Rhodium-Catalyzed Tandem Isomerization-Allylation: From Diallyl Carbonates to α-Quaternary Aldehydes

Article abstract of DOI:10.1021/acscatal.9b04128

We report a Rh-catalyzed tandem isomerization-allylation sequence for the generation of α-quaternary aldehydes, starting from unsymmetrical diallyl carbonates. This reaction features a highly selective oxidative addition of the rhodium catalyst, leading to the discrimination of electrophilic and nucleophilic elements of various diallyl carbonates. A rhodium-enolate and an allyl electrophile are produced catalytically in situ in a controlled fashion, enabling this reaction to occur with high chemoselectivity and regioselectivity. Mechanistic investigation via reaction progress kinetic analysis uncovered second-order kinetics in rhodium, suggesting that an unexpected dual metal pathway may be operative for the key C-C bond-forming step.

Full text of DOI:10.1021/acscatal.9b04128

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Letter
Rhodium-Catalyzed Tandem Isomerization-Allylation:
From Diallyl Carbonates to #-Quaternary Aldehydes
Jeanne Masson-Makdissi, Young Jin Jang, Liher Prieto, Mark S. Taylor, and Mark Lautens
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04128 • Publication Date (Web): 19 Nov 2019
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ACS Catalysis
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Rhodium-Catalyzed Tandem Isomerization-Allylation: From Diallyl
Carbonates to α-Quaternary Aldehydes
Jeanne Masson-Makdissi,†,[a] Young Jin Jang,†,[a] Liher Prieto,†,‡ Mark S. Taylor,†,* Mark Lautens†,**
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†Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6
‡ Department of Organic Chemistry II, University of the Basque Country (UPV/EHU), P. O. Box 644, 48080 Bilbao, Spain.
KEYWORDS. Allylation, allylic alcohol, isomerization, RPKA, rhodium
ABSTRACT: We report a Rh-catalyzed tandem isomerization-allylation sequence for the generation of α-quaternary aldehydes
starting from unsymmetrical diallyl carbonates. This reaction features a highly selective oxidative addition of the rhodium catalyst,
leading to the discrimination of electrophilic and nucleophilic elements of various diallyl carbonates. A rhodium-enolate and an allyl
electrophile are produced catalytically in situ in a controlled fashion, enabling this reaction to occur with high chemo- and
regioselectivity. Mechanistic investigation via reaction progress kinetic analysis (RPKA) uncovered second order kinetics in rhodium,
suggesting that an unexpected dual metal pathway may be operative for the key C–C bond forming step.
The palladium-catalyzed rearrangement of allyl enol
carbonates is an efficient and a versatile method to access
stereochemically enriched α-allylated carbonyl containing
compounds (Scheme 1a).1 In contrast to classical enolate
alkylation chemistry, these reactions avoid the requirement of
stoichiometric strong base, allowing for better functional group
tolerance and high chemo- and regioselectivity.2
rearrangement of unsymmetrical diallyl carbonates (1a) to α-
quaternary allylated aldehydes (2a) is presented (Scheme 1c).10
a) Enantio- and regioselective palladium-catalyzed allylation (Tsuji/Stoltz)
O
O
O
R1
O
O
R1
Pd(0) / L*
- CO2
R1
Since the seminal report by Tsuji in 1983,3 the reaction has
been further elaborated by the Stoltz and Trost groups and
utilized by others in numerous syntheses.4 Although there exists
an abundance of reports describing the allylation of cyclic
ketones, amides and esters, methods to directly α-allylate
aldehydes via this method are limited.5 Moreover, despite the
excellent chemo- and regioselectivity achieved through this
masked enol strategy, the ability to use simpler starting
materials, that do not require the use of strong base, will
potentially enhance the utility of this methodology.
not observed
b) Enantioselective rhodium-catalyzed isomerization of allylic alcohols
R2
H
R2
R1
H
R2
R1
H
H
Rh(I) / L*
H+
R1
OH
O
O
OH
enol intermediate
c) Rhodium-catalyzed isomerization-allylation reaction (this work)
1st Generation
Among the catalytic approaches for the production of enols
or enolates in situ, the rhodium-catalyzed isomerization of
allylic alcohols and amines represents an appealing process as
it occurs under very mild and neutral conditions (Scheme 1b).6
Reports by Bosnich and Motherwell demonstrated that the in
situ generated enols were sufficiently stable in solution to be
further reacted with suitable electrophiles.7 Despite the
potential synthetic utility of this transformation, there are
limited reports on catalytic tandem reactions exploiting the
nucleophilic properties of the enol intermediates generated
from the allylic alcohol.8
O
Ph
Rh(I) cat.
80% yield
OH
H
O
O
CF3
Me Ph
3a
3ab
2a
2nd Generation
O
H
O
Rh(I) cat.
88% yield
O
O
Me Ph
Ph
H
1a
2a
bimetallic
rate-limiting step
Considering rhodium is known to catalyze both the
isomerization of allylic alcohols and the allylation of enolates
derived from aldehydes,9 we postulated that allylic alcohols
could be used as enolate surrogates in allylation reactions.
Herein we demonstrate allylic alcohols (3a) as aldehyde enolate
surrogates in rhodium-catalyzed isomerization-allylation
O
P
P
P
Cl
Rh
Ph
Rh
P
Me
Scheme 1. Metal-Catalyzed Allylation and Isomerization
Reactions
reaction (Scheme 1c).
Additional atom-economical
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reacted to yield products 2b and 2c. In general, it was found that
Page 2 of 6
Table 1. Deviations from Standard Conditions[a]
1
2
3
4
electron-neutral or electron-poor substrates (2a–2f) worked
well but the anisole derived product (2g) was obtained in low
yield..
[Rh(cod)Cl]2 (2.5 mol%)
Me Allyl
Ph CHO
rac-BINAP (5 mol%)
O
O
Ph
THF (0.80 M), 60 °C, 16 h
O
Table 2. Scope Table[a]
1a
2a
5
6
7
8
9
[Rh(cod)Cl]2 (2.5 mol%)
rac-BINAP (5 mol%)
O
O
Entry
Deviations
None
%Conversion[b]
%Yield[b]
Allyl
R2
R2
O
O
H
R1
THF (0.80 M), 60 °C, 16 h
R1
1
2
3
>95
<5
88
0
1a-s
2a-s
no rac-BINAP
From terminal alkenes (R2 = H)
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[Rh(cod)2]BF4
instead of
[Rh(cod)Cl]2
<5
0
Me Allyl
Me Allyl
Me Allyl
CHO
Me Allyl
CHO
O
CHO
CHO
O
CF3
, 64% yield
4
5
Pd2(dba)3 instead
of [Rh(cod)Cl]2
84
65
0
5
2a
2b
2c
2d
, 88% yield
Me Allyl
, 75% yield
, 74% yield
Me Allyl
2e
2f
2g
2h
2i
[Ir(cod)Cl]2
instead of
[Rh(cod)Cl]2
, R = Cl, 82% yield
, R = CF3, 77% yield
CHO
O
X
CHO
, R = OMe, 29% yield
, R = COMe, 74% yield
, R = CO2Me, 63% yield
R
6
PPh3 (10 mol%)
instead of rac-
BINAP
46
0
i
2j
, X = O Pr, 89% yield
Me Allyl
CHO
Me
Allyl
2k
N
, X =
7
8
dppe instead of
rac-BINAP
>95
44
0
N
S
CHO
Me
2l
2m
, 66% yield
, 70% yield
Me Allyl
50% yield
Me Allyl
40 ºC instead of
60 ºC
13
85
74
30
36
Me Allyl
CHO
O
CHO
H
9
DCE instead of
THF
>95
>95
74
CHO
O
Me
2n
2o
2p
, 60% yield
, 62% yield
, 45% yield
10
11
12
PhMe instead of
THF
From non-terminal alkenes (R2  H)
acetone instead of
THF
Me Allyl
CHO
Ph Allyl
CHO
Me Allyl
CHO
THF (0.20 M)
51
[b]
2q
2r
, 47% yield
, 67% yield
Gram-scale
2s
2a
, 69% yield
[a] Standard conditions: [Rh(cod)Cl]2 (2.5 mol%, 4.9 mg), rac-
BINAP (5 mol%, 6.2 mg) and allyl carbonate 1a (0.20 mmol, 44
mg) in THF (0.25 mL), under argon atmosphere, heated at 60 °C
for 16 hours. [b] Yields were determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard.
[Rh(cod)Cl]2 (1.25 mol%)
rac-BINAP (2.5 mol%)
1a
, 7.5 mmol
, 81% yield
1.06 g
THF (1.6 M), 60 °C, 16 h
At the outset of our investigation, we noted that the
rhodium(I)-(±)-BINAP combination was a particularly efficient
catalyst for the desired transformation (Table 1, entry 1), in
accordance with several reports utilizing this catalyst for the
isomerization of allylic alcohols.11 Reactions conducted in the
absence of bidentate phosphine ligand (entry 2) or with
[Rh(cod)2]BF4 (entry 3) did not afford any product. The
isomerization of allylic alcohols seems to be unique to rhodium,
as using palladium or iridium catalysts led to no appreciable
yields of the desired product (entry 4 and 5). Employing other
common phosphine ligands such as triphenylphosphine (entry
6) and dppe (entry 7) failed to promote this transformation. The
yield of 2a decreases with lower temperatures (entry 8). Various
solvents can be used for this reaction. The product can be
obtained in similar yield in dichloroethane (entry 9) and in
slightly lower yield in toluene (entry 10). Acetone gives lower
yields of the desired product (entry 11). Conducting the reaction
at a lower concentration leads to lower conversion into the
product (entry 12).12
[a] Standard conditions: [Rh(cod)Cl]2 (2.5 mol%, 4.9 mg), rac-
BINAP (5 mol%, 13 mg) and allyl carbonate 1a (0.40 mmol, 87
mg) in THF (0.50 mL), under argon atmosphere, heated at 60 °C
for 14 hours. [b] Reaction stirred for 48 hours.
The high chemoselectivity of our protocol is best illustrated by
the tolerance of functional groups such as ketones (Table 2, 2h
and 2p), Michael acceptors (2p) and esters (2i and 2j). Notably,
our reaction displays good selectivity even in the presence of
other enolizable centers (2j–2k and 2p). By contrast, this type
of selectivity would be hard to achieve by traditional synthetic
routes. Heteroaromatic substrates afforded aldehydes bearing
thiophene (2l), indole (2m) and furan (2n) moieties. Aliphatic
allylic alcohols were converted to the corresponding aldehydes
in moderate to good yields (2o and 2p). Allyl carbonates with
non-terminal alkenes, a mixture of E/Z, could also be
isomerized, providing the desired products in moderate to
excellent yields (2q–2s). Finally, a gram scale reaction of 1a
Next we investigated the scope of this transformation (Table
2). Substrates with ortho-substituents on the aromatic ring
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was accomplished with a reduced catalyst loading of 1.25
1
mol%, affording the product in 81% yield.
2
3
4
5
6
7
8
9
[Rh(cod)Cl]2 (x mol%)
(S)-BINAP (2x mol%)
To gain further understanding of this unique catalytic
process, control and cross-over experiments were conducted
(Scheme 2). A competition experiment with allyl carbonate 1f
and allylic alcohol 3a was conducted (Scheme 2a). Both
allylated aldehydes were formed, demonstrating that the allylic
alcohol is a competent intermediate en route to product. Next, a
cross-over experiment between two different allyl carbonates
was undertaken (Scheme 2b). Upon subjecting substrates 1a-d1
and 1f under the standard conditions, extensive crossover of the
mono-deuterated allyl group was observed. To further
investigate the selectivity between C− and O−alkylation
following the isomerization, the corresponding allyl enol ether
4a was synthesized (Scheme 2c). Subjecting the enol allyl ether
4a to the standard conditions resulted in the recovery of the
starting material, which indicates that the Claisen
rearrangement of 4a is not involved in the formation of the
desired product.
Me Allyl
Ph CHO
O
O
Ph
PhMe (0.50 M), 80 °C
O
2a
1a (SM)
a) rate vs. [1a]
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a) Allyl alcohol as competent intermediate to product
O
Ar
Me Allyl
2f,
CHO
b) rate/[Rh] vs. [1a]
Ar
O
O
[Rh(cod)Cl]2 (2.5 mol%)
rac-BINAP (5 mol%)
1f
46% yield
Ar = (4-CF3C6H4)
Ph
CHO
THF (0.8 M), 60 °C, 16 h
Ph
OH
Me Allyl
2a,
28% yield
3a
(1 equiv)
b) Crossover experiment of rhodium-allyl electrophile
H/D
O
O
D
Ph
Ar
H
H/D
O
O
Me Ph
1a-d1
standard
conditions
2a-d1
52% d1-allyl incorporation
H/D
+
O
O
H
O
O
c) rate/[Rh]2 vs. [1a]
H/D
Me Ar
1f
(1 equiv)
Ar = (4-CF3C6H4)
2f-d1
-
48% d1 allyl incorporation
c) Probing the Claisen rearrangement
standard conditions
O
Ph
O
H
Me
Me Ph
4a
(3:1 E/Z)
not observed
Scheme 2. Competition and Control Experiments
Next, we performed reaction progress kinetic analysis
(RPKA) using React-IR spectroscopy to gain additional
mechanistic information (Scheme 3).13 Three experiments were
conducted with different catalyst loadings to determine the
order in catalyst. When normalizing the rates as a function of
[Rh], we did not observe overlap of the curves, ruling out first
order kinetics in catalyst (Scheme 3b). Good overlay of the
curves was obtained when normalizing the rates assuming [Rh]2
(Scheme 3c), which supports a mechanism that is second order
in rhodium.14 This observation suggests that two rhodium
species may be involved in the rate-limiting step of the reaction.
Moreover, the linear relationship obtained when plotting the
rate against [1a] is in agreement with first order kinetics in
substrate.
Scheme 3. Reaction Progress Kinetic Analysis
The second order kinetics suggests that the C–C bond
formation step may operate via a rate-limiting bimetallic
pathway (Scheme 4). It should be noted that the extensive
crossovers observed in the competition experiments (Scheme
2a & b) are also consistent with this proposal. Upon formation
of the rhodium(I)-BINAP complex Rh-1, the catalyst
undergoes selective oxidative addition into the less hindered
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allyl component of the carbonate 1a leading to the formation of
ASSOCIATED CONTENT
1
2
3
4
5
6
7
8
rhodium (III) complex Rh-2. As first order kinetics in substrate
is observed, we propose the oxidative addition step to be
reversible. Decarboxylation can then lead to the formation of
Rh-allyl complex Rh-3, releasing the allylic alkoxide 3a. The
allylic alkoxide 3a by-product is then proposed to undergo
ligand exchange with another Rh-1 species to form rhodium(I)
alkoxide Rh-4. Following ligand exchange, β-hydride
elimination can occur to generate the rhodium(I) complex Rh-
5 bearing a coordinating α,β-unsaturated aldehyde. Next,
migratory insertion delivers rhodium(I) enolate Rh-6. The
rhodium allyl species Rh-3 and the rhodium enolate complex
Rh-6 can then provide aldehyde 2a, regenerating two
equivalents of the active Rh-1 catalyst. This last step is likely
to be rate-limiting as it requires two catalytic species to meet in
solution. A simplified version of this mechanism gives rise to a
theoretical rate law that is second order in [Rh] and first order
in [1a], which is consistent with our experimental data (see
Supporting Information).
Supporting Information. Experimental procedures, characterization
1
data, H/13C spectra, additional optimization data.This material is
available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We thank the University of Toronto, the National Science and
Engineering Research Council (NSERC), Alphora Research Inc as
well as Kennarshore Inc. for financial support. J.M.M. thanks
NSERC for a graduate fellowship (PGS D). L. P. acknowledges the
Basque Government (Grupos IT908-16) and UPV/EHU for
financial support. We also thank Johnson-Matthey for their
generous donation of [Rh(cod)Cl]2.
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ABBREVIATIONS
RPKA, Reaction Progress Kinetic Analysis.
REFERENCES
(1)
(a) Tsuji, J.; Minami, I. New Synthetic Reactions of Allyl
oxidative
ligand
addition
exchange
Alkyl Carbonates, Allyl .Beta.-Keto Carboxylates, and Allyl Vinylic
Carbonates Catalyzed by Palladium Complexes. Acc. Chem. Res. 1987,
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Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. (c) Tunge,
J. A.; Burger, E. C. Transition Metal Catalyzed Decarboxylative
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You, S.-L.; Dai, L.-X. Enantioselective Palladium‐Catalyzed
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Development of Chemo- and Enantioselective Palladium-Catalyzed
Decarboxylative Asymmetric Allylic Alkylation of α-Nitroesters.
Angew. Chem. Int. Ed. 2019, 58, 11820–11825.
O
O
Cl
P
P
Ph
Cl
Rh
Ph
O
Ph
P
P
O
Rh
Rh-4
-hydride
elimination
3a
Rh-2
O
H
P
O
O
P
Rh
decarboxylation
Rh Cl Ph
1a
P
- CO2
P
O
Rh-1
isomerization
ionization
Rh-5
O
Ph
3a
+ Cl
migratory
insertion
O
P
P
P
Cl
2a
Rh
Rh
P
C-C bond formation
via bimetallic
Me
Ph
mechanism
Rh-3
Rh-6
Scheme 4. Proposed Catalytic Cycle
(2)
(a) Mohr, J. T.; Stoltz, B. M. Enantioselective Tsuji
In conclusion, we have successfully developed a convenient
method to make α-allylated quaternary aldehydes starting from
easily accessible diallyl carbonates. This rhodium-catalyzed
reaction involves the catalytic generation of a rhodium-enolate
and an allyl electrophile which allows for an overall increase in
chemo- and regioselectivity. A key element of the reaction is
the selectivity of the catalyst to differentiate between the pro-
nucleophilic and the pro-electrophilic elements of the
unsymmetrical diallyl carbonates. RPKA studies uncovered a
second order dependence in rhodium on the reaction rate; this
piece of information will be valuable for the design of an
enantioselective variant of this reaction. We anticipate this
work will stimulate further development of other tandem
reactions exploiting the isomerization of allylic alcohols to
allylations. Chem. Asian. J. 2007, 2, 1476−1491. (b) Mohr, J. T.; Ebner,
D. C.; Stoltz, B. M. Catalytic Enantioselective Stereoablative
Reactions: An Unexploited Approach to Enantioselective Catalysis.
Org. Biomol. Chem. 2007, 5, 3571−3576.
(3)
(a) Tsuji, J.; Minami, I.; Shimizu, I. Palladium-Catalyzed
Allylation of Ketones and Aldehydes via Allyl Enol Carbonates.
Tetrahedron Lett. 1983, 24, 1793–1796. (b) Tsuji, J.; Minami, I.;
Shimizu, I. Synthesis of γ,δ-Unsaturated Ketones by the Intramolecular
Decarboxylative Allylation of Allyl β-Keto Carboxylates and Alkenyl
Allyl Carbonates Catalyzed by Molybdenum, Nickel, and Rhodium
Complexes. Chem. Lett. 1984, 13, 1721–1724. (c) Tsuji, J.; Yamada,
T.; Minami. I.; Yuhara, M.; Nisar, M.; Shimizu, I. Palladium-Catalyzed
Decarboxylation-Allylation of Allylic Esters of .alpha.-
Substituted .beta.-Keto Carboxylic, Malonic, Cyanoacetic, and
Nitroacetic Acids. J. Org. Chem. 1987, 52, 2988–2995. (d) Minami, I.;
Nisar, M.; Shimizu, I.; Tsuji, J. New Methods for the Syntheses of α,β-
Unsaturated Ketones, Aldehydes, and Nitriles by the Palladium-
Catalyzed Reactions of Allyl β-Oxo Esters, Allyl 1-Alkenyl Carbonates,
and Allyl α-Cyano Ester. Synthesis, 1987, 1987, 992–998. (e) Nokami,
J.; Mandai, T.; Watanabe, H.; Ohyama, H.; Tsuji, J. The Palladium-
Catalyzed Directed Aldol Reaction of Aldehydes with Ketone Enolates
Generated by the Decarboxylation of Allyl .beta.-Keto Carboxylates
under Neutral Conditions. J. Am. Chem. Soc. 1989, 111, 4126-4127. (f)
Nokami, J.; Watanabe, H.; Mandai, T.; Kawada, M.; Tsuji, J. The
Palladium-Catalyzed Michael Addition Reaction of the Ketone
Enolates Generated by the Decarboxylation of Allyl β-Keto
Carboxylates under Neutral Conditions. Tetrahedron Lett. 1989, 30,
4829–4832.
enols as
a general and practical approach to obtain
functionalized quaternary carbonyl compounds.
AUTHOR INFORMATION
Corresponding Author
** email: mark.lautens@utoronto.ca
* email: marks.taylor@utoronto.ca
Author Contributions
[4]
For reviews, see: (a) Trost, B. M.; Crawley, M. L.
[a] These authors contributed equally.
Asymmetric Transition-Metal-Catalyzed Allylic Alkylations:ꢀ
Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921−2943. (b)
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Weaver, J. D.; Recio, A. Grenning, A. J.; Tunge J. A. Transition Metal-
Tandem Reactions Catalysed by Transition Metal Complexes. Dalton
Trans. 2012, 41, 1660–1670; (b) Lin, L., Yamamoto, K.; Matsunaga,
S.; Kanai, M. Rh‐Catalyzed Aldehyde-Aldehyde Cross‐Aldol Reaction
under Base‐Free Conditions: InꢁSitu Aldehyde‐Derived Enolate
Formation through Orthogonal Activation. Chem. - Asian J. 2013, 8,
2974–2983. For tandem isomerization/functionalization reactions
exploiting the electrophilic properties of the tautomerized enol
intermediate (aldehyde), see: (c) Sahli, Z.; Sundararaju, B.; Achard, M.;
Bruneau, C. Ruthenium-Catalyzed Reductive Amination of Allylic
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Oxidation and Alkylation of Spectinomycin Derivatives: Synthesis of
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Enantioselective Rhodium-Catalyzed Allylic Alkylation of Prochiral
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Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2016, 138,
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Allylation with Alkynes and Allenes. Acc. Chem. Res. 2016, 49, 1524–
1536.
[10] The 2nd generation will be presented herein. For more
experimental details on the 1rst generation, see Supporting Information.
[11] See ref 8d and: (a) Liu, T.-L.; Wei Ng, T.; Zhao, Y.
Rhodium-Catalyzed Enantioselective Isomerization of Secondary
Allylic Alcohols. J. Am. Chem. Soc. 2017, 139, 3643−3646; (b) Huang,
R.-Z.; Lau, K. K.; Li, Z.; Liu, T.-L.; Zhao, Y. Rhodium-Catalyzed
Enantioconvergent Isomerization of Homoallylic and Bishomoallylic
Secondary Alcohols. J. Am. Chem. Soc. 2018, 140, 14647−14654; (c)
Kress, S.; Johnson, T.; Weisshar, F.; Lautens, M. Synthetic and
Mechanistic Studies on the Rhodium-Catalyzed Redox Isomerization
of Cyclohexa-2,5-dienols. ACS Catal. 2016, 6, 747-750.
[12] We also attempted to develop an enantioselective variant of
this reaction, but we were not successful in doing so. A chiral ligand
screen is presented in the Supporting Information (Table S2).
[13] (a) Blackmond, D. G. Reaction Progress Kinetic Analysis:
A Powerful Methodology for Mechanistic Studies of Complex
Catalytic Reactions. Angew. Chem. Int. Ed. 2005, 44, 4302-4320; (b)
Blackmond, D. G. Kinetic Profiling of Catalytic Organic Reactions as
a Mechanistic Tool. J. Am. Chem. Soc. 2015, 137, 10852-10866.
[14] Second order kinetics were also determined when using
Burés graphical method analysis (see Supporting Information for
details): Burés, J. A Simple Graphical Method to Determine the Order
in Catalyst. Angew. Chem. Int. Ed. 2016, 55, 2028-2031.
[5]
[6]
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4897–4905. For selected reviews, see (b) Van der Drift, R. C.;
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Alcohols into Carbonyl Compounds Mediated by Transition Metal
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Platinum Metals in the Catalytic Asymmetric Isomerization of Allylic
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[8]
(a) Ahlsten, N.; Bartoszewicza, A.; Martín-Matute, B.
Allylic Alcohols as Synthetic Enolate Equivalents: Isomerisation and
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nucleophile
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