A new class of chiral lewis basic metal-free catalysts for stereoselective allylations of aldehydes

Article abstract of DOI:10.1055/s-2008-1072509

A new class of amine N-oxides derived from trans-2,5-diphenylpyrrolidine were synthesized in enantiomerically pure form and tested as metal-free catalysts in the reaction of aldehydes with allyl(trichloro)silane to afford homoallylic alcohols. The products were obtained in fair to good yields and up to 85% ee. The behavior of structurally different catalysts and the influence of a coordinating unit present in the organocatalyst on controlling the stereochemical efficiency of the reaction were also investigated. Noteworthy a catalyst capable of promoting the allylation of aliphatic aldehydes with an almost unprecedent and unusually high enantioselectivity, up to 85%, was identified. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072509

LETTER
1061
A New Class of Chiral Lewis Basic Metal-Free Catalysts for Stereoselective
Allylations of Aldehydes
A
N
ewClass of Ch
a
iral
L
ewis
l
Basic
M
e
etal-Free
n
Catalysts tina Simonini,a Maurizio Benaglia,*a Luca Pignataro,a Stefania Guizzetti,a Giuseppe Celentanob
a
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
Fax +39(02)50314159; E-mail: maurizio.benaglia@unimi.it
b
Istituto di Chimica Organica, Facoltà di Farmacia, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
Received 21 January 2008
cleophilic activation of organosilicon reagents.7 A few ef-
ficient systems were developed, but the high level of
stereocontrol achieved was the result of an extensive opti-
mization of the stereochemical features of the catalysts,
Abstract: A new class of amine N-oxides derived from trans-2,5-
diphenylpyrrolidine were synthesized in enantiomerically pure
form and tested as metal-free catalysts in the reaction of aldehydes
with allyl(trichloro)silane to afford homoallylic alcohols. The prod-
ucts were obtained in fair to good yields and up to 85% ee. The be- the synthesis of which required long and tedious proce-
havior of structurally different catalysts and the influence of a
dures, sometimes involving also a resolution step. Fur-
coordinating unit present in the organocatalyst on controlling the
thermore a difficult-to-control stereogenic element such
stereochemical efficiency of the reaction were also investigated.
as a stereogenic axis in the catalyst is often required to
Noteworthy a catalyst capable of promoting the allylation of ali-
achieve high levels of stereocontrol.
phatic aldehydes with an almost unprecedent and unusually high
enantioselectivity, up to 85%, was identified.
Even if systems of relatively easy synthesis were devel-
oped,8 including chiral bispyridine N,N¢-dioxides,9 or sim-
Key words: N-oxides, allyltrichlorosilane, homoallylic alcohol,
enantioselective catalysis, organocatalysis
ple pyridine N-oxides easily assembled from inexpensive
aminoacids,10 the search of new, readily available, effi-
cient chiral organocatalysts for the reaction of trichlorosi-
lyl compounds is still very active.
The design and the synthesis of novel chiral Lewis bases
which are able to act both as metal ligand as well as metal-
free catalysts is a topic of paramount interest in the field
of stereoselective catalysis.1 Recently, special attention
has been given to the development of an environmentally
benign methodology that involves the use of nontoxic sil-
icon-based reagents.2 The coordination of a Lewis base to
a tetracoordinated silicon atom leads to hypervalent sili-
cate species of increased Lewis acidity at silicon center.
As a consequence, such extracoordinated organosilicon
compounds become very reactive carbon nucleophiles or
hydride donors with a strong electrophilic character at sil-
icon and an enhanced capability to transfer a formally
negative-charged group to an acceptor.3
In this field an element of novelty was brought by Hovey-
da which developed an N-oxide prolinamide derivative,
the only representative of aliphatic tertiary amine N-ox-
ides so far reported, that presents a stereogenic center at
the nitrogen.11 We decided to synthesize a new family of
rigid, aliphatic N-oxides bearing the stereocenters close to
the catalytic site. To avoid the problem of the diastereose-
lective oxidation of the amine group, a cyclic structure
was selected, where the nitrogen atom, although chiro-
topic, is not stereogenic. In this context, here we describe
a new class of amine N-oxides derived from trans-2,5-
diphenylpyrrolidine as novel metal-free catalysts for the
addition of allyltrichlorosilane to aldehydes.
According to a known procedure12 starting from the com-
mercially available 1,4-diphenyl-1,4-butandione the
enantiomerically pure (1R,4R)-1,4-diphenyl-1,4-butandi-
ol was obtained through reduction mediated by borane-
(S)-diphenylprolinol complex. Conversion of the diol to
the corresponding bismesylate derivative, followed by re-
action with an excess of a proper amine afforded generally
in good yields the trans-(2R,5R)-2,5-diphenylpyrrolidine
derivative (Scheme 1).13 Finally, the oxidation of the ter-
tiary amine to the corresponding N-oxide was accom-
plished by reaction with MCPBA at low temperature.14
A paradigmatic example of successful chiral Lewis base
catalyzed reaction is represented by the allylation of alde-
hydes with allyltrichlorosilanes to afford homoallylic al-
cohols with high enantioselectivity. Among the different
classes of compounds which have been employed as
chiral Lewis bases to catalyze the reaction,4 chiral phos-
phoramides,5 and less often diphosphine oxides6 have
been employed with excellent results.
Among Lewis basic catalysts, one class of compounds
that deserve a special attention are chiral N-oxides derived
from tertiary amines and pyridines. The high nucleophi-
licity of the oxygen in N-oxides, coupled with a high af-
finity of silicon for oxygen represent ideal properties for
the development of synthetic methodology based on nu-
The outlined general synthetic procedure allowed to pre-
pare several molecules characterized by different structur-
al features. Selected examples of the synthesized
compounds are shown in Figure 1.
SYNLETT 2008, No. 7, pp 1061–1065
Advanced online publication: 17.03.2008
DOI: 10.1055/s-2008-1072509; Art ID: G02208ST
x
x.
x
x.
2
0
0
8
The catalytic ability of such new trans-(2R,5R)-2,5-
diphenylpyrrolidine-derived N-oxides was then studied in
© Georg Thieme Verlag Stuttgart · New York

1062
V. Simonini et al.
LETTER
Ph
Ph·B(OMe)3
OH
OH
O
N
H
BH3·SMe2
OH
O
1. MsCl
2. RNH2 (excess)
R
N
R
O
MCPBA, K2CO3
N
Scheme 1 General procedure for the synthesis of catalysts 1–9
OMe
N
O
N
O
O
N
N
1
2
3
H
O
N
O
NH
O
O
N
NH
O
N
O
N
4
5
6
Ph
Ph
H
O
O
O
P
N
NH
NH
O
O
O
N
N
N
7
8
9
Figure 1 trans-(2R,R)-2,5-Diphenylpyrrolidine derivatives 1–9
the test reaction of the addition of allyltrichlorosilane to tween the two chelating units may play a decisive role in
benzaldehyde (Scheme 2). In a typical procedure 0.1 mol determining the chemical and stereochemical efficiency
equivalents of catalyst, 1.2 mol equivalents of allyltrichlo- of the catalyst. For this reason in this new family of metal-
rosilane, and 3 mol equivalents of DIPEA in acetonitrile free catalysts different silicon-coordinating moieties were
were reacted 48 hours at different temperatures.15 Isolated used, such as pyridine, pyridine N-oxides, formamide, and
yields and ee, as determined by HPLC, are collected in amide groups, located at variable distances from the pyr-
Table 1; the R absolute configuration was assigned to the rolidine N-oxide. The results of entries 3–5 of Table 1
predominant isomer of 10a on the basis of its optical rota- show that a distance of five atoms between the coordinat-
tion. A comparison of the results obtained with catalysts 1 ing elements proved to afford a good balance of activity
and 2 (entries 1 and 2 of Table 1) clearly showed that the and stereocontrol. Catalyst 5, bearing a formamide group
presence of a chelating element on the N-alkyl chain was as secondary binding unit with a five-atom distance be-
necessary in order to have a chemically active catalyst. tween the two coordinating oxygen atoms, offered the
These findings are in accordance with the general pro- best performance and was able to promote the reaction at
posed transition state for the reaction involving the coor- 0 °C in decent yield and 81% ee (entry 5 of Table 1).
dination of the silicon atom by two binding units.16
The substitution of the formamide with a benzamide (en-
Not only the nature of the ancillary coordinating element try 6), as well as with other coordinating elements such as
besides the aliphatic N-oxide but also the distance be- a diphenylphosphine oxide or another tertiary amine N-
Synlett 2008, No. 7, 1061–1065 © Thieme Stuttgart · New York

LETTER
A New Class of Chiral Lewis Basic Metal-Free Catalysts
1063
OH
Table 2 Stereoselective Addition of Allyltrichlorosilane to Differ-
ent Aldehydes Promoted by Catalysts 5a
SiCl3
RCHO
R
cat. 5, DIPEA, MeCN
Entry
Temp
(°C)
Yield
(%)b
ee
10a–f
Product
R
(%)c
R = Ph (10a)
4-O2NC6H4 (10b)
4-ClC6H4 (10c)
2-MeOC6H4 (10d)
(E)-PhCH=CH (10e)
PhCH2CH2 (10f)
Me(CH2)9CH2 (10g)
1
0
0
10a
10b
10c
10d
10e
10f
10f
10f
10g
Ph
51
35
50
71
33
23
67
17
47
81
55
60
67
63
81
85
67
81
2
4-NO2C6H4
4-ClC6H4
3
0
4
0
2-OMeC6H4
(E)-PhCH=CH
PhCH2CH2
PhCH2CH2
PhCH2CH2
Me(CH2)10
Scheme 2 Addition of allyltrichlorosilane to different aldehydes
promoted by catalysts 1–9.
5
0
6
0
Table 1 Addition of Allyltrichlorosilane to Benzaldehyde Promot-
ed by Catalysts 1–9a
7d
8e
9d
0
Entry Temp (°C) Catalyst (10 mol%)
Yield (%)b ee (%)c
25
0
1
2
0
0
1
2
3
4
5
6
7
8
9
5
5
n.r.
45
55
24
51
11
33
24
n.r.
45
65
n.d.
11
17
21
81
23
33
11
n.d.
61
61
a Reaction conditions: DIPEA (0.9 mmol), allyltrichlorosilane (0.36
mmol), aldehyde (0.3 mmol), catalyst (0.03 mmol), 48 h in MeCN.
b Yields determined after chromatographic purification.
c The ee determined by HPLC (Chiracel OD).
d Reaction run with 30% cat mol.
3
25
25
0
4
e Reaction run at 25 °C for 60 h.
5
6
0
poor aldehydes reacted slower than benzaldehyde, which
reacted in lower yield than the electron-rich 2-methoxy
benzaldehyde (entries 2 and 3 vs. entry 1, entry 1 vs. entry
4).
7
0
8
0
9
0
The 5-catalyzed allylations of cinnamaldehyde and 3-
phenylpropanal were also attempted. While the former
gave adduct 10e in low yield (33%) and fair ee (63%), sur-
prisingly the latter proved to be poorly reactive, but the
product 10f was isolated in high enantioselectivity (23%
yield, 81% ee, entry 6). It must be noted that this result
represents an element of novelty, compared to all the other
known catalytic systems, which usually afforded the ali-
phatic homoallylic alcohol 10f in low stereoselectivities.18
10d
11e
0
25
a Reaction conditions: DIPEA (0.9 mmol), allyltrichlorosilane (0.36
mmol), aldehyde (0.3 mmol), catalyst (0.03 mmol), 48 h in MeCN.
b Yields determined after chromatographic purification.
c The ee determined by HPLC (Chiracel OD).
d Reaction run in CH2Cl2.
e Reaction run at 25 °C for 60 h.
By increasing the catalyst loading the product 10f was ob-
tained in 67% yield and a very interesting 85% ee (entry 8
of Table 2). The use of catalyst 5 with other aliphatic al-
dehydes was also attempted; while the reaction with cy-
clohexanecarboxaldehyde did not lead to the product in
appreciable yields, the addition of allyltrichlorosilane to
dodecanaldehyde afforded the homoallylic alcohol 10g in
47% yield and 81% ee. The result suggests that the pres-
ence of an aryl group in the aldehydic substrate does not
play a decisive role in determining the stereochemical out-
come of the reaction.
oxide (entries 7 and 8) resulted in much less active cata-
lysts. As further demonstration of the importance of the
distance between the chelating units, compound 9 bearing
a C3 alkyl chain instead of a C2 alkyl chain present in cat-
alyst 5 was completely ineffective in promoting the addi-
tion of allyltrichlorosilane to benzaldehyde (entry 9).
Among various tested solvents catalyst 5 performed better
in dichloromethane and specially in acetonitrile;17 the
chemical yield was not dramatically improved even for
longer reaction times, while an increase of the reaction
temperature up to 25 °C led to a decreased enantioselec-
tivity of 61% (entries 8 and 9).
Finally, the use of catalyst 5 was extended to the reaction
of benzaldehyde with a 81:19 mixture of (E)- and (Z)-cro-
tyltrichlorosilane. A mixture of diastereoisomeric alco-
hols anti-11 and syn-11 in 78:22 ratio was obtained in
37% yield, the anti isomer having a 85% ee (Scheme 3).
The fact that the anti/syn diastereoisomeric ratio reflected
the E/Z ratio of the starting silane is generally considered19
a strong indication that a six-membered cyclic chair-like
Having thus identified the trans-(2R,5R)-2,5-diphen-
ylpyrrolidine derivative 5 as the more efficient catalyst, its
use was extended to the allylation of other aldehydes to af-
ford alcohols 10b–g (Scheme 2 and Table 2). Interesting-
ly, the chemical yield seemed to depend on the electronic
nature of the aryl substituents in the aldehydes. Electron-
Synlett 2008, No. 7, 1061–1065 © Thieme Stuttgart · New York

1064
V. Simonini et al.
LETTER
(11) (a) Traverse, J. F.; Zhao, Y.; Hoveyda, A. H.; Snapper, M. L.
Org. Lett. 2005, 7, 3151. (b) See also: Shang, D.; Xin, J.;
Liu, Y.; Zhou, X.; Liu, X.; Feng, X. J. Org. Chem. 2008, 73,
630.
OH
Me
SiCl3
E/Z = 8:2
cat. 5, DIPEA, MeCN
Ph
PhCHO
Me
(12) Aldous, D. J.; Dutton, W. M.; Steel, P. G. Tetrahedron:
Asymmetry 2000, 11, 2455.
anti-11 + syn-11
anti isomer 85% ee
(13) Reaction of (1R,4R)-1,4-Bis-(methansulfonyl)-1,4-
diphenylbutan with Ethylene Diamine and Formylation
Reaction
Scheme 3 Addition of (Z)-crotyltrichlorosilane to benzaldehyde
promoted by catalysts 5
A solution of ethylene diamine (8.45 g. 8.45 mmol) in
CH2Cl2 (3 mL) was added under dry atmosphere at 0 °C to
(1R,4R)-1,4-bis-(methansulfonyl)-1,4-diphenylbutan (0.587
g, 1.47 mmol). The reaction mixture was allowed to react at
0 °C for 16 h, then ethylene diamine and the solvent were
evaporated under reduced pressure. The crude product was
purified by a short column on silica gel (CH2Cl2–MeOH =
8:2 as eluent mixture). A white waxy solid was obtained and
used as such in the step (>98% yield). To a solution of the
amine (0.428 g, 1.6 mmol) in formic acid (2.9 g, 63.4 mmol)
cooled to 0 °C, Ac2O (1.15 g, 11.2 mmol) was added
dropwise. The reaction mixture was allowed to stir at r.t. for
20 h, then it was quenched with H2O and solid K2CO3 to
make the solution alkaline. The aqueous phase was extracted
3 times with CH2Cl2, the organic phase was then dried over
Na2SO4 and evaporated under reduced pressure. The
purification by flash chromatography (CH2Cl2–EtOAc = 7:3
as eluent mixture) afforded the diol as colorless oil (53%
yield). 1H NMR (300 MHz, CDCl3): d = 8.01 (s, 1 H), 7.39–
7.21 (m, 10 H), 5.68 (br s, 1 H), 3.07 (m, 2 H), 2.57 (m, 2 H),
2.46 (m, 2 H), 1.96 (m, 2 H). MS (ESI+): m/z = 317.5 [M +
Na]+. [a]23 –131.0 (c 0.41, CHCl3). IR (CH2Cl2):
transition structure is involved in the allylation. Accord-
ing to this model, the hypervalent silicon atom (common-
ly believed to be involved in this type of reactions) would
be coordinated by the N-oxide oxygen and the formamide
group in an even-membered chelate ring.9,10
In conclusion a new class of Lewis bases to be used as
metal-free catalysts in the addition of allyltrichlorosilane
to aldehydes has been developed.
The proximity of the catalytically active N-oxide group to
the stereocenters, the possibility to modulate the distance
and the nature of a second silicon-binding unit, and the
easy preparation in enantiomerically pure form in only
three or maximum four steps from commercially available
reagents are all positive features of the new catalytic sys-
tem. Interestingly, a member of this new class of organo-
catalysts has shown an unusual ability to promote the
allylation of aliphatic aldehydes with high enantioselec-
tivity. Further studies directed to the development of new
members of this new class of Lewis bases are under way
in order to improve their stereochemical and specially
their chemical activity.
n
C=O = 1685.5 cm–1.
(14) N-Oxidation
To a solution of the N-formyl pyrrolidine (0.11 g, 0.35
mmol) in CH2Cl2 (7 mL) at –78 °C under nitrogen
atmosphere K2CO3 (0.10 g, 0.76 mmol) and MCPBA 70%
(0.092 g, 037 mmol) were added; the reaction mixture was
stirred at –78 °C, followed by TLC and stopped after 6 h by
filtering the mixture onto Celite cake. The organic phase was
washed 3 times with K2CO3 sat. soln, dried over Na2SO4 and
evaporated under reduced pressure. The purification by flash
chromatography (CH2Cl2–MeOH = 95:5 as eluent mixture)
afforded catalyst 5 as white solid (73% yield); mp 139–
141 °C; [a]23 –229.3 (c 0.48 in CHCl3). IR: nC=O = 1669.09
cm–1. 1H NMR (300 MHz, CDCl3): d = 8.65 (br s, 1 H), 7.91
(s, 1 H), 7.65 (m, 4 H), 7.50 (m, 5 H), 7.40 (m, 3 H), 5.00 (dd,
1 H), 4.55 (dd, 1 H), 3.45 (m, 1 H), 3.15 (m, 1 H), 3.00 (m,
1 H), 2.85 (m, 1 H), 2.65 (m, 1 H), 2.5 (m, 1 H), 2.25 (m, 1
H). 13C NMR (125 MHz, CDCl3): d = 160.8, 137.1, 132.4,
131.7, 129.8, 129.7, 129.5, 129.4, 128.2, 86.1, 76.8, 59.0,
34.2, 29.6, 28.2. MS (ESI+): m/z 333.5 [M + Na]+. Anal.
Calcd for C19H22N2O2: C, 72.52; H, 7.14; N, 9.03. Found: C,
72.45; H, 7.18; N, 9.08.
Acknowledgment
This work was supported by MIUR: ‘Nuovi metodi catalitici stereo-
selettivi e sintesi stereoselettiva di molecole funzionali’.
References and Notes
(1) Orito, Y.; Nakajima, M. Synthesis 2006, 1391.
(2) Benaglia, M.; Guizzetti, S.; Pignataro, L. Coord. Chem. Rev.
2008, , DOI: 10.1016/j.ccr.2007.10.009.
(3) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev.
1993, 93, 1371.
(4) See ref. 1, 2, and: Rendler, S.; Oestreich, M. Synthesis 2005,
1727.
(5) (a) Denmark, S. E.; Fu, J.; Coe, D. M.; Su, X.; Pratt, N. E.;
Griedel, B. D. J. Org. Chem. 2006, 71, 1513; and references
cited therein. (b) Denmark, S. E.; Fu, J. Chem. Rev. 2003,
103, 2763.
(15) Allylation Reaction – Typical Procedure
To a stirred solution of catalyst (0.03 mmol) in MeCN (2
mL) kept under nitrogen, an aldehyde (0.3 mmol) and
DIPEA (0.154 mL, 0.9 mmol) were added in this order. The
mixture was then cooled to 0 °C and allyl(trichloro)silane
(0.054 mL, 0.36 mmol) was added dropwise by means of a
syringe. After 48 h stirring at 0 °C the reaction was quenched
by the addition of a saturated aqueous solution of NaHCO3
(1 mL). The mixture was allowed to warm up to r.t. and H2O
(2 mL) and EtOAc (5 mL) were added. The organic phase
was separated and the aqueous phase was extracted 3 times
with EtOAc. The combined organic phases were dried over
Na2SO4, filtered, and concentrated under vacuum at r.t. to
afford the crude products. These were purified by flash
(6) (a) Nakajima, M.; Kotani, S.; Ishizuka, T.; Hashimoto, S.
Tetrahedron Lett. 2005, 46, 157. (b) Kotani, S.; Hashimoto,
S.; Nakajima, M. Tetrahedron 2007, 63, 3122.
(7) Malkov, A. V.; Kočovský, P. Eur. J. Org. Chem. 2007, 29.
(8) Malkov, A. V.; Dufkovà, A.; Farrugia, L.; Kocovsky, P.
Angew. Chem. Int. Ed. 2003, 42, 3674.
(9) (a) Pignataro, L.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Celentano, G. Chirality 2005, 17, 396. (b) Chelucci, G.;
Belmonte, N.; Benaglia, M.; Pignataro, L. Tetrahedron Lett.
2007, 48, 4037.
(10) Pignataro, L.; Benaglia, M.; Annunziata, R.; Cinquini, M.;
Cozzi, F. J. Org. Chem. 2006, 71, 1458.
Synlett 2008, No. 7, 1061–1065 © Thieme Stuttgart · New York

LETTER
chromatography with different hexanes–ethyl acetate
A New Class of Chiral Lewis Basic Metal-Free Catalysts
1065
(17) The reaction performed in other solvents such as toluene,
hexane, or THF afforded the product with lower
stereoselectivity.
(18) Enantioselectivities reported for product 10f were very often
lower than 50%. For the only notable exception, see: Chai,
Q.; Song, C.; Sun, Z.; Ma, Y.; Ma, C.; Dai, Y.; Andrus, M.
B. Tetrahedron Lett. 2006, 47, 8611.
mixture as eluents. Yields and ee for each reaction are
indicated in Tables 1 and 2. The assignment of the R
absolute configuration to the predominant isomer formed in
each reaction rests on comparison of sign of optical rotation
with those reported in the literature, or on the reasonable
assumption that the absolute configuration of the alcohols
obtained by the reaction with a given catalyst is independent
on the structure of the aldehyde.
(19) See: Denmark, S. E.; Fu, J.; Lawler, M. J. J. Org. Chem.
2006, 71, 1523; and references cited therein.
(16) For a discussion on the proposed transition states for these
reactions, see ref. 2, 5, and 7.
Synlett 2008, No. 7, 1061–1065 © Thieme Stuttgart · New York

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