Contemporaneous Dual Catalysis: Aldol Products from Non-Carbonyl Substrates

Article abstract of DOI:10.1002/chem.201502973

The aldol reaction represents an important class of atom-economic carbon-carbon bond-forming reactions vital to modern organic synthesis. Despite the attention this reaction has received, issues related to chemo- and regioselectivity as well as reactivity of readily enolizable electrophiles remain. To help overcome these limitations, a new direct approach toward aldol products that does not rely upon carbonyl substrates is described. This approach employs room-temperature contemporaneous lanthanum/vanadium dual catalysis, whereby a vanadium-catalyzed 1,3-transposition of allenols is coupled with a lanthanum-catalyzed Meinwald rearrangement of epoxides in situ to directly form aldol products.

Full text of DOI:10.1002/chem.201502973

DOI: 10.1002/chem.201502973
Communication
&
Organic Synthesis
Contemporaneous Dual Catalysis: Aldol Products from Non-
Carbonyl Substrates
[a]
Barry M. Trost* and Jacob S. Tracy
Abstract: The aldol reaction represents an important class
of atom-economic carbon–carbon bond-forming reactions
vital to modern organic synthesis. Despite the attention
this reaction has received, issues related to chemo- and
regioselectivity as well as reactivity of readily enolizable
electrophiles remain. To help overcome these limitations,
a new direct approach toward aldol products that does
not rely upon carbonyl substrates is described. This ap-
proach employs room-temperature contemporaneous lan-
thanum/vanadium dual catalysis, whereby a vanadium-
catalyzed 1,3-transposition of allenols is coupled with
a lanthanum-catalyzed Meinwald rearrangement of epox-
ides in situ to directly form aldol products.
trophiles are low yielding and plagued by side reactions as
[
3]
highlighted by the reaction given in Equation. (1).
Methods utilizing silicon or boron enolates have had modest
success in overcoming the reactivity issue of such readily eno-
[
4–6]
lizable aldehydes.
However, in addition to stoichiometric
base and cryogenic temperatures, these methods also rely
upon stoichiometric amounts of a silicon or boron reagent in
the pre-formation of enolates that ultimately results in an in-
crease in downstream waste generation and preclude the cata-
lytic formation of an enolate in the presence of an electrophilic
partner. Additionally, the synthesis of a requisite non-commer-
cial aldehyde can be a tedious process. Crimmins has de-
scribed the need to synthesize 3-butenal through a two-step
sequence from a commercially-available glyoxal in order to
achieve reasonable yields in the subsequent addition of boron
Traditional catalysis has generally relied upon the selective for-
mation of a catalyst-activated intermediate that is subsequent-
ly trapped by a second coupling partner present in stoichio-
metric quantities. Contemporaneous dual catalysis expands on
this traditional use of catalysis by allowing for the simultane-
ous in situ activation of both coupling partners of a reaction
[
7]
enolates. To overcome the sensitivity of b,g-unsaturated alde-
hydes while eliminating all stoichiometric additives and by-
products, we envisioned a new approach to the aldol reaction
that would utilize non-carbonyl substrates in the construction
of aldol products. In such an approach, both the enolate
donor and the carbonyl acceptor would be catalytically gener-
ated in situ and subsequently coupled in a mild manner to
provide aldol products.
[1]
through the use of two distinct catalysts. The resulting two
catalyst-activated intermediates are coupled with one another
in preference over reactivity with stoichiometric amounts of
unactivated substrates present in the reaction flask. Use of this
type of dual catalysis has resulted in the disclosure of novel re-
activities as well as products that have been difficult to obtain
under traditional one-catalyst approaches.
As part of our group’s continuing interest in the catalytic
generation of enolates, we wondered whether we could apply
the principles of this dual catalysis to the aldol reaction. While
the aldol condensation was initially described as an atom-eco-
nomic reaction, modern variants developed to overcome
issues of chemo- and regioselectivity tend to suffer from the
need to utilize stoichiometric base to pre-form enolates and re-
As part of our work in the catalytic generation of enolates,
we have previously reported on the ability of propargylic and
allenic alcohols to undergo a vanadium oxo-catalyzed 1,3-
transposition to form vanadium allenoate and enolate inter-
mediates, respectively. Subsequent trapping by aldehydes,
imines, and p-allylpalladium intermediates was shown to be
possible, despite the presence of a competitive protonation
pathway that would lead to the Meyer–Schuster rearrange-
[2]
quire cryogenic temperatures. Even with these methods, cer-
tain substrate classes, such as aldehydes containing readily
enolizable a-protons, owing to additional activation from the
presence of vinyl and phenyl substituents, remain problematic.
Attempts to utilize traditional aldol conditions for these elec-
[
8]
ment product. Since our initial reports, others have expanded
[
9]
this methodology to include the trifluoromethyation, aryla-
[
10]
[11]
tion, and halogenation of allenoates generated from the
1,3-transposition of propargyl alcohols. Related work has suc-
cessfully utilized the redox isomerization of allylic alcohols to
form transition-metal enolates that can be trapped by a range
[
a] Prof. Dr. B. M. Trost, J. S. Tracy
Department of Chemistry, Stanford University
Stanford, CA 94305 (USA)
[12]
of electrophiles.
In looking to develop this non-carbonyl substrate approach
to the aldol reaction, we wondered whether we could couple
this catalytic 1,3-transposition of allenols to form vanadium
E-mail: bmtrost@stanford.edu
Supporting information and ORCID(s) from the author(s) for this article is
available on the WWW under http://dx.doi.org/10.1002/chem.201502973.
Chem. Eur. J. 2015, 21, 15108 – 15112
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Communication
enolates with the Meinwald rearrangement of epoxides to
form aldehyde acceptors. The use of commercially available
and easily accessed vinyl and styrenyl epoxides would allow
for the in situ formation of readily enolizable b,g-unsaturated
aldehydes that typically require multiple steps to access and,
as discussed earlier, have issues of variability in their reactivity
under traditional aldol conditions. Being able to concurrently
generate both the nucleophile and electrophile in a mild, cata-
lytic fashion from starting materials disparate from the tradi-
tional coupling partners would represent an attractive new ap-
proach to aldol reactions.
[a]
Table 1. Optimization studies.
[
b,c]
[b]
Lewis acid
Cat. Epoxide
Product
d.r.
(loading [mol%]) -X
equivalents ratio (6:7)
(syn:anti)
1
2
3
4
5
6
7
8
9
La(OTf)
La(OTf)
La(OTf)
La(OTf)
La(OTf)
La(OTf)
La(OTf)
La(OTf)
La(OTf)
3
3
3
3
3
3
3
3
3
(8)
(8)
(8)
(8)
(16)
(25)
(16)
(16)
(16)
(8)
1
1
2
2
2
2
2
2
2
1
1
1
1
1.5
1.5
1.5
1.5+5
1.5+1.5
1.5+1.5
3.0
1.0+1.0
0.75+0.75 1.2:1 (44%)
1.3:1
1:2.9
1.8:1
4:1
3:1
4:1
4.5:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
Despite the appeal of this process, the compatibility of the
two catalytic processes is not a trivial assumption. The allenols
can be sensitive to the types of Lewis acids required for the
Meinwald rearrangement during the initial 1,3-transposition as
well as during the subsequent competitive tautomerization of
the enolate to form the Meyer–Schuster rearrangement prod-
[
d]
[e]
4.2:1 (71%)
5.0:1 (68%)
2.5:1 (59%)
2.4:1 (59%)
2.1:1 (50%)
[
e]
e]
[
[e]
[
13]
uct.
Additionally, alcohols are known to be capable of
[e]
[
14]
[f]
adding to activated epoxides under Lewis acidic conditions.
10 Eu(OTf)
Ho(OTf)
Ba(OTf)
Eu(acac)
3
1.5+1.5
1.5+1.5
1.5+1.5
<1:5
<1:5
<1:10
[
f]
f]
1
1
3
(8)
(8)
Finally, the enolizable aldehydes formed from the Meinwald re-
arrangement may undergo competitive self-aldol reactions
under these Lewis acidic and Brønsted basic conditions. Even if
the processes are found to be compatible, the relative rates of
nucleophile and electrophile formation must be carefully con-
trolled to ensure that the two cycles are able to intersect and
avoid the formation of the simple Meyer–Schuster rearrange-
ment product (Scheme 1).
[
1
1
2
3
2
[f]
[g]
3
(8)
(8)
(8)
0.75+0.75 transposition
NA
inhibited
[h]
[e]
14 La(OTf)
3
3
2
2
1.5+1.5
1.5+1.5
none 1.5+1.5
1:1.1
<1:15
4.5:1
[
[
e]
e]
[g]
1
1
5
6
none
La(OTf)
NA
[g]
<5% transposition NA
[
a] Unless otherwise noted: cat.-1 or cat.-2 and the Lewis acid were dis-
solved in DCE (0.3 mL) at 238C. The epoxide was added all at once fol-
lowed by a slow addition of allenol (0.2 mmol) in DCE (0.2 mL) over 10 h.
b] Determined by NMR integration of crude reaction mixture. [c] Isolated
yield of 6 reported in parentheses. [d] Allenol was added all at once in
one portion. [e] This portion of epoxide was added slowly to the reaction
with the allenol. [f] This portion of epoxide was added after 5 h. [g] NA =
not available. [h] Slow addition over 20 h.
To probe the compatibility of these two processes, the cou-
pling of allenol 4 and butadiene monoepoxide was explored
[
initially using lanthanum triflate (La(OTf) ) as the Meinwald cat-
3
alyst and [OV(OSiPh ) ] (cat.-1) as the 1,3-transposition catalyst
3
3
[
Eq. (2)].
Selected results of the optimization are shown in Table 1. A
slow addition of the allenol to the reaction mixture was found
to be necessary (Table 1, entries 1 and 2) and is in line with
previous work that has shown excess alcohol to be the source
of protons for the undesired Meyer-Schuster rearrangement
[
15]
product. A slight improvement in the ratio of aldol product
was observed upon switching from cat.-1 to the more elec-
tron-deficient [OV{OSi(p-ClC H ) } ] (cat.-2) (Table 1, entry 3). In-
6
4 3 3
creasing the epoxide loading to 6.5 equivalents resulted in
a good isolated yield (Table 1, entry 4). This yield could be
maintained by decreasing the epoxide loading to 1.5 equiva-
lents added at the start of the reaction with an additional
1
.5 equivalents added slowly with the allenol, and by increas-
ing the La(OTf) loading to 16 mol% (Table 1, entry 5). Further
3
increasing the Lewis acid loading or adding all three equiva-
lents of epoxide at the start of the reaction gave lower yields
(
Table 1, entries 6 and 7), as did further decreasing the epoxide
loading (Table 1, entries 8 and 9). However, as subsequent ex-
periments show, the epoxide loading for some substrates can
be lowered to as little as 1.2 equivalents (vide infra). Changing
the Lewis acid to other Period 6 Lewis acids resulted in the de-
tection of trace aldol product (Table 1, entry 10–13). Extending
the duration of the slow addition of the allenol and epoxide to
20 h resulted predominantly in the Meyer–Schuster product 7
Scheme 1. Proposed dual catalytic coupling of allenols with vinyl epoxides.
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Communication
(
Table 1, entry 14). Control experiments showed that both, the
(558C) and catalyst loading (10% cat.-2) (Table 2, entry 6). In
vanadium transposition catalyst and the lanthanum Meinwald
catalyst were necessary for the formation of aldol product
each of these cases, the major diastereomer was characterized
1
as the syn isomer based upon an analysis of H NMR coupling
[
18]
(
Table 1, entry 15 and 16). Varying reaction concentration, or in-
constants
and by comparison to similar known com-
[
19]
creasing the amount of cat.-2 or reaction temperature failed to
provide any improvement. A solvent screen indicated that
switching from dicholorethane (DCE) to other solvents resulted
in predominantly Meyer–Schuster product (see Table S1 in the
Supporting Information for more details). The marked depend-
ence of the reaction on the amount and the nature of the
Lewis acid species used for the Meinwald rearrangement, the
Lewis acidity of the vanadium transposition catalyst, and the
rate of addition of the allenol and epoxide, all highlight the
challenge in coupling the rates of enolate and aldehyde gener-
pounds.
Having established the compatibility of this process with
a broad range of allenols, the scope of the electrophilic partner
was probed. Utilizing the more activated isoprene monoepox-
ide, reasonable yields could be obtained with as little as
1.5 equivalents of epoxide (Table 3, entry 1). Under these con-
ditions, around 15% of the product corresponding to migra-
tion of the alkene to an internal position could be observed
[
16]
ation.
Table 3. Electrophile scope for the formation of aldol products from the
addition of allenols to epoxides.
With an optimized set of conditions in hand, the scope of
the allenol nucleophile was probed (Table 2). While allenols are
not commercially available, they are readily synthesized; their
ease of synthesis must be compared to the synthesis of largely
unavailable enones that would be required to obtain these
[a]
Allenol
Epoxide
Product
Yield
[%]
d.r.
(syn:anti)
[17]
[b]
[c]
1
2
3
4
5
4
4
4
4
4
60
47:26:16:11
aldol products using traditional enolate chemistry. An unsub-
stituted allene proceeded with only a slight reduction in yield
[d]
(
Table 2, entry 2). Placing a more sterically hindered isopropyl
83
73:27
substituent on the allene resulted in a further drop in yield but
did not impact on the diastereomeric ratio (d.r.). (Table 2,
entry 3). Replacing the phenyl substituent on the carbenol
carbon with a dialkyl was tolerated (Table 2, entries 4 and 5).
The use of less activated alkyl monosubstituted allenol 16 re-
sulted in a good yield but required a higher temperature
[e]
49
80:20
[
[
f]
74
4
76:24
73:27
g]
6
[f]
4
5
0
6
82:18
79:21
[h]
[
[
f]
6
8
9
3
78:22
78:22
6
4
h]
Table 2. Nucleophile scope for the formation of aldol products from the
[
a]
addition of allenols to butadiene monoepoxide.
[f]
4
6
6
9
82:18
80:20
7
8
9
1
4
4
8
8
[h]
[
[
f]
6
7
0
1
76:24
77:23
h]
Allenol
Product
Yield
%]
d.r.
(syn:anti)
[b]
18
24
62
61:39
[
[
[
h]
f]
[i]
0
65
NA
1
2
3
68
61
53
80:20
7
7
1
9
[i]
[b]
11
8
NA
NA
[h]
[
[
f]
1
1
2
3
16
16
3
73
78:22
80:20
81:19
h]
35
4
5
6
55
49
62
77:23
79:21
72:28
[
3
a] Standard conditions utilized La(OTf) (16%), cat.-2 (5%) dissolved in
DCE (0.3 mL). 50% of the epoxide is added at the start of the reaction
and 50% added slowly with allenol (0.2 mmol) over 10 h in of DCE
0.2 mL). [b] 1.5 equiv of epoxide all added slowly over 10 h. [c] syn–
syn:syn–anti:anti–syn:anti–anti. [d] cat.-2 (15%) and 3.0 equiv of epoxide.
e] 3.0 equiv of epoxide (1.5 equiv premixed with the vanadium and lan-
thanum catalyst for 12 h and the second 1.5 equiv added slowly over
10 h with the allenol), 10% cat.-2 and La(OTf) (40%) at 308C.
(
[
c]
[
[
3
a] Standard conditions utilized La(OTf) (16%) and cat.-2 (5%) dissolved
in DCE (0.3 mL). 50% of the epoxide is added at the start of the reaction
and 50% is slowly added with allenol (0.2 mmol) over 10 h in DCE
3
[f] 1.2 equiv of epoxide. [g] 1.2 equiv of epoxide and La(OTf)
3
(5%).
(
0.2 mL). [b] NA = not available. [c] 558C, cat.-2 (10%).
[h] 3.0 equiv of epoxide. [i] NA = not available.
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and was separated from the desired mixture of diastereomers.
The relative stereochemistry of the stereocenters formed by
the creation of the carbon–carbon bond was determined from
coupling constants. To determine the relative stereochemistry
of the methyl group originating on the isoprene unit, the two
major products (19a and 19b) were isolated and subjected to
ring-closing metathesis. From these cyclic products, NOE analy-
sis was used to assign the major product 19a as syn–syn, while
the second major product 19b was assigned as syn–anti
tolerant of readily enolizable aldehydes containing b,g-unsatu-
ration formed in situ; also represents a new general approach
for the formation of aldol products. While most of the cases at
present were best performed with excess epoxide, in several
instances 1.2–1.5 equivalents gave good results. Indeed, it
should be noted that the use of excess acceptor aldehyde in
the aldol reaction is common. At present time, the d.r. is ap-
proximately 80:20, which constitutes a significant improve-
ment compared to the traditional use of lithium enolates
adding to aldehydes as illustrated in Equation (1).
(
Figure 1). By analogy, the two minor products were assigned
Acknowledgements
We thank the NSF (CHE-1360634) for their generous support of
our program.
Keywords: aldol reaction · contemporaneous dual catalysis ·
lanthanum · rearrangement · vanadium
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Figure 1. Determination of relative stereochemistry of 19.
as anti–syn and anti–anti. This metathesis transformation high-
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the aldol products resulting from the diene monoepoxides and
allenols, which allows ready access to highly functionalized cy-
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oxides worked especially well and could give high yields utiliz-
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case, dropping the lanthanum loading to as low as 5% result-
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proved less efficient than electron-deficient systems, while het-
eroaromatic epoxides could proceed with good yield utilizing
[
[
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tuted allenol 8 under the conditions developed with methyl-
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the dual catalytic approach can be directly compared with the
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2
1% yield obtained under traditional aldol conditions utilizing
the same ratio of nucleophile to electrophile [Table 3, entry 12
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In summary, we have developed a mild set of conditions for
the direct formation of aldol products, which furthermore does
not rely upon carbonyl starting materials for either partner.
The present vanadium–lanthanum dual catalytic approach is
[
[
[
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Communication
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Received: July 29, 2015
Published online on September 3, 2015
Chem. Eur. J. 2015, 21, 15108 – 15112
www.chemeurj.org
15112
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