es)
94% from ( )-
97% from ( )-
Z
)-
)-
76%
from (S)-(E)-
E
from ( )-
rac- E 4na
4k
Me
2,3-substituted dienes
Me
H
O
O
O
Me
Me
Me
H
H
O
H
H
Me
O
OTBS
OH
Me
Me
Me
Me
Me
MeO
HO
6o
6p
6q
R
6r
R
6r'
)-
--
(
)-
(
4o
4o
4o
4o
90% from (Z)-
60% from (E)-
94% from (Z)-
85% from (E)-
4pb
(E/Z) 4q (38/62)b
Z
4rb,c,d
6s
86% from (Z)-
70% from
-
84% from ( )-
4s
80% from (Z)-
90% from (
Z)-4p
74% from (E/Z)-4q (38/62)
--
78% from (Z)-4rd
4s
83% from (Z)-
1,3-substituted dienes
1,2,3-substituted dienes
1,1',3-substituted dienes
1,1',2,3-substituted dienes
Me
Me
Me
Me
Me
Z,Z 11m
15s
18s
(E)-
82% from (Z)-
Me
Me
13mc
Me
11sc
13sc
86% from (Z)-
Me
MeO
MeO
Me
Me
MeO
(E)-15s
18s
19s
Me
Me
Me
14m
92% from (
92% from (
(Z)-
17m
88% from (E,Z)-
>99% conv.
15s:16s
>99% conv.
14m
14m
(E,Z)-
(E,Z)-
)-
)-
E,Z 11m
Z,Z 11m
18s 19s
(43:57)
Z)-11s
:
(33:67)
13s
Me
13m
88% from (E,Z)-
from (
from (Z)-
MeO
14m
14m
(E,Z)-
(E,Z)-
88% from (
88% from (
)-
Me
Me
)-
E,Z 11m
16s
Figure 5. Substrate scope (0.1-0.2 mmol scale). Isolated yields after column chromatography. a 1 mol% of 3. b 10 mol% of 3.
c4 h. d Enantiospecificity not determined.
to (Z)-10a-e,j-g,l-m,o-r in moderate to good yields using
5.0 equiv. of LiCl and otherwise identical reaction condi-
tions. Pd-catalyzed stereo-retentive Negishi cross-
couplings using in situ generated (trimethylsi-
lyl)methylzinc chloride followed by enoate reduction with
di-isobutyl aluminum hydride delivered the primary al-
lylic alcohols in geometrically pure form and good yields
over these two steps.19 Overall, our synthetic strategy en-
abled to rapidly assemble a collection of 24 different si-
lylated primary allylic alcohols with a high level of struc-
tural diversity and molecular complexity (polycyclic, ter-
tiary and quaternary α‒stereocenters) along with an array
of functional groups (aryl, perfluoroaryl, alcohol, ether,
thioether, silyl ether, acetal, N- heterocycles, protected
amine, alkene). Substrate 4s which features a tetrasubsti-
tuted C=C bond was prepared according to the same se-
quence after simple C-alkylation of 9g into 9s. Both geo-
metrical isomers of secondary allylic alcohol 11m were
obtained starting from (E)-4m and (Z)-4m by oxidation to
the corresponding α,β‒unsaturated aldehydes followed by
1,2-addition of methylmagnesium bromide. The corre-
sponding tertiary allylic alcohol (E)-13m was obtained in
71% yield by treatment of enoate (E)-12m with 3 equiva-
lents of MeLi. Similar sequences gave access to (Z)-11s and
(Z)-13s a secondary and a tertiary allylic alcohol respec-
tively, both featuring a tetrasubstituted C=C bond.
Comparative study between 3 and HBArF for the vi-
nylogous Peterson elimination. The complete collec-
tion of primary, secondary and tertiary allylic alcohols
was subsequently subjected to the prototypical reaction
conditions developed for the vinylogous Peterson elimi-
nation catalyzed by 3 (5 mol%, activation with molecular
hydrogen, room temperature, 24 h) and HBArF (5 mol%,
room temperature, 4 h). The vast majority of silylated
primary allylic alcohols tested proved competent in un-
dergoing a 1,4 elimination reaction with catalyst 3 and
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Page 6 of 10
HBArF but some important differences were noted for
rine reagents used for vinylogous Peterson eliminations.9
1
2
3
4
5
6
7
8
several substrates (Figure 5). Specifically, substrates with
either electron-neutral (4a), electron-rich (4g) or elec-
tron-poor (4h-i) aryl substituents at C3 were converted
quantitatively and isolated in excellent yield with HBArF.
In contrast, 4h required increased catalyst loading of 3 (10
mol%) to isolate 6h in an acceptable 59% yield while no
reaction was observed with 4i. Similarly, 6i which is char-
acterized by a N-methyl protected indole motif, was iso-
lated in 81% using 10 mol% of 3 while nor modifications of
protocol B were necessary to achieve similar performanc-
es with HBArF (5 mol%, 4 h). The stereospecific nature of
the reaction with the iridium precatalyst was again noted
in eliminations using (Z)- and (E)-4b, as the latter was
reacted with a loading as low as 1 mol%. Interestingly, the
optically active silylated allylic alcohols 4e and 4k – which
both possess a tertiary stereocenter adjacent to C3 – un-
derwent the 1,4-Peterson elimination with virtually per-
fect enantiospecificity and furnished the corresponding
chiral products in excellent yields with both catalytic sys-
tems. The configurational stability of these stereocenters
using 3 is particularly remarkable because isomerization
of 4e and 4k with catalyst 1 led to the exclusive formation
of the corresponding tetrasubstituted homoallylic alco-
hols, implying migratory insertion at C3 and β-H elimina-
tion at C4.20 Noticeably, a methionine-derived silylated
allylic alcohol was successfully engaged in the elimination
reaction, affording 6f in 44% yield with 3 and 91% with
the Brønsted catalyst.21 The compatibility of both meth-
ods with isolated C=C bonds was demonstrated with sub-
strates 4l-n, leading to 6l-n in satisfactory to excellent
yields (45-95% with 3; 76-97% with HBArF). Of note, no
isomerization of the remote (Z)-configured 1,2-
disubstituted double bond was noted in the reaction with
(Z,Z)- and (E,Z)-4m.22 The presence of a tertiary and -
more remarkably - of a quaternary stereocenter adjacent
to the allylic system does not affect the efficiency of both
processes as the stereochemically complex scaffolds 6o,
6p and 6q were obtained in excellent yield upon vinylo-
gous elimination of the appropriate allylic alcohols. These
results also highlight the compatibility of the metal-based
catalyst and the Brønsted acid catalyst with an endocyclic
homoallylic alcohol (4o), an endocyclic diene system (4p)
and a galactose acetonide derivative (4q).23,24 The pres-
ence of a diene at these strategic positions of the terpene
derivatives bodes well for rapid installation and diversifi-
cation of heterocyclic ring systems via cycloaddition reac-
tions. The ability of complex 3 to perform a high-yielding
vinylogous Peterson elimination on a particularly acid-
sensitive silyl protected derivative such as 4r is simply
remarkable (6r: 84% yield) especially because HBArF led
to the corresponding deprotected secondary alcohol 6r’
(78% yield). These contrasted outcomes reinforce the
notion that 3 and HBArF certainly operate via distinct
reaction mechanism and that the catalytic activity of 3
does not result from traces of acid that might have been
generated upon catalyst decomposition.14-16 It is also
worth mentioning that a silyl-protected alcohol would
certainly not be compatible with the classical basic fluo-
Interestingly, (Z)-4s, a primary allylic alcohol with a
tetrasubstituted C=C bond, delivered 6s in 80-83% yield
with 3 and HBArF, thus offering a potential complement
to Heck-type cross-coupling with allenes or thermolysis
of sulfones, two methods which typically deliver related
2,3-disubstituted diene motifs.25
The scope of 1,3-dienes accessible with both protocols
was further explored by subjecting secondary and tertiary
allylic alcohols (11m,s and 13m,s) to the optimized reac-
tion conditions for the two catalytic systems. All five sub-
strates underwent vinylogous Peterson elimination with
the iridium catalyst and afforded the corresponding
dienes in excellent yields (82-92%). Noticeably, (E,Z)-14m
was obtained in identical yields starting indifferently from
(Z,Z)-11m or (E,Z)-11m, indicating that the metal-
catalyzed process is stereoconvergent in nature. The elim-
ination reactions of 11m and 13m led to comparable re-
sults when conducted with HBArF. The vinylogous Peter-
son elimination of 11s and 13s shed additional light on the
striking differences between the organometallic and the
organic catalysts. While with 3, 15s and 18s were isolated
in excellent yield (15s: 82%; 18s: 86%), with HBArF gener-
ation of these 1,2,3- and 1,1’,2,3-dienes was accompanied
by the formation of the inseparable indenes 16s and 19s.
Indene 19s was obtained exclusively when the reaction
time was extended, indicating that it is generated by a
formal hydroarylation of transient diene 18s.16e,l
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Overall, from a synthetic point of view, the diversity of
substitution patterns available with both protocols is
simply remarkable as it provides direct access to 2-, 2,3-,
1,3-, 1,2,3-, 1,1’,3- and 1,1’,2,3-substituted dienes. Existing
alternatives are at best scarce, limited in scope and often
require harsh reaction conditions.25-27
Preliminary mechanistic insights. On the basis of the
control experiments conducted on substrates (E)-4e and
(Z)-4e (Table 1) and the results of the vinylogous Peterson
elimination conducted on the silylated primary allylic
alcohols (E)-4f, (Z)-4h, (Z)-4i, (Z)-4l, (E)-4o, (E/Z)-4q,
(Z)-4r and on the silylated secondary allylic alcohols (Z)-
11s and (Z)-13s (Figure 5), it appears clearly that 3 and
HBArF operate via different mechanisms.
Figure 6. Proposed mechanism for the vinylogous Peter-
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ACS Catalysis
non-coordinating base, quantitative formation of diene
son elimination catalyzed by HBArF exemplified with (Z)-
13s.
An intuitive proposal that accounts for diene for-
mation when HBArF is employed is depicted on Figure 6.
It is represented using (Z)-13s as it also allows to propose
a rationale for the obtention of indene 19s resulting from
the hydroarylation reaction.
1
2
3
4
5
6
7
6b was observed after 24 h, suggesting that potential trac-
es of acid that may be liberated upon decomposition of
the iridium dihydride generated by activation with mo-
lecular hydrogen are not responsible for catalytic activi-
ty.14-16 In contrast, in the presence of 10 mol% of TEMPO −
a notorious trap for transition metal hydrides − no prod-
uct formation was observed, thus advocating the direct
involvement of [Ir−H] intermediates in the operating
mechanism for the vinylogous Peterson elimination.4c,28
Of additional note, the absence of ring-opened product in
the reaction with the cyclopropyl-containing substrate
(E)-4n rules out a potential cage-escaped radical mecha-
nism.28 Finally, the complete loss of catalytic activity ob-
served in the presence of 4Å molecular sieves supports
the notion that liberated water plays an important role in
the overall catalytic process. Conversely, when (E)-4b was
subjected to catalysis with HBArF in the presence of
TEMPO (10 mol%) or 4Å molecular sieves, reactivity was
still observed (33% conversion and >99% conversion re-
spectively; see SI for details).
In contrast, the mode of action of the dihydrido-
iridium complexes generated upon activation of 3 by mo-
lecular hydrogen appears less obvious. In an effort to
gather preliminary information on the mechanism by
which catalyst 3 may operate to effect the vinylogous Pe-
terson elimination, a series of additional control experi-
ments was conducted using (E)-4b as model substrate
(Table 2).
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Control experimentsa
Although additional experiments are needed, based on
these results and on observations made while investigat-
ing the scope of the reaction, we display on Figure 7 a
tentative rationale that may account for the vinylogous
Peterson elimination catalyzed by 3. Activation of com-
plex 3 by molecular hydrogen generates the catalytically
active cationic Ir(III) dihydride A.12,13 Upon reaction with
the silylated allylic alcohols, production of the cationic
iridium-allyl complexes (B and/or C) accompanied by
concomitant formation of one molecule of water seems
reasonable. The decreased or absence of reactivity for
arylated substrates with a para-electron-withdrawing sub-
stituent at C3 may be explained by the difficulty in access-
ing or stabilizing intermediate C. Because of the stereo-
specific nature of the reaction, we believe that iridium-
allyl formation is the rate determining step of the catalyt-
ic process and that one of the hydride ligands is responsi-
ble for activation of the hydroxy functionality of the sub-
strate. The water molecule generated (which may or may
not leave the first coordination sphere of the iridium at-
om) subsequently participates in elimination of the silyl
fragment. Intermediate D is postulated to precede a relat-
ed 6-membered pericyclic transition state leading to the
formation of the diene and simultaneous regeneration of
A.
entry
additive
conv. (%)b
>99 (93)
>99
1
none
2
3
4
DTBMP (10 mol%) c
TEMPO (10 mol%) d
4 Å MS (excess)
<5
<5
a
Reaction conditions: (E)-4b (0.1 mmol), 1 min. activation
b
with H2 followed by degassing. Conversion into 6b deter-
mined by H NMR of the crude reaction mixture. In paren-
thesis, yield of isolated product after purification by column
chromatography.
methylpyridine. TEMPO = (2,2,6,6-Tetramethylpiperidin-1-
yl)oxyl.
1
c
DTBMP
=
2,6-di-tert-butyl-4-
d
■ CONCLUSION
In this article, we have reported the serendipitous dis-
covery of two distinct catalysts for the vinylogous Peter-
son elimination of a variety of silylated allylic alcohols
leading to valuable dienes. The first catalyst, a cationic
iridium complex supported by a chelating (P,N) ligand,
was identified while investigating the site selectivity of
[Ir−H] insertion across the C=C bond of silylated allylic
alcohols. The second catalytic system, a Brønsted acid
(HBArF), was discovered when assessing whether traces of
acid that might be generated upon decomposition of the
active form of the iridium complex were responsible for
Figure 7. Tentative mechanism for the vinylogous Peter-
son elimination catalyzed by 3.
When the reaction was run in presence of 10 mol% of
2,6-di-tert-butyl-4-methylpyridine (DTBMP),
a
bulky
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catalytic activity. To delineate the synthetic potential of scenario involving iridium-allyl intermediates. Compara-
1
2
3
4
5
6
7
8
both entities a systematic comparative study was pursued
on a vast number of silylated allylic alcohols. This re-
quired the design of a modular sequence based on some
of the most recent cross-coupling methods to access the
substrates in geometrically pure form with the possibility
to introduce up to four substituents on the C=C bond and
a representative diversity of functional groups. Overall,
both systems were found to react with a variety of prima-
ry silylated allylic alcohols to afford the expected 2- and
2,3-substituted dienes in usually good to excellent yields −
independently of the extent of substitution of the olefinic
moiety, the stereochemical complexity and the congested
nature of proximal stereocenters. The two catalysts were
found to be both stereo- and enantiospecific. Several sen-
sitive functional groups that would not be compatible
with more conventional reagents were also perfectly tol-
erated by the organic and the organometallic catalyst.
Nonetheless, for some specific substrates, clear reactivity
differences were noted. For instance, the Brønsted acid
catalyst appeared more appropriate to effect the elimina-
tion of a methionine derived substrate but it proved not
compatible with silyl-protected alcohol functionalities. In
the latter case, the iridium catalyst led to the expected
diene without cleavage of the acid-sensitive silicon-
oxygen bond. While all substrates with an aromatic sub-
stituent at C3 were perfectly engaged in the elimination
reaction with HBArF, a net decrease in reactivity was ob-
served with the iridium complex upon para-substitution
with electron-withdrawing substituents. Alkyl containing
secondary and tertiary silylated allylic alcohols were
equally reactive with both systems and the corresponding
1,3- and 1,1’,3-substituted dienes were isolated in usually
high yields. Analogues with an aromatic ring at C3 were
converted smoothly to dienes with the organometallic
species while a competing hydroarylation leading to in-
tractable mixtures of products occurred with the organic
catalyst.
tive study with other iridium catalysts clearly suggest that
subtle variations in ligand design strongly influence site-
selectivity for [Ir−H] insertion across the C=C bond of
silylated allylic alcohols. Further experimental and com-
putational studies into the origin of the reactivity and
selectivity of these different catalytic systems are under-
way in our laboratories.
9
ASSOCIATED CONTENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information. Experimental procedures, charac-
terization of all new compounds and spectral data. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Prof. Clément Mazet. University of Geneva, Organic Chemis-
try Department. Quai Ernest Ansermet 30, Geneva 1211 -
Switzerland. clement.mazet@unige.ch
Notes
The authors declare no competing financial interests.
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
We thank the University of Geneva and the Swiss National
Science Foundation (PP00P2_133482) for financial support
and Johnson Matthey for a generous gift of iridium precur-
sors. This article is dedicated to Prof. Alexandre Alexakis for
his constant support and friendship.
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