Enantiomerically pure bithiophene diphosphine oxides as catalysts for direct double aldol reactions

Article abstract of DOI:10.1002/chir.22190

The direct aldol reaction between aryl methyl ketones with aromatic aldehydes in the presence of tetrachlorosilane and a catalytic amount of a chiral bithiophene diphosphine oxide was studied; the product of double aldol addition was isolated as diacetate in good diastereoselectivity (up to 95:5) and enantioselectivities up to 91%. The reaction with heteroaromatic aldehydes was also investigated leading to the corresponding 1,3 diols, in some cases with excellent stereoselectivities. Chirality 25:643-647:, 2013. 2013 Wiley Periodicals, Inc.

Full text of DOI:10.1002/chir.22190

CHIRALITY (2013)
Enantiomerically Pure Bithiophene Diphosphine Oxides as Catalysts
for Direct Double Aldol Reactions
1
1
1
ANDREA GENONI, MAURIZIO BENAGLIA, SERGIO ROSSI, AND GIUSEPPE CELENTANO2
*
1Dipartimento di Chimica, Universita’ degli Studi di Milano, Milano, Italy
2Dipartimento di Scienze Farmaceutiche, Universita’ degli Studi di Milano, Milano, Italy
ABSTRACT
The direct aldol reaction between aryl methyl ketones with aromatic aldehydes
in the presence of tetrachlorosilane and a catalytic amount of a chiral bithiophene diphosphine
oxide was studied; the product of double aldol addition was isolated as diacetate in good
diastereoselectivity (up to 95:5) and enantioselectivities up to 91%. The reaction with
heteroaromatic aldehydes was also investigated leading to the corresponding 1,3 diols, in some
cases with excellent stereoselectivities. Chirality 00:000–000, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: aldol reaction; Lewis bases; organocatalysis; stereoselectivity; tetrachlorosilane
determination was performed on an Agilent 1100 or 1200 instrument un-
INTRODUCTION
der the conditions reported below. Mass spectra (MS) were performed
at CIGA (Centro Interdipartimentale Grandi Apparecchiature), with mass
spectrometer APEX II and Xmass software (Bruker Daltonics).All reac-
tants were freshly distilled (if liquid) or crystallized (if solid) before use.
The use of tetrachlorosilane in combination with catalytic
amount of chiral Lewis bases to promote stereoselective
reactions nowadays is a well-established methodology.1–3
Seminal works by Denmark and colleagues4–6 with chiral
phosphoroamides have shown the versatility of the catalytic
system that opened avenues to several different synthetic ap-
plications.7 Soon after, Nakajima and colleagues8–14 and
we15–17 demonstrated that phosphine oxides could also
coordinate SiCl4 and generate hypervalent cationic silicon
species in situ as chiral Lewis acids able to promote
stereoselective direct aldol reactions.
Double Aldol Reaction: Typical Procedure
To a stirred solution of (S)-tetra-Me-BITIOPO (0.016 mmol, 0.1 equiv)
in CH2Cl2 (2 mL), DIPEA (diisopropylethylamine) (0.8 mmol, 5 equiv.)
and the ketone (0.16 mmol, 1 equiv.) were added. The mixture was
cooled to –40ꢀC, then freshly distilled tetrachlorosilane (0.64 mmol, 4
equiv.) was added dropwise with a syringe. After 15 min, aldehyde
(0.352 mmol, 2.2 equiv.) was added. The mixture was stirred for 20 h.
After this time, the reaction was quenched by the addition of a saturated
aqueous solution of NH4Cl (2 mL). The mixture was allowed to warm to
room temperature and stirred for 30 min, then CH2Cl2 (15 mL) was
added. The two-layer mixture was separated and the aqueous layer was
extracted with CH2Cl2 (15 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under vacuum at room tempera-
Recently, it was reported18 that the binaphthyl-based phos-
phine oxide BINAPO catalyzed the double aldol reaction19,20
of acetophenone with benzaldehyde, leading to the formation
of the corresponding products as a mixture of two diastereo-
isomers and 60% e.e for the major isomer. By looking for
the best experimental conditions it was found that a mixture
of DCM and propionitrile as reaction solvent in combination
with the use of dicyclohexylmethylamine allowed an increase
in the stereoselectivity up to 70% enantiomeric excess (e.e.)
Only with 2-furyl and 2-cyclopropyl methyl ketones was 90%
of enantioselectivity reached.
We were interested in applying our catalytic methodologies
to the transformation; in our previous studies of Lewis-based
catalyzed reactions in the presence of silicon tetrachloride the
use of biheteroaromatic diphosphine oxides, more electron-
rich than the commonly used binaphthyl diphosphine deriva-
tives, has often led to the formation of the desired products with
enantioselectivities higher than those obtained with BINAPO21;
therefore we decided to investigate the behavior of (S)-
tetramethyl-bithiophene phosphine oxide, (S)-TetraMe-
BITIOPO, in the direct double aldol reaction between aryl
methyl ketones and aromatic aldehydes.
1
ture to give the crude 1,3-diols, as confirmed by H-NMR.
The crude products were then treated with acetic anhydride
(1.76 mmol, 11 equiv) in 2 mL of pyridine at room temperature (RT). After
stirring for 20 h, the mixture was quenched with H2O (10 mL) and
extracted with CH2Cl2 (2 x 15 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under vacuum at RT. The
diastereoisomeric ratio was calculated by 1H-NMR spettroscopy. Yields
were determined after chromatographic purification on silica gel with dif-
ferent hexane/ethyl acetate mixtures as eluent (see below). The e.e. was
determined by high-performance liquid chromatography (HPLC) on a
chiral stationary phase. Attributions were performed using racemic
mixtures as references. (S)-tetra-Me-BITIOPO was quantitatively recov-
ered by further elution with 10% MeOH in CH2Cl2 without any loss of
optical purity.
(3-acetoxy-2-(10-acetoxy(phenyl)methyl)-1,3-diphenylpropan-
1-one (3). This product was purified by flash column chromatography
on silica gel with a 8:2 hexane/ethyl acetate mixture as eluent. The
purification afforded a mixture of chiral and meso adducts.
MATERIALS AND METHODS
General
TLC was performed on Merck silica gel 60 TLC plates F254 and visual-
ized using UV or phosphomolibdic acid. Flash chromatography was car-
ried out on silica gel (230–400 mesh). 1H NMRs were recorded at
300 MHz (Bruker Fourier 300 or AMX 300) with the indicated solvent.
13C NMRs were obtained at 75 MHz with complete proton decoupling.
Chemical shifts were determined relative to tetramethylsilane (for hydro-
gen atoms) and residual solvent peaks (for carbon atoms). HPLC for e.e.
Additional Supporting Information may be found in the online version of
this article.
*Correspondence to: Maurizio Benaglia, Dipartimento di Chimica, via C.
Golgi 19, I-20133 Milano, Italy. E-mail: maurizo.benaglia@unimi.it
Received for publication 11 February 2013; Accepted 25 April 2013
DOI: 10.1002/chir.22190
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2013 Wiley Periodicals, Inc.

GENONI ET AL.
4.42 (t, 1H, J = 9 Hz, meso), 1.93 (s, 3H, chiral), 1.80 (s, 6H, meso), 1.76
Rf ¼ 0:24ð8 : 2 hexane=ethyl acetateÞ:
(s, 3H, chiral). 13C NMR (300MHz, CDCl3) d: 198.59, 169.68, 138.47,
136.95, 136.43, 134.71, 133.48, 129.41, 129.02, 128.92, 128.75, 128.22,
74.0, 74.41, 73.66, 55.95, 21.14, 21.00. HRMS Mass (ESI+): m/z = calc
for C26H22Cl2O5Na+ = 507.07, found 507.20 [M+ Na].
Data for chiral (3a): 1H NMR (300 MHz, CDCl3) d: 7.99 (d, 2H,
J = 9 Hz), 7.44 (d, 2H, J = 6 Hz), 7.35-7.11 (m, 11H), 6.37 (d, 1H,
J = 6 Hz), 6.22 (d, 1H, J = 9 Hz), 4.55 (dd, 1H, J = 9 Hz, J = 6 Hz), 2.03
(s, 3H), 2.01 (s, 3H). 13C NMR (300 MHz, CDCl3) d: 198.59, 169.47,
169.38, 138.47, 138.22, 137.64, 132.60, 128.50, 128.23, 128.08, 127.78,
127.65, 127.2, 74.90, 74.05, 55.91, 20.83, 20.65.
The e.e. was determined by chiral HPLC with a Daicel Chiralpak AD
column, eluent: 8:2 Hex/IPA; 0.8 mL/min flow rate, detection: 242 nm, tR
10.52 min (chiral, minor), tR 14.81min (chiral, major), tR 26.10 min (meso).
HRMS Mass (ESI+): m/z = calc for C26H24O5Na+ = 439.46, found
439.15 [M + Na].
Data for meso (3b): 1H NMR (300 MHz, CDCl3) d: 8.10 (d, 2H,
J = 9 Hz), 7.68 (d, 2H, J = 9 Hz), 7.35-7.11 (m, 11H), 5.95 (d, 2H,
J = 6 Hz), 4.40 (t, 1H, J = 6 Hz), 1.78 (s, 6H).
3-acetoxy-2-(10-acetoxy-10-(4-nitrohenyl)methyl)-1-phenyl-3-(4-
nitrophenyl)-propan-1-one (Table 2, entry 4). This product was
purified by flash column chromatography on silica gel with a 8:2 hexane/
ethyl acetate mixture as eluent. The purification afforded a mixture of chiral
and meso adducts. Rf = 0.12 (8:2 hexane/ethyl acetate).
The e.e. was determined by chiral HPLC with Daicel Chiralpak AD
column, eluent: 8:2 Hex/IPA; 0.8 mL/min flow rate, detection: 254 nm,
tR 9.44 min (chiral, minor), tR 12.51 min (chiral, major), tR 17.63 min
(meso). (Table 1)
Data for a chiral/meso mixture: 1H NMR (300 MHz, CDCl3) d: 8.09-
8.01 (m, 4H chiral + 4H meso), 7.64-7.17 (m, 9H chiral + 9H meso),
6.44 (d, 1H, J = 6 Hz, chiral), 6.30 (d, 1H, J = 9 Hz, chiral), 6.01
(d, 2H, J = 6 Hz, meso), 4.58 (dd, 1H, J = 9 Hz, J = 6 Hz, chiral), 4.46
(t, 1H, J = 9 Hz, meso), 2.06 (s, 3H, chiral), 1.97 (s, 6H, meso), 1.89
(s, 3H, chiral). 13C NMR (300 MHz, CDCl3) d: 195.44, 169.98, 144.84,
140.30, 139.26, 136.96, 134.27, 133.39, 129.82, 129.59, 128.73, 127.09,
123.93, 123.70, 73.02, 71.64, 55.43, 20.74. HRMS Mass (ESI+): m/z =
calc for C26H22N2O9Na+ = 529.12, found 529.3 [M + Na].
3-acetoxy-2-(10-acetoxy-10-(4-chlorophenyl)methyl)-1-phenyl-3-
(4-chlorophenyl)-propan-1-one (Table 2, entry 3). This product was
purified by flash column chromatography on silica gel with a 9:1 hexane/
ethyl acetate mixture as eluent. The purification afforded a mixture of
chiral and meso adducts. Rf = 0.25 (8:2 hexane/ethyl acetate).
Data for a chiral/meso mixture: 1H NMR (300 MHz, CDCl3) d: 7.67
(d, 2H, J = 9 Hz, meso), 7.48 (d, 2H, J = 6 Hz, chiral), 7.45-7.06 (m, 11H
chiral + 11H meso), 6.27 (d, 1H, J = 9 Hz, chiral), 6.14 (d, 1H, J = 9 Hz,
chiral), 5.92 (d, 2H, J = 9 Hz, meso), 4.56 (dd, 1H, J = 9 Hz, J = 6 Hz, chiral),
The enantiomeric excess was determined by chiral HPLC with Daicel
Chiralcell OD-H column, eluent: 8:2 Hex/IPA; 0.8 mL/min flow rate,
TABLE 1. Tetra-Me-BITIOPO-catalyzed condensation of acetophenone with benzaldehyde
Entry
R. time (h)
R. temp (ꢀC)
Yield (%)a
Diast. ratiob
e.e major isomerc (%)
1d
2e
3f
20
24
20
20
20
20
72
-40
-40
-40
-40
-40
-78
-78
65
90
31
35
61
n.r.
35
84/16
81/19
79/21
86/14
88/12
—
53
60
31
61
75
—
69
4g
5h
6h
7h
75/25
aReactions were run with 4 mol equiv. of SiCl4, 1 mol equiv of ketone,2.2 mol equiv of aldehyde and 10 mol % amount of catalyst; yields were determined after chro-
matographic purification on the diacetate derivative;
bdiastereoisomeric ratio was determined by 1H-NMR and confirmed by HPLC;
ce.e. was determined by HPLC on chiral column (see Supporting Information);
d(S)-BINAPO was used;
eLit. data, Ref. 18; (S)-BINAPO was used;
f(S)-BINAPO was used with Cl3SiOTf;
gthe reaction was quenched with NaHCO3 sat. sol.
hthe reaction was quenched with NH4Cl sat. sol.
TABLE 2. Tetra-Me-BITIOPO-catalyzed condensation of acetophenone with differently substituted aldehydes
Entry
Ar
Yield (%)a
Diast. ratiob
e.e major isomerc (%)
1
2
3
4
5
6
7
8
9
Ph
4-CF3Ph
4-ClPh
4-NO2Ph
4-OMePh
4-MePh
1-Naphth
2-furyl
61
63
65
51
40
43
55
45
25
88/12
90/10
80/20
70/30
73/27
89/11
89/11
92/8
75
41
70
26
91
80
41
71
90
2-thienyl
90/10
aReactions were run with 4 mol equiv. of SiCl4, 1 mol equiv of ketone,2.2 mol equiv of aldehyde and 10 mol % amount of catalyst for 20 h at -40ꢀC; yields were deter-
mined after chromatographic purification on the diacetate derivative;
bdiastereoisomeric ratio was determined by 1H-NMR;
ce.e. was determined by HPLC on chiral column (see Supporting Information).
Chirality DOI 10.1002/chir

ORGANOCATALYTIC DIRECT DOUBLE ALDOL REACTION
detection: 254 nm, tR 12.73min (chiral, major), tR 13.97min (chiral, minor),
R 15.9 min (meso).
Daicel Chiralpak AD column, eluent: 9:1 Hex/IPA; 0.8 mL/min flow
rate, detection: 225.8 nm, tR 12.71 min (chiral, minor), tR 54.14 min
(chiral, major).
Data for meso product: 7.82 (d, 2H, J = 6 Hz), 7.66 (d, 2H, J = 6 Hz),
7.51-7.18 (m, 13H), 7.04 (t, 2H, J = 9 Hz), 6.61 (d, 2H, J = 6 Hz), 5.11
(br, 1H), 2.00 (s, 6H).
t
3-acetoxy-2-(10-acetoxy-10-(4-methoxyphenyl)methyl)-1-phenyl-3-
(4-methoxyphenyl)-propan-1-one (Table 2, entry 5). This product
was purified by flash column chromatography on silica gel with a 8:2
hexane/ethyl acetate mixture as eluent. The purification afforded a mix-
ture of chiral and meso adducts.
RESULTS AND DISCUSSION
The reaction between 1 mol/eq. of acetophenone and
2.2 mol/eq. of benzaldehyde was first investigated in the
presence of stoichiometric amounts of SiCl4 and a catalytic
amount of enantiomerically pure (S)-Tetra-Me-BITIOPO
(0.1 mol/eq.) (Scheme 1). At the end of reaction the
quenching and the work up with NH4Cl sat.sol. allowed
isolating the product as a mixture of diastereoisomers, as
clearly indicated by 1H NMR of the crude reaction mix-
ture; however, any attempt to purify the 1,3 diol led to de-
composition and low isolation yields.22 Therefore, the
crude products were reacted with acetic anhydride to af-
ford the corresponding diacetate derivatives, which were
obtained as pure compounds and properly analysed and
characterized.23
Different experimental conditions of solvent, temperature,
and stoichiometric ratios were screened in order to optimize
the performance of the Lewis base; a few selected results
are shown in Table 1. At –40ꢀC in DCM the reaction was
found to proceed after 20 h in 35% yield, 86/14 ratio between
the chiral isomer 3a and the achiral species 3b, with 55% e.e.
for the major isomer (it must be noted that 3b is an achiral
molecule that may exist in two diastereoisomers because
carbon in a to carbonyl group is an achirotopic stereogenic
center; however, NMR showed one set of signals only and
by HPLC analysis one peak was detected under many
attempted conditions). For sake of comparison the reaction
was performed under the same experimental conditions
with (S)-BINAPO as a chiral catalyst: the product was
obtained in comparable yields and stereoselectivities. The
use of trichlorosilyl triflate did not bring any improvement
to the process. It was also observed that the experimental
conditions of the reaction work up strongly influenced the
level of the enantioselectivity of the isolated products: it was
found that quenching with ammonium chloride gave best
results and it allowed to obtain the 1,3 diacetate 3a as major
product in good yield, 88/12 diastereoisomeric ratio and
higher enantioselectivities, up to 75% e.e. (entry 5 of Table 1).
In the attempt to improve the stereoselectivity the reaction
temperature was further lowered to –78ꢀC; as expected,
the condensation was promoted in lower yield but without
any appreciable increase of the enantioselectivity. Therefore,
it was decided to further explore the general scope of the
methodology by performing the reaction at –40ꢀC for
20 hours in the presence of 10% mol amount of (S)-BITIOPO.
At first the acetophenone reaction with differently substituted
aromatic aldehydes was investigated (see Scheme 2): the
results are collected in Table 2.
Rf ¼ 0:13ð8 : 2 hexane=ethyl acetateÞ:
Data for a chiral/meso mixture: 1H NMR (300 MHz, CDCl3) d: 7.72 (d,
2H, J = 9 Hz, meso), 7.59 (d, 2H, J = 6 Hz, chiral), 7.53-7.28 (m, 5H chi-
ral + 5H meso), 7.18-7.10 (m, 2H chiral + 2H meso), 6.85-6.68 (m, 4H
chiral + 4H meso) 6.26 (d, 1H, J = 6 Hz, chiral), 6.16 (d, 1H, J = 9 Hz, chi-
ral), 5.96 (d, 2H, J = 9 Hz, meso), 4.69 (dd, 1H, J = 9 Hz, 10.5Hz, chiral)
4.49 (t, 1H, J = 9 Hz, meso), 3.79 (s, 3H, chiral), 3.76 (s, 6H, meso), 3.71
(s, 3H, chiral), 1.92 (s, 3H, chiral), 1.73 (s, 3H, chiral), 1.66 (s, 6H,
meso). 13C NMR (300 MHz, CDCl3) d: 195.84, 169.53, 159.55, 138.62,
132.63, 130.22, 129.56, 129.06, 128.76, 128.30, 128.17, 128.11, 127.87,
113.86, 113.59, 74.82, 73.86, 56.33, 55.29, 55.13, 20.89. HRMS Mass
(ESI+): m/z = calc for C28H28O7Na+ = 499.17, found 499.3 [M + Na].
The e.e was determined by chiral HPLC with a Daicel Chiralpak AD
column, eluent: 8:2 Hex/IPA; 0.8 mL/min flow rate, detection: 225 nm,
tR 13.86 min (chiral, minor), tR 20.59 min (chiral, major), tR 30.22 min
(meso).
3-acetoxy-2-(10-acetoxy-10-(4-methylphenyl)methyl)-1-phenyl-3-
(4-methylphenyl)-propan-1-one (Table 2, entry 6). This product
was purified by flash column chromatography on silica gel with a 9:1
hexane/ethyl acetate mixture as eluent. The purification afforded a
mixture of chiral and meso adducts.
Rf ¼ 0:4ð8 : 2 hexane=ethyl acetateÞ:
Data for a chiral/meso mixture: 1H NMR (300 MHz, CDCl3) d: 7.63 (d,
2H, J = 6 Hz, meso), 7.51 (d, 2H, J = 9 Hz, chiral), 7.46-7.21 (m, 5H chi-
ral + 5H meso), 7.11-6.92 (m, 6H, chiral + 6H meso), 6.24 (d, 1H,
J = 9 Hz, chiral), 6.14 (d, 1H, J = 9 Hz, chiral), 5.92 (d, 2H, J = 6 Hz,
meso) 4.65 (dd, 1H, J = 10.5Hz, J = 9 Hz, chiral), 4.44 (t, 1H, J = 6 Hz,
meso), 2.26 (s, 3H, chiral), 2.25 (s, 6H, meso), 2.18 (s, 3H, chiral),
1.90 (s, 3H, chiral), 1.69 (s, 3H, chiral), 1.26 (s, 6H, meso).
13C NMR (300 MHz, CDCl3) d: 198.70, 169.48, 169.37, 138.63, 138.08,
135.15, 134.53, 132.51, 129.07, 128.88, 128.08, 127.90, 127.65, 127.31,
126.83, 74.97, 74.02, 55.65, 21.05, 20.89. HRMS Mass (ESI+): m/z =
calc for C28H28O5Na+ = 467.18, found 467.18 [M + Na].
The e.e. was determined by chiral HPLC with a Daicel Chiralpak AD col-
umn, eluent: 95:5 Hex/IPA; 0.8 mL/min flow rate, detection: 225nm, tR
18.62min (chiral, minor), tR 44.06 min (chiral, major), tR 50.69min (meso).
3-acetoxy-2-(10-acetoxy-10-(1-naphthyl)methyl)-1-phenyl-3-(1-naph
thyl)-propan-1-one (Table 2, entry 7). This product was purified by
flash column chromatography on silica gel with a 9:1 hexane/ethyl
acetate mixture as eluent.
Rf ¼ 0:4ð8 : 2 hexane=ethyl acetateÞ:
Data for chiral product: 1H NMR (300 MHz, CDCl3) d: 8.50 (d, 1H,
J = 6 Hz), 8.40 (d, 1H, J = 6 Hz), 7.83 (d, 1H, J = 9 Hz), 7.74-7.68 (m,
2H), 7.67-7.45 (m, 6H), 7.40-7.20 (m, 4H), 7.18-7.12 (m, 2H), 6.99 (d,
2H, J = 6 Hz), 6.87 (d, 2H, J = 6 Hz), 5.27 (dd, 1H, J = 9 Hz, J = 3Hz),
2.15 (s, 3H), 1.76 (s, 3H). 13C NMR (300 MHz, CDCl3) d: 197.53,
168.51, 138.40, 133.85, 133.10, 132.48, 130.24, 129.09, 127.90, 127.52,
126.41, 125.69, 125.25, 124.89, 122.90, 53.32, 20.90.
Generally speaking, aldehydes bearing electron-withdrawing
groups reacted with acetophenone in higher yields than
benzaldehyde, while electron-rich aldehydes were less
reactive; however, the opposite trend was observed for the
enantioselectivity.
Indeed, while the diastereoselectivity seems not to be
influenced by electronic characteristics of the substrates,
enantioselectivities ranging from 80–91% were obtained
Chirality DOI 10.1002/chir
HRMS Mass (ESI+): m/z = calc for C28H28O5Na+ = 467.18, found
467.18 [M + Na].The e.e. was determined by chiral HPLC with a

GENONI ET AL.
O
HO Ph
Ph Ph
HO Ph
Ph Ph
OH
O
(S)-BITIOPO (0.1 eq)
SiCl4 (1.5 eq), DIPEA
+
H
+
O
OH
O
1
2
Ac2O / Py
AcO Ph
Ph Ph
AcO Ph
Ph Ph
OAc
+
O
OAc
O
3a
3b
S
O
PPh2
(S) - Tetra-Me-BITIOPO
PPh2
O
S
Scheme 1. Double aldol reaction between benzaldehyde and acetophenone.
1) (S)-BITIOPO (0.1 eq)
O
AcO Ar
Ph
AcO Ar
Ph
O
SiCl4, DIPEA
+
Ar
Ar
Ar
H
+
2) Ac2O
O
OAc
O
OAc
Scheme 2. Double aldol reaction between acetophenone and different aromatic aldehydes.
1) (S)-BITIOPO (0.1 eq)
SiCl4, DIPEA
O
AcO
O
AcO
O
Ar
Ar
O
+
+
Ar
OAc
Ar
OAc
Ar
H
2) Ac2O
R
R
R
Scheme 3. Double aldol reaction between differently substituted aryl methyl ketones and different aromatic aldehydes.
TABLE 3. Tetra-Me-BITIOPO-catalyzed condensation of aryl methyl ketones with differently substituted aldehydes
Entry
Ar
R
Yield (%)a
Diast. ratiob
e.e major isomer(%)c
1
2
3
4
5
6
7
8
Ph
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
45
71
51
70
71
45
30
35
25
40
35
85/15
85/15
86/14
95/5
84/16
77/23
70/30
88/12
55/45
83/17
61/39
43
25
27
15
11
51
83
55
80
90
90
4-CF3Ph
4-OMePh
3,4-di-OMePh
2-furyl
2-thienyl
Ph
4-CF3Ph
4-OMePh
2-furyl
9
10
11
2-thienyl
aReactions were run with 3 mol equiv. of SiCl4, 1 mol equiv of ketone,2.2 mol equiv of aldehyde and 10 mol % amount of catalyst for 20 h at -40ꢀC; yields were deter-
mined after chromatographic purification on the diacetate derivative;
bdiastereoisomeric ratio was determined by 1H-NMR;
ce.e. was determined by HPLC on chiral column (see Supporting Information).
Chirality DOI 10.1002/chir

ORGANOCATALYTIC DIRECT DOUBLE ALDOL REACTION
for the reaction of 4-tolualdehyde, 4-anisaldehyde, and
LITERATURE CITED
2-thiophene caboxyaldehyde.
1. Reviews: Denmark SE, Beutner GL. Lewis base catalysis in organic syn-
4-Chloro benzaldehyde afforded the 1,3-diacetate in good
yield and enantioselectivity comparable to that observed with
benzaldehyde; reaction with 4-trifluoromethyl benzaldehyde
gave the product even in 41% e.e., while the analogous
4-nitro derivative was isolated with 26% e.e. only (entries 2
and 4), probably due to the interference in the reaction mech-
anism of the nitro group, able to coordinate tetrachlorosilane.
The behavior of electronically different aryl methyl ketones
was then studied (Scheme 3); 4-methoxyphenyl methyl
ketone was reacted with two equivalents of different aromatic
aldehydes (entries 1–6 of Table 3).
The reaction generally afforded the double aldol reac-
tion products in good yields, with aldehydes functional-
ized both with electron-withdrawing or electron-donating
groups; diastereoselectivities vary from 77/23 up to 95/
5. Unfortunately, the reaction with the aryl ketone
substituted with the electron-donating group as the
methoxy group afforded the products generally with
lower enantioselectivities than those with acetophenone.
With benzaldehyde and 2-thiophencarboxyaldehyde, e.e.
up to 43% and 51%, respectively, for the major isomer
were obtained.
thesis. Angew Chem Int Ed 2008;47:1560–638.
2. Benaglia M, Guizzetti S, Pignataro L. Steroselective reactions involving
hypervalent silicate complexes. Coord Chem Rev 2008;252:492–512.
3. Benaglia M, Guizzetti S, Rossi S. Silicate-mediated stereoselective reac-
tions catalyzed by chiral Lewis bases. In: Catalytic methods in asymmetric
synthesis. Hoboken, NJ: John Wiley & Sons; 2011. p 579–624.
4. Denmark SE, Stavenger RA. Asymmetric catalysis of aldol reactions with
chiral Lewis bases. Acc Chem Res 2000;33:432–440.
5. For more recent contributions see ref. 3 and Denmark SE, Eklov BM,
Yao PJ, Eastgate MD. On the mechanism of Lewis base catalyzed
aldol addition reactions: kinetic and spectroscopic investigations using
rapid-injection NMR. J Am Chem Soc 2009;131:11770–11787 and refer-
ences cited.
6. See also: Massa A, Roscigno A, De Caprariis P, Filosa R, Di Mola A.
Trimethylchlorosilane and silicon tetrachloride in two novel methodolo-
gies for the efficient and mild aldol addition of b-keto esters and malonates
to aldehydes. Adv Synth Catal 2010;352:3348–3354 and references cited.
7. Rossi S, Benaglia M. Chiral phosphine oxides in present-day
organocatalysis. Org Biomol Chem 2010;8:3824–3830.
8. Kotani S, Hashimoto S, Nakajima M. Chiral phosphine oxide BINAPO as
a Lewis base catalyst for asymmetric allylation and aldol reaction of
trichlorosilyl compounds. Tetrahedron 2007;63:3122–3132.
9. Sugiura M, Sato N, Kotani S, Nakajima M. Lewis base-catalyzed conjugate
reduction and reductive aldol reaction of a,b-unsaturated ketones using
trichlorosilane. Chem Commun 2008;0:4309–4311.
On the other hand, as expected, 4-nitrophenyl methyl ketone
was shown to be less reactive than acetophenone and did not af-
ford the desired product in appreciable yields with the poorly
reactive electronrich aldehydes; however, the reaction with p-
anisaldehyde led to the formation of the desired product in
80% e.e., although in low yields and diastereoselectivity. It must
be mentioned that the heteroaromatic substrates like 2-furyl
carboxyaldehyde and 2-thienyl carboxyaldehyde also reacted
and afforded the corresponding 1,3-diacetate, in modest yields
but with 90% of enantioselectivity.
10. Sugiura M, Kumahara M, Nakajima M. Asymmetric synthesis of 4H-1,3-
oxazines: enantioselective reductive cyclization of N-acylated b-amino
enones with trichlorosilane catalyzed by chiral Lewis bases. Chem
Commun 2009;0:3585–3587.
11. Kotani S, Shimoda Y, Sugiura M, Nakajima M. Novel enantioselective di-
rect aldol-type reaction promoted by a chiral phosphine oxide as an
organocatalyst. Tetrahedron Lett 2009;50:4602–4605.
12. Sugiura M, Sato N, Sonoda Y, Kotani S, Nakajima M. Diastereo- and
enantioselective reductive aldol reaction with trichlorosilane using chiral
Lewis bases as organocatalysts. Chem Asian J 2010;5:478–481.
13. Osakama K, Sugiura M, Nakajima, M, Kotani S. Enantioselective reduc-
tive aldol reaction using tertiary amine as hydride donor. Tetrahedron
Lett 2012;53:4199–4201.
CONCLUSIONS
14. Aoki S, Kotani S, Sugiura M, Nakajima M. Trichlorosilyl triflate-mediated
enantioselective directed cross-aldol reaction between ketones using a
chiral phosphine oxide as an organocatalyst. Chem Commun
2012;48:5524–5526.
15. Rossi S, Benaglia M, Cozzi F, Genoni A, Benincori T. Organocatalytic
stereoselective direct aldol reaction of trifluoroethyl thioesters. Adv Synth
Catal 2011;353:848–854.
16. Rossi S, Benaglia M, Genoni A, Benincori T, Celentano G. Biheteroaromatic
diphosphine oxides-catalyzed stereoselective direct aldol reactions. Tetrahe-
dron 2011;67:158–166.
17. Bonsignore M, Benaglia M, Cozzi F, Genoni A, Rossi S, Raimondi L. Read-
ily available (S)-proline-derived organocatalysts for the Lewis acid-
mediated Lewis base-catalyzed stereoselective aldol reactions of activated
thioesters. Tetrahedron 2012;68:8251–8255.
In conclusion, the double aldol reaction of aryl methyl ke-
tones with aromatic aldehydes was studied in the presence
of catalytic amounts of diheteroromatic diphosphine oxide
as chiral Lewis base; the reaction products were isolated as
1,3-diacetate derivatives in yields depending on the electronic
characteristics of the reactive substrates: from the chemical
activity point of view the best results were obtained by
employing an electron-rich aryl methyl ketone and electron-
poor aromatic aldehydes.
However, while the diastereoisomeric ratio seems to be quite
independent from the substrate variation, ranging typically
from 70/30 to 90/10, the highest enantioselectivities were ob-
served in the reaction with aldehydes bearing electron-
donating groups and heteroaromatic aldehydes: in those cases,
e.e. up to 91% was obtained, showing that (S)-TetraMe-
BITIOPO favorably compares with the BINAPO-derived ligand,
leading with different substrates to the products in higher
enantioselectivities. Further studies are needed in order to bet-
ter address the diastereoselectivity of the process and the
chemical activation of the less-reactive substrates.
18. Shimoda Y, Kotani S, Sugiura M, Nakajima M. Enantioselective double al-
dol reaction catalyzed by chiral phosphine oxide. Chem Eur
J
2011;17:7992–7995.
19. For recent review on direct aldol reactions see: Mukherjee S, Yang JW,
Hoffmann S, List B. Asymmetric enamine catalysis. Chem Rev
2007;107:5471–5569.
20. For a recent review on domino reactions see: Pellisier H. Recent develop-
ments in asymmetric organocatalytic domino reactions. Adv Synth Catal
2012;354:237–294.
21. See ref. 15–17 and Simonini V, Benaglia M, Benincori T. Novel chiral
biheteroaromatic diphosphine oxides for Lewis base activation of Lewis
acids in enantioselective allylation and epoxide opening. Adv Synth Catal
2008;350:561–564.
ACKNOWLEDGMENTS
This work was supported by: MIUR (project "Nuovi metodi
catalitici stereoselettivi e sintesi stereoselettiva di molecole
funzionali"). M.B. thanks the European COST Action
CM0905-Organocatalysis.
22. From NMR analysis of the crude reaction mixture only minor amounts
(<10%) of the mono-aldol product were typically detected.
23. See Supporting Information for detailed experimental procedures and
product characterization.
Chirality DOI 10.1002/chir