Copper-catalyzed asymmetric addition of diethylzinc to Boc-protected imines

Article abstract of DOI:10.1016/j.tetasy.2008.07.020

A new class of substrates has been tested in the addition of Et₂Zn, catalyzed by copper and phosphoramidite, providing the expected α branched protected amine in quantitative conversion, good yield and excellent enantioselectivity up to 97%.

Full text of DOI:10.1016/j.tetasy.2008.07.020

Tetrahedron: Asymmetry 19 (2008) 1871–1874
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Copper-catalyzed asymmetric addition of diethylzinc to Boc-protected imines
*
Quentin Perron, Alexandre Alexakis
University of Geneva, Department of Organic Chemistry, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of substrates has been tested in the addition of Et2Zn, catalyzed by copper and phosphorami-
Received 10 July 2008
Accepted 17 July 2008
Available online 8 August 2008
dite, providing the expected
a branched protected amine in quantitative conversion, good yield and
excellent enantioselectivity up to 97%.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
report on the use of copper and phophoramidite ligands on such
additions. However, a recent article, by Feringa et al., disclosing a
similar approach onto formylimines, prompted us to report our
own results.13 Herein, we report the use of other phosphoramidite
ligands, and a wider scope of electron-donating and -withdrawing
substituent on the starting material.
Chiral
a branched amines are important functionalities in bio-
logically active molecules. As a result, they have become a very
important topic in asymmetric catalysis. Due to their poor reactiv-
ity, imines have not been studied as much as the carbonyl func-
tions;1 they have to be protected by an electron-withdrawing
group in order to activate the azomethine carbon. In the case of
Lewis base activation, Soai was the first to use N-diphenylphosphi-
noyl imines to activate the addition of dialkylzinc, catalyzed by
chiral amino alcohols.2 Recently, Gong reported the in situ forma-
tion of the N-formyl imine from a stable precursor.3 In Lewis acid
activation, Tomioka was the first to report, in 2000, the Cu-cata-
lyzed addition of diethylzinc to N-sulfonyl imines.4 Many authors
followed this up; for example, Wang et al. reported the use of a fer-
rocene-derived ligand on the same substrate.5 Charette used his
efficient monophosphine oxide ligand, under the same conditions
as others, on N-diphenylphosphinoyl imines.6 The in situ formation
of N-diphenylphosphinoyl imines starting from the amine–sulfi-
nate adduct was introduced.7 He also designed an innovative
way to add dialkylzincs to aryl trifluoromethyl ketimines, gener-
ated in situ from a stable hemiaminal-bearing ethoxide as the leav-
ing group, providing the expected compound in excellent
enantiomeric excess.8 Hoveyda and Snapper examined the addi-
tion of dialkylzinc reagents to orthomethoxyphenyl-protected imi-
nes, catalyzed by a Zr–dipeptide complex.9 Other nucleophiles
such as Grignard reagent or lithium derivatives have been investi-
gated by Toru et al.10 Tomioka11 and Alexakis12 on N-(pyridylsulfo-
nyl) imines or paramethoxyphenylimines.
2. Results and discussion
All substrates were easily prepared according to a described
procedure.14 Aromatic aldehydes have been mixed with benze-
nesulfinic acid sodium salt or p-toluenesulfinic acid sodium salt
in the presence of tert-butyl carbamate under acidic conditions at
room temperature to yield the amine–sulfinate adduct, which
was converted to the Boc-protected imine under basic conditions
in refluxing THF (Scheme 1).
The simplest starting material (Ar = phenyl) was then used in
the addition of diethylzinc in toluene at 0 °C with the simplest
biphenol-based phosphoramidite ligand 8 and the most used cop-
per salt, Cu(OTf)2. This first experiment allowed us to obtain the
expected compound in complete conversion after 15 min and with
75% enantiomeric excess. After a quick screening of the tempera-
ture, we observed that in all cases the conversion was complete,
and that ꢀ40 °C appeared to be the optimal one (Table 1).
We then turned our attention to the ligand. A large num-
ber have been tried under the same conditions as described
above. Some of the most interesting results are presented in
Scheme 2.
All of these approaches rely on different protecting groups on
the imines, but in most cases the protected amines obtained seem
to be difficult to cleave. Facing this difficulty, we decided to intro-
duce a different protecting group, for imines, such as tert-butoxy-
carbonyl. At the beginning of our study, there was no literature
With these results we can understand that the amine part of the
ligand should not be too hindered (8 vs 9), in contrast to the biphe-
nyl part, where the tetramethyl-substituted phosphoramidite li-
gand induces more selectivity (8 vs 10). The binaphthyl ligand 11
was also been tested, but it induced lower enantioselectivity than
10. Its diastereoisomer was also tested, but with less selectivity.
We also wanted to see the activity of one of the new Simplephos
ligands, recently described in our laboratories,15 but unfortunately
with less success than its phosphoramidite analogues (10 vs 13).
* Corresponding author. Tel.: +41 22 379 65 22; fax: +41 22 379 32 15.
E-mail address: alexandre.alexakis@chiorg.unige.ch (A. Alexakis).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.020

1872
Q. Perron, A. Alexakis / Tetrahedron: Asymmetry 19 (2008) 1871–1874
O
MeOH/H2O,
Formic acid, RT.
O
HN
O
SO2Na
H2N Boc
Ar
Ar'
Ar
SO2Ar'
O
Na2SO4, K2CO3,
THF, Reflux 15h
N
O
Ar
Scheme 1.
Carbene 12, ferrocene 14 and phosphite 15 ligands were also
tested, but without any noteworthy results.
We then tested the influence of the solvent, and dichlorometh-
ane appeared to be the best in terms of conversion and selectivity.
We finally performed a screening of the copper salt in this solvent
(Table 2).
First, we observed that the copper salt did not have a great
influence on the selectivity; therefore we decided to work with
CuBr. We also studied the ratio of the ligand versus copper salt,
and a 1/1 ratio appeared to be the best one in terms of conversion
and enantiomeric excess (Table 3).
With these condition in hand, we applied our methodology to
different substrates. The results are summarized in Table
(Scheme 3).
4
We observed that the conversion and the selectivity were in the
same range as the test substrate and were not dependent on the
electronicity of the substituent on the aromatic part of the sub-
strate (entry 4 vs entry 5). It seems that the selectivity was slightly
dependent on the hindrance of the aromatic part, if we compare
product 6, entry 7, versus product 7, entry 8. We were also inter-
ested in the amount of the catalyst, and under the same conditions
Table 2
Study of copper salts
Table 1
Study of the temperature
Entry
CuX
ee (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu[OTf]2ꢁbenzene
CuBr
CuCl
CuI
90
91
93
93
91
91.5
93
92.5
91
Entry
Product
T (°C)
ee (%)
1
2
3
4
0
ꢀ20
ꢀ40
ꢀ60
75
83
86
86
O
HN
O
CuTC
CuBrꢁMe2S
Cu(OAc)2ꢁH2O
Cu(OAc)2
1
Three equivalents of Et2Zn, 3.6 mol % of 8, 3 mol % of Cu(OTf)2, in toluene.
Three equivalents of Et2Zn, 3.6 mol % of 10, 3 mol % of CuX, in DCM at ꢀ40 °C.
O
O
O
O
O
O
O
O
P
N
P N
P
N
P
N
10
ee= 89%
11
ee= 82%
8 ee= 86%
9 ee= 78%
-
PF6
H
P(Cy)2
P(Cy)2
P
N
N
N
O
O
P
O
Fe
HO
13
14
15
ee= 7%
12
ee= 66%
ee= 51%
ee= 23%
Scheme 2.

Q. Perron, A. Alexakis / Tetrahedron: Asymmetry 19 (2008) 1871–1874
1873
Table 3
Study of the ratio between 10 and CuBr
Entry
10 (mol %)
CuBr (mol %)
Conv (%)
ee (%)
O
O
P N
1
2
3
5
6
7.5
2.5
5
5
87
92
91
92
93
93
(S,S)
Three equivalents of Et2Zn, x mol % of 10, y mol % of CuBr, in DCM at ꢀ40 °C.
Boc
Boc
10
(6 mol%), CuBr (5 mol%)
HN
N
Ar
Table 4
Ar
(S)
Et2Zn (3 eq) in 1M Hexane sol.,
DCM, -40°C, 2h.
Study of the scope of the reaction
Entry
Product
Conv. (%)
Yld (%)
ee (%)b
Scheme 3.
O
1
92
81
88
—
93 (ꢀ)
51 (ꢀ)
2a
HN
O
The use of Et3Al has also been approached. Here, we present our
best results, entry 2. As a Lewis base, triethylamine was added to
reduce the nucleophilicity of the Et3Al by coordination to the
empty orbital of the aluminium atom. If the reaction was per-
formed without it, no selectivity was observed. Me3Al has also
been tried, but only addition to the carbonyl functionality of the
Boc group without Et3N and recovery of the starting material with
Et3N have been observed.
1
O
HN
O
3
4
94
99
83
90
94 (ꢀ)
96 (ꢀ)
2
O
3. Conclusion
HN
O
O
Herein we have reported a new approach to obtain
a chiral
branched Boc-protected amine. Excellent conversion, isolated yield
and enantioselectivity have been observed.
3
F3C
O
4. Experimental
HN
HN
HN
5
6
7
100
100
100
85
85
83
93 (ꢀ)
94 (ꢀ)
90 (ꢀ)
4.1. General procedure
4
To a clean and dry Schlenk tube were added CuBr (0.02 mmol),
ligand (0.024 mmol) and substrate (0.4 mmol), then dry dichloro-
methane (5 ml) was added and the whole mixture was cooled to
ꢀ40 °C. Then Et2Zn (1.2 mmol, 1 M solution in hexane) was added
dropwise to the mixture. After 2 h, drops of methanol were added,
and the whole mixture was warmed to room temperature. Then
3 ml of 1 M HCl solution was added and the product was extracted
with 3 ml of DCM three times. Organics were dried over sodium
sulfate and concentrated under rotary evaporation. The crude
product was purified by column chromatography on silica gel
eluted with a mixture of pentane/ether, 20:1.
O
O
O
O
O
5
O
O
6
4.2. tert-Butyl 1-phenylpropylcarbamate 1
O
Purification by column chromatography on silica gel eluted
with a mixture of pentane/ether, 20:1, to yield 88% of the expected
HN
O
compound as a white solid. mp = 46 °C, ½a D20
¼ ꢀ53:5 (c 1.025,
ꢂ
8
100
87
97 (ꢀ)
CHCl3); 1H NMR (CDCl3, d = ppm, J = Hz): d 0.9 (t, 3H, J = 7.3), 1.4
(s, 9H), 1.75 (m, 2H), 4.55 (br s, 1H), 4.85 (br s, 1H), 7.2–7.4 (m,
5H); 13C NMR (CDCl3, d = ppm, J = Hz): d 10.7, 28.4, 29.7, 56.3,
79.3, 126.4, 127, 128.5, 142.8, 155.3; IR (neat): 3385, 2971, 2922,
2873, 1682, 1515, 1495, 1455, 1363, 1264, 1258, 1029, 798, 701,
581; MS (m/z) 236 (M+1) 223, 201, 180, 155; HRMS calcd for
7
O
a
Reaction performed at ꢀ30 °C with 1.5 equiv of Et3Al, 1 equiv of Et3N, 10 mol %
of ligand 10 and 5 mol % of CuBr in ether for 1 h.
b
The absolute configuration of 1 has been determined thanks to the specific
rotation sign of its corresponding unprotected product (S)-(ꢀ)-1-phenylpropan-
C14H21NO2Na 258.1464, found 258.1470.
1-amine. The absolute configuration of compounds 2–7 was determined by analogy
to 1.
4.3. tert-Butyl 1-p-tolylpropylcarbamate 2
with only 1% of ligand 10 and CuBr, we obtained in quantitative
conversion to product 1 in 90% enantiomeric excess. Also, 1.5 equiv
of Et2Zn has been tested without eroding the conversion or
selectivity.
Purification by column chromatography on silica gel eluted
with a mixture of pentane/ether, 20:1, to yield 83% of the expected
compound as a white solid. mp = 58 °C, ½a D20
¼ ꢀ60:7 (c 1.02,
ꢂ
CHCl3); 1H NMR (CDCl3, d = ppm, J = Hz): d 0.9 (t, 3H, J = 7.4), 1.4

1874
Q. Perron, A. Alexakis / Tetrahedron: Asymmetry 19 (2008) 1871–1874
(s, 9H), 1.75 (m, 2H), 2.45 (s, 3H), 4.5 (br s, 1H), 4.8 (br s, 1H), 7.15
(m, 4H); 13C NMR (CDCl3, d = ppm, J = Hz): d 10.7, 21, 28.4, 29.7, 56,
79.2, 125.8, 129.2, 136.6, 139.8, 155.3; IR (neat): 3387, 2977, 2929,
2873, 1682, 1513, 1167, 816; MS (m/z) 249 (M+1) 235, 220, 194,
164; HRMS calcd for C15H23NO2Na 272.1621, found 272.1617.
4.8. tert-Butyl 1-(furan-2-yl)propylcarbamate 7
Purification by column chromatography on silica gel eluted
with a mixture of pentane/ether, 20:1, to yield 87% of the expected
compound as a colorless oil. ½a D20
ꢂ
¼ ꢀ99:8 (c 0.995, CHCl3); 1H NMR
(CDCl3, d = ppm, J = Hz): d 0.9 (t, 3H, J = 7.2), 1.45 (s, 9H), 1.85 (m,
2H), 4.65 (br s, 1H), 4.85 (br s, 1H), 6.15 (s, 1H), 6.3 (s, 1H), 7.35
(s, 1H); 13C NMR (CDCl3, d = ppm, J = Hz): d 10.5, 27.7, 28.6, 50.3,
79.7, 106.1, 110.3, 141.9, 155.2, 155.5; IR (neat): 3337, 2971, 234,
2878, 1694, 1501, 1366, 1164, 1008, 731; MS (m/z) 226 (M+1)
211, 196, 192, 170; HRMS calcd for C12H20NO3 226.1437, found
226.1442.
4.4. tert-Butyl 1-(4-(trifluoromethyl)phenyl)propylcarbamate 3
Purification by column chromatography on silica gel eluted with
a mixture of pentane/ether, 20:1, to yield 90% of the expected com-
pound as a white solid. mp = 78 °C, ½a D20
ꢂ
¼ ꢀ41:5 (c 0.99, CHCl3); 1H
NMR (CDCl3, d = ppm, J = Hz): d 0.9 (t, 3H, J = 7.3), 1.4 (s, 9H), 1.75
(m, 2H), 4.6 (br s, 1H), 4.8 (br s, 1H), 7.4 (d, 2H, J = 8), 7.6 (d, 2H,
J = 8); 13C NMR (CDCl3, d = ppm, J = Hz): d 10.8, 28.6, 30, 56.3,
79.9, 123, 125.7, 126.9, 129 (q, J = 319), 147.4, 155.5; IR (neat):
3373.3, 2979, 2935, 1683.2, 1522.3, 1331, 1159.4, 1118.1, 613;
MS (m/z) 304 (M+1) 289, 280, 248, 200, 187, 167, 159; HRMS calcd
for C15H20F3NO2Na 326.1338, found 326.1339.
Acknowledgements
We thank the Swiss National Science Foundation (No. 200020-
113332) for financial support. Special thanks, also, to Stéphane
Rosset (University of Geneva) for his help in the separation of
enantiomers on chiral SFC.
4.5. tert-Butyl 1-(4-methoxyphenyl)propylcarbamate 4
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Purification by column chromatography on silica gel eluted
with a mixture of pentane/ether, 20:1, to yield 85% of the expected
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compound as a white solid. mp = 73 °C, ½a D20
¼ ꢀ70:7 (c 0.995,
ꢂ
CHCl3); 1H NMR (CDCl3, d = ppm, J = Hz): d 0.9 (t, 3H, J = 7.2), 1.4
(s, 9H), 1.75 (m, 2H), 3.8 (s, 3H), 4.5 (br s, 1H), 4.8 (br s, 1H), 6.9
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155.3, 158.6; IR (neat): 3371.9, 2968, 2935, 1683, 1526, 1512,
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Purification by column chromatography on silica gel eluted
with a mixture of pentane/ether, 20:1, to yield 85% of the expected
compound as a white solid. mp = 52 °C, ½a D20
¼ ꢀ63:1 (c 0.995,
ꢂ
CHCl3); 1H NMR (CDCl3, d = ppm, J = Hz): d 0.9 (t, 3H, J = 7.3), 1.4
(s, 9H), 1.75 (m, 2H), 4.4 (br s, 1H), 4.8 (br s, 1H), 5.9 (s, 2H), 6.7
(m, 3H); 13C NMR (CDCl3, d = ppm, J = Hz): d 10.9, 28.6, 30.1, 56.4,
79.6, 101.2, 107, 108.4, 119.9, 137.2, 146.7, 148, 155.5; IR (neat):
3372, 2974, 2930, 1679, 1520, 1487, 1441, 1241, 1167, 1039,
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Purification by column chromatography on silica gel eluted
with a mixture of pentane/ether, 20:1, to yield 83% of the expected
compound as a white solid. mp = 73 °C, ½a D20
¼ ꢀ58:1 (c 1.03,
ꢂ
CHCl3); 1H NMR (CDCl3, d = ppm, J = Hz): d 0.9 (t, 3H, J = 7.3), 1.45
(s, 9H), 1.85 (m, 2H), 4.65 (br s, 1H), 4.9 (br s, 1H), 7.35–7.5 (m,
3H), 7.7 (s, 1H), 7.8 (m, 3H); 13C NMR (CDCl3, d = ppm, J = Hz): d
11, 28.6, 30, 56.7, 79.6, 124.9, 125.4, 125.9, 126.3, 127.9, 128.1,
128.6, 133, 133.6, 140.4, 155.6; IR (neat): 3381, 2966, 2931,
2872, 1689, 1520, 1505, 1241, 1165, 1074, 1030, 822, 741, 612;
MS (m/z) 286 (M+1) 271, 230, 200, 169; HRMS calcd for
C18H24NO2 286.1801, found 286.1810.