New enantiopure N-ferrocenylmethyl azetidin-2-yl(diphenyl)methanol and its application in catalytic asymmetric ethylation and arylation of arylaldehydes

Article abstract of DOI:10.1055/s-2006-956474

A novel, facile and practical approach to preparation of new enantiopure N-ferrocenylmethyl azetidin-2-yl(diphenyl)methanol has been developed. In the presence of a catalytic amount of the chiral N-ferrocenylmethyl azetidin-2-yl(diphenyl)methanol, the enantioselective ethylation and arylation of arylaldehydes afforded addition products with enantioselectivities of up to 98.4% ee and 95.7% ee, respectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956474

LETTER
3443
New Enantiopure N-Ferrocenylmethyl Azetidin-2-yl(diphenyl)methanol
and Its Application in Catalytic Asymmetric Ethylation and Arylation of
Arylaldehydes
Enantiopure
N
-Ferroce
i
nylmet
n
hyl
A
zetidin
-
-2-yl(dip
C
henyl)methanol an Wang,* Wen-Xian Zhao, Xiao-Dan Wang, Mao-Ping Song*
Department of Chemistry, Zhengzhou University, Zhengzhou, Henan 450052, P. R. of China
Fax +86(371)67769024; E-mail: wangmincan@zzu.edu.cn
Received 1 September 2006
easily prepared and effective chiral ligands is an important
challenge for the practical applications of arylation reac-
tions.
Abstract: A novel, facile and practical approach to preparation of
new enantiopure N-ferrocenylmethyl azetidin-2-yl(diphenyl)meth-
anol has been developed. In the presence of a catalytic amount of
the chiral N-ferrocenylmethyl azetidin-2-yl(diphenyl)methanol, the
enantioselective ethylation and arylation of arylaldehydes afforded
addition products with enantioselectivities of up to 98.4% ee and
95.7% ee, respectively.
More recently, we reported the synthesis of a series of
chiral ferrocenyl aziridino alcohols 117 and pyrrolidino al-
cohols 218 and their application in the catalytic asymmet-
ric addition of Et2Zn to aldehydes. Moreover, it was
discovered that the replacement of the phenyl group on
the nitrogen atom of heterocycle-based skeleton with a
ferrocenyl unit led to a dramatic improvement in the enan-
tioselectivity when used as the catalyst in the addition of
diethylzinc to benzaldehyde in the presence of five mol%
of chiral ligands (Figure 1). In order to examine the
generality of this finding, in this article, we present our
preliminary results on the synthesis of enantiopure N-
ferrocenylmethyl azetidin-2-yl(diphenyl)methanol (6)
and its application in catalytic asymmetric ethylation and
arylation of arylaldehydes.
Key words: asymmetric addition, diethylzinc, aryl boronic acids,
ethylation, arylation
Since the initial report of Oguni and Omi on the reaction
of diethylzinc with benzaldehyde in the presence of a cat-
alytic amount of (S)-leucinol producing an addition prod-
uct with moderate enantioselectivity (49% ee) in 1984,1
great progress has been made in the catalytic asymmetric
addition of organozinc reagents to aldehydes using chiral
amino alcohols as ligands, and products with excellent
enantiomeric excesses have been achieved with all types
of substrates.2 In addition, the reaction of diethylzinc with
aldehydes has also become a classical test in the design of
new ligands for catalytic enantioselective synthesis. Re-
cently, the enantioselective arylation of aldehydes has re-
ceived a special attention in the presence of catalytic
amounts of chiral ligands because the arylation products
of this reaction are chiral diarylmethanols,3–15 some of
which are key intermediates for the preparation of phar-
macologically and biologically important compounds.16
In this context, the asymmetric arylation of aldehydes
using aryl boronic acids as aryl resources,9–15 instead of
Ph2Zn or Ph2Zn–Et2Zn as aryl resources,4–8,10c becomes an
attractive method for the preparation of diarylmethanols
in high enantioselectivity. This new protocol allows the
easy preparation of several substituted arylzinc reagents
and therefore the synthesis of a wide range of substituted
chiral diarylmethanols. In addition, phenylboronic acids
offer a cheaper alternative to the expensive diphenyl zinc
and the background reaction generated by use of Ph2Zn
itself as aryl resource is avoided. Unfortunately, ligands
that effectively catalyze the asymmetric arylation of alde-
hydes using aryl boronic acids as aryl resource with high
ee values are relatively rare. So, the development of new,
Ph
Ph
Ph
Ph
Ph
Ph
N
HO
N
N
HO
HO
R
R
R
1
2
3
R = Ph, Fc
Figure 1
The preparation of azetidino alcohol 6 is shown in
Scheme 1. The starting material 4 for the synthesis of
enantiopure compound 5 was prepared readily from
commercially available L-2-amino-4-bromobutanoic
acid. Treatment of L-2-amino-4-bromobutanoic acid with
methanol saturated with anhydrous hydrogen chloride
afforded methyl L-2-amino-4-bromobutanoate (4) in 89%
yields.
1) MeOH, Et3N,
CO2Me
Br
N
FcCHO
Fe
+NH3Cl–
2) NaBH4
67%
MeO2C
4
5
N
PhMgBr
97%
Fe
Ph
Ph
HO
SYNLETT 2006, No. 20, pp 3443–3446
1
8
.1
2
.2
0
0
6
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956474; Art ID: W18206ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of 6

3444
M.-C. Wang et al.
LETTER
Construction of the four-membered ring heterocycle from whether or not the designed chiral ligands induce high
acyclic compound is a key step in this synthesis. Ferro- enantioselectivities. With the new chiral ligand 6 in hand,
cenecarboxaldehyde was first condensed with the we first examined the enantioselective addition of di-
compound 4 in methanol in the presence of triethylamine, ethylzinc to benzaldehyde in the presence of 3 mol% of
and then reduced by sodium borohydride. Incidentally, the chiral ligands 6 in toluene at 0 °C to room temperature
the cyclization reaction also took place during the conden- (Equation 1).20 The reactions using 6 as catalyst afforded
sation reaction to give the desired methyl (S)-N-ferro- 1-phenylpropanol (S configuration) in excellent yield
cenylmethyl azetidine-2-carboxylate (5). The reaction of (97%) with outstanding enantiomeric excess (98.4% ee).
5 with excess phenylmagnesium bromide furnished the
Recently, Zwanenburg et al. reported a similar type of
chiral ligand 3 (R = Ph) for the addition of diethylzinc to
corresponding b-amino alcohol ligand 6 (97%).19
As described above, the reaction of diethylzinc with benz- benzaldehyde with good enantioselectivities (88% ee) in
aldehyde has become a typical reaction to examine the presence of 20% mol of 3.21 A comparison of our re-
sults (98.4% ee, 3% mol 6) with those (88% ee, 20% mol
O
OH
3) of Zwanenburg et al. demonstrated that the replacement
of the phenyl group on the nitrogen atom of azetidine-
based skeleton with a ferrocenyl unit led to a remarkable
improvement in the enantioselectivity when used as the
catalyst in the addition of diethylzinc to benzaldehyde.
These results also suggested that the steric hindrance pro-
Et2Zn, 6 (3 mol%)
Ph
Ph
H
toluene, 0–5 °C, r.t., 48 h
yield: 97%
ee: 98.4%
Scheme 2 Asymmetric ethylation of benzaldehyde
Table 1 Asymmetric Arylation of Arylaldehydes Catalyzed by 6a
O
OH
Ar'B(OH)2, Et2Zn, 6
*
Ar
H
toluene
Ar
Ar'
Ar¢
Ph
Entry
1
Ar
6 (mol%)
10
Temp (°C)
0
Yield (%)b
96
ee (%)c
89.0
92.0
88.5
84.0
92.1
83.9
87.1
83.3
93.9
83.4
90.0
83.1
85.7
91.1
88.2
95.5
95.7
70.0
Config.d
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
m-PhOC6H4
o-ClC6H4
m-ClC6H4
p-ClC6H4
m-BrC6H4
o-CF3C6H4
3,4-OCH2OC6H3
Ferrocenyl
Ph
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
R
2
Ph
10
–20
–40
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
95
3
Ph
10
71
4
Ph
5
88
5
Ph
15
96
6
Ph
10
86
7
Ph
10
99
8
Ph
10
95
9
Ph
10
94
10
11
12
13
14
15
16
17
18
Ph
10
94
Ph
10
98
Ph
10
80
Ph
10
97
Ph
10
92
Ph
10
99
Ph
10
84
o-MeC6H4
Naph
10
88
Ph
10
79
a The molar ratio of Ar¢B(OH)2–Et2Zn–aldehyde was1:3:1.
b Isolated yields.
c Determined by HPLC using a chiral column: Chiralcel OD, Chiralcel OB or Chiralpak AD.
d Absolute configuration was assigned by comparison with the known elution order from a Chiralcel OD, OB and AD columns according to the
literature.10–14
Synlett 2006, No. 20, 3443–3446 © Thieme Stuttgart · New York

LETTER
Enantiopure N-Ferrocenylmethyl Azetidin-2-yl(diphenyl)methanol
3445
vided by the ferrocenyl group, compared to a phenyl 95.7% ee, respectively, in the presence of a catalytic
group, played an important role in the enantioselectivities. amount of the new chiral ligand 6. Further applications of
The outstanding enantioselectivity of the new chiral chiral compound 6 for asymmetric synthesis are under in-
ligand 6, as compared with 3 (R = Ph), gave further sup- vestigation in our laboratory.
port to the generality of the advantage of the replacement
of the phenyl group on the nitrogen atom of heterocycle-
based skeleton with a ferrocenyl unit.
Acknowledgment
We are grateful to the National Natural Sciences Foundation of Chi-
na (NNSFC: 20672102), the Ministry of Education of China, and
Henan Innovation Project for University Prominent Research Ta-
lents for the financial supports.
This exciting result encouraged us to examine the effi-
ciency of the asymmetric arylation of arylaldehyde in the
presence of the chiral ligand 6 using aryl boronic acids as
aryl resources.22 The results are summarized in Table 1.
The asymmetric phenylation of 4-tolualdehyde was tested
(Table 1, entries 1–5). The phenylzinc reagent was pre-
pared in situ by heating a mixture of diethylzinc and
phenylboronic acid in hexanes to 60 °C for 12 hours. We
first investigated the effect of reaction temperature on the
enantioselectivity in the presence of ten mol% of the
chiral ligand 6. Decreasing the reaction temperature from
0 °C to –20 °C led to an increase in the enantioselectivity
from 89.0% to 92.0% (Table 1, entries 1 and 2). We at-
tempted to further decrease the reaction temperature in or-
der to have a better enantioselectivity, but a substantial
decrease in both the yield and the enantioselectivity was
observed when the reaction was performed at –40 °C
(Table 1, entry 3). We then examined the effects of the
chiral ligand loading on the enantioselectivity. Lowering
the ligand amount from 10% to 5% led to a decrease in
both the yield and the enantioselectivity at –20 °C
(Table 1, entries 4 vs. 1). Increasing the ligand loading
from 10% to 15% did not result in the improvement of
yield and enantioselectivity (Table 1, entries 2 and 5).
References and Notes
(1) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
(2) For reviews on enantioselective organozinc additions to
aldehydes, see: (a) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49. (b) Soai, K.; Niwa, S. Chem.
Rev. 1992, 92, 833. (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001,
101, 757.
(3) For reviews on asymmetric arylation reactions, see:
(a) Bolm, C.; Hildebrand, J. P.; Muñiz, K.; Hermanns, N.
Angew. Chem. Int. Ed. 2001, 40, 3284. (b) Noyori, R.;
Ohkurna, T. Angew. Chem. Int. Ed. 2001, 40, 40. (c)Corey,
E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986.
(4) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62,
444.
(5) (a) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222.
(b) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64,
7940. (c) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41,
145.
(6) Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4, 3759.
(7) (a) Bolm, C.; Muniz, K. Chem. Commun. 1999, 1295.
(b) Bolm, C.; Kessilgraber, M.; Hermanns, N.; Hildebrand,
J. P.; Raabe, G. Angew. Chem. Int. Ed. 2001, 40, 1488.
(c) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muniz, K.
Angew. Chem. Int. Ed. 2000, 39, 3465. (d) Hermanns, N.;
Dahmen, S.; Bolm, C.; Brase, S. Angew. Chem. Int. Ed.
2002, 41, 3692. (e) Rudolph, J.; Bolm, C.; Norrby, P.-O. J.
Am. Chem. Soc. 2005, 127, 1548.
These reaction conditions were tested on other arylalde-
hydes in the presence of the ligand 6 (Table 1, entries 6–
16). As can be seen from Table 1, good to excellent enan-
tioselectivities could be achieved for various aromatic al-
dehydes containing ortho-, para- and meta-substituents
on the benzene ring. The presence of electron-donating or
electron-withdrawing substituents on the aromatic ring
also furnished the corresponding products in good to out-
standing levels of enantioselectivity. The best asymmetric
induction (with as high as 95.5% ee) was found by using
a ferrocenyl aldehyde as the substrate (Table 1, entry 16).
(8) Fontes, M.; Verdaguer, X.; Solá, L.; Pericás, M. A.; Riera,
A. J. Org. Chem. 2004, 69, 2532.
(9) (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124,
14850. (b) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org.
Chem. 2004, 69, 3997. (c) Rudolph, J.; Schmidt, F.; Bolm,
C. Synthesis 2005, 840. (d) Ozcubukcu, S.; Schmidt, F.;
Bolm, C. Org. Lett. 2005, 7, 1407. (e) Park, J. K.; Lee, H.
G.; Bolm, C.; Kim, B. M. Chem. Eur. J. 2005, 11, 945.
(f) Rudolph, J.; Loumann, M.; Bolm, C.; Dahmen, S. Adv.
Synth. Catal. 2005, 347, 1361.
(10) (a) Wu, X.; Liu, X.; Zhao, G. Tetrahedron: Asymmetry 2005,
16, 2299. (b) Liu, X.; Wu, X.; Chai, Z.; Wu, Y.; Zhao, G.;
Zhu, S. J. Org. Chem. 2005, 70, 7432. (c) Zhao, G.; Li, X.-
G.; Wang, X.-R. Tetrahedron: Asymmetry 2001, 12, 399.
(11) Ji, J.-X.; Wu, J.; Au-Yeung, T. T.-L.; Yip, C.-W.; Haynes, R.
K.; Chan, A. S. C. J. Org. Chem. 2005, 70, 1093.
(12) (a) Braga, A. L.; Lüdtke, D. S.; Vargas, F.; Paixão, M. W.
Chem. Commun. 2005, 2512. (b) Braga, A. L.; Lüdtke, D.
S.; Schneider, P. H.; Vargas, F.; Schneider, A.; Wessjohann,
L. A.; Paixão, M. W. Tetrahedron Lett. 2005, 46, 7827.
(13) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71,
833.
In order to examine if different aryl groups could be trans-
ferred to aldehydes with the same levels of enantioselec-
tivity, the aryl transfer reaction of some substituted
phenylboronic acids with benzaldehyde was investigated
(Table 1, entries 17 and 18). Excellent enantioselectivity
of up to 95.7% ee was obtained when ortho-methyl
phenylboronic acid was used as the aryl transfer reagent.
In conclusion, we have developed a novel, facile and prac-
tical approach to asymmetric preparation of new enan-
tiopure N-ferrocenylmethyl azetidin-2-ylmethanol. In the
key cyclization step, a three-step, one-pot protocol for the
construction of the chiral azetidine ring was developed.
The enantioselective ethylation and arylation of arylalde-
hyde gave the enantioselectivity of up to 98.4% ee and
(14) Dahmen, S.; Lormann, M. Org. Lett. 2005, 7, 4597.
(15) Ito, K.; Tomita, Y.; Katsuki, T. Tetrahedron Lett. 2005, 46,
6083.
Synlett 2006, No. 20, 3443–3446 © Thieme Stuttgart · New York

3446
M.-C. Wang et al.
LETTER
(16) For selected active pharmaceutical ingredients, see:
(a) Meguro, K.; Aizawa, M.; Sohda, T.; Kawarnatsu, Y.;
Nagaoka, A. Chem. Pharm. Bull. 1985, 33, 3787. (b) Toda,
F.; Tanaka, K.; Roshiro, K. Tetrahedron: Asymmetry 1991,
2, 873. (c) Stanchev, S.; Rakovska, R.; Berova, N.; Snatzke,
G. Tetrahedron: Asymmetry 1995, 6, 138. (d) Casy, A. F.;
Drake, A. F.; Ganellin, C. R.; Merce, A. D.; Upton, C.
Chirality 1992, 4, 356. (e) Torrens, A.; Castrillo, J. A.;
Claparols, A.; Redondo, J. Synlett 1999, 765.
(17) (a) Wang, M.-C.; Hou, X.-H.; Xu, C.-L.; Liu, L.-T.; Li, G.-
L.; Wang, D.-K. Synthesis 2005, 3620. (b) Wang, M.-C.;
Wang, D.-K.; Zhu, Y.; Liu, L.-T.; Guo, Y.-F. Tetrahedron:
Asymmetry 2004, 15, 1289. (c) Wang, M.-C.; Liu, L.-T.;
Zhang, J.-S.; Shi, Y.-Y.; Wang, D.-K. Tetrahedron:
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was added to the mixture. The resulting mixture was stirred
for 10 h at 0–5 °C and was allowed to warm to the r.t., and
stirring was continued for another 38 h at the same
temperature. The reaction was quenched by the addition of
sat. aq NH4Cl (4 mL). The mixture was extracted with Et2O
(3 × 8 mL). The combined organic layers were washed with
brine, dried over anhyd Na2SO4 and evaporated under
reduced pressure. Purification of the residue by the
preparative silica gel TLC plate (hexane–EtOAc = 4:1)
afforded the (S)-1-phenyl-1-propanol. The ee was
determined by HPLC analyses using a chiral column (a
Chiralcel OD); hexane–i-PrOH = 100:2, flow rate: 0.6 mL/
min, tR(R) = 19.6 min, tR(S) = 23.8 min.
(21) Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.; Zwanenburg, B.
Tetrahedron Lett. 2001, 42, 4243.
(22) Asymmetric Arylation of Arylaldehydes Catalyzed by 6;
General Procedure: A dried Schlenk tube containing
toluene (2 mL), aryl boronic acid (122 mg, 1 mmol), and
diethylzinc (3 mmol, 1.0 M solution in hexanes) was heated
at 60 °C for 12 h. After the mixture was cooled to r.t., the
chiral amino alcohol ligand 6 (43.7 mg, 0.1 mmol) was
added. The mixture was stirred for another 15 min. It was
cooled to –20 °C, and the aldehyde (1 mmol) was
(18) Xu, C.-L.; Wang, M.-C.; Hou, X.-H.; Liu, H.-M.; Wang, D.-
K. Chin. J. Chem. 2005, 23, 1443.
(19) Compound 6: mp 122.7–123.9 °C; [a]D20 –27.2 (c = 0.32,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.87–2.09 (m, 1
H), 1.92–2.03 (m, 1 H), 2.81, 2.87 (dd, J = 13.2 Hz, 2 H),
2.89–2.93 (m, 1 H), 3.18 (t, J = 6.0 Hz, 1 H), 3.83–4.05 (m,
9 H), 4.27 (t, J = 7.2 Hz, 1 H), 5.20 (s, 1 H), 7.18–7.61 (m,
10 H). MS (ESI): m/z [M + H]+ calcd for C27H27FeNO: 438;
found: 438.
subsequently added under nitrogen atmosphere. After 48 h at
–20 °C, the reaction was quenched by the addition of sat. aq
NH4Cl (8 mL). The mixture was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were washed with
brine, dried over anhyd Na2SO4 and evaporated under
reduced pressure. Purification of the residue by the
preparative silica gel TLC plate (hexane–EtOAc) afforded
the pure diarylmethanol. The ee was determined by HPLC
analyses using a chiral column: Chiralcel OB, Chiralcel OD
or Chiralpak AD.
(20) Enantioselective Addition of Diethylzinc to
Benzaldehyde: A solution of diethylzinc (1 M in n-hexane,
1.1 mL) was added to a solution of a chiral catalyst 6 (0.015
mmol, 3 mol%) in anhyd toluene under a nitrogen
atmosphere. The mixture was cooled to 0 °C, and stirred for
30 min. Freshly distilled benzaldehyde (0.05 mL, 0.5 mmol)
Synlett 2006, No. 20, 3443–3446 © Thieme Stuttgart · New York