Enantioselective addition of dialkylzinc to aromatic aldimines mediated by camphor-derived chiral β-amino alcohols

Article abstract of DOI:10.1002/asia.201403240

The enantioselective addition of diethylzinc or dimethylzinc to N-(diphenylphosphinoyl)imines mediated by 1 or 2 could be achieved in high yields (70-97%) and enantioselectivities (85-98% ee). The catalytic loading of 1 or 2a could be reduced to 10 mol% f

Full text of DOI:10.1002/asia.201403240

DOI: 10.1002/asia.201403240
Full Paper
Enantioselective Synthesis
Enantioselective Addition of Dialkylzinc to Aromatic Aldimines
Mediated by Camphor-Derived Chiral b-Amino Alcohols
Wei-Ming Huang and Biing-Jiun Uang*[a]
Abstract: The enantioselective addition of diethylzinc or di-
methylzinc to N-(diphenylphosphinoyl)imines mediated by
1 or 2 could be achieved in high yields (70–97%) and enan-
tioselectivities (85–98% ee). The catalytic loading of 1 or 2a
could be reduced to 10 mol% for methylation or ethylation
of imines in high yields and enantioselectivities (79–96%)
when the reaction was conducted in the presence of
1.8 equiv of methanol. N-Monosubstituted amino alcohols
induced higher enantioselectivity than their N,N-disubstitut-
ed congener in our catalytic system.
Introduction
Chiral amines are widely used in the synthesis of natural prod-
ucts, physiologically active substances, and pharmaceuticals.
They are also used as chiral auxiliaries in asymmetric synthe-
sis.[1] Recently, many N,O-ligands have been developed to cata-
lyze the enantioselective addition of dialkylzinc to imines with
high enantioselectivity.[2–10] Representative ligands include 2-
azanorbornylmethanol,[2] 9-fluorenone derivatives,[3] 1,2-di-
phenyl-2-aminoethanols,[4] chiral oxazoline,[5] cinchonine and
cinchonidine,[6] norephedrine,[7] and prolinol derivatives.[8] Al-
though additions to imines that are derived from aromatic al-
dehydes have been extensively studied, excess dialkylzinc re-
agent and a stoichiometric amount of chiral ligand are normal-
ly required to ensure high conversion and enantioselectivity
due to the poor electrophilic character of imines. Therefore,
the development of a more easily accessible and economical
enantioselective catalytic system is still worthwhile.
Figure 1. Chiral b-amino alcohols 1 and 2a–i.
Results and Discussion
At the outset, imine 3a[12] was dissolved in toluene, due to the
poor solubility of 3a in hexanes, and reacted with diethylzinc
(5 equiv, 1.0m in hexanes) in the absence of 1 at 288C for 48 h.
It was found that a 1:1 mixture of addition product 4a and re-
duction product 4a’ was present after work-up of the reaction
mixture (Table 1, entry 1). To our delight, no reduction product
4a’ was detected when the reaction was conducted in the
presence of 0.5 equiv of 1 for 48 h and it gave addition prod-
uct 4a in 82% yield with 91% ee (Table 1, entry 2). We then
turned to examine the enantioselective addition of diethylzinc
to imine 3a at different loadings of 1 (0.4 and 0.6 equiv) and
at different reaction temperatures in the co-solvent system
(toluene/hexanes). The enantioselectivity decreased to 85%
when 0.4 equiv of 1 was used (Table 1, entry 3). However, the
enantioselectivity was improved to 93% if the amount of
1 was increased to 0.6 equiv (Table 1, entry 4). High enantiose-
lectivity was maintained while the amount of organozinc was
decreased from 5 equivalents to 4 or 3 equivalents (Table 1, en-
tries 5–6). When the reaction was conducted at 08C or À108C,
there was no substantial improvement concerning the enantio-
selectivity, and the reaction took a longer time to give a reason-
able yield (Table 1, entries 7–8). A slight decrease in enantiose-
lectivity was observed when the reaction was carried out at
508C (Table 1, entry 9). Therefore, the condition in entry 6 was
selected for the study of substrate scope and limitations.
We previously reported that (+)-(1S,2R)-1-morpholinoisonor-
borneol (Figure 1) is an effective catalyst to catalyze the asym-
metric addition of diethylzinc to aldehydes with high enantio-
selectivities.[11] Herein, we report our findings on the use of
1 and N-monosubstituted amino alcohols (2a–i) (Figure 1) as
efficient promoters for the enantioselective addition of dialkyl-
zinc to N-(diphenylphosphinoyl)imines.
[a] W.-M. Huang, Prof. B.-J. Uang
Department of Chemistry
National Tsing Hua University
Hsinchu 300 (Taiwan)
Fax: (+886)3-571-1082
E-mail: bjuang@mx.nthu.edu.tw
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403240.
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Table 1. The addition of diethylzinc to 3a mediated by b-amino alcohol
1.
Table 3. Enantioselective addition of dimethylzinc to imines mediated by
.
1[a]
Entry 1 [equiv] Et2Zn [equiv][a] T [oC] t [h] Yield [%][c] ee [%][d]
Entry]
Imine 3 (Ar)
1 [equiv]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
–
5
5
5
5
4
3
3
3
3
28
28
28
28
28
28
0
48
48
82
48
48
42
48
44 (43)[e]
82
82
87
90
93
91
-
1
3a (Ph)
3a (Ph)
3a (Ph)
3d (4-Me-Ph)
3g (4-MeO-Ph)
3k (4-MeO2C-Ph)
0
0.6
1
1
1
48
168
24
24
24
24
-
-
0.5
0.4
0.6
0.6
0.6
0.6
0.6
0.6
91
85
93
93
92
93
93
90
2[d]
3
70
86
85
86
86
96
97
97
98
97
4
5
6
1
[a] The reaction was conducted by using Me2Zn (10 Wt% Me2Zn in hex-
anes, 5 equiv) with imine (0.065m) in toluene/hexanes (1.4:1). [b] Isolated
yield. [c] Determined by HPLC using a Chiralcel OD-H column, and the ab-
solute configuration of the major isomer was assigned to be (R) by the
comparison of the optical rotation and the retention time with literature
data;[2–10] Product 5k was tentatively assigned to be (R) by the retention
times of the enantiomers on HPLC analysis according the observations
with products 5d and 5g. [d] Me2Zn (10 wt% in hexanes, 3 equiv) were
used.
À10
50
139 88
94
5
[a] 1.0m Et2Zn in hexanes. [b] tol=toluene, hex=hexanes; [imine]=con-
centration of imine. [c] Isolated yield. [d] Determined by HPLC using
a Chiralcel OD-H column, and the absolute configuration of the major
isomer was assigned to be (R) by the comparison of the optical rotation
and the retention time with literature data.[2–10] [e] Yield of the corre-
sponding reduction product is given in parenthesis.
It had been reported previously that dimethylzinc is much
less reactive than diethylzinc.[2a,8a,13] The addition reaction of di-
methylzinc to imine 3a gave neither the addition product nor
the reduction product in the absence of 1 (Table 3, entry 1).
The methylation of 3a with dimethylzinc (3 equiv) in the pres-
ence of 1 (0.6 equiv) gave 5a in 70% yield and 96% ee at
288C (Table 3, entry 2). To improve the yield of 5a, methylation
of 3a by using 5 equivalents of dimethylzinc and a stoichiomet-
ric amount of 1 was conducted and gave 5a in 86% yield and
97% ee (Table 3, entry 3). Other imines (3d, 3g, 3k) were also
examined. The corresponding addition products were obtained
with excellent enantioselectivities (97–98% ee) and high yields
(85–86%) (Table 3, entries 4–6).
Table 2. Enantioselective addition of diethylzinc to N-(diphenyphosphi-
noyl)imines promoted by 1[a]
.
Entry
Ar
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
2-Tol
3-Tol
4-Tol
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
4-MeO2C-Ph
42
51
51
51
25
25
25
25
30
25
25
93 (4a)
90 (4b)
93 (4c)
95 (4d)
97 (4e)
87 (4 f)
88 (4g)
92 (4h)
84 (4i)
92
89
93
93
92
93
98
85
87
90
87
It had been reported that N-monosubstituted amino alco-
hols exhibited slightly higher enantioselectivities than their
N,N-disubstituted congener.[4b,c] Although 1 was successfully
employed for the addition of dialkylzinc to imines with high
enantioselectivity, we surveyed the N-monosubstituted amino
alcohols 2a–i for the feasibility of promoting the enantioselec-
tive addition reaction.
9
10
11
92 (4j)
97 (4k)
[a] The reaction was conducted by using Et2Zn (3 equiv) with imine
(0.085m) in toluene/hexanes (3:1). [b] Isolated yield. [c] Determined by
HPLC using a Chiralcel OD-H or AS-H column, and the absolute configura-
tion of the major isomer was assigned to be (R) by the comparison of the
optical rotation and the retention time with literature data;[2–10] Products
4 f and 4k were tentatively assigned to be (R) by the retention times of
the enantiomers on HPLC analysis according the observations with prod-
ucts 4c and 4d.
N-monosubstituted amino alcohols 2a–i were prepared ac-
cording the synthetic route of scheme 1. The reduction of
chiral amino ketone 6[11] with NaBH4 in the presence of
CeCl3·7H2O afforded the exo-aminoalcohol 7 exclusively. Subse-
quently, exo-amino alcohol 7 was converted into 2a–i in mod-
erate to good yields by reductive amination with the corre-
sponding aldehyde in the presence of NaBH(OAc)3.
With the optimal reaction conditions in hand, we explored
the scope and limitations of the reaction with other imines.[12]
The results are summarized in Table 2. In the presence of 1,
imines 3a–k gave the corresponding addition products in high
enantioselectivities (85–98%) and yields (84–97%), regardless
the electronic nature of the substituent on the aromatic ring.
The enantioselective addition of diethylzinc to imine mediat-
ed by N-monosubstituted amino alcohols 2 were investigated
by using conditions reported in Table 2, and the results are
summarized in Table 4. It was found that N-monosubstituted
amino alcohols 2 were also good ligands for the enantioselec-
tive addition of diethylzinc to imine 3a and gave good yields
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Table 5. The effects of additives on the addition of diethylzinc to 3a
mediated by 2a.
Entry 2a [equiv] Et2Zn [equiv] Additive [equiv] t [h] Yield [%][a] ee [%][b]
1
2
3
4
5[c]
6
7
8
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.05
0.2
0.2
0.2
3
3
3
3
3
3
3
3
4
5
5
5
5
5
5
5
5
5
5
5
–
68.5 86
43 76
48 97
48 86
43 29
24 87
24 91
24 81
24 90
24 89
24 90
24 90
24 88
24 86
24 84
48 82
24 86
24 95
48 54
24 76 (7)[e]
71
70
70
73
85
77
83
88
87
88
92
93
93
91
86
86
86
73
81
86
TIPSCl (1.0)
B(OMe)3 (0.3)
B(OMe)3 (0.9)
TIPSCl (1.0)
MeOH (0.4)
MeOH (0.7)
MeOH (1.1)
MeOH (1.1)
MeOH (1.1)
MeOH (1.5)
MeOH (1.8)
MeOH (2.2)
MeOH (1.8)
MeOH (1.5)
MeOH (1.8)
EtOH (1.8)
iPrOH (1.7)
H2O (0.8)
Scheme 1. The preparation of N-monosubstituted amino alcohols 2a–i.
Table 4. Diethylzinc addition to N-(diphenylphosphinoyl)imine 3a in the
presence of chiral amino alcohols 2[a]
.
9
10
11
12
13
14
15
16
17
18
19
Entry
Ligand
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2 f
2g
2h
2i
24
48
48
25
48
48
48
45.5
45.5
91
94
99
87
91
94
93
94
92
93
91
94
95
95
93
92
92
91
20[d] 0.1
MeOH (1.8)
[a] Isolated yield. [b] Determined by HPLC using Chiralcel OD-H column,
and the absolute configuration of the major isomer was assigned to be
(R) by the comparison of the optical rotation and the retention time with
literature data.[2–10] [c] The reaction was performed at À208C. [d] Using
1 as chiral ligand. [e] In bracket, yield of the corresponding reduction
product.
[a] The reaction was conducted by using Et2Zn (3 equiv) with imine
(0.085m) in toluene/hexanes (3:1). [b] Isolated yield. [c] Determined by
HPLC using a Chiralcel OD-H column, and the absolute configuration of
the major isomer was assigned to be (R) by the comparison of the optical
rotation and the retention time with literature data.[2–10]
(3 equiv) and imine 3a in the presence of 2a (20 mol%) at
288C was allowed to react for 68.5 h, and it gave the addition
product in 86% with 71% ee (Table 5, entry 1). Then, the reac-
tion was examined in the presence of a Lewis acid such as trii-
sopropylsilyl chloride (TIPSCl), trimethyl borate (B(OMe)3), or
methanol as an additive due to some beneficial effects on the
zinc system.[14] There was no substantial change on the enan-
tioselectivity when the addition reaction was conducted at
288C in the presence of TIPSCl or trimethyl borate (Table 5, en-
tries 2–4). When the reaction was conducted in the presence
of TIPSCl at À208C, the enantioselectivity increased to 85%,
but the yield dramatically decreased to 29% (Table 5, entry 5).
Contradictory results on using methanol as an achiral addi-
tive for the enantioselective addition of dialkylzinc to imines
have been reported. One group reported that there was no
effect on the enantioselectivity in the presence of 1 equiv of
methanol.[2c] However, another group reported that the enan-
tioselectivity improved significantly upon addition of 2 equiva-
lents of methanol to the addition reaction.[6b] The drawback of
the latter system is that a large excess of diethylzinc (12 equiv)
was used to ensure a moderate yield (70%). We examined the
effect of methanol in our system, and the results are summar-
ized in Table 5 as entries 6–16. The enantioselectivity was in-
creased to 88% when the amount of methanol was increased
with similar enantioselectivites. There is no substantial effect
on enantioselectivity and yield for the substituent on the
benzyl group of the ligands.
The addition of achiral additives and Lewis acid had been
found to have some effect on the enantioselectivity and chem-
ical yield of enantioselective addition reactions.[14] It was re-
ported that a bulky silylating agent could further activate the
imine substrate and enhance the reaction rate in a dual cata-
lytic system (amino alcohol and halosilane) for the asymmetric
addition of diethylzinc to imine 3a. However, a stoichiometric
amount of ligand was required to ensure high conversion and
enantioselectivity.[3] It had been demonstrated that the yield of
adduct was primarily controlled by the silylating agent and the
enantioselectivity was mainly dependent on the amount of the
chiral ligand in the reaction.[7l]
To examine the possibility of using a lower catalytic amount
of ligand 1 or 2 in the addition of dialkylzinc to imine 3, the re-
action was conducted in the presence of an additive. At the
outset, ligand 2a was selected for the investigation due to its
higher catalytic ability and easier preparation. Diethylzinc
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from 0.4 equiv to 1.1 equiv, but the yield slightly decreased
from 87% to 81% (Table 5, entries 6–8). The yield was im-
proved to 89% without affecting enantioselectivity when the
amount of diethylzinc was increased from 3 equiv to 5 equiv in
the presence of methanol (1.1 equiv) (Table 5, entries 8–10). A
further increase in the amount of methanol from 1.1 equiv to
2.2 equiv resulted in a slight increase in the enantioselectivity
to 93% (Table 5, entries 11–13). When the amount of 2a was
reduced to 0.1 equiv, the enantioselectivity and yield (Table 5,
entry 14) of the addition reaction were similar to the result of
entry 12. Interestingly, when the amount of methanol was re-
duced to 1.5 equiv, the enantioselectivity and yield were both
slightly decreased (Table 5, entry 15). The reaction took
a longer time for completion with lower enantioselectivity
when the amount of 2a was further reduced to 0.05 equiv
(Table 5, entry 16). Methanol was found to be the best achiral
additive so far in our catalytic system when compared with
other protic additives such as ethanol, 2-propanol, and water
(Table 5, entries 12, 17–19). N-Monosubstituted amino alcohol
2a exhibited higher enantioselectivity than their N,N-disubsti-
tuted congener 1 in this system (Table 5, entry 20).
imines bearing an ortho-substituted group gave a lower yield
along with the reduction product (Table 6, entries 1, 5, 8) than
meta-substituted and para-substituted imines. The reason is
presumably the steric hindrance imposed by the ortho-substi-
tuted group on the phenyl ring. Interestingly, the presence of
methanol could suppress the formation of reduction product
and enhance the yield of the addition product (Table 6, en-
tries 4–5).
Methylation of 3a with dimethylzinc (5 equiv) in the pres-
ence of a stoichiometric amount of 2a at 288C for 31 h gave
the addition product 5a in 92% yield with 97% ee (Table 7,
entry 1). The yield and enantioselectivity were decreased when
Table 7. Enantioselective addition of dimethylzinc to imine mediated by
2a.[a]
With the optimal conditions for the diethylzinc addition to
imine 3a (Table 5, entry 14) in hand, we examined the addition
to imines 3b–k to determine the scope and limitations. In the
presence of 2a, the addition of diethylzinc to imines 3b–k
gave the corresponding addition products in good enantiose-
lectivities (84-92%) and yields (60–92%) (Table 6). It should be
noted that the position of substitution on the phenyl ring of
the imine had a dramatic influence on the reaction. Generally,
Entry
2a [equiv]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5[d]
6[d]
7[d,e]
8[d]
1.0
0.6
0.4
0.1
0.1
0.1
0.1
0.2
31
48
48
48
48
72
72
72
92
75
64
33
71
70
78
77
97
99
94
87
96
95
93
95
[a] The reaction was conducted by using 5 equiv of Me2Zn (10 wt% in
hexanes) with imine (0.065m) in toluene/hexanes (1.6:1). [b] Isolated
yield. [c] Determined by HPLC using a Chiralcel OD-H column, and the ab-
solute configuration of the major isomer was assigned to be (R) by the
comparison of the optical rotation and the retention time with literature
data.[2–10] [d] MeOH (1.8 equiv) was added. [e] The reaction was conducted
by using 5 equiv of Me2Zn (1.2m in toluene) with imine (0.24m).
Table 6. The enantioselective addition of diethylzinc to N-(diphenyphos-
phinoyl)imines 3b–k catalyzed by 2a.[a]
the amount of 2a was decreased (Table 7, entries 2–4). Methyl-
ation of 3a in the presence of methanol (1.8 equiv) was also
found to improve both yield (71%) and enantioselectivity
(96%) when compared with the reaction in the absence of
methanol (Table 7, entries 4–5). No substantial change in yield
and enantioselectivity was observed on prolonging the reac-
tion time from 48 h to 72 h. When the reaction was conducted
either at a higher concentration (0.24m) or in the presence of
0.2 equiv of 2a, it resulted in a slight increase in the yield to
78% and 77%, respectively (Table 7, entries 7–8).
Entry
Ar
t [h]]
Yield [%][b,c]
ee [%][d]
1
2
3
4[e]
5
6
7
8
9
10
11
2-Tol
3-Tol
4-Tol
2-MeO-Ph
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
2-Cl-Ph
41
44
30
24
44
30
30
41
43
30
40
60(b)(24)
76(c)(8)
83(d)(4)
52(e)(47)
71(e)(28)
87(f)(6)
86(g)
68(h)(24)
84(i)(6)
86(j)(3)
92(k)
89
89
92
79
87
88
91
84
85
89
84
3-Cl-Ph
4-Cl-Ph
4-MeO2C-Ph
The presence of a small amount of methanol not only en-
hanced the catalytic cycle but also improved the enantioselec-
tivity. The exact role of methanol in our catalytic system is not
fully understood at this stage.[14,15] However, based on litera-
ture reports,[2a,b,8b,13] the rationale of the stereochemical out-
come of the addition reaction is shown in Figure 2. The coordi-
nation of imine and chiral aminoalcohol to both zinc atoms
would lead to a favored bicyclic transition state A. The transfer
of one of the ethyl groups on ZnB to imine 3 would then give
[a] The reaction was conducted by using Et2Zn (5 equiv) and MeOH
(1.8 equiv) with imine (0.072m) in toluene/hexanes (1.76:1). [b] Isolated
yield. [c] In brackets, yields of the corresponding reduction products.
[d] Determined by HPLC using Chiralcel OD-H or AS-H column, and the
absolute configuration of the major isomer was assigned to be (R) by the
comparison of the optical rotation and the retention time with literature
data;[2–10] Products 4 f and 4k were tentatively assigned to be (R) by the
retention times of the enantiomers on HPLC analysis according the obser-
vations with products 4c and 4d. [e] Without MeOH.
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vacuo. Subsequent purification by silica gel column chromatogra-
phy with MeOH/CH2Cl2 (1:40–1:20) as eluent afforded the corre-
sponding addition product as a white solid.
General procedure for the enantioselective addition of dime-
thylzinc to imines (Table 3):
N-(Diphenylphosphinoyl)imine
3 (0.34 mmol) and 1 (76.6 mg,
Figure 2. A plausible transition state for the addition of diethylzinc to imine
3.
0.34 mmol) were dissolved in dry toluene (3 mL) under argon, and
the mixture was stirred for 10 min at 288C. The solution was
cooled to 08C, and then Me2Zn in hexanes (10 Wt%, 2.2 mL,
1.7 mmol) was added dropwise. The cooling bath was removed
and the mixture was allowed to warm to 288C. The reaction mix-
ture was stirred for an additional 24 h. The reaction was then
quenched with saturated aqueous ammonium chloride (4.0 mL)
followed by the addition of hydrochloric acid (1.0 N, 3.0 mL). The
aqueous layer was extracted with CH2Cl2 (3ꢁ10 mL), and the com-
bined organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Subsequent purification by silica gel
column chromatography with MeOH/CH2Cl2 (1:40–1:20) as eluent
afforded the corresponding addition product as a white solid.
the addition product with the observed stereochemistry (R-
form).
Conclusions
We have demonstrated that the addition of diethylzinc or di-
methylzinc to N-(diphenylphosphinoyl) imines mediated by
1 or 2 could be achieved with high yields and enantioselectivi-
ties. The catalytic loading of 1 or 2a could be reduced to
10 mol% for methylation or ethylation of imines when the re-
action was conducted in the presence of 1.8 equivalents of
methanol. The reaction is able to tolerate a wide range of func-
tionalities. N-Monosubstituted amino alcohols induced higher
enantioselectivity than their N,N-disubstituted congener in this
catalytic system. This catalytic system provides an additional
efficient entry for the preparation of chiral secondary benzylic
amines.
General procedure for the enantioselective addition of diethyl-
zinc or dimethylzinc to N-diphenylphosphinoylimines with ad-
ditive (Tables 6 and 7):
A solution of N-(diphenylphosphinoyl)imine 3 (0.34 mmol) and 2a
(8.3 mg, 0.034 mmol) in dry toluene (3 mL) was added to MeOH
(25 mL, 0.61 mmol) under argon. The mixture was stirred for 10 min
at 288C. The solution was then cooled to 08C and Et2Zn in hexanes
(1.0m, 1.7 mL, 1.7 mmol) or Me2Zn in hexanes (10 Wt%, 2.2 mL,
1.7 mmol) was added dropwise. The cooling bath was removed,
and the mixture was allowed to warm to 288C. The reaction mix-
ture was stirred for an additional 24–44 h. The reaction was then
quenched with saturated aqueous ammonium chloride (4.0 mL)
followed by the addition of hydrochloric acid (1.0 N, 3.0 mL). The
aqueous layer was extracted with CH2Cl2 (3ꢁ10 mL) and the com-
bined organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Subsequent purification by silica gel
column chromatography with EtOAc/hexanes (1:5–1:1) as eluent
afforded the corresponding addition product as a white solid.
Experimental Section
Standard procedure for the preparation of (1S,2R,4R)-N-aryl-
1-amino-2-exo-hydroxy-7,7-dimethyl-bicyclo[2.2.1]heptane
(2a–2i):
A solution of (1S,2R,4R)-1-amino-2-exo-hydroxy-7,7-dimethyl-bicy-
clo[2.2.1]heptane 7 and aryl aldehyde (1.1 equiv) in anhydrous di-
chloromethane was added to sodium triacetoxyborohydride
(1.4 equiv) and acetic acid (1.1 equiv). The reaction mixture was
stirred at 288C for 3–39 h and was then quenched with aqueous
NaOH (1.0m). The aqueous phase was extracted with CH2Cl2 (3ꢁ
30 mL), and the combined organic layer was washed with brine for
three times. The organic layer was dried over anhydrous sodium
sulfate and evaporated to dryness under reduced pressure. Purifi-
cation of the crude product by silica gel column chromatography
with EtOAc/hexanes (1:5) as eluent gave 2a–2i.
Acknowledgements
Financial support provided by the Ministry of Science and
Technology (NSC-99-2113M-007-010-MY3 and 102–2113M-007-
009-MY3) and the National Tsing Hua University are gratefully
acknowledged.
General procedure for the enantioselective addition of diethyl-
zinc to N-diphenylphosphinoylimines (Table 2):
Keywords: achiral additive
·
aldimine
·
dialkylzinc
·
N-(Diphenylphosphinoyl)imine
3 (0.34 mmol) and 1 (46.0 mg,
enantioselective addition
methods
·
b-amino alcohol ·
synthetic
0.20 mmol) were dissolved in dry toluene (3 mL) under argon, and
the mixture was stirred for 10 min at 288C. The solution was
cooled to 08C, and then Et2Zn in hexanes (1.0m, 1.0 mL, 1.0 mmol)
was added dropwise. The cooling bath was removed, and the mix-
ture was allowed to warm to 288C. The reaction mixture was
stirred for an additional 25–51 h and was then quenched with sa-
turated aqueous ammonium chloride (4.0 mL) followed by the ad-
dition of hydrochloric acid (1.0 N, 3.0 mL). The aqueous layer was
extracted with CH2Cl2 (3ꢁ10 mL), and the combined organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated in
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Received: October 31, 2014
Published online on && &&, 0000
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FULL PAPER
Enantioselective Synthesis
Add it up: The enantioselective addi-
tion of diethylzinc or dimethylzinc to N-
(diphenylphosphinoyl)imines mediated
by 1 or 2 could be achieved in high
yields and enantioselectivities. The cata-
lytic loading of 1 or 2a could be re-
duced to 10 mol% for methylation or
ethylation of imines in high yields and
enantioselectivities (79–96%) when the
reaction was conducted in the presence
of 1.8 equiv of methanol.
Wei-Ming Huang, Biing-Jiun Uang*
&& – &&
Enantioselective Addition of
Dialkylzinc to Aromatic Aldimines
Mediated by Camphor-Derived Chiral
b-Amino Alcohols
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These are not the final page numbers! ÞÞ