Enantioselective organocatalytic α-alkylation of ketones by S N1-type reaction of alcohols

Article abstract of DOI:10.1002/ejoc.201101509

The enantioselective α-alkylation reaction of cyclic ketones is described. Our catalyst, based on a "privileged" pyrrolidine ring bearing a chiral thioxotetrahydropyrimidinone ring, is a highly reactive catalyst for cyclic ketones. When this catalyst was coupled with in situ generated carbocations derived from alcohols, the corresponding α-alkylated adducts were obtained in moderate to quantitative yields and low to high enantioselectivities (up to 80% ee). The catalyst loading can be efficiently reduced to 10%, which is the lowest value reported in the literature for such an organocatalytic transformation.

Full text of DOI:10.1002/ejoc.201101509

FULL PAPER
DOI: 10.1002/ejoc.201101509
Enantioselective Organocatalytic α-Alkylation of Ketones by SN1-Type
Reaction of Alcohols
Maria Trifonidou[a] and Christoforos G. Kokotos*[a]
Keywords: Alkylation / Organocatalysis / Ketones / Enantioselectivity / Nucleophilic substitution
The enantioselective α-alkylation reaction of cyclic ketones
is described. Our catalyst, based on a “privileged” pyrrolid-
ine ring bearing a chiral thioxotetrahydropyrimidinone ring,
is a highly reactive catalyst for cyclic ketones. When this cat-
alyst was coupled with in situ generated carbocations de-
rived from alcohols, the corresponding α-alkylated adducts
were obtained in moderate to quantitative yields and low to
high enantioselectivities (up to 80% ee). The catalyst loading
can be efficiently reduced to 10%, which is the lowest value
reported in the literature for such an organocatalytic transfor-
mation.
highlighted that typical aminocatalysts such as proline, di-
arylprolinols, α-amino acids and primary amines based on
cinchona alkaloids lead to either low reactivity (producing
mainly byproducts) or low enantioselectivity.[10] Although
FCILs led to good enantioselectivities (up to 87% ee), a
rather high catalyst loading (25%) was needed for the reac-
tion to be viable and to lead to 80% yield.
Introduction
The enantioselective α-alkylation of carbonyl com-
pounds has long been considered a daunting challenge.[1]
Before the development of organocatalysis,[2,3] asymmetric
phase-transfer catalysis was the sole successful approach,
although it mainly dealt with the enantioselective synthesis
of α-amino acids by the alkylation of glycine derivatives.[4]
The dramatic expansion of the field of organocatalysis has
led to a large number of new organic transformations along
with the development of novel activation modes.[5] In the
early years of organocatalysis, enamine aminocatalysis led
to the first successful α-alkylation reactions; however, these
were limited to intramolecular transformations.[6] Thus, the
intermolecular α-alkylation of carbonyl compounds still re-
mained a challenge, mainly due to the depletion of catalytic
activity through the undesired N-alkylation of the amino-
catalysts. With the introduction of novel activation modes
in organocatalysis, namely organo-SOMO and photoredox
catalysis, MacMillan and co-workers developed new meth-
odologies that efficiently deliver novel transformations in-
cluding α-alkylation reactions.[7] Inspired by the elegant
contributions of Melchiorre[8] and Cozzi[9] and their co-
workers on the α-alkylation of aldehydes by enamine cataly-
sis by SN1-type reactions, we recently questioned whether it
might be possible to expand this methodology to the use of
ketones. The sole successful example in the literature docu-
ments the use of functionalized chiral ionic liquid (FCIL)
organocatalysts as the optimum catalysts to induce high
enantioselectivity in this transformation.[10] It has to be
Based on our previous experience of organocatalysis,[11]
we recognized the possibility of using the pyrrolidine-
thioxotetrahydropyrimidinone catalyst 4 as an efficient cat-
alyst for the α-alkylation of ketones. Organocatalyst 4 has
been very recently reported to catalyze Michael reactions
between cyclohexanone and nitro olefins with low catalyst
loadings (1–2.5%).[11] Thus, we envisaged combining its
catalytic properties with the well-established generation of
stabilized carbocations. Herein, we present our results on
the α-alkylation of various cyclic ketones through SN1-type
reaction with alcohols.
Results and Discussion
We envisaged the formation of a nucleophilic enamine
through the reaction of thioxotetrahydropyrimidinone 4
with cyclohexanone (1), and at the same time the presence
of an acid co-catalyst would generate a carbocation from
the appropriate alcohol.[9,10,12,13] The coupling of these two
reactive intermediates would furnish the desired product
(Scheme 1).
In our previous studies with thioxotetrahydropyrimid-
inone 4, we found that the presence of 4-nitrobenzoic acid
(4-NBA) and water gave the optimum results. Thus, in an
initial experiment, the α-alkylated product was produced in
69% yield and 68% ee (Entry 1, Table 1). Note that along
with the desired product, a small amount of benzhydrol di-
mer was observed (ca. 5%), in accordance with the litera-
[a] Laboratory of Organic Chemistry, Department of Chemistry,
University of Athens,
Panepistimiopolis, Athens 15771, Greece
Fax: +30-210-727-4761
E-mail: ckokotos@chem.uoa.gr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101509.
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M. Trifonidou, C. G. Kokotos
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Table 1. Organocatalyzed reaction between cyclohexanone and
benzhydrol 2 in various solvents.[a]
Entry
Solvent
Additive
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15[d]
THF
THF
THF
THF
benzene
xylene
4-NBA, H2O
4-NBA
TFA, H2O
69
49
38
56
17
23
70
71
18
6
76
71
89
81
–
68
64
62
65
70
68
70
67
64
54
67
67
67
72
–
Scheme 1. Organocatalytic α-alkylation of cyclohexanone.
TFA
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
ture.[10] Change of the acid and removal of water did not
lead to better results (Entries 2–4, Table 1). As a conse-
quence, the reaction solvent was studied (Entries 5–14,
Table 1). Both polar and nonpolar solvents led to decreased
yields with few exceptions, and the enantioselectivity of the
reaction did not vary significantly. The α-alkylated product
was isolated in good to high yields in a small number of
solvents, namely chlorinated solvents, EtOAc, Et2O and
toluene. However, other solvents favour the formation of
the dimer (ca. 20%), and thus low yields of the desired
product were obtained. Dichloromethane afforded the best
results, affording a high yield and good ee, and no byprod-
uct was observed (Entry 14, Table 1). It is well established
in organocatalysis that in some cases lowering of the reac-
tion temperature has a beneficial impact on the enantio-
toluene
Et2O
MeCN
MeOH
EtOAc
CH2ClCH2Cl
CHCl3
CH2Cl2
CH2Cl2
[a] Reaction conditions: catalyst 4 (10 mol-%), acid (10 mol-%),
H2O (10 mol-%), solvent (0.2 mL), benzhydrol 2 (0.2 mmol) and
cyclohexanone (2 mmol) for 18 h. 4-NBA: 4-nitrobenzoic acid;
TFA: trifluoroacetic acid. [b] Isolated yield after column
chromatography. [c] The ee was determined by chiral-phase HPLC.
[d] The reaction was performed at –20 °C for 48 h.
selectivity of the reaction. However, in this case, when the enantioselectivity remained at the same level (Entry 6,
reaction was performed at –20 °C, only the benzhydrol di- Table 2). A prolonged reaction time in the absence of water
mer was observed (Entry 15, Table 1).
led to full benzhydrol consumption and the best results with
Once dichloromethane was proven to be the solvent of almost quantitative yield (98%) and increased enantio-
choice, the effect of the nature of the acid co-catalyst was selectivity (80% ee, Entry 7, Table 2). Because an acid co-
studied (Table 2). First, the appropriate amount of acid to catalyst is required to generate the carbocation, the nature
use was explored (Entries 1–7, Table 2). It is clear that an of the acid is certain to play a role in the reaction outcome.
increase of the amount of acid leads to an increase in the Thus, a variety of acids were tested (Entries 8–15, Table 2).
amount of in situ generated carbocation. This much faster Acids with similar acidities [pKa values in H2O of 4-nitro-
generation of the carbocation led to lower yields, because benzoic acid (3.44), 4-cyanobenzoic acid (3.55) and 4-(tri-
the desired transformation competes with the production of fluoromethyl)benzoic acid (3.60)] did not deliver the same
the benzhydrol dimer; however, the enantioselectivity of the levels of reactivity (Entries 7–9, Table 2). These results
reaction remained the same (Entries 2–5, Table 2). Thus, it strengthen our hypothesis that 4-NBA plays a dual role in
is important to regulate the in situ formation of the carbo- the reaction by facilitating enamine formation between the
cation. The use of a smaller amount of acid leads to pro- catalyst and the ketone as well as the formation of the
longed reaction times, because the carbocation is generated carbocation. Weaker and stronger acids gave similar results
more slowly. On the other hand, an excess of acid leads to (Entries 10–15, Table 2) although it is worth mentioning
an increased concentration of the reactive carbocation in that 2,4-dinitrobenzoic acid led to a lower yield due to di-
the reaction medium, which – upon not finding enamine to mer production (18%) but similar enantioselectivity (En-
react with – dimerizes. Bearing this in mind, combined with try 13, Table 2).[14] We assume that 4-NBA forms a unique
the fact that there is still unreacted benzhydrol 2 after 18 h, pairing with the thioxotetrahydropyrimidinone catalyst
the amount of catalyst was increased to push the reaction leading to improved catalytic properties, because acids with
to completion, because an increase in the concentration of similar pKas do not lead to the same levels of enantioinduc-
the in situ formed enamine could lead to full reagent con- tion. Similar results are seen in Luo and co-worker’s cata-
sumption and probably suppress the formation of the di- lytic system in which phthalic acid afforded higher yields
mer. Indeed, a higher yield was observed although the than any other acid co-catalyst.[10]
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Enantioselective Organocatalytic α-Alkylation of Ketones
Table 2. Optimization of the nature and amount of the acid co- mental effects. A lower amount of the ketone, that is, a de-
catalyst.[a]
crease of the rate of enamine formation, led to lower yields
and selectivities accompanied by a small amount of dimer
(13%; Entry 10, Table 3), but when the temperature was in-
creased, a lower enantioselectivity was observed (Entry 11,
Table 3). Lowering of the catalyst loading to 5% led to a
drop in the yield to 61% (Entry 12, Table 3). This procedure
differs from the literature procedure[10] in the use of dichlo-
romethane as solvent instead of 1,2-DCE and an equimolar
amount of 4-NBA instead of a slight excess of phthalic
acid. Furthermore, the use of only 10 mol-% catalyst to af-
Entry
Additive
Reaction time Yield
ee
[h]
[%][b] [%][c]
ford the optimum results is the main advantage of the cur-
rent methodology; in literature procedures the use of no less
than 25 mol-% catalyst can be expected.
1
2
3
4-NBA, H2O
4-NBA (15%), H2O
4-NBA (20%), H2O
4-NBA (50%), H2O
4-NBA (100%), H2O
4-NBA (20%), H2O
4-NBA
18
18
18
18
18
18
44
44
44
44
44
44
44
44
44
81
80
61
58
57
88
98
64
62
17
63
48
56
61
15
72
71
69
71
70
70
80
70
69
39
64
74
74
42
58
4
5
Table 3. Effect of concentration and other factors on the reaction
6[d]
7
between cyclohexanone and benzhydrol 2.[a]
8
9
4-CBA
4-TBA
PhCOOH
HCOOH
phthalic acid
2,4-DNBA
10
11
12
13
14
15
TFA
CSA
[a] Reaction conditions: catalyst 4 (10 mol-%), acid (10 mol-%), sol-
vent (0.2 mL), benzhydrol (0.2 mmol) and cyclohexanone
(2 mmol). 4-NBA: 4-nitrobenzoic acid, 4-CBA: 4-cyanobenzoic
acid, 4-TBA: 4-(trifluoromethyl)benzoic acid, 2,4-DNBA: 2,4-dini-
trobenzoic acid, TFA: trifluoroacetic acid, CSA: camphorsulfonic
acid. [b] Isolated yield after column chromatography. [c] The ee was
determined by chiral-phase HPLC. [d] 20 mol-% of catalyst was
used.
Entry
CH2Cl2
[mL]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
0.2
0.4
0.1
0.05
0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
98
48
89
68
71
61
81
68
78
68
82
61
80
65
78
74
70
68
70
77
70
70
48
78
6[d]
7[e]
8[f]
9[f,g]
10[h]
11[i]
12[j]
Furthermore, the effect of the concentration of the reac-
tants was investigated, and it seems to have an impact on
both the yield and selectivity (Entries 1–5, Table 3). There
is an optimum concentration at which high yields and good
enantioselectivities are obtained, because more dilute con-
ditions led to lower yields and an increase in dimer prod-
uction (22%) and higher concentrations also seemed to
have a negative impact on the reaction outcome. A lower
yield was obtained when the reaction was carried out neat.
At high dilution, the concentration of the nucleophilic en-
amine is so low that the carbocation, which is formed in
situ and is extremely reactive, dimerizes readily leading to
[a] Reaction conditions: catalyst 4 (10 mol-%), 4-NBA (10 mol-%),
CH2Cl2 (0.2 mL), benzhydrol 2 (0.2 mmol) and cyclohexanone
(2 mmol) for 44 h. [b] Isolated yield after column chromatography.
[c] The ee was determined by chiral-phase HPLC. [d] The reaction
took place in the presence of 4 Å molecular sieves. [e] The reaction
took place in the presence of Na2SO4. [f] Dry CH2Cl2 was used.
[g] The reaction was performed under inert conditions. [h] Ketone/
benzhydrol, 5:1. [i] The reaction was performed at reflux tempera-
lower yields. When there is less solvent, the solvent interac- ture. [j] 5 mol-% catalyst was used.
tions are weaker, and thus lower yields and ees are ob-
tained. Because commercially available solvents were used
and previous experiments had shown a negative impact of
Once the optimum reaction conditions had been found,
water on both the yield and selectivity, we investigated we became interested in exploring the scope and limitations
whether a small amount of water was still needed. The use of the thioxotetrahydropyrimidinone catalyst in the α-alk-
of molecular sieves as well as drying agents led to inferior ylation reactions of ketones (Table 4).[15] Cyclic ketones
results (Entries 6 and 7, Table 3). Furthermore, the reaction bearing heteroatoms such as oxygen and sulfur afforded the
was performed with freshly distilled CH2Cl2 and under an desired products (3b and 3c) in high yields and with good
inert gas: diminished yields and selectivities were obtained enantioselectivities (Entries 2 and 3, Table 4), whereas ni-
(Entries 8 and 9, Table 3). It is clear that the small amount trogen-containing cyclic ketones led to lower yields and
of water present in the commercially available solvents helps selectivities (Entries 4 and 5, Table 4). Desymmetrization of
the reaction, but an increased amount of water has detri- 4-monosubstituted cyclohexanones was also possible, pro-
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M. Trifonidou, C. G. Kokotos
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ducing a single diastereomer (3f) in high enantioselectivity 10, Table 4). 1,4-Cyclohexanedione led to high yields but
and moderate yield (Entry 6, Table 4). Disubstituted cyclo- low selectivities, whereas cyclopentanone, which has not
hexanones were well tolerated, albeit giving lower yields been reported to produce the desired alkylated product by
and selectivities in accordance with previous observations any other means,[10] was alkylated in low yield and low
(Entries 7 and 8, Table 4).[10] A prolonged reaction time was enantioselectivity. Finally, when ketones were replaced by
required for much more difficult substrates (Entries 9 and aldehydes (for example, 3-phenylpropanal), excellent yield
but low enantioselectivity were observed (Entry 11,
Table 4). When 1,4-cyclohexanedione was replaced by 1,2-
cyclohexanedione (5), an inseparable mixture of products 6
and 7 was isolated (Scheme 2); The desired alkylated prod-
uct 7 was obtained in low yield along with the product de-
rived from O-alkylation of the enolate.
Table 4. Enantioselective α-alkylation of ketones by SN1 alkylation
of benzhydrol 2.[a]
Scheme 2. Organocatalytic α-alkylation reaction of benzhydrol 2
with 1,2-cyclohexanodione.
To further expand the reaction scope and discover the
limits of this methodology, the carbocation was replaced
(Schemes 3 and 4). On consideration of Mayr’s electrophi-
licity scale,[16] ferrocenyl-derived alcohol 8 was employed,
but no reaction took place (Scheme 3, top). However, when
4-NBA was replaced by TFA, 9 was isolated in a moderate
yield and with low diastereoselectivity and low enantio-
selectivity (18% ee for the major diastereomer and 21% ee
for the minor diastereomer). However, these results are the
best having been obtained with the ferrocenyl substrate, be-
cause the highest selectivities reported in the literature are
8 and 18% ee, respectively.[10] In the alkylation of ketones,
only secondary alcohols, the corresponding carbocations of
which are stabilized by two electron-rich aromatic moieties,
have been used. In contrast, in the case of aldehydes, there
are a few reports of secondary alcohols bearing aryl and
alkenyl moieties having been employed in the presence of
InBr3 leading to α-allylated aldehydes.[17] Thus, 1,3-di-
phenylprop-2-en-1-ol (10) was used as the carbocation pre-
cursor (Scheme 3, bottom). When 4-NBA was used, no re-
action took place. In contrast, the use of InBr3 led to a high
yield with 1:1 diastereoselectivity, as expected,[17] and low
enantioselectivity. Although the enantioselectivity was low,
this is the first example of such a reaction between cyclic
ketones and aryl-allyl alcohols performed under organocat-
alysis.[18,19] When the electron-rich substituents were re-
moved and simple benzhydrol (12) was used, no reaction
took place (Scheme 4). In the case of xanthol (13), although
1
the product can be observed in the H NMR spectrum of
the crude mixture, the α-alkylated adduct was probably un-
stable under silica gel purification and decomposed
(Scheme 4). Furthermore, the corresponding alkynyl deriva-
tive 14, which has been used successfully with aldehydes,[20]
was used, albeit with no success (Scheme 4). Stabilization
of the carbocation formed from an alcohol bearing an aro-
[a] Reaction conditions: catalyst 4 (10 mol-%), 4-NBA (10 mol-%),
CH2Cl2 (0.2 mL), benzhydrol 2 (0.2 mmol) and ketone (2 mmol)
for 44 h. [b] Isolated yield after column chromatography. [c] The ee
was determined by chiral-phase HPLC. [d] Reaction time: 6 d.
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Enantioselective Organocatalytic α-Alkylation of Ketones
matic moiety and a carboxylic derivative was also envisaged ring of the catalyst.[11] The best results were obtained by
(Scheme 4). However, the use of mandelic acid (15) and using an equimolar amount of acid with respect to the cata-
methyl mandelate (16) did not lead to the desired product. lyst. We assume that a sacrificial amount of acid is enough
To shed more light on this interesting allylation reaction, for the catalyst to assimilate the ketone and produce the
alcohols 17 and 18 were used. Unfortunately, in both cases nucleophilic enamine. The rest of the acid is used to gener-
complicated mixtures were obtained. In the case of 17, at ate the carbocation, which is coupled to the enamine.
least three different isomers of the desired product could be Furthermore, because thioxotetrahydropyrimidinone 4 does
identified in the reaction mixture; however, the yield was not have an ionic-liquid-type structure but still catalyzes the
low. In the case of 18, the reaction mixture was so compli- reaction as efficiently as the ionic catalyst of Luo and co-
cated that we could not identify any desired product.
workers, it is likely that their ionic-liquid-type catalyst is
not involved in any interaction with the carbocation other
than shielding efficiently one of the potential faces of ad-
dition.
Scheme 5. Proposed mechanism for the α-alkylation of ketones.
Scheme 3. Succesful examples of organocatalytic α-alkylation reac-
tions of cyclohexanone with alcohols.
Conclusions
The first example of a non-ionic-liquid-type organocata-
lyst that can catalyze the “difficult” α-alkylation of ketones
has been reported herein. The reduced catalyst loading (10
vs. 25 mol-%) is the main advantage of the thioxotetra-
hydropyrimidinone catalyst 4 over the previously known
catalyst system[10] providing similar yields and selectivities.
An effort to acquire a better understanding of the reaction
mechanism and the development of new applications are
under way.
Scheme 4. Alcohols used unsuccesfully in this study.
Experimental Section
To account for the stereochemical outcome of the reac-
tion, a possible mechanism is proposed in Scheme 5. Ini-
tially, the catalyst binds to the ketone to form a nucleophilic
enamine. Once the carbocation has been generated, the
thioxotetrahydropyrimidinone ring may either facilitate the
alkylation from the front face through stabilizing interac-
tions between the ring and the carbocation or from the
back face as a result of steric hindrance of the front face.
Luo and co-workers assumed their ionic catalyst efficiently
blocks the front face and that addition occurs from the
back face.[10] Because the same enantiomer was obtained as
in the Luo and co-workers’ catalytic system,[10] we assume
that the s-trans enamine of the cyclic ketone, which is more
stable and suffers from the least steric interactions, couples
to the carbocation. To obtain the correct enantiomer of the
product, the carbocation must react from the front side. We
assume that the carbocation is positioned there through sta-
General Procedure for the α-Alkylation of Ketones by SN1 Reaction
of Alcohols: 4-Nitrobenzoic acid (1.74 mg, 0.01 mmol) was added
to a stirred solution of catalyst 4 (3 mg, 0.01 mmol) in CH2Cl2
(0.2 mL). Alcohol (0.10 mmol) was added followed by cyclohexa-
none (0.10 mL, 1.00 mmol). The reaction mixture was stirred for
44 h. The solvent was evaporated, and the crude product was puri-
fied by flash column chromatography eluting with an appropriate
mixture of petroleum ether (40–60 °C)/EtOAc to afford the desired
product.
(S)-2-{Bis[4-(dimethylamino)phenyl]methyl}cyclohexanone:[10] Table 4,
Entry 1. White solid. Yield 98%; m.p. 156–159 °C. [α]2D0 = –98.0 (c
1
= 0.025, CHCl3). H NMR (200 MHz, CDCl3): δ = 7.15–7.05 (m,
4 H, ArH), 6.70–6.60 (m, 4 H, ArH), 4.17 (d, J = 11.5 Hz, 1 H,
CHAr2), 3.29–3.18 (m, 1 H, CHCO), 2.91–2.82 [m, 12 H, 2 N(CH3)
2], 2.53–2.23 (m, 2 H, CH2CO), 1.98–1.76 (m, 4 H, 2 CH2), 1.68–
1.44 (m, 2 H, CH2) ppm. 13C NMR (50 MHz, CDCl3): δ = 213.3,
148.8, 148.6, 132.3, 131.7, 128.6, 128.0, 112.7, 55.3, 48.8, 41.9, 40.6,
32.8, 29.1, 23.6 ppm. MS (ESI): m/z (%) = 351 (100) [M + H]+.
bilizing interactions from the thioxotetrahydropyrimidinone The enantiomeric excess was determined by HPLC analysis on a
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Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details, NMR spectra and HPLC data.
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Received: October 16, 2011
Published Online: January 20, 2012
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Eur. J. Org. Chem. 2012, 1563–1568