The catalytic asymmetric α-benzylation of aldehydes

Article abstract of DOI:10.1002/anie.201306037

The first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents has been developed. Using a sterically demanding proline derived catalyst, racemic α-branched aldehydes are reacted with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities. A sterically demanding proline derivative promotes the first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents. Racemic α-branched aldehydes react with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201306037

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Angewandte
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DOI: 10.1002/anie.201306037
Aminocatalysis
Hot Paper
The Catalytic Asymmetric a-Benzylation of Aldehydes**
ˇ
´
Benjamin List,* Ilija Coric, Oleksandr O. Grygorenko, Philip S. J. Kaib, Igor Komarov,
Anna Lee, Markus Leutzsch, Subhas Chandra Pan, Andrey V. Tymtsunik, and
Manuel van Gemmeren
Dedicated to Professor Johann Mulzer
Abstract: The first aminocatalyzed a-alkylation of a-branched
aldehydes with benzyl bromides as alkylating agents has been
developed. Using a sterically demanding proline derived
catalyst, racemic a-branched aldehydes are reacted with
alkylating agents in a DYKAT process to give the correspond-
ing a-alkylated aldehydes with quaternary stereogenic centers
in good yields and high enantioselectivities.
developed a new bicyclic proline analogue that catalyzes this
reaction, delivering aldehydes with a quaternary center in a-
position in high enantioselectivity.
A main difficulty in the aminocatalytic intermolecular a-
alkylations of aldehydes with SN2-type alkylating agents is the
tendency of inherently Lewis basic amine catalysts to undergo
N-alkylation. This process is normally irreversible and results
in the complete deactivation of the aminocatalyst, at least
unless SN1-reactive benzhydryl-type alkylating reagents are
utilized. The unproductive catalyst-alkylation reaction is
further enhanced by the stoichiometric base, which is added
to neutralize the strong acid formed in the a-alkylation, and
which in principle can also be alkylated itself. The tendencies
of aldehydes to undergo self-aldolization and racemization
provide for additional complications.
After exploring several different and yet more or less
unsuccessful strategies over the years, we hypothesized that
a direct asymmetric aldehyde alkylation may be realizable, if
a-branched aldehydes are utilized, as the corresponding
products are stable and do not undergo racemization and, if
an organic mixed acid/base “buffer” system is used instead of
a base alone. Such a reaction medium was expected 1) to
accelerate enamine formation through mild acid catalysis,
2) to “neutralize” the acid by-product, and 3) to suppress the
alkylation of base and/or catalyst. It has been shown
previously that mixtures of acids and bases can be beneficial
in related SN1 alkylations.[12]
A
symmetric SN2 a-alkylations of carbonyl compounds with
alkyl halides are powerful transformations that commonly
involve chiral auxiliaries and phase-transfer catalysts.[1]
Recently, however, organocatalysis has significantly advanced
this area by providing new strategies for the direct catalytic
asymmetric a-alkylation of aldehydes.[2] For example, our
group has described an intramolecular a-alkylation reaction
of haloaldehydes using proline-based enamine catalysis.[3]
Subsequently, other groups have contributed additional
aminocatalytic methods for the asymmetric a-alkylation of
aldehydes, including strategies that combine enamine catal-
ysis with radical or cationic (SN1) reaction pathways.[4–13]
Despite these unquestionable advancements though, the
asymmetric intermolecular SN2 a-alkylation of aldehydes
with simple alkyl halides has remained a long-standing
challenge for enamine catalysis (Scheme 1).[2]
Here we report progress with the first catalytic enantio-
selective a-benzylation of a-branched aldehydes. We have
Indeed, when we reacted hydratropaldehyde (1a) with
benzyl bromide (2a) in the presence of (S)-proline (3a,
50 mol%) and a combination of both p-anisidic acid and
Hꢀnigꢁs base (diisopropylethylamine, iPr2NEt), the desired
product 4a could be detected for the first time (Table 1,
entry 1). Essentially no product was obtained in the absence
of buffer and with acid or base alone. While both yield (12%)
and enantioselectivity (51:49 e.r.) were poor and a significant
amount of N-benzylated (S)-proline was still formed as a side
product, we were encouraged by this result. A broader screen
of aminocatalysts towards improving the enantioselectivity
and yield was therefore initiated. We investigated various
types of organocatalysts, of which selected examples are
summarized in Table 1. In contrast to what we found
previously in our intramolecular variant, the use of (S)-a-
methylproline 3b as catalyst did not result in improved yield
or enantioselectivity (Table 1, entry 2). Imidazolidinone cata-
lysts such as 3c[14] and prolinol ether catalyst 3d[15] proved to
be ineffective in catalyzing this reaction (Table 1, entries 3
and 4). (S)-Proline derivative 3e and primary amino acids
Scheme 1. The catalytic asymmetric a-alkylation of aldehydes: A chal-
lenge for enamine catalysis.
ˇ
´
[*] Prof. Dr. B. List, Dr. I. Coric, P. S. J. Kaib, Dr. A. Lee, M. Leutzsch,
Dr. S. Chandra Pan, M. van Gemmeren
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
Dr. O. O. Grygorenko, Prof. Dr. I. Komarov, A. V. Tymtsunik
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv (Ukraine)
[**] Generous support from the Max-Planck-Society and the Fonds der
Chemischen Industrie is gratefully acknowledged. We also thank the
members of our HPLC and GC departments for their support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306037.
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Table 1: Catalyst evaluation.[a]
a theoretical study, azabicyclic proline analogues were
predicted to give higher selectivities than simple proline in
aldol reactions, due to better preorganization of the transition
state and we reasoned that this might also be of help for our a-
alkylation reaction.[16] Indeed, very interesting results were
obtained when we tested the sterically more demanding
secondary amino acid catalysts 3j–l (Table 1, entries 10–12).
High enantioselectivity (93.5:6.5 e.r.) was observed in the
presence of catalyst 3l even though the product was obtained
in modest yield (Table 1, entry 12). Amino acid 3l was
developed by the group of Komarov in 2006,[17] but had not
previously been investigated in asymmetric catalysis.
With these intriguing results in hand, we were curious
whether real turnover could be accomplished by optimizing
the reaction conditions. In earlier studies, we found that the
added base has a pronounced effect on both the reactivity and
stereoselectivity in the a-alkylation of aldehydes. Therefore,
different bases were investigated and selected examples are
summarized in Table 2.
Entry
1
Catalyst
Yield [%][b]
12
e.r.[c]
51:49
2
3
10
51:49
–
n.r.
4
n.r.
–
5
6
65
52
80:20
60:40
Table 2: Influence of the base.[a]
7
8
46
55
79.5:20.5
86.5:13.5
Entry
Base
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
DMAP
imidazole
DBU
1,3-diphenylguanidine
1,3-di-(o-tolyl)guanidine
1,1,3,3-tetramethylguanidine
2’,2’-(naphthalene-1,8-diyl)-
bis(1,1,3,3-tetramethylguanidine)
30
33
20
60
63
80
80
65:35
61:39
79:21
88:12
90:10
95.5:4.5
53:47
9
n.r.
–
[a] Reaction conditions: aldehyde 1a (0.1 mmol) and benzyl bromide 2a
(0.5 mmol), catalyst 3l (0.03 mmol), p-anisic acid (0.5 mmol), base
(0.5 mmol), 4 ꢁ M.S. (80 mg) in chloroform (0.5 mL) at 508C for 144 h.
[b] Determined by GC-MS using n-dodecane as an internal standard.
[c] Determined by GC analysis on a chiral stationary phase. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, DMAP=4-(dimethylamino)pyridine.
10
11
12
20
22
25
62.5:37.5
90.5:9.5
93.5:6.5
Gratifyingly, after an extensive screening of various bases
(see the Supporting Information for more details), we found
the addition of guanidines to be beneficial (Table 2, entries 4–
7). In particular, 1,1,3,3-tetramethylguanidine not only gave
some turnover but also did so with an even improved e.r.
> 95:5 (Table 2, entry 6).
We also explored various acids as additives and found that
p-anisic acid consistently gave the best results (see the
Supporting Information). It is noteworthy that a significant
improvement in yield and enantioselectivity was achieved
when we used an excess of tetramethylguanidine, p-anisic
acid, and benzyl bromide (5 equivalents each) under the
optimized reaction conditions.[18]
[a] Unless otherwise noted, reactions were conducted with aldehyde 1a
(0.1 mmol) and benzyl bromide 2a (0.3 mmol), catalyst 3 (0.05 mmol),
iPr2NEt (0.3 mmol), p-anisic acid (0.3 mmol), 4 ꢁ M.S. (80 mg) in
chloroform (0.5 mL) at 508C for 120 h. [b] Determined by GC-MS using
n-dodecane as an internal standard. [c] Determined by GC analysis on
a chiral stationary phase. n.r.: no reaction.
3 f–h gave moderate yields but promising enantioselectivities
(Table 1, entries 5–8). A cinchona-derived primary amine
catalyst (3i) was found to be inactive in the reaction (Table 1,
entry 9). This catalyst rapidly reacts with benzyl bromide and
N-benzylated amines were detected by GC-MS analysis. In
After identifying a suitable catalyst and establishing
optimized reaction conditions, we next investigated the
scope of our catalytic asymmetric a-alkylation of a-branched
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Table 3: Substrate scope.[a]
aldehydes (Table 3). The reaction turned out to be tolerant of
both electron-deficient and electron-rich aromatic substrates.
The desired products were obtained in moderate to good
yields (55–82%) and high enantioselectivities (e.r. up to
98.5:1.5). a-Branched aldehydes that possess meta or para
substituents on the aromatic structure furnish the correspond-
ing alkylated products in good yields and enantioselectivities
(Table 3, entries 2–11 and 17). In general, the reaction takes
place slowly at 508C. However, with aldehyde 1d and
electrophile 2j, the reaction could be carried out at lower
temperature (Table 3, entries 5–7 and 14–16). Excellent
enantioselectivities were observed in both cases (up to
98.5:1.5 e.r. with 1d and 97.5:2.5 e.r. with 2j). Unfortunately,
aliphatic aldehydes did not lead to product formation under
our reaction conditions. We also attempted using linear
aldehydes as substrates. However, in this case no desired
product could be isolated. A GC-MS analysis of the crude
reaction mixture revealed the predominant formation of
products resulting from double alkylation and self-aldoliza-
tion.
Entry
1
Substrate 1
Product 4
Yield [%]
80
e.r.[b]
95.5:4.5
2
3
82
77
95:5
95:5
4
70
65
60
60
92:8
95:5
97.5:2.5
98.5:1.5
5[c]
6[d]
7[e]
The absolute configuration of product 4a was determined
to be R by comparison of the optical rotation with the
literature value.[19] The absolute configuration is consistent
with the proposed transition state A (Scheme 2). In previous
8
9
72
71
90:10
91:9
10
11
12
70
68
80
86:14
84:16
94:6
Scheme 2. Proposed transition state A of the intermolecular a-alkyla-
tion. Calculated transition state B of the intramolecular a-alkylation.
DFT-based calculation studies on the asymmetric intramo-
lecular a-alkylation of aldehydes,[20] we showed that the base-
assisted reaction is more facile and exhibits a different
stereoselectivity. In the corresponding transition state B, the
added base is present as a trialkylammonium carboxylate,
which activates the leaving group in the SN2-type nucleophilic
substitution, by providing an electrostatic stabilization of the
developing negative charge at the halide. Based on this study,
we propose the analogous transition state A for the inter-
molecular a-alkylation of a-branched aldehydes, which may
be further stabilized by p–p interactions.[21]
13
80
75
65
55
91.5:8.5
93.5:6.5
95:5
14[c]
15[f]
16[d]
97.5:2.5
17
65
88:12
In conclusion, we have developed the first catalytic
asymmetric a-alkylation of a-branched aldehydes using
simple alkylating agents via enamine catalysis. Racemic a-
branched aldehydes can be converted into the corresponding
enantiomerically enriched products with e.r. values of up to
98.5:1.5 in a dynamic kinetic asymmetric transformation
(DYKAT). Our reaction also features a new sterically
demanding proline-derived catalyst, which can be easily
synthesized in both enantiomeric forms and which may be
of use in other challenging asymmetric reactions.
[a] Reaction conditions: Aldehyde 1 (0.5 mmol), benzyl bromide 2
(2.5 mmol), catalyst 3l (0.15 mmol), p-anisic acid (2.5 mmol), base
(2.5 mmol), 4 ꢁ M.S. (400 mg) in chloroform (2.5 mL) at 508C for 144 h.
[b] Determined by GC or HPLC analysis on a chiral stationary phase.
[c] At RT. [d] At 08C for 168 h. [e] At À158C for 168 h. [f] At 208C for
168 h.
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General procedure for the catalytic asymmetric a-alkylation of a-
branched aldehydes: The catalyst 3l (0.15 mmol, 0.3 equiv) and p-
anisic acid (2.5 mmol, 5 equiv) were dissolved in CHCl3 (0.2m) and
4 ꢂ molecular sieves (400 mg) were added. The starting aldehyde
(0.5 mmol, 1 equiv) was added to the solution followed by the
alkylating agent (2.5 mmol, 5 equiv). Tetramethylguanidine
(2.5 mmol, 5 equiv) was added at the end. The mixture was stirred
at the optimized temperature. After stirring for 144 h, the reaction
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sion was not observed. For details see the Supporting Informa-
tion.
Keywords: a-alkylation · a-branched aldehydes · DYKATt ·
enamine catalysis · organocatalysis
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