Organocatalytic stereoselective α-alkylation of aldehydes with stable carbocations

Article abstract of DOI:10.1002/asia.201000160

The organocatalytic stereoselective alkylation of aldehydes is carried out with the four stable carboca-tions 1-4 in the presence of a catalytic amount (20mol%) of MacMillan imi-dazolidinones 5-6. In all reactions, luti-dine was used as a base. The alkylation reactions are investigated at different temperatures with linear and branched aldehydes. In the case of carbocation tropylium fluoroborate, an interesting reversal of alkylation product configuration was observed, which is driven by entropic effects in the reaction. The absolute configuration of the products obtained is determined by chemical correlation and found to be in general agreement with the model proposed by MacMillan to justify the stereoselectiv-ity obtained in the reactions promoted by catalysts of type 5-6.

Full text of DOI:10.1002/asia.201000160

DOI: 10.1002/asia.201000160
Organocatalytic Stereoselective a-Alkylation of Aldehydes with Stable
Carbocations
Fides Benfatti, Elena Benedetto, and Pier Giorgio Cozzi*[a]
Abstract: The organocatalytic stereose-
lective alkylation of aldehydes is car-
ried out with the four stable carboca-
tions 1–4 in the presence of a catalytic
amount (20 mol%) of MacMillan imi-
dazolidinones 5–6. In all reactions, luti-
dine was used as a base. The alkylation
reactions are investigated at different
temperatures with linear and branched
aldehydes. In the case of carbocation
tropylium fluoroborate, an interesting
reversal of alkylation product configu-
ration was observed, which is driven by
entropic effects in the reaction. The ab-
solute configuration of the products
obtained is determined by chemical
correlation and found to be in general
agreement with the model proposed by
MacMillan to justify the stereoselectiv-
ity obtained in the reactions promoted
by catalysts of type 5–6.
Keywords: alkylation
·
carboca-
tions · Macmillan catalysts · Mayrꢀs
scale · organocatalysis
Introduction
generalizations, it is possible to make a quantitative predic-
tion of a reaction between a nucleophile and an electrophile
through Equation (1). As a “rule of thumb”, a SN1-type re-
action could be observed at room temperature in a reasona-
ble amount of time (3 h) if Equation (2) is satisfied:[1a]
The reactivity of carbocations with a nucleophile can be ra-
tionalized by Mayrꢀs scale through the assignment of the pa-
rameter E.[1] Mayrꢀs work also provided the most compre-
hensive nucleophilicity scale presently available. The scales
are based on the reaction of benzhydrilium ions (Ar2CH+)
and structurally related quinone methides with different n,
p, and s nucleophiles.[2] By varying the nature of the sub-
stituents present in the para position of diarylmethanes it is
possible to alter the reactivity with an established nucleo-
phile by up to 16 orders of magnitude, according to the
linear free-energy relationship [Eq. (1)]:[3]
E þ N > ꢁ5
ð2Þ
Based on the suggestions of stability and reactivity of car-
bocations resulting from the meticolous work published by
Mayr,[1,3–5] we recently reported an organocatalytic stereose-
lective a-alkylation of aldehydes.[6] Furthermore, we have
established that the generation of stabilized carbocations
ꢁ
coupled with organocatalysis can be realized by direct C H
bond functionalization.[7] In both the studies, the carboca-
tions were obtained in situ, by starting from the correspond-
ing alcohols or from the alkanes.
kð20 ꢀCÞ ¼ sðN þ EÞ
ð1Þ
This relationship was established as a powerful instrument
for the experimental prediction of the rate of SN1-type reac-
tions.[4] In Equation (1), the electrophiles are characterized
by a parameter, E, whereas the different nucleophiles have
been classified by the parameter N and by the nucleophilic
specific slope parameter s. As a consequence of the Mayr
However, stable carbocations are easily generated and
even commercially available.[1] In this manuscript we have
investigated the organocatalyzed addition of aldehydes to
easily prepared and stable carbocations 1–4, providing addi-
tional useful information about the stereoselective a-alkyla-
tion of aldehydes, and showing the applicability of the pres-
ent methodology with stable and isolated carbocations to
access enantioenriched building blocks.
[a] Dr. F. Benfatti, E. Benedetto, Prof. P. G. Cozzi
Dipartimento di Chimica “G. Ciamician”
Institution ALMA MATER STUDIORUM Universitꢁ di Bologna
Via Selmi 2, 40126 Bologna (Italy)
Results and Discussion
Fax : (+39)051-209-9456
E-mail: piergiorgio.cozzi@unibo.it
Many organocatalysis experts have long sought methodolo-
gies to enable the intermolecular a-alkylation of aldehydes,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000160.
Chem. Asian J. 2010, 5, 2047 – 2052
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPERS
Scheme 1. Stereoselective alkylation of aldehydes by alcohols promoted
by a MacMillan catalyst.
carbocations in the stereoselective alkylation reaction of al-
dehydes, we selected, as model carbocations, the compounds
1–4. Tropylium tetrafluoroborate 1 is commercially avail-
able, whereas 2–4 were prepared by simple reactions de-
scribed in the literature (see the Supporting Information).
The carbocation 1 (E=ꢁ3.72 in Mayrꢀs scale) was selected
for optimization of the reaction. Tropylium tetrafluorobo-
rate was used as received and no particular precaution was
necessary for the reaction, as the carbocation is rather
stable. In general, the reactions with the carbocations were
run in the presence of the MacMillan imidazolidinonium or-
ganocatalysts 5–6,[14] with the addition of a base for neutral-
izing the tetrafluoroboric acid produced during the reaction.
Et3N, iPr2NEt, 2,6-dimethylpyridine, 2,6-di-tert-butylpyri-
dine, K2CO3, Na2CO3, and K3PO4 were investigated. Better
results in terms of yields were obtained with 2,6-dimethyl-
pyridine (2,6-lutidine), which was used as the standard base
in all reactions. However, the MacMillan imidazolidinonium
catalyst 5 gave low selectivity. To improve the selectivity, we
have performed the reaction in the presence of different
acids by the preparation of the corresponding MacMillan
catalysts as salts.[7] After several attempts and trials, we have
studied the reaction of the aldehydes 7a–d in the presence
of 20 mol% of the imidazolidinonium catalyst 6, a p-nitro-
benzoate salt, obtaining the results that are collected in
Table 1. The alkylation reactions were conducted in CH2Cl2.
Among all the MacMillan imidazolidinonium catalysts in-
vestigated, the imidazolidinonium catalyst 6 gave the best
results in term of selectivity. The absolute configuration of
the product 8a was influenced by the nature of the acid. In
particular, with the electron-rich 3,4,5-trimethoxybenzoic
acid, the corresponding MacMillan imidazolidinonium cata-
lyst gave the S product at room temperature, whereas the p-
nitrobenzoic acid (imidazolidinonium catalyst 6) gave, under
the same conditions, the corresponding R product. As noted
by the data collected in Table 1, the stereoselectivity of the
reaction was also a function of the temperature. This pecu-
liar behavior was already noted in organocatalytic reac-
tions.[15] In addition, this dependency is determined by the
steric hindrance of the aldehydes. We investigated the reac-
tion at a higher temperature (408C) changing the solvent
from CH2Cl2 to dichloroethane, but no increase of the selec-
tivity was observed. Also, the base has an influence on the
selectivity (Table 1, entry 8), as the employment of K2CO3
changed the facial selection obtained at room temperature.
The results are not determined by thermodynamics, as the
with simple amines catalyzing this process.[8] In fact, the a-
alkylation of simple aldehydes constitutes a fundamental
ꢁ
step in C C bond-forming reactions. During the “gold rush”
of enamine catalysis[9] by secondary amines,[10] it was as-
sumed that a-alkylation represented an obvious and easily
accessible target. However, little progress was made towards
this goal prior to 2009 despite the enormous efforts of many
research groups.[11] During our research devoted to estab-
lishing new compounds containing ferrocene for molecular
computation, we used stabilized ferrocenyl derivatives,
which generated the corresponding carbocations by Lewis
acid catalysis[12] or “on water”.[13] We established a funda-
mental correlation among the carbocations generated “on
water” and their position on the Mayr scale. Based on that
correlation, we developed a methodology that allows the
enantioselective direct alkylation of aldehydes with unfunc-
tionalized alcohols, only limited by the nature of the alcohol,
which must stabilize the carbocationic intermediate
(Scheme 1).[6]
The attack on stabilized carbocations formed in situ from
the corresponding alcohols by an enamine intermediate af-
forded the desired alkylated adducts in good to excellent
enantioselectivities. To verify the possibility of using isolated
Abstract in Italian: La reazione organocatalitica di alchila-
zione stereoselettiva di aldeidi ꢃ stata condotta con i quattro
carbocationi stabili 1–4 in presenza di quantitꢁ catalitiche
(20 mol%) degli imidazolidinoni di MacMillan 5–6. In tutte
le reazioni un equivalente di lutidina ꢃ stato usato come
base. Le reazioni di alchilazione sono state investigate a di-
verse temperature con aldeidi lineari e ramificate. Nel caso
del carbocatione 1 (tropilio tetrafluoroborato) si ꢃ osservato
un interessante inversione di configurazione del prodotto di
alchilazione, determinato da effetti entropici della reazione.
La configurazione assoluta dei prodotti ottenuti ꢃ stata de-
terminata attraverso una correlazione chimica ed ꢃ risultata
essere in accordo al modello generale proposto da MacMil-
lan per giustificare la stereoselezione ottenuta nelle reazioni
organocatalitiche promosse dai catalizzatori del tipo 5–6.
2048
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 2047 – 2052

Organocatalytic Stereoselective a-Alkylation of Aldehydes
Table 1. Alkylation of aldehydes with carbocation 1 (tropylium fluorobo-
Table 2. Alkylation of aldehydes with the carbocation 2.
rate).
Entry
R
Product
T [8C]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
nC6H13
nC6H13
nC6H13
iPr
Et
Me
9a
9a
9a
9b
9d
9e
4
RT
40
RT
4
4
23
4
24
22
22
96
86
74
–
99
75
34
39
32
–
56
65
Entry
R
Product T [8C] t [h] Yield [%][a] ee [%][b] (config.)
1
2
3
4
nC6H13
nC6H13
nC6H13
nC6H13
nC6H13
nC6H13
nC6H13
nC6H13
iPr
iPr
iPr
Bn
Bn
8a
8a
8a
8a
8a
8a
8a
8a
8b
8b
8b
8c
8c
8c
8c
8d
8d
8d
RT
RT
0
ꢁ25
RT
4
ꢁ25
RT
RT
0
ꢁ25
RT
0
4
17
5
25
4
65
67
50
46
67
50
37
64
55
30
41
73
65
78
92
77
28
14
50 (R)
51 (R)
40 (S)
47 (S)
51 (S)
49 (R)
37 (S)
20 (S)
72 (S)
80 (S)
62 (S)
46 (R)
9 (S)
[c]
4
5c
6d
7
[a] Yield after chromatographic purification. [b] The enantiomeric excess
was evaluated by chiral HPLC analysis. See the Supporting Information
for details. [c] No reaction.
2
26
22
4
5
25
5
8e
9
10
11
12
13
14
15
16
17
18
Methylacridinium carbocation (3), readily prepared by al-
kylation of acridine with MeI,[18] is a stable salt, positioned
at ꢁ7.15 of the Mayr scale. It is a very stable cation and can
be isolated by filtration and stored in air. In contrast with
the reactions described for cations 1 and 2, we used DMF as
the reaction solvent, as the cation was completely insoluble
in CH2Cl2. No reaction occurred after several days in
CH2Cl2. The results obtained in the reaction with the alde-
hydes are reported in Table 3. The process conduced at 48C
(Table 3, entry 1) was carried out with long reaction times.
However, in such conditions a decrease in the enantiomeric
excess was observed, relative to the reaction carried out at
higher temperatures with a shorter reaction time. Particular-
ly intriguing were the results obtained in the case of the ad-
dition of hydrocinnamaldehyde to the carbocation 3. The
7
Bn
Bn
Et
Et
ꢁ25
ꢁ25
RT
0
25
45
24
24
24
30 (S)
27 (S)
22 (R)
7 (S)
Et
ꢁ25
20 (S)
[a] Yield after chromatographic purification. [b] The enantiomeric excess
(ee) was evaluated by chiral HPLC analysis. See the Supporting Informa-
tion for details. [c] The (S,S)-MacMillan catalyst ent-5 was employed in
the reaction. [d] Dichloroethane was employed as the reaction solvent.
[e] K2CO3 was used as a base.
products 8a–d are stable in solution in the presence of
20 mol% of the imidazolidinonium organocatalyst 5 or 6.[16]
The temperature is crucial for the stereoselection, and
good results were obtained at low temperature. Finally, the
(S,S)-MacMillan imidazolidinonium catalyst ent-5 was em-
ployed in the reaction at a low temperature, giving a compa-
rable result (Table 1, entry 5). Then, the behavior of carbo-
cations 2 and 3, more stabilized than tropylium, was investi-
gated. The bis(4-dimethylamino-phenyl)methylium tetra-
fluoroborate (2) is positioned at ꢁ7.02 of the Mayr scale
and was obtained from the corresponding alcohol through
the reaction with HBF4.[17] As in the case of 1, the com-
pound is highly stable and the blue carbocation can be han-
dled in open air and it is not decomposed by traces of
water. It is a bench-stable product, stable for months in a
flask. The temperature did not influence the stereoselectiv-
ity of the a-alkylation reaction, and slight variation of the
enantiomeric excess was recorded at different temperatures
(Table 2, entries 1–3). In the case of the cation 2, isovaleral-
dehyde was not reactive (entry 4). The sterical hindrance
among the carbocation and the enamine formed in situ was
crucial, as indicated by the stereoselection obtained with
linear aldehydes, which was increased when short aliphatic
aldehydes were employed.
Table 3. Alkylation of aldehydes with the carbocation 3.
Entry
R
Product
T [8C]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
nC6H13
nC6H13
nC6H13
nC6H13
iPr
iPr
Bn
Bn
Bn
10a
10a
10a
10a
10b
10b
10c
10c
10c
10d
4
RT
40
RT
RT
RT
4
RT
60
50
22
5
4
3
3
72
43
21
7
83
41
60
59
–
55
64
64
19
–
–
3
7
7
4[c]
5
6[c]
7
–
49
51
50
66
8
9
10
Et
8
63
[a] Yield after chromatographic purification. [b] The enantiomeric excess
was evaluated by chiral HPLC analysis. See the Supporting Information
ꢁ
for details. [c] The SbF6 salt was used and the reaction was performed in
CH3CN.
Chem. Asian J. 2010, 5, 2047 – 2052
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G. Cozzi et al.
FULL PAPERS
enantiomeric excesses obtained were quite low, and proba-
bly some p interactions among the carbocation and the alde-
hyde were taking place, although we do not have a detailed
explanation for this behavior. We also investigated the
effect of the counter-anion in the reaction by exchanging the
iodide with ꢁSbF6 (hexafluoroantimonate) through silver
metathesis. The reaction conduced at room temperature was
faster than at 48C (Table 3, entry 4 vs 1), but a lower enan-
tiomeric excess was recorded.
To examine the behavior of the stereogenic carbocation,
flavylium triflate (4) was readily synthesized by the de-
scribed procedure.[19] In general, flavylium ions are basic
constituents of the anthocyanin pigment in plants. Besides
their use as food colorants and dyes, an increased attention
over their synthesis was also determined by their biological
properties.[20] Electrophilicity properties of the flavylium
cation were described by Mayr.[19] The flavylium ion consid-
ered in our study is positioned at ꢁ3.45 of the Mayr scale.
From the application of Equation (2), it is possible to con-
clude that flavylium will react with nucleophiles of N>ꢁ1.5.
As enamines are strong nucleophiles, positive reactivity is
expected. In fact, we observed (Table 4) the formation of
the desired products in the reaction of the aldehydes 7a–c
in the presence of the MacMillan imidazolidinonium catalyst
5 used in a catalytic amount (20 mol%). It is worth men-
moderate to good with linear aldehydes, whereas the yields
were reduced when operating with hindered aldehydes.
The results in terms of stereoselectivity of the process can
be rationalized in relation to the different reactivity of the
carbocations. With the less electrophilic carbocations 2 and
3, moderate to low selectivity was obtained at room temper-
ature. The reaction became more selective at low tempera-
tures with the more electrophilic carbocations 1 and 4. The
inversion of absolute configuration of the products isolated
with linear aldehydes in the case of the carbocation 1 is par-
ticularly intriguing. The results are kinetically controlled. In
fact the isolated product 8a of S configuration, obtained in
the reaction at ꢁ258C, is not equilibrated to the R enantio-
mer in the presence of the MacMillan imidazolidinonium
catalyst 6 at room temperature, and the enantiomeric excess
does not change over 6–8 h. It is commonly assumed that
the MacMillan imidazolidinone catalyst forms selectively E
enamine isomer I with aldehydes, which avoids sterical inter-
action with the tert-butyl group (Scheme 2.[21] The small
facial preference showed by carbocation 1, a function of the
temperature, could be related to the smaller size of the car-
bocation, relative to the others.
The attack on the Si face is favored at low temperature
with linear aldehydes. With a more hindered aldehyde
(Table 1, entry 9–11), the carbocation cannot approach from
both sides of the nucleophile, at
low temperatures and at room
temperature. The peculiar be-
Table 4. Alkylation of aldehydes with the carbocation 4.
havior of the tropylium cation
arises from a nonideal tempera-
ture effect,[22] a phenomenon
that was recently described in
organocatalytic reactions.[23]
The proposed catalytic cycle
for the reaction is depicted in
Scheme 2. As a first step, we
propose the formation of the
enamine by reaction of the
MacMillan catalyst as a salt
with the corresponding alde-
Entry
R
Product
T [8C]
t [h]
Yield [%][a]
d.r.[b]
ee [%] (major)[c]
ee [%] (minor)[d]
1
2
nC6H13
nC6H13
nC6H13
iPr
iPr
iPr
11a
11a
11a
11b
11b
11b
11c
11c
0
ꢁ25
ꢁ25
0
2
2.5
3
24
21
74
22
22
90
68
13
34
51
41
97
88
4:1
9:1
1.1:1
4:1
4:1
2.3:1
2.3:1
7:3
78
80
22
77
92
71
52
69
2
10
11
64
62
76
16
24
3[e]
4
5
6
7
8
ꢁ25
0
hydes.
The
stoichometric
Bn
Bn
0
ꢁ25
amount of acid (HX) formed
during the reaction is trapped
by 2,6-lutidine (B). Water
formed during the catalytic step
is necessary to the process and
it is a possible nucleophile, able
to react with the carbocations.
As a matter of fact, when the
[a] Yield after chromatographic purification. [b] d.r.=diastereomeric ratio. Determined by 1H NMR spectros-
copy on the crude reaction mixture. The syn/anti ratio was not assigned and is indicated as the major versus
minor diastereoisomer. [c] The enantiomeric excess was evaluated by chiral HPLC analysis. See the Support-
ing Information for details. The enantiomeric excess values are indicated for the major diiastereoisomer.
[d] Enantiomeric excess values for the minor diastereoisomer. [e] The BF4ꢁ salt was used.
tioning that the reaction of 4 with 1-(trimethylsiloxy)cyclo-
hexene gave a low yield of adducts as a mixture of two dia-
stereoisomers in a ratio of 79:21. The simple diastereoselec-
tion obtained in our reaction with enamines formed in situ
was close to the result reported by Mayr.
The simple stereoselection and the enantioselectivity in-
creased when the reaction was carried out at ꢁ258C
(Table 4, entries 2, 5, and 8). Yields of isolated product were
bis-bis(4-methoxy-phenyl)methylium cation, positioned at
point 0 of the Mayrꢀs scale, was reacted with octanal and the
catalyst 5 in the usual reaction conditions, only the corre-
sponding alcohol was isolated. Water (N=5.2 in Mayr
scale)[24] generated during the catalytic cycle reacted very
fast with the unstable carbocation, hampering the reaction
with the enamine.
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Chem. Asian J. 2010, 5, 2047 – 2052

Organocatalytic Stereoselective a-Alkylation of Aldehydes
Conclusions
We have investigated, with four
model carbocations, the a-alky-
lation of aldehydes promoted
by the MacMillan catalyst salts
5–6. In general, the reaction of
isolated and stable carbocations
is possible, and takes place with
moderate to good selectivity in
the presence of a stoichiometric
amount of 2,6-lutidine as
a
base. Steric hindrance of the
carbocation and of the enamine
formed in situ by condensation
of the aldehyde with the Mac-
Millan catalyst salts 5–6 is influ-
encing the process. With less
hindered carbocations, the reac-
tion with hindered aldehydes
takes place. Temperature is also
a controlling factor in the selec-
Scheme 2. Proposed catalytic cycle for the stereoselective alkylation of stabilized cations.
The stereoselectivity of the process can be explained by
considering the model illustrated in Scheme 3, in which the
less hindered face of the enamine is attacking the carbocat-
ion.[25]
Scheme 4. Absolute configuration of the product 8 through an established
reaction sequence. TEA=triethylamine.
Scheme 3. Sterochemical model for the addition of enamine to the carbo-
cation.
tivity of the process. In particular, we have discovered an in-
teresting entropic effect within the reaction of tropylium tet-
rafluoroborate with enamine. The facial selectivity is tem-
perature-dependent and one MacMillan catalyst, operating
at a different temperature, is able to furnish both enantio-
mers of the compounds, although in modest selectivity. Even
if the chemical correlation for the isolated product 13 con-
firms the proposed model of attack, much work is still nec-
essary to enhance the generality of our reaction by the use
of less stabilized carbocations and by a more profound un-
derstanding of the selectivity of organocatalytic SN1-type re-
actions.
This model was confirmed in our precedent studies[6,7] by
correlation with a product of established absolute configura-
tion. However, as the behavior of the tropylium cation was
very different from other cations, we established the abso-
lute configuration of the product 8d, isolated by the attack
of butanal on the carbocation 1 at ꢁ258C. The product was
correlated to a known compound, obtained by a reaction se-
quence (Scheme 4). The synthetic sequence started with the
reaction of the tropylium fluoroborate (1) with the enolate
of ethyl acetate.
After a successful hydrolysis, the resulting acid was treat-
ed with (S)-benzyl oxazolidin-2-one, and the derivative 12
was alkylated according to Evans procedure.[26] Reduction
of the compound with superhydride gave the alcohol 13,
identical for the sign of optical rotation and HPLC traces to
the alcohol obtained by reduction with NaBH4 of the prod-
uct 8d obtained at ꢁ258C.
Acknowledgements
The European Commission through the project FP7-201431 (CATA-
FLU.OR), PRIN (Progetto Nazionale Stereoselezioni in Chimica Organi-
ca: Metodologie ed Applicazioni), and Bologna University are acknowl-
edged for financial support for this research.
Chem. Asian J. 2010, 5, 2047 – 2052
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2051

G. Cozzi et al.
FULL PAPERS
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Received: February 26, 2010
Revised: March 23, 2010
Published online: July 6, 2010
2052
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