Organocatalytic α-Allylation of α-Branched Aldehydes by Synergistic Catalysis of Br?nsted Acids and Amines

Article abstract of DOI:10.1002/ejoc.201600725

Herein, we describe the first, fully organocatalytic Tsuji–Trost-type direct α-allylation of α-branched aldehydes by the combined use of N-triflyl amides and secondary amines. Aliphatic, aromatic aldehydes as well as allyl alcohols are converted into the

Full text of DOI:10.1002/ejoc.201600725

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Accepted Article
Title: Organocatalytic -Allylation of -Branched Aldehydes by Synergistic Catalysis of
Brønsted Acids and Amines
Authors: Filip Stanek; Maciej Stodulski
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Organocatalytic α-Allylation of α-Branched Aldehydes by
Synergistic Catalysis of Brønsted Acids and Amines
Filip Stanek and Maciej Stodulski*
Abstract: Herein, we describe the first, fully organocatalytic Tsuji-
Trost-type direct α-allylation of α-branched aldehydes process by the
combined use of N-triflyl amides and secondary amines. Aliphatic,
aromatic aldehydes as well as allyl alcohols are converted to the
corresponding α-allylated products in moderate to high yields.
by Córdova.[10] By combining secondary amine with palladium
catalyst α-allylic alkylated aldehydes and cyclic ketones were
obtained in high yields. Another representative example of α-
allylation of aldehydes via enamine and palladium catalyst was
presented by List and coworkers.[11] Soon after, Breit,[12]
Saicic[13] and Yoshida[14] have also described useful combination
of palladium and enamine catalysis for allylation purposes.
Conversely, Cozzi and coworkers demonstrated combination of
indium and amine catalysis that promoted α-allylation process
with good results.[15] Most recently, two distinct catalysts: iridium
and amine were used to successfully promoted allylation of α-
branched aldehydes in a stereoselective way by Carreira
(Scheme 1a). [16]
Herein, we report the first direct intermolecular α-allylation
of α-branched aldehydes process using allyl alcohols by dual-
catalysis concept without use of any metal for activation of allyl
alcohol or carbonyl compound (Scheme 1b). Using the obtained
protocol, various structurally diverse unsaturated derivatives are
accessible in a selective manner. Starting from allyl alcohol and
α-branched aldehyde, products 3 are formed with moderate to
high efficiency.
Introduction
An important challenge in organic synthesis is the development
of new transformations and strategies to prepare novel products
and complex molecules.[1] One of the extremely useful process
for the construction of new carbon-carbon bond is the metal-
catalyzed allylic substitution of alcohols and their derivatives with
diverse C-nucleophiles, known as the Tsuji-Trost reaction.[2] This
process, although one of the most studied, has been dominated
mostly by transition-metal catalysis.[3] Despite plenitude
variations of this reaction, its organocatalytic version constitute a
notable challenge, therefore only a few examples has been
reported, mainly related with heteroaromatic nucleophiles.[4]
Even with these important advances, direct organocatalytic
allylation process with the new C-C bond formation between
aldehydes and allyl alcohols is unknown and constitute a
remarkable challenge.
Recently, Rueping and Du described substitution of allyl
alcohols by oxygen and nitrogen nucleophiles in
a
stereoselective way using Brønsted acid catalysis.4e, 4h Allylation
is based on the contact ion-pair[5] formed from allyl alcohol and
acid which is further intercepted by appropriate nucleophile.
Following this approach we wondered whether the formed from
allyl alcohol and Brønsted acid contact ion-pair could be
intercepted with an enamine generated in situ from aldehydes.
We envisioned that planned transformation could be feasible by
the combination of two catalysts to activate both of the reagents
and will lead to α-allylated aldehydes with the new C-C bond
formation.
The merger of two catalytic systems has led recently to
powerful strategy and brought a new insight into synthesis
because leads to previously unattainable for single catalyst
transformations. This field has experienced meaningful progress
over the last few years and many of new strategies have been
elaborated based on dual metal-metal, metal-organo or organo-
organo catalysis concepts.[6]
Scheme 1. Direct α-allylation of aldehydes with unprotected allyl alcohols by
synergistic effect of two catalytic units
Results and Discussion
First, two-component catalysts system with Pd were
presented by Sawamura and Ito,[7] Trost[8] and Krische.[9] Soon
after, direct intermolecular α-allylation of aldehydes by using
enamine- and transition metal-catalysis together was presented
To develop an efficient organocatalytic process of allylation of α-
branched aldehydes, we began our studies by establishing set
of catalysts and conditions. As a model we chose reaction
between allyl alcohol 1 and aldehyde 2 (Table 1). Our set of
choice was based on Mayr reactivity scale which indicates that
reaction between allyl carbocations and enamines proceeds
easily.[17] We postulate therefore, that in situ generated
carbocations and enamines should also led to products 3. First,
set of Brønsted acids 5-6 and amines 7-9 were examined
(entries 1–7). By separate use of BA 5-6 only partial dimerization
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka
44/52, 01-224 Warsaw, Poland. E-Mail: maciej.stodulski@icho.edu.pl
Supporting information for this article is available.
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European Journal of Organic Chemistry
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of allylic alcohol was observed and no desired product at all
(entries 1–2). Moreover, no reaction was observed in case,
where only amine was used as catalyst (entry 3). Further
experiments revealed that, both Brønsted acid and amine are
necessary to promote allylation process successfully (entries 4-
7). We observed that N-triflyl amide 6 in the combination with
amine 7 in 3:2 ratio successfully promotes reaction between allyl
alcohol and aldehyde (Table 1, entry 5). In this case allylated
aldehyde 3 was isolated in 15 % yield. Afterwards, different
amines (7–9) were explored. While primary amine facilitates
allylation, secondary amine 8 was found as the best of choice
and promoted reaction in 56% yield. Encouraged by this results,
we tested different combination ratio of amine and Brønsted acid
(Table 1, entries 5-11). Our optimization studies showed that the
best results were achieved using catalytic amount of BA 6 with
amine 8 in 2:1 ratio. This combination promoted formation of
aldehyde 3 in 70% yield and only trace amount of dimer 4
(Table 1, entry 11). Interestingly, after 15 min isolated yield of
dimer 4 was 70% and only trace amount of product 3 (Table 1,
entry 12), indicating that during reaction dimer participates in the
reaction cycle. In all cases, allylation occurred in α-position to
carbonyl group indicated that, enolization of aldehyde took place.
With the optimized catalysts combination in hand, different
solvents were probed to examine impact on the reaction. The
best results were obtained using toluene as a solvent and other
polar or non-polar protic/aprotic solvents gave unsatisfactory
results (see ESI). Also, the temperature had great impact on the
reaction. Temperature below 0 °C gave worse results and at -
78 °C blocked reaction completely. In rt or higher temperature
the decomposition of aldehyde was observed. Therefore, after a
screening of various reaction conditions, optimum conditions for
direct α-allylation of α-branched aldehydes were identified as N-
triflyl amide 6 and amine 8 in 2:1 ratio in toluene at 0 °C.
Table 1. Reaction between allyl alcohol 1 and aldehyde 2 under various
reaction conditions. [a]
Entry
Brønsted acid (BA)
Amine
Yield of 3/4 (%) [b]
1
5 (20 mol%)
6 (20 mol%)
—
—
0 / 57
2
—
0 / 62
3
7 (20 mol%)
7 (20 mol%)
7 (20 mol%)
8 (20 mol%)
9 (20 mol%)
8 (20 mol%)
8 (5 mol%)
8 (50 mol%)
8 (10 mol%)
8 (10 mol%)
8 (10 mol%)
8 (10 mol%)
8 (10 mol%)
0 / 0
4
5 (30 mol%)
6 (30 mol%)
6 (30 mol%)
6 (30 mol%)
6 (20 mol%)
6 (10 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
trace / 52
15 / trace
56 / trace
13 / 39
5
6
7
8
0 / 0
9
13 / 7
10
11
12
13
14
15
0 / 0
70 / trace
trace / 70 [c]
trace / 29 [d]
49 / trace [e]
trace / trace[f]
[a] Conditions: 0.20 mmol of allyl alcohol, 1.00 mmol of aldehyde. Solvent:
PhMe, volume: 2 mL, temperature: 0 °C. Reaction time was 16h. [b] Isolated
Yield. [c] Reaction time: 15 min; [d] Molecular sieves 4Å (powdered, 500 mg)
was added. [e] reaction temp. was -24 °C; [f] reaction temp. was -78 °C
Scheme 2. Substrate scope of the organocatalytic Tsuji-Trost-type allylation.
a) The yield was determined after isolation of product. b) Geometry of double
bond was determined by Karplus correlation.
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European Journal of Organic Chemistry
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Moreover, in this reaction conditions after 16h only trace amount
of dimerized allyl alcohol was observed.
product was observed indicating that reaction pathway doesn’t
concern Sn2’ mechanism. Moreover, water is also crucial and
participates in catalytic cycle. The reaction between 1 and 2 with
addition of molecular sieves leads only to dimerized allyl alcohol
4 (Table 1, entry 13). Mechanism of the transformation has not
been studied in details and obviously more experiments are
needed to clarify its path-way, but based on obtained results, a
plausible reaction pathway of the process is depicted in Scheme
4. The presented transformation proceeds in a similar manner to
that for metal/enamine catalysed allylation of aldehydes and
involves formation of an allylic carbocation which is further
intercepted by enamine formed from aldehyde.
We also investigated stereoselective version of the allylic
alkylation reaction. In preliminary studies, optically active various
secondary amines and N-triflyl amides were tested and provided
α-allylated alcohols 10 in yields up to 96% although without any
selectivity (see ESI).
With the optimized conditions in hand, we surveyed the
reaction scope using a series of allyl alcohols and α-branched
aldehydes (Scheme 2). The allylation process generally
occurred in good yields (34–77%). Variation of the aromatic
functionality in allyl alcohol showed that electron donating as
well as electron withdrawing substituents at the aromatic ring are
tolerated, leading to the corresponding products (10a‒10i) in
34–77% yield. A broad range of functional groups, such as
methyl (10b), chloro (10c), bromo (10d) or naphtyl (10g) were
compatible with this protocol. Substituents in o- and m-positions
were likewise accepted in this transformation. In case of electron
withdrawing groups (10c–d), slightly higher yields were obtain
compared to (10a), which might be related with better
stabilization of the formed carbocation. It was observed that allyl
alcohols containing strongly electron donating groups, like OMe
easily dimerize and no allylation reaction was observed. Notably,
allyl alcohols containing para- and meta-substituents led to
desired products with higher yields than the reagents containing
corresponding orto-substituents due to steric/stereoelectronic
interactions. For orto-substitutents generally lower yields were
observed (34–54%).
Aliphatic α-branched aldehydes such as isobutyraldehyde
(10i–10k) and aliphatic allyl alcohols were tested next, leading to
allylated products in 47–67% yield. Here, even (E)-4-phenylbut-
3-en-2-ol was selectively converted into 10l in 46% yield
indicating that, not only aromatic aldehydes or allyl alcohols but
aliphatic as well are reacting easily. Moreover, unsymmetrical
aldehydes like 2-phenylpropionaldehyde or aliphatic not-
branched aldehydes react easily, and appropriate products 10m-
10o are formed with 27-60% yield as
a
mixture of
diastereoizomers syn:anti 1:1. Unfortunately, the reaction didn’t
work with mono-substituted allylic alcohols, such as cinnamyl, α-
vinylbenzyl or aliphatic allylic alcohols due to their relative low
reactivity that comes from poor stabilization of formed
carbocation.
Scheme 4. Plausible mechanism for the allylation of aldehydes using
combined Brønsted acid – enamine catalysis. BA – Brønsted acid
Conclusions
In conclusion, we have disclosed a first, fully organocatalytic α-
allylation of α-branched aldehydes process by synergistic effect
of Brønsted acids and secondary amines. The method delivers
unsaturated aldehydes/alcohols with moderate to high yields in
mild conditions. Presented studies depicted that, allylation of
aldehydes previously reserved only for metal catalysis can be
realized by combination of two organocatalysts. Further studies
toward detailed mechanism, application in the stereoselective
synthesis and the development of other dual-catalytic reactions
is currently in progress.
Scheme 3. Control experiments using dimerized allyl alcohol 4
To gain more information about possible mechanistic path
of this reaction several additional experiments were carried out
(Scheme 3). First, reaction between dimer 4 and aldehyde 2 in
standard reaction conditions was studied (path A). In this case
we observed formation of aldehyde 3 in 88% yield, what
indicates that this reaction may occur through Sn2’ process, or
dimer 4 is reversibly converted to allyl carbocation. To prove this
hypothesis, the second experiment was conducted using
catalytic amount of morpholine only (path B). In this case no
Experimental Section
Typical procedure for the synthesis of 3: To the cooled mixture (0 °C)
of allyl alcohol (1) (0.20 mmol, 1.0 eq.) in dry toluene (2 mL, 0.10 M)
aldehyde (2) (0.18 ml, 1.00 mmol, 5.0 eq.), 2M solution of amine (7-9)
(0.02 mmol, 0.1 eq.) and Brønsted acid 5-6 (0.04 mmol, 0.2 eq.) were
added. The reaction mixture was stirred for 16h at 0 °C under Ar
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European Journal of Organic Chemistry
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COMMUNICATION
atmosphere and monitored by TLC (benzene: hexane 1:1). Solvent was
evaporated and product was purified by PTLC (hexane and ethyl acetate
85:15).
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Typical procedure for the synthesis of 10: To the cooled mixture
(0 °C) of allyl alcohol (1) (0.20 mmol, 1.0 eq.) in dry toluene (2 mL, 0.10
M) aldehyde (2) (0.18 ml, 1.00 mmol, 5.0 eq.), 2M solution of morpholine
8 in PhMe (10μl, 0.02 mmol, 0.1 eq.) and N-triflyl amide 6 (0.04 mmol,
0.2 eq.) were added. The reaction mixture was stirred for 16h at 0 °C
under Ar atmosphere and monitored by TLC (benzene: hexane 1:1).
After specified time to the reaction mixture MeOH (2 mL) and NaBH4
(0.04 g, 1.00 mmol, 5.0 eq.) was added and stirred for next 1h at room
temperature. The mixture was extracted 3 times with ethyl acetate,
combined organic layers were washed with brine and dried over
anhydrous MgSO4. Solvent was evaporated and the crude mixture was
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Keywords: organocatalysis • Brønsted acids • allylation •
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European Journal of Organic Chemistry
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Organocatalytic allylation
Filip Stanek and Maciej Stodulski *
Page No. – Page No.
Organocatalytic α-Allylation of α-
Branched Aldehydes by Synergistic
Catalysis of Brønsted Acids and
Amines
Fully organocatalytic α-allylation of α-branched aldehydes process by synergistic
effect of Brønsted acids and secondary amines is reported. Unprotected allyl
alcohols and aldehydes are activated by two distinct catalytic units in a Tsuji-Trost-
type organocatalytic process.
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