Organocatalytic asymmetric alkylation of aldehydes by SNreaction of alcohols

Article abstract of DOI:10.1002/anie.200805423

Work-alcoholic! The elusive enantioselective catalytic α-alkylation of aldehydes, a widely sought transformation, was brought to execution by the use of alcohols capable of forming stabilized carbocations (see scheme, TFA=trifluoroacetic acid).

Full text of DOI:10.1002/anie.200805423

Angewandte
Chemie
DOI: 10.1002/anie.200805423
Organocatalysis
Organocatalytic Asymmetric Alkylation of Aldehydes by SN1-Type
Reaction of Alcohols**
Pier Giorgio Cozzi,* Fides Benfatti, and Luca Zoli
The direct nucleophilic substitution of alcohols represents a
valuable methodology for the preparation of a variety of
derivatives, as water is the only by-product of the trans-
formation.[1,2] We have recently demonstrated the direct
substitution of optically active ferrocenyl alcohols[3] and
benzylic alcohols[4] with several nucleophiles “on water”[2h]
without using Brønsted or Lewis acids. The direct nucleo-
philic substitution “on water” was possible because of the
ability of water to form a hydrogen-bond network,[5] and was
driven by the stability of the generated carbocations. On the
basis of the electrophilicity parameters introduced by Mayr
et al.[6] (see Table 1 in the Supporting Information), we
decided to use less reactive carbocations, generated from
alcohols, for exploring a direct nucleophilic enantioselective
substitution. Mayr et al. have also classified nucleophiles
using a related nucleophilicity scale,[6] in which the highly
nucleophilic enamines are placed at the top of the list (see
Table 2 in the Supporting Information).[7] Notably, chiral
enamines[8] are key intermediates in many organocatalytic
methodologies which have been explored in recent years.[9]
On this basis, we hypothesized that the elusive a-alkylation of
Figure 1. Reaction of n-octanal with 1 performed in the presence of
different solvents and conditions (R=n-C6H13). Tf=trifluorosulfonyl,
PTS=p-toluenesulfonic acid, TFA=trifluoroacetic acid.
an aldehyde might be realized in an effective and simple way
by using enamine catalysis coupled with the generation of
stabilized carbocations.[10] Recently, the formation of such a
stabilized carbocation was invoked by Enders et al.,[11] and by
Petrini and Melchiorre et al.[12] in their organocatalytic
asymmetric alkylations involving indole derivatives. We
report herein a practical, direct asymmetric alkylation of
aldehydes realized by nucleophilic substitution of alcohols
with aldehydes.
Bis(4-dimethylamino-phenyl)methanol 1, which can form
a stabilized carbocation,[13] was used in the model reaction
with n-octanal. Different organocatalysts were tested in the
model reaction and they were used as either the free amine or
as a salt (Figure 1) . Among all the pyrrolidine derivatives
tested, only l-proline (A) gave the desired product in MeOH,
albeit in racemic form. After an extensive survey of various
organocatalysts and conditions, we were delighted to find that
the MacMillan catalysts,[14] F, G, H and I, displayed unique
and remarkable reactivities in the model reaction performed
with n-octanal (Table 1).
By using the selected reaction conditions (catalyst G, Et2O
as the reaction solvent), and on the basis of the correlation
established between the stability of the carbocations and their
reactivities “on water”,[4] we selected the alcohols reported in
Figure 2 for demonstrating the scope of our alkylation.
Alcohol 6 and alcohols that form more reactive carbocations,
such as benzhydrol 7, which are placed at the top of Mayr list
(see the Supporting Information), showed no reactivity in our
reaction. In contrast, alcohols 2–5 smoothly reacted under our
reaction conditions with different aldehydes, and the results
obtained are reported in Table 2. The enantiomeric excesses
obtained the reaction of alcohol 1 with each of the aldehydes
tested are in the range of 60 to 78% ee. Slightly inferior
results in terms of enantiomeric excess were obtained with the
alcohols 2 and 3. Notably, in all cases yields ranging from
moderate to excellent were obtained.
[*] Prof. Dr. P. G. Cozzi, Dr. F. Benfatti, Dr. L. Zoli
Dipartimento di Chimica “G. Ciamician”
ALMA MATER STUDIORUM Universitꢀ di Bologna
Via Selmi 2, 40126 (Italy)
Fax: (+30)051-209-9456
E-mail: piergiorgio.cozzi@unibo.it
[**] The European Commission through the project FP7-201431 (CAT-
AFLU.OR), PRIN (Progetto Nazionale Stereoselezioni in Chimica
Organica: Metodologie ed Applicazioni) and Bologna University are
acknowledged for financial support for this research. We thank
Professors C. Melchiorre and M. Roberti for the use of the
polarimeter.
Quite remarkable results were obtained with the ferro-
cenyl alcohol 4. The reaction performed with the optically
active 4 (94% ee) and racemic organocatalyst G gave the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805423.
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Communications
Table 1: Reaction of n-octanal with 1 performed in the presence of
different solvents, conditions, and catalysts (R=n-C6H13).
Table 2: Reaction of the alcohols 1–5 with different aldehydes in the
presence of catalyst G.
Entry[a]
Cat.
Solvent
ee [%][b]
1
2
3
4
5
6
F
F
F
F
Et2O
CH2Cl2
DME
tBuOMe
AcOEt
CH3CN
CH3CN/H2O
THF/H2O
H2O
Et2O
Et2O
Et2O
toluene
Et2O
70
55
60
66
55
50
53
68
70
38
18
70
76
80
80
80
80
78
54
50
Entry[a] t [h]
Product
Yield d.r.[c]
[%][b]
ee [%][d]
77 (S)
69
F
G
G
G
F
D
E
G
G
G
G
G
G
G
H
I
1[a]
24
18
95
79
–
–
7[c,d]
8[c,e]
9[c,f]
7[c]
8[c]
2[a]
9[c]
10[c]
11[c]
12[c,g]
13[c,h]
14[c,i]
15[c]
16[c]
17[c]
Et2O
Et2O
Et2O
toluene
Et2O
3
20
79
–
69
Et2O
4
5
6
4
77
63
92
–
–
–
77
60
78
[a] Reaction conditions: 0.1 mmol scale using 3 equiv of n-octanal until
complete conversion, which was monitored by TLC (4–24 h). In all the
reactions 35 mol% of the catalyst (with respect to the alcohol 1) and
35 mol% of CF3COOH were added in sequence to the reaction mixture.
[b] Enantiomeric excess was determined by chiral HPLC analysis. [c] The
reaction was carried out with 35 mol% of the catalyst which was added
as the salt. [d] Reaction was performed with 1 mL of CH3CN/H2O (1:1).
Yield of isolated product after 24 h was 53%. [e] Reaction was performed
with 1 mL of THF/H2O (1:1). Yield of isolated product after 24 h was
73%. [f] Reaction was performed with 1 mL of H2O. Yield of isolated
product after 24 h was 78%. [g] The reaction was carried out with
15 mol% of the catalyst which was added as the TFA salt. Yield of the
isolated product after 24 h was 90%. [h] The reaction was carried out
with 10 mol% of the catalyst which was added as the TFA salt. Yield of
isolated product after 24 h was 66%. [i] The reaction was carried out with
5 mol% of the catalyst which was added as the TFA salt. Yield of isolated
product after 24 h was 40%.
9
21
7[e]
1
85
73
56
95
90
–
–
–
–
–
78
74
77
78
80
8
24
24
24
90
9
10
11[f]
90
12g]
24
24
48
30
1:3
(2S,3R) syn
Figure 2. Alcohols selected for direct organocatalytic alkylation.
70
(2S,3R) syn
77
13
1:1.3
desired product in a diastereoisomeric ratio of 3:1 with a
slight loss in stereochemical information. However, to
accomplish the reaction it was necessary to increase the
catalyst loading to 90 mol%. The same reaction performed
(2S,3S) anti
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Table 2: (Continued)
Entry[a] t [h]
Product
Yield d.r.[c]
[%][b]
ee [%][d]
88
(2S,3S) anti
78
14
2
80 1.5:1
(2S,3R) syn
92
(2S,3S) anti
86
(2S,3R) syn
15[h]
42
96
48 2.6:1
90
(2S,3S) anti
68
16[h]
76
3:1
(2S,3R) syn
[a] Reaction conditions: reactions were carried out at room temperature
on a 0.1 mmol scale using 3 equivalents of aldehydes and 20 mol% of
the catalyst which was added as the trifluoroacetate salt. In the case of
reactions in entries 12–16 only the configuration of the major diaste-
reoisomer is indicated. [b] Yield of isolated product after chromato-
graphic purification. [c] Determined by 1H NMR or by chiral HPLC
analysis on the crude reaction mixture. The ratio indicated is anti/syn.
[d] Determined by chiral HPLC analysis (see the Supporting Information
for details). [e] The reaction was carried out without adding solvent.
[f] The reaction was carried out at 08C. [g] The reaction was carried out
using the enantioenriched alcohol (S)-4 (94% ee) and 90 mol% of the
racemic catalyst G. [h] The reaction was carried out at À258C.
Figure 3. Proposed catalytic cycle for the organocatalytic transforma-
tion.
catalytic cycle is placed at E = À7 on the Mayr scale.[21] The
equilibrium established between the enamine and the carbo-
cation might be possible with alcohols that are able to
generate relatively stable carbocations of the same or slightly
higher electrophilicity relative to enamine.
with optically active organocatalyst G gave the product in low
yield with an enantiomeric excess of 70%.[15] The reaction of
ferrocenyl racemic alcohols with aldehydes represents a new
and effective way to prepare optically active ferrocene
building blocks.[16] In addition, alcohol 5 is a representative
of a class of useful starting materials for easy access to
relevant indolyl derivatives.[17] Alcohol 5 smoothly reacted in
a fast reaction at room temperature to afford the desired
product (Table 2, entry 14) in high enantiomeric excess, but
with low control of the diastereoselection. Performing the
reaction at low temperature (À258C, Table 2, entry 15)
provided better control of the stereoselection at the expense
of the yield.
The absolute configuration of the products derived from
alcohol 1 was established by correlation to known derivatives
obtained by using a methodology reported by Paras and
MacMillan[18,19] (see the Supporting Information). The abso-
lute configuration of the products derived from alcohol 5 was
assigned by comparison of the elution order of the products
from a chiral phase HPLC column to those reported in the
literature.[20] The absolute configuration of the products
obtained can be explained by a model in which a carbocation
attacks the less hindered face of the E enamine obtained
in situ by the reaction of the aldehyde with the amine catalyst
(see the Supporting Information). In the catalytic cycle
illustrated in Figure 3 the formation of the free acid (HX) is
probably responsible for the generation of the carbocation.
Notably, the iminium ion formed in the first step of the
In summary, we have reported an effective and very
simple method to effect the enantioselective direct alkylation
of aldehydes with unfunctionalized alcohols.[22] This method-
ology opens several opportunities for realizing cascade,
consecutive, and multicomponent organocatalytic reactions
that include benzylic alcohols in their synthetic design. The
scope of the present reaction, as well as the use of ketones and
other nucleophiles in the organocatalytic, enantioselective
direct nucleophilic substitution of alcohols, is presently under
active investigation in our laboratory.
Experimental Section
Organocatalyst G (20 mol%), alcohol 1 (1 equiv), and the aldehyde
(3 equiv) were placed in a vial and dissolved in Et2O (0.1m). The
solution immediately turned deep blue, and the reaction mixture was
stirred until the disappearance of the blue color, indicating complete
reaction. The mixture was evaporated and purified by column
chromatography (eluent hexane/Et2O 8:2).
Received: November 6, 2008
Keywords: alcohols · aldehydes · carbocations · enamines ·
.
organocatalysis
À
À
À
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Angew. Chem. Int. Ed. 2009, 48, 1313 –1316
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