Synthesis of highly enantiomerically enriched amines by the diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)imines

Article abstract of DOI:10.1016/j.tetasy.2008.10.012

The reaction of triorganozincates with (R)-N-(tert-butanesulfinyl) imines gives the expected α-branched sulfinamides in good to excellent yields with diastereomeric ratios of up to 98:2. The N-sulfinyl group of the products can be easily removed by acidic treatment, affording the corresponding chiral primary amines in enantiomeric excesses of up to 96%. The reactivity and the selectivity shown by the triorganozincates are different from the ones observed with the corresponding Grignard reagents, which allows, in several cases, the preparation of both enantiomers of an amine from the same imine substrate. When mixed triorganozincates are used, one can take advantage of the slow transfer rate of the methyl group to use it as a non-transferable one. Both aromatic and aliphatic aldimines, as well as activated ketimines, are good substrates for these addition reactions.

Full text of DOI:10.1016/j.tetasy.2008.10.012

Tetrahedron: Asymmetry 19 (2008) 2484–2491
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Tetrahedron: Asymmetry
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Synthesis of highly enantiomerically enriched amines by the diastereoselective
addition of triorganozincates to N-(tert-butanesulfinyl)imines
*
*
Raquel Almansa, David Guijarro , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2008
Accepted 14 October 2008
The reaction of triorganozincates with (R)-N-(tert-butanesulfinyl)imines gives the expected a-branched
sulfinamides in good to excellent yields with diastereomeric ratios of up to 98:2. The N-sulfinyl group
of the products can be easily removed by acidic treatment, affording the corresponding chiral primary
amines in enantiomeric excesses of up to 96%. The reactivity and the selectivity shown by the triorgano-
zincates are different from the ones observed with the corresponding Grignard reagents, which allows, in
several cases, the preparation of both enantiomers of an amine from the same imine substrate. When
mixed triorganozincates are used, one can take advantage of the slow transfer rate of the methyl group
to use it as a non-transferable one. Both aromatic and aliphatic aldimines, as well as activated ketimines,
are good substrates for these addition reactions.
This paper is dedicated to Professor Ernesto
Carmona on the occasion of his 60th
anniversary
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the nucleophile. In contrast to these groups, organozinc reagents8
tolerate several functional groups and can lead to polyfunctiona-
The asymmetric preparation of chiral amines has been a subject
of great interest over the last few years due to the fact that the
amine functionality is present in many pharmaceuticals, natural
products and biologically active compounds.1 Optically active
amines are also extensively used as resolving agents2 and chiral
auxiliaries in asymmetric synthesis.3 A valuable method for the
synthesis of amines is the addition of organometallic reagents to
imines.4 The asymmetric version of this reaction is very conve-
nient,5 and the diastereoselective addition of carbon nucleophiles
to imines bearing removable chiral auxiliaries connected to the
nitrogen atom represents an attractive approach for the prepara-
lised organic compounds by reaction with electrophiles. However,
the reactivity of the most common organozinc reagents, dialkyl-
zincs and alkylzinc halides, is quite limited.9 Triorganozincates8d,10
have emerged as very useful zinc reagents since they are generally
more reactive than organozinc halides and diorganozincs. They
have been involved in reactions such as additions to aldehydes
and ketones,11 conjugate additions to ,b-unsaturated ketones,8d,9b
a
cross-couplings,12 nucleophilic substitutions12b,13 and halogen-
zinc exchanges with alkyl,13,14 alkenyl12a and aryl halides.13 How-
ever, to the best of our knowledge, there are only two reports on
the addition of organozincates to imines derived from a phenethyl-
tion of
a
-branched chiral primary amines.4c,5a One of these chiral
amine, an a
-aminoester or an O-protected b-aminoalcohol.15 The
auxiliaries, which has turned out to be very efficient, is the sulfinyl
group. Enantiomerically pure N-sulfinylimines have shown to be
versatile substrates for asymmetric synthesis,6 especially for the
preparation of chiral primary amines.6b,c,f The chiral and elec-
tron-withdrawing sulfinyl group plays a dual role as an activating
and a stereodirecting group. The addition of Grignard and organo-
lithium reagents to the C@N bond takes place in a diastereoselec-
tive manner6 and provides sulfinamides that can be readily
converted into primary amines by desulfinylation of the nitrogen
atom by simple acidic treatment.7 However, the high basicity of
these organometallic reagents can be a problem when the sub-
strate is an enolisable imine and their high reactivity makes them
incompatible with other functional groups in either the imine or
participation of trialkylzincates in the zinc chloride catalysed addi-
tion of Grignard reagents to N-phenyl- and N-tosylimines has also
been postulated.11b Continuing our research on the addition of
organozinc reagents to imines,16 we herein report our results on
the diastereoselective addition of triorganozincates to N-(tert-
butanesulfinyl)imines17 and the application to the synthesis of
highly enantiomerically enriched amines.
2. Results and discussion
We were interested in the addition of organozinc reagents to
N-sulfinylimines. First, we attempted the reaction between Et2Zn
and (R)-N-(tert-butanesulfinyl)benzaldimine 1a (Scheme 1), but
no reaction was observed after stirring for several hours at room
temperature. As a result, we decided to change to more reactive
* Corresponding authors. Fax: +34 965903549 (D.G.).
E-mail addresses: dguijarro@ua.es (D. Guijarro), yus@ua.es (M. Yus).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.012

R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 2484–2491
2485
the zincate. The use of Me2Zn and EtMgBr could allow us to com-
pletely transfer the ethyl group of the Grignard reagent, which
would be very convenient in the case of using more sophisticated
R2 groups. In this way, the methyl group would act as a non-trans-
ferable group.19 Thus, a mixture of EtMgBr (1.5 equiv) and Me2Zn
(1.7 equiv) was added to a solution of imine 1a in THF at ꢀ78 °C
and, after 1 h, an 85% yield of the addition products was obtained
with a 2aa:3aa ratio of 98:2 (Table 1, entry 8). In order to prove
that the Grignard reagent itself was not the actual nucleophile,
the latter reaction was repeated in the absence of Me2Zn, which
gave a lower diastereoselectivity (Table 1, entry 9). The effect of
the solvent was also studied. The reactions in CH2Cl2 and toluene
were much slower than the reactions in THF: after stirring for
12 h, the addition products were obtained in low yields and with
a diastereoselectivity of 88:12 in both solvents (Table 1, entries
10 and 11).
We assumed that Me2Zn was regenerated after the transfer of
the ethyl group from the mixed trialkylzincate to the imine,
according to Eq. 1. For this reason, we decided to try the reaction
using a substoichiometric amount of Me2Zn, with the hope that
the regenerated Me2Zn would react with another molecule of
EtMgBr, regenerating in this way the trialkylzincate and closing a
possible catalytic cycle. Unfortunately, when EtMgBr (1.5 equiv)
was added dropwise to a solution of Me2Zn (0.5 equiv) and imine
1a in THF at ꢀ78 °C, only a 47% yield of the addition products
was obtained after stirring for 12 h, although the diastereoselectiv-
ity was as high as 94:6 (Table 1, entry 12). At the moment, we do
not have a good explanation for this slow reaction rate.
O
S
O
S
O
S
i,ii
N
t-Bu
HN
t-Bu
HN
t-Bu
+
Ph
H
Ph
Ph
1a
2aa
3aa
Scheme 1. Reagents and conditions: (i) R2MgBr, R23Zn, solvent, T; (ii) NH4Cl (aq).
organozinc reagents, such as the triorganozincates. Since trialkyl-
zincates can be prepared by the reaction of dialkylzincs with Grig-
nard reagents,8d,18 we added MeMgBr (1 equiv) to a solution of
Et2Zn and imine 1a (1 equiv each) in THF at 0 °C and obtained a
very promising 93:7 ratio of diastereomeric products 2aa and
3aa (Scheme 1); however, the yield was very low after stirring
for 5 h (Table 1, entry 1). We then tried to mix the organometallic
reagents before adding them to the imine. Thus, MeMgBr and Et2Zn
(1 equiv each) were stirred for 15 min at room temperature and
the resulting solution of the mixed trialkylzincate was transferred
to a solution of imine 1a at 0 °C. The reaction was complete after
only 1 h and the expected addition products 2aa and 3aa were
obtained in 91% yield with a diastereomeric ratio of 86:14, respec-
tively (Table 1, entry 2). Encouraged by this result, we tried to
optimise the reaction conditions. We were pleased to see that
the diastereomeric ratio increased when the temperature was low-
ered (Table 1, entries 2–5), reaching a 98:2 value at ꢀ78 °C,
although the yield was only 66% (Table 1, entry 5). In order to
try and improve the yield, the latter reaction was repeated while
increasing the amounts of MeMgBr (1.5 equiv) and Et2Zn
(1.7 equiv). These conditions afforded product 2aa in quantitative
yield and with a 97:3 diastereomeric ratio (Table 1, entry 6). A fur-
ther decrease in the temperature was detrimental for both the
yield and diastereoselectivity (Table 1, entry 7).
O
S
O
S
BrMg
Ph
+
EtMe2ZnMgBr
+
Me2Zn
N
But
N
But
Ph
H
ð1Þ
Having established the optimum reaction conditions, we then
tested the transfer of other alkyl groups to imine 1a (Scheme 2
and Table 2). The transfer of the methyl group was attempted by
using trimethylzincate as the nucleophile. Imine 1a was treated
with a mixture of MeMgBr (1.5 equiv) and Me2Zn (1.7 equiv) at
ꢀ78 °C. After stirring for 12 h at the same temperature, only 13%
Two interesting features of this reaction could be extracted
from all these experiments: (a) only the ethyl group added to the
imine, the corresponding methylation product could not be de-
tected in the crude mixture; (b) despite the presence of two ethyl
groups in the mixed trialkylzincate, only one of them was trans-
ferred. These observations made us think about interchanging
the alkyl groups on the organometallic reagents utilised to prepare
Table 1
Diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)benzaldimine 1aa: Optimisation of the reaction conditions.
Entry
R2MgBr
R32Zn
Solvent
T (°C)
Time (h)
Product
R2
Equiv
R3
Equiv
No.b
Yieldc (%)
2:3 ratiod
1e
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
1
1
1
1
Et
Et
Et
Et
Et
Et
Et
Me
—
1
1
1
1
THF
THF
THF
THF
THF
THF
THF
THF
0
0
5
1
1
1
1
1
1
1
1
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
22f
91
83
93:7
86:14
91:9
95:5
98:2
97:3
87:13
98:2
79:21
88:12
88:12
94:6
ꢀ30
ꢀ50
ꢀ78
ꢀ78
ꢀ100
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
94
1
1
66f
99
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.7
1.7
1.7
—
1.7
1.7
0.5
56f
85
THF
91
10
11
12
Me
Me
Me
CH2Cl2
Toluene
THF
12
12
12
43f
37f
47f
a
All reactions were performed by the dropwise addition of a mixture of dialkylzinc and the Grignard reagents over ca. 5 min to a stirred solution of imine 1a (0.5 mmol) in
anhydrous THF (3 mL) under argon at the indicated temperature.
b
Product number corresponding to the major diastereoisomer.
c
The crude reaction mixture only showed the mixture of diastereoisomers 2aa + 3aa (300 MHz 1H NMR) without any noticeable by-product. The yields are calculated
according to the amount of crude mixture that was obtained after work-up, and are based on the starting imine 1a.
d
Diastereomeric ratio determined from the crude reaction mixture by HPLC using a ChiralCel OD-H column. The absolute configuration of the major diastereoisomer was
deduced by removal of the N-sulfinyl group and by comparison of the sign of the specific rotation of the free primary amine with the reported data.
e
The Grignard reagent was added over ca. 10 min to a stirred solution of imine 1a (0.5 mmol) and Et2Zn in anhydrous THF (3 mL) under argon at the temperature indicated.
f
Yield estimated by 1H NMR using diphenylmethane as an internal standard. The reaction was not complete.

2486
R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 2484–2491
O
S
O
S
O
S
i, ii
NH2
R4
NH2
R4
iii
N
t-Bu
HN
t-Bu
HN
t-Bu
+
+
Ph
Ph
Ph
H
Ph
R4
Ph
R4
1a
2
3
4
ent-4
aa: R4 = Et
ab: R4 = Me
4
ac
: R = n-Bu
ad: R4 = n-C5H11
ae: R4 = PhCH2
4
af
: R = i-Pr
ag: R4 = Cy
ah: R4 = CH2=CH
Scheme 2. Reagents and conditions: (i) R2MgBr, R23Zn, THF, ꢀ78 °C; (ii) NH4Cl (aq); (iii) HCl, MeOH.
Table 2
Diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)benzaldimine 1aa: Preparation of amines 4.
Entry
R2MgBr
R32Zn
Time (h)
Sulfinamides 2 + 3
Amines 4 + ent-4
R2
Equiv
R3
Equiv
R4
Yieldb (%)
2:3 ratioc
No.d
Yielde (%)
eef (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Et
Et
Me
Me
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Me
—
1.7
—
1
1
12
1
1
1
1
1
12
1
3
12
1
1
1
12
Et
Et
Me
85
91
13g
94
99
98
88
92
70g
99
81
21g
99
80
93
28g
98:2
4aa
4aa
4ab
4ac
4ac
4ac
4ac
4ad
4ad
4ae
4af
4af
4af
4ag
4ah
4ah
77
82
—
96
58
—
79:21
54:46
94:6
96:4
94:6
77:23
96:4
49:51
90:10
94:6
60:40
92:8
93:7
h
h
Me
n-Bu
n-Bu
Me
—
Me
—
Me
Me
—
1.7
1.7
1.7
1.7
—
1.7
—
1.7
1.7
—
n-Bu
n-Bu
n-Bu
n-Bu
n-C5H11
n-C5H11
PhCH2
i-Pr
i-Pr
i-Pr
Cy
CH2@CH
CH2@CH
68
72
70
65
70
88
92
88
54
92
Mei
n-Buj
n-Buj
n-C5H11
n-C5H11
PhCH2
i-Pr
i-Pr
h
h
—
—
k
80
72
80
88
h
h
—
—
Me
i-Pr
Me
Me
—
1.7
1.7
1.7
—
74
45
75
84
86
90
Cyl
CH2@CH
CH2@CH
95:5
44:56
h
h
—
—
a
All addition reactions were performed by the dropwise addition of the mixture of the dialkylzinc and the Grignard reagents over ca. 5 min to a stirred solution of imine 1a
(0.5 mmol) in anhydrous THF (3 mL) under argon at ꢀ78 °C and stirring was continued for the time indicated.
b
The crude reaction mixture only showed a mixture of diastereoisomers 2 + 3 (300 MHz 1H NMR) without any noticeable by-product. The yields are calculated according to
the amount of crude mixture that was obtained after work-up.
c
The diastereomeric ratio was determined from the crude reaction mixture by HPLC using a ChiralCel OD-H column. The absolute configuration of the major diaste-
reoisomer was deduced by removal of the N-sulfinyl group and by comparison of the sign of the specific rotation of the free primary amine with the reported data.
d
Product number corresponding to the major enantiomer.
e
Isolated yield of the free primary amine based on the starting imine 1a. All isolated compounds were P95% pure (GC and/or 300 MHz 1H NMR).
f
Determined for the N-benzoyl amine by HPLC using a ChiralCel OD-H column. The absolute configuration of the major enantiomer of the amine was (R).
g
Yield estimated by 1H NMR using diphenylmethane as an internal standard. The reaction was not complete.
h
Not determined.
MeLi was used instead of MeMgBr.
n-BuLi was used instead of n-BuMgBr.
PhCH2MgCl was used.
i
j
k
l
CyMgCl was used.
of the expected addition product was obtained as a 54:46 mixture
of diastereoisomers (Table 2, entry 3). This result shows the slow
rate for the transfer of the methyl group and supports our idea of
using this group as a non-transferable one. Thus, Me2Zn was com-
bined with several Grignard reagents and the generated triorgano-
zincates were added to imine 1a. In all cases, the R2 group of the
Grignard reagent was the only one that added to the imine, irre-
spective of its nature. Primary (Table 2, entries 1, 8 and 10) and
secondary alkyls (Table 2, entries 11 and 14) and the vinyl group
(Table 2, entry 15) were effectively transferred to imine 1a, giving,
after desulfinylation, the expected amines 4a in good yields and
with ee’s ranging from 80% to 96%. With the aim of proving that
the reactivities of the triorganozincate solutions and the
corresponding Grignard reagents were different, the imine 1a
was treated with EtMgBr, n-C5H11MgBr, i-PrMgBr and CH2@
CHMgBr (1.5 equiv of each) in four separate experiments. Except
in the case of EtMgBr, all reactions were very slow, and were not
complete after stirring for 12 h at ꢀ78 °C. The yield was high only
with Grignard reagents bearing a primary alkyl group and in all
cases the 2:3 ratio was much lower than in the reactions with
the corresponding organozincates (compare entry 1 with entry 2,
entry 8 with entry 9, entry 11 with entry 12 and entry 15 with en-
try 16 in Table 2).
The addition of the n-butyl and the isopropyl groups by using
the combination (n-Bu)2Zn or (i-Pr)2Zn, respectively, and MeMgBr
was also attempted, giving the expected sulfinamides in very good
yields and with high diastereomeric ratios (Table 2, entries 4 and
13). It is interesting to note that when the two possible combina-

R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 2484–2491
2487
tions to prepare the mixed trialkylzincates were tested, namely,
RMgBr + Me2Zn or MeMgBr + R2Zn (R being the desired group to
be added), the diastereoselectivities were very similar in both cases
and the yield was slightly higher in the latter combination (com-
pare entry 6 with entry 8 in Table 1 or entry 11 with entry 13 in
Table 2). The combination MeMgBr + R2Zn could be very useful,
especially when considering that the R2Zn is more easily accessible
than the RMgBr or when the R group of interest is functionalised,
although at the expense of transferring only one R group.
Organolithium compounds could be used instead of Grignard
reagents as precursors of the trialkylzincates. The reactions pro-
ceeded with the same efficiency as with the Grignard reagents,
while both yields and diastereoselectivities were very good (Table
2, entries 5 and 6). The change of magnesium to lithium as the
countercation of the trialkylzincate only gave a slight improve-
ment of the diastereoselectivity (compare entries 4 and 5 in Table
2). As was the case with the Grignard reagents, the reactivity of the
triorganozincate generated by mixing an organolithium compound
and Me2Zn was different from the reactivity of the alkyllithium
itself. For instance, the zincate prepared from n-BuLi and Me2Zn
gave a 2:3 ratio of 94:6 (Table 2, entry 6), much higher than the
77:23 ratio obtained with n-BuLi alone (Table 2, entry 7).
After the addition of the triorganozincates to the imine, the 2:3
ratios were determined in the crude reaction mixtures by HPLC
using a ChiralCel OD-H column. In all the reactions that reached
completion, the only products that could be detected in the crude
reaction mixtures were the two diastereoisomers 2 and 3, which
were submitted to the desulfinylation procedure without further
purification. The removal of the N-sulfinyl group was easily
achieved by treatment of the crude reaction mixtures with HCl in
MeOH, affording the expected primary amines. By comparison of
the sign of their specific rotation with the data reported in the lit-
erature, the absolute configuration of the major enantiomer 4 or
ent-4 (Scheme 2) could be determined. The enantiomeric excesses
of the free primary amines were determined by benzoylation of the
nitrogen atom and by analysis of the obtained benzamides by HPLC
using a ChiralCel OD-H column. Table 2 shows all the results
obtained, including both the diastereoselectivities of the sulfina-
mides 2 + 3 and the enantioselectivities of the free amines 4. As
can be seen from Table 2, there was no loss of enantiomeric purity
during the desulfinylation process: the ee values of the free amines
match perfectly well with the corresponding 2:3 diastereomeric
ratios.20
the reaction at room temperature in order to obtain a fast reaction.
After 1 h, the expected sulfinamides were quantitatively formed in
a 20:80 diastereomeric ratio, which was exactly the same as that
obtained when the reaction was set up only with p-tolylmagne-
sium bromide. According to these results, it seems that the aryl-
dimethylzincate did not form, and the Grignard reagent itself
was the only one which gave the addition reaction.
Next, we decided to investigate the scope of this reaction by
testing some other imine substrates 1b–i (Scheme 3 and Table
3). All the imines 1 were prepared from the corresponding alde-
hydes or ketones according to literature procedures.21 Et-
Me2ZnMgBr22 was used as the nucleophile in all the reactions,
which were stirred for 1 h at ꢀ78 °C and then hydrolysed. The
2:3 ratio was determined in the crude reaction mixtures by HPLC
using a ChiralCel OD-H column. These crude mixtures were sub-
mitted to the desulfinylation process, giving the expected primary
amines without any detectable racemisation. The absolute config-
urations and the enantiomeric excesses of the amines 4 or ent-4
(Scheme 3) were determined as indicated above. All the results
are listed in Table 3. As can be seen, all imines 1a–c, derived from
aromatic aldehydes, gave the (R) amines 4aa–c with very good ees
regardless of the electronic nature of the substituents on the aro-
matic ring (Table 3, entries 1, 3 and 4). At this point, the influence
of the substituent on the sulfur atom was studied by using N-(p-
toluenesulfinyl)benzaldimine as a substrate, which led to amine
4aa with only 24% ee (Table 3, entry 2). This result shows the
importance of using the tert-butyl group on the sulfur atom of
the imine in order to obtain high stereoselectivities. The hetero-
aromatic imine 1d gave an 83% yield of the amine 4d with an ee
of 88% (Table 3, entry 5), which was much higher than the one
obtained under the same reaction conditions but in the absence
of Me2Zn (40% ee).
The addition of EtMe2ZnMgBr to the aliphatic imines 1e–f gave
the expected mixtures of sulfinamides in good yields but with
moderate 2:3 ratios. The (RS,S)-diastereoisomer 3f was the major
product of the addition to imine 1f (Table 3, entry 8). Unfortu-
nately, all attempts to determine the absolute configuration of
the major product of the addition to imine 1e were unsuccessful.
The absolute configuration of amine 4e was tentatively assigned
according to the order of elution of the two benzoylated enantio-
mers in the HPLC analysis by analogy to compounds N-benzoyl
4f and N-benzoyl ent-4f. It is interesting to note that the addition
of EtMgBr to the same substrates gave the reverse diastereoselec-
tivity (compare entry 6 with entry 7 and entry 8 with entry 9 in
Table 3).23 This could be very useful, since it would allow the
preparation of both enantiomers of the final amine, 4 and ent-4,
from a common imine substrate just by choosing the right nucleo-
We also tried to add an aryl group to imine 1a. p-Tolylmagne-
sium bromide (2.25 equiv) and Me2Zn (2.5 equiv) were mixed
and then added to the solution of the imine. It was necessary to
use a higher excess of the nucleophilic mixture and to perform
O
O
O
S
i, ii
iii
R5
R1
R5
R1
NH2
NH2
S
S
N
t-Bu
+
+
R5
R1
R5
R1
HN
t-Bu
HN
t-Bu
R1
R5
1
2
3
4
ent-4
: R1 = Ph, R5 = H
b: R1 = 4-ClC6H4, R5 = H
c: R1 = 4-MeOC6H4, R5 = H
a
: R1 = 2-f uryl, R5 = H
d
e: R1 = Me(CH2)7, R5 = H
f: R1 = PhCH2CH2, R5 = H
: R1 = MeO2C(CH2)3, R5 = H
g
h: R1 = Ph, R5 = CO2Et
i: R1 = Ph, R5 = CO2 i-Pr
Scheme 3. Reagents and conditions: (i) EtMgBr, Me2Zn, THF, ꢀ78 °C; (ii) NH4Cl (aq); (iii) HCl, MeOH.

2488
R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 2484–2491
Table 3
Diastereoselective addition of EtMe2ZnMgBr to N-(tert-butanesulfinyl)imines 1a: Preparation of amines 4.
Entry
Imine
Equiv EtMgBr
Equiv Me2Zn
Sulfinamides 2 + 3
Yieldb (%) 2:3 ratioc
Amines 4 + ent-4
Yielde (%) eef (%)
No.d
Config.g
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1ah
1b
1c
1d
1e
1e
1f
1.5
1.5
1.5
2.25
1.5
2.25
2.25
2.25
2.25
2.25
2.25
2.25
2.25
2.25
1.7
1.7
1.7
2.5
1.7
2.5
—
2.5
—
2.5
2.5
—
85
96
92
86
99
75
77
81
69
64
87
79
82
78
98:2
62:38
98:2
96:4
94:6
70:30
32:68
29:71
83:17
81:19
91:9
15:85
79:21
21:79
4aa
4aa
4b
4c
4d
77
80
72
67
83
70
61
60
64
63
60
60
65
66
96
24
96
92
88
40
36
42
66
62
82
70
58
58
(R)
(R)
(R)
(R)
(R)
(R)i
(S)i
(S)
4e
ent-4e
ent-4f
4f
5
4h
ent-4h
4i
ent-4i
1f
(R)
(R)
(R)
(S)
1g
1h
1h
1i
2.5
—
(R)j
(S)j
1i
a
All addition reactions were performed by the dropwise addition of the mixture of Me2Zn and EtMgBr over ca. 5 min to a stirred solution of imine 1 (0.5 mmol) in
anhydrous THF (3 mL) under argon at ꢀ78 °C, and stirring was continued for 1 h.
b
The crude reaction mixture only showed the mixture of diastereoisomers 2 + 3 (300 MHz 1H NMR) without any noticeable by-product. The yields are calculated according
to the amount of crude mixture that was obtained after work-up.
c
The diastereomeric ratio was determined from the crude reaction mixture by HPLC using a ChiralCel OD-H column. The absolute configuration of the major diaste-
reoisomer was deduced by removal of the N-sulfinyl group and by comparison of the sign of the specific rotation of the free primary amine with the reported data.
d
Product number corresponding to the major enantiomer.
e
Isolated yield of the free primary amine based on the starting imine 1. All isolated compounds were P95% pure (GC and/or 300 MHz 1H NMR).
f
Determined for the N-benzoyl amine by HPLC using a ChiralCel OD-H column.
The absolute configuration of the major enantiomer was determined by comparison of the sign of the specific rotation of the free primary amine with the one reported in
g
the literature.
h
The N-(p-toluenesulfinyl)benzaldimine was used as a substrate instead of the N-(tert-butanesulfinyl)benzaldimine 1a. The reaction was performed in toluene at room
temperature for 1 h.
i
The absolute configuration of the major enantiomer was tentatively assigned according to the order of elution of the two benzoylated enantiomers in the HPLC analysis by
analogy to compounds N-benzoyl 4f and N-benzoyl ent-4f.
j
The absolute configuration of the major enantiomer was tentatively assigned according to the order of elution of the two benzoylated enantiomers in the HPLC analysis by
analogy to compounds N-benzoyl 4h and N-benzoyl ent-4h.
philic reagent. Aliphatic imine 1g, bearing an ester group, gave
sulfinamides 2g and 3g in an 81:19 ratio (Table 3, entry 10). How-
ever, when this mixture was submitted to the desulfinylation pro-
cess, the major product was lactam 5 instead of the expected
amine 4g (Fig. 1). The formation of product 5 can be explained
by intramolecular nucleophilic substitution on the ester moiety
of 4g by the initially formed free amino group.
reagent instead of the trialkylzincate, a reversal of the diastereo-
selectivity was observed, the 2:3 ratios were in this case 15:85
and 21:79, respectively (Table 3, entries 12 and 14). The products
of the reaction between the nucleophile and the ester moieties of
1h and 1i were not detected.
As can be seen in Table 3, in order to obtain completion of the
reactions in 1 h under the reaction conditions, a higher excess of
the nucleophilic mixture (2.25 equiv of EtMgBr and 2.5 equiv of
Me2Zn) had to be used with the aromatic imine 1c (bearing an
electron-releasing group on the aromatic ring), with all the ali-
phatic imines 1e–g and with the ketimines 1h–i derived from
ketoesters.
O
S
N
t-Bu
O
NH2
O
N
Ph
1j: R5 = Me
1k : R5 = i-Pr
1l
R5
H
O
4g
5
: R5 = 4-MeC6H4
3. Conclusions
Figure 1.
In conclusion, the reaction of triorganozincates with N-(tert-
butanesulfinyl)imines is a very efficient procedure to effect the
diastereoselective addition of alkyl and alkenyl groups to the imine
carbon atom. Reactions are fast and provide the expected sulfinam-
ide products in good yields and with very high diastereomeric
ratios. Due to the low transfer ability of the methyl group, it can
be used as a non-transferable group in mixed triorganozincates.
Although the diastereoselectivities obtained with aliphatic aldi-
mines and activated ketimines are lower, a very interesting rever-
sal of the diastereoselectivity is observed when the reactions with
the trialkylzincates and the corresponding Grignard reagents are
compared. Since the N-sulfinyl group can be easily removed, this
methodology represents a new and very efficient procedure for
the asymmetric synthesis of primary amines. Further efforts to
elucidate the mechanism of the reaction and to find synthetic
We also tested the reaction between EtMe2ZnMgBr and several
N-(tert-butanesulfinyl)ketimines. Unfortunately, all attempts to
perform the addition of the ethyl group to imines 1j and 1k
(Fig. 1), derived from the corresponding phenones, were unsuc-
cessful, and the starting material was recovered unchanged. The
reaction between EtMe2ZnMgBr and imine 1l (Fig. 1) gave an al-
most 1:1 mixture of the corresponding sulfinamides after stirring
for 2 h at ꢀ78 °C. However, we were glad to see that the results im-
proved when imines 1h and 1i, derived from the corresponding
ketoesters, were used as substrates. The ethylation products were
obtained in good yields and with 2:3 ratios of 91:9 and 79:21,
respectively (Table 3, entries 11 and 13). Interestingly, as was the
case with imines 1e and 1f, when the nucleophile was the Grignard

R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 2484–2491
2489
applications of this methodology are currently underway in our
laboratories.
(CH2), 127.8 (2C), 128.8 (2C), 132.6, 133.1 (ArC), 163.3 (C@N),
165.8 (C@O); m/z 281 (M+, <1%), 225 (35), 179 (29), 152 (10),
151 (100), 105 (11), 104 (28), 103 (24), 57 (34), 41 (10). HRMS:
M+ found 224.0362, C10H10NSO3 requires 224.0381.
4. Experimental
4.1. General
4.2.4. (R)-Isopropyl [(tert-butylsulfinyl)imino](phenyl)-
acetate 1i
92% Yield; yellow oil; Rf 0.30 (hexane/ethyl acetate: 1:1);
For general experimental information, see Ref. 16a. When men-
tioned, an Rf value measured on deactivated silica gel means that
the TLC plate was eluted with a mixture of 5% triethylamine in hex-
ane and dried before applying the sample. All starting materials
needed for the synthesis of imines 1 and the solutions of MeMgBr
(3 M in Et2O, Aldrich), EtMgBr (1 M in THF, Aldrich), n-BuLi (1.6 M
in hexane, Chemetall), n-C5H11MgBr (2 M in Et2O, Aldrich),
PhCH2MgCl (1 M in THF, Acros), i-PrMgBr (2 M in THF, Aldrich),
CyMgCl (2 M in THF, Aldrich), CH2@CHMgBr (1 M in THF, Aldrich),
Me2Zn (2 M in toluene, Aldrich), Et2Zn (1.1 M in toluene, Aldrich),
(n-Bu)2Zn (1 M in heptane, Fluka) and (i-Pr)2Zn (1 M in toluene,
Aldrich) were commercially available and were used as received.
Optical rotations were measured on a Perkin–Elmer 341 polarime-
ter. HPLC analyses were performed at 25 °C on a JASCO apparatus,
equipped with a PU-2089 Plus pump, a MD-2010 Plus detector and
an AS-2059 Plus automatic injector. The HRMS (EI) were per-
formed by the Technical Services of the University of Alicante on
a Finnigan MAT 95S apparatus.
½
a 2D0
ꢁ
¼ ꢀ115:0 (c 1.0, CHCl3);
m(film) 3083, 3065, 3022, 1572
(HC@C), 1732 (C@O), 1603 (C@N), 1210 (CO), 1097 cmꢀ1 (SO); dH
1.34 (9H, s, 3 ꢂ MeC), 1.40, 1.42 (3H each, 2 d, J = 6.4 Hz each,
2 ꢂ MeCH), 5.36 (1H, heptet, J = 6.4 Hz, CHO), 7.41–7.57, 7.73–
7.81 (3H and 2H, respectively, 2m, ArH); dC 21.6, 21.8 (2 ꢂ MeCH),
23.0 (3C, 3 ꢂ MeC), 59.4 (CMe3), 70.5 (CHO), 127.8 (2C), 128.8 (2C),
132.5, 133.2 (ArC), 163.4 (C@N), 165.2 (C@O); m/z 295 (M+, <1%),
239 (29), 197 (42), 179 (22), 152 (12), 151 (100), 118 (16), 105
(49), 104 (29), 103 (25), 77 (20), 57 (64), 43 (34), 41 (24). HRMS:
M+ found 236.0744, C12H14NSO2 requires 236.0745.
4.3. Addition of triorganozincates to imines 1. Preparation of
sulfinamides 2 and 3. General procedure
A solution of the Grignard reagent (0.75 mmol for imines 1a, 1b
and 1d; 1.1 mmol for imines 1c and 1e–i) was added to the solu-
tion of the dialkylzinc reagent (0.86 mmol for imines 1a, 1b and
1d; 1.3 mmol for imines 1c and 1e–i) under argon at room temper-
ature and the mixture stirred for 15 min. The resulting solution of
the triorganozincate was then transferred dropwise via syringe
over ca. 5 min to a solution of the sulfinylimine 1 (0.5 mmol) in
anhydrous THF (3 mL) under argon at ꢀ78 °C, and the mixture
was stirred for 1 h at the same temperature. The reaction was
hydrolysed with an aqueous saturated solution of NH4Cl (2 mL).
Water (5 mL) was added and the mixture was extracted with
diethyl ether (3 ꢂ 5 mL). The combined organic layers were
washed with brine (5 mL) and then dried over Na2SO4. After filtra-
tion and evaporation of the solvents, the mixtures of tert-butane-
sulfinamides 2 and 3 were obtained in yields as shown in Tables
1–3. These mixtures were analysed by HPLC on a ChiralCel OD-H
column using a 254 nm UV detector, 10% i-PrOH in hexane as elu-
ent and a flow rate of 0.5 mL/min. The retention times were 8.7
(2aa), 10.8 (3aa), 9.5 (2ab), 14.4 (3ab), 6.5 (2ac), 9.2 (3ac), 7.9
(2ad), 9.7 (3ad), 11.0 (2ae), 12.8 (3ae), 7.8 (2af), 12.1 (3af), 10.6
(2ag), 16.9 (3ag), 9.5 (2ah), 11.1 (3ah), 9.0 (2b), 11.4 (3b), 10.9
(2c), 12.1 (3c), 9.8 (2d), 10.8 (3d), 10.8 (2e), 7.8 (3e), 13.9 (2f),
12.2 (3f), 11.5 (2g), 8.6 (3g), 12.9 (2h; ChiralCel AD column,
254 nm UV detector, 5% i-PrOH in hexane as eluent), 14.1 (3h; Chi-
ralCel AD column, 254 nm UV detector, 5% i-PrOH in hexane as elu-
ent), 8.4 (2i) and 10.6 (3i). The diastereomeric ratios are indicated
in Tables 1–3. The absolute configuration of the asymmetric carbon
atom of the major diastereoisomers was determined by treatment
of the crude reaction mixtures with HCl in methanol and by com-
parison of the sign of the specific rotation of the obtained free
amines with the reported data.
4.2. Synthesis of imines 1
Imines 1 were prepared by reaction of the corresponding alde-
hydes or ketone with (R)-tert-butanesulfinamide, according to lit-
erature procedures.21 Compounds 1a,21a 1b,24 1c,24 1d25 and 1f26
were characterised by comparison of their physical and spectro-
scopic data with the ones reported in the literature. The corre-
sponding physical, spectroscopic and analytical data for
compounds 1e, 1g, 1h and 1i follow.
4.2.1. (R)-2-Methyl-N-nonylidenepropane-2-sulfinamide 1e
60% Yield; yellow oil; Rf 0.30 (hexane/ethyl acetate: 4:1);
½
a 2D0
ꢁ
¼ ꢀ207:0 (c 0.4, CHCl3);
m
(film) 1622 (C@N), 1088 cmꢀ1
(SO); dH 0.88 (3H, t, J = 6.7 Hz, MeCH2), 1.20 (9H, s, 3 ꢂ MeC),
1.23–1.43, 1.57–1.67, 2.48–2.55 (10H, 2H and 2H, respectively,
3m, 7 ꢂ CH2), 8.07 (1H, t, J = 4.7 Hz, CHN); dC 14.1 (MeCH2), 22.3
(3C, 3 ꢂ MeC), 22.6, 25.5, 29.1, 29.2, 29.3, 31.8, 36.1 (7 ꢂ CH2),
56.5 (C), 169.8 (CHN); m/z 245 (M+, 2%), 205 (12), 189 (15), 149
(17), 141 (11), 83 (10), 71 (12), 70 (14), 69 (16), 57 (100), 55
(18), 43 (40), 41 (27).
4.2.2. (R)-Methyl 5-[(tert-butylsulfinyl)imino]pentanoate 1g
78% Yield; colourless oil; Rf 0.12 (hexane/ethyl acetate: 1:1);
½
a 2D0
ꢁ
¼ ꢀ206:4 (c 1.7, CHCl3);
m(film) 1737 (C@O), 1622 (C@N),
1163 (CO), 1081 cmꢀ1 (SO); dH 1.20 (9H, s, 3 ꢂ MeC), 1.92–2.05,
2.40–2.44, 2.56–2.61 (2H each, 3m, 3 ꢂ CH2), 3.69 (3H, s, MeO),
8.08 (1H, t, J = 4.1 Hz, CHN); dC 20.4 (CH2CH2CH2), 22.2 (3C,
3 ꢂ MeC), 33.1 (CH2CN), 35.1 (CH2CO), 51.6 (MeO), 56.5 (CMe3),
168.3 (CHN), 173.3 (C@O); m/z 233 (M+, <1%), 177 (19), 146 (14),
145 (15), 129 (86), 57 (100), 56 (23), 55 (19), 41(27). HRMS: M+
found 202.0937, C9H16NSO2 requires 202.0902.
4.4. Desulfinylation of compounds 2 and 3. Isolation of amines
4. General procedure
The crude mixture of the addition reaction was dissolved in a
1.5 M solution of HCl in methanol (4 mL; prepared by dropwise
addition of SOCl2 to methanol at 0 °C) and stirred overnight at
room temperature. Then, the solvent was evaporated, a 2 M aque-
ous HCl solution (5 mL) was added and the mixture was extracted
with ethyl acetate (3 ꢂ 5 mL). The organic layers were discarded.
The aqueous layer was basified with a buffer solution of NH3
(1 M)/NH4Cl (1 M) and extracted with CH2Cl2 (3 ꢂ 10 mL). The
combined organic phases were dried over Na2SO4. After filtration
4.2.3. (R)-Ethyl [(tert-butylsulfinyl)imino](phenyl)acetate 1h
90% Yield; yellow oil; Rf 0.30 (hexane/ethyl acetate: 1:1);
½
a 2D0
ꢁ
¼ ꢀ95:8 (c 0.9, CHCl3);
m(film) 3112, 3092, 3065, 1571
(HC@C), 1738 (C@O), 1601 (C@N), 1206 (CO), 1093 cmꢀ1 (SO); dH
1.35 (9H, s, 3 ꢂ MeC), 1.41 (3H, t, J = 7.1 Hz, MeCH2), 4.39–4.52
(1H, m, CH2), 7.43–7.55, 7.76–7.78 (3H and 2H, respectively, 2m,
ArH); dC 13.9 (MeCH2), 23.0 (3C, 3 ꢂ MeC), 59.5 (CMe3), 62.3

2490
R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 2484–2491
and evaporation of the solvent, pure amines 4 were obtained in the
yields indicated in Tables 2 and 3. Amine 4aa, commercially avail-
able, was characterised by comparison with an authentic sample.
Amines 4ac,27 4ad,28 4ae,27 4ah,29 and 4d30 were characterised
by comparison of their physical and spectroscopic data with the
ones reported in the literature. The corresponding physical, spec-
troscopic and analytical data for the other amines 4 and lactam 5
follow.
128.3, 142.3 (ArC); m/z 163 (M+, 3%), 146 (26), 134 (56), 117
(35), 91 (100), 65 (11), 58 (94).
4.4.7. (R)-Ethyl 2-amino-2-phenylbutanoate 4h38
Yellow oil; Rf 0.40 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢁ
¼ ꢀ11:6 (c 1.0, EtOH, 82% ee);
m(film) 3400 (NH), 3088,
3063, 3027, 1612, 1502, (HC@C), 1728 (C@O), 1228 (CO),
1104 cmꢀ1 (CN); dH 0.89 (3H, t, J = 7.3 Hz, MeCH2C), 1.23 (3H, t,
J = 7.2 Hz, MeCH2O), 1.91 (2H, br s, NH2), 1.96–2.08, 2.12–2.26
(1H each, 2 m, CH2C), 4.08–4.25 (2H, m, CH2O), 7.24–7.44, 7.47–
7.52 (3H and 2H, respectively, 2m, ArH); dC 8.4 (MeCH2C), 14.1
(MeCH2O), 32.7 (CH2C), 61.3 (CH2O), 64.0 (CN), 125.5 (2C), 127.2,
128.2 (2C), 143.2 (ArC), 175.6 (C@O); m/z 207 (M+ <1%), 135 (16),
134 (100), 117 (11), 104 (32), 77 (12), 56 (12).
4.4.1. (R)-2-Methyl-1-phenylpropan-1-amine 4af31
Colourless oil; Rf 0.14 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢁ
¼ þ6:4 (c 0.6, CHCl3, 88% ee);
m(film) 3305 (NH), 3085, 3061,
3027, 1602, 1492 (HC@C), 1121 cmꢀ1 (CN); dH 0.77, 0.98 (3H each,
2d, J = 6.7 Hz each, 2 ꢂ Me), 1.60 (2H, br s, NH2), 1.80–1.91 (1H, m,
CHMe), 3.60 (1H, d, J = 7.3 Hz, CHN), 7.20–7.35 (5H, m, ArH); dC
18.9, 19.8 (2 ꢂ Me), 35.4 (CHMe), 62.4 (CN), 126.7, 127.0 (2C),
128.1 (2C), 145.4 (ArC); m/z 149 (M+, <1%), 106 (100), 79 (15).
4.4.8. (R)-Isopropyl 2-amino-2-phenylbutanoate 4i
Yellow oil; Rf 0.36 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢁ
¼ ꢀ56:0 (c 1, CHCl3, 58% ee);
m(film) 3400 (NH), 3078, 3050,
4.4.2. (R)-Cyclohexyl(phenyl)methanamine 4ag32
3018, 1600, 1494, (HC@C), 1721 (C@O), 1231 (CO), 1106 cmꢀ1
(CN); dH 0.90 (3H, t, J = 7.3 Hz, MeCH2), 1.16–1.24 (6H, m,
2 ꢂ MeCH), 1.97–2.04, 2.12–2.35 (1H and 3H, respectively, 2m,
CH2 and NH2), 5.04 (1H, J = 6.2 Hz, heptet, CHMe2), 7.23–7.37,
7.47–7.53 (3H and 2H, respectively, 2m, ArH); dC 8.4 (MeCH2)
21.5, 21.6 (2 ꢂ MeCH), 32.4 (CH2), 64.0 (CN), 68.9 (CO), 125.5
(2C), 127.2, 128.3 (2C), 143.0 (ArC), 174.9 (C@O); m/z 221 (M+
<1%), 134 (36), 121 (55), 120 (22), 104 (100), 91 (11), 87 (10), 77
White solid; Rf 0.15 (ethyl acetate, deactivated silica gel); mp
97 °C; ½a 2D0
ꢁ
¼ þ9:3 (c 1.0, EtOH, 86% ee);
m(film) 3379 (NH), 3091,
3058, 3018, 1602, 1449 (HC@C), 1262 cmꢀ1 (CN); dH 0.85–1.29,
1.40–1.80 (5H and 7H, respectively, 2m, 5 ꢂ CH2 ring and NH2),
1.97–2.04 (1H, m, CHCN), 3.59–3.64 (1H, m, CHN), 7.26–7.34 (5H,
m, ArH); dC 26.2 (2C), 26.4, 29.5, 30.1 (5 ꢂ CH2 ring), 45.2 (CHCN),
61.7 (CN), 126.7, 127.1 (2C), 128.1 (2C), 145.5 (ArC); m/z 189 (M+,
<1%), 106 (100), 104 (14), 79 (13), 77 (10).
(10). HRMS: M+ꢀCO2Pri found 134.1013, C9H12
N requires
134.0970.
4.4.3. (R)-1-(4-Chlorophenyl)propan-1-amine 4b33
Colourless oil; Rf 0.20 (ethyl acetate, deactivated silica gel);
4.4.9. (R)-6-Ethylpiperidin-2-one 539
½
a 2D0
ꢁ
¼ þ15:0 (c 1.2, CHCl3, 96% ee);
m
(film) 3365, 3307 (NH),
Colourless oil; Rf 0.15 (ethyl acetate, deactivated silica gel);
3089, 3052, 3021, 1594, 1491 (HC@C), 1091 cmꢀ1 (CN); dH 0.85
(3H, t, J = 7.3 Hz, Me), 1.44–1.80 (4H, m, NH2 and CH2), 3.80 (1H,
t, J = 6.7 Hz, CHN), 7.23–7.31 (4H, m, ArH); dC 10.8 (Me), 32.4
(CH2), 57.1 (CN), 127.8 (2C), 128.4 (2C), 132.3, 144.8 (ArC); m/z
169 (M+, <1%), 142 (32), 140 (100), 77 (14).
½
a 2D0
ꢁ
¼ ꢀ3:0 (c 1, CHCl3, 62% ee) {literature40
½
a 2D0
for ent-5 +10.5
ꢁ
(c 0.4, CHCl3)}; m
(film) 3211 (NH), 1658 (C@O), 1265 cmꢀ1 (CN);
dH 0.95 (3H, t, J = 7.5 Hz, Me), 1.20–1.45, 1.47–1.57, 1.61–1.77,
1.85–1.97 (1H, 2H, 1H and 2H, respectively, 4m, CH2CH2CH and
CH2Me), 2.21–2.43 (2H, m, CH2CO), 3.25–3.33 (1H, m, CH); dC 9.4
(Me), 19.4 (CH2CH2CO), 27.5 (CH2Me), 29.5 (CH2CH2CH), 30.9
(CH2CO), 54.5 (CH), 159.9 (C@O); m/z 127 (M+, 5%), 98 (100), 55
(39).
4.4.4. (R)-1-(4-Methoxyphenyl)propan-1-amine 4c34
Colourless oil; Rf 0.20 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢁ
¼ þ15:0 (c 1.0, EtOH, 92% ee);
m(film) 3335 (NH), 3072,
3032, 3005, 1584, 1513 (HC@C), 1248 cmꢀ1 (CN); dH 0.85 (3H, t,
J = 7.3 Hz, MeCH2), 1.57 (2H, br s, NH2), 1.61–1.77 (2H, m, CH2),
3.76 (1H, t, J = 6.9 Hz, CHN), 3.80 (3H, s, MeO), 6.84–6.89, 7.21–
7.26 (2H and 2H, respectively, 2m, ArH); dC 11.0 (MeCH2), 32.4
(CH2), 55.2 (MeO), 57.2 (CN), 113.7 (2C), 127.4 (2C), 138.5, 158.5
(ArC); m/z 165 (M+, <1%), 136 (100), 109 (12).
4.5. Determination of the enantiomeric excesses of amines 4
Benzoyl chloride (1.4 mmol) was added to a solution of amine 4
(0.5 mmol) and triethylamine (1.4 mmol) in CHCl3 (0.9 mL) at 0 °C.
After stirring for 3 h at room temperature, a 2 M aqueous HCl solu-
tion (0.5 mL) was added and the mixture was extracted with
CH2Cl2 (2 ꢂ 5 mL). The combined organic layers were washed with
water (5 mL) and then dried over Na2SO4. After filtration and evap-
oration of the solvents, the expected benzamides were purified by
column chromatography (silica gel, hexane/ethyl acetate). These
benzamides were analysed by HPLC on a ChiralCel OD-H column
using a 254 nm UV detector, 10% i-PrOH in hexane as eluent and
a flow rate of 0.5 mL/min. The retention times were 17.8 (N-ben-
zoyl 4aa), 29.0 (N-benzoyl ent-4aa), 15.4 (N-benzoyl 4ac), 26.6
(N-benzoyl ent-4ac), 15.6 (N-benzoyl 4ad), 29.7 (N-benzoyl ent-
4ad), 33.0 (N-benzoyl 4ae), 47.8 (N-benzoyl ent-4ae), 14.5 (N-
benzoyl 4af), 18.5 (N-benzoyl ent-4af), 13.0 (N-benzoyl 4ag), 20.1
(N-benzoyl ent-4ag), 19.7 (N-benzoyl 4ah), 30.7 (N-benzoyl
ent-4ah), 19.3 (N-benzoyl 4b), 28.3 (N-benzoyl ent-4b), 15.4 (N-
benzoyl 4c), 27.1 (N-benzoyl ent-4c), 15.8 (N-benzoyl 4d), 19.2
(N-benzoyl ent-4d), 15.2 (N-benzoyl 4e), 12.4 (N-benzoyl ent-4e),
35.0 (N-benzoyl 4f), 26.4 (N-benzoyl ent-4f), 14.6 (N-benzoyl 4h;
5% i-PrOH in hexane as eluent), 21.1 (N-benzoyl ent-4h; 5% i-PrOH
in hexane as eluent), 17.5 (N-benzoyl 4i), 24.3 (N-benzoyl ent-4i),
21.4 (N-benzoyl 5), and 19.0 (N-benzoyl ent-5). The enantiomeric
excesses obtained are collected in Tables 2 and 3.
4.4.5. (R)-Undecan-3-amine 4e
Colourless oil; Rf 0.10 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢁ
¼ ꢀ2:3 (c 1.2, CHCl3, 40% ee);
m(film) 3376, 3345 (NH),
1135 cmꢀ1 (CN); dH 0.86–0.93 (6H, m, 2 Me), 1.19–1.50 (18H, m,
8 ꢂ CH2 and NH2), 2.58–2.64 (1H, m, CH); dC 10.4, 14.1 (2 ꢂ Me),
22.7, 26.2, 29.3, 29.6, 29.8, 30.7, 31.9, 37.6 (8 ꢂ CH2), 52.7 (CN);
m/z 171 (M+, <1%), 143 (10), 142 (99), 58 (100), 56 (16), 55 (11).
HRMS: M+ found 171.1963, C11H25N requires 171.1987.
4.4.6. (S)-1-Phenylpentan-3-amine ent-4f35
Colourless oil; Rf 0.14 (ethyl acetate, deactivated silica gel);
½
a 2D0
ꢁ
¼ þ7:5 (c 1.0, MeOH, 42% ee); ½a D20
ꢁ
for ent-4fꢃHCl36 ꢀ4.0 (c
1.5, MeOH, 42% ee) {literature37
½
a 2D3
ꢁ
¼ ꢀ17:8 (c 1.58, MeOH)};
m
(film) 3334 (NH), 3092, 3065, 3026, 1581, 1495 (HC@C),
1181 cmꢀ1 (CN); dH 0.93 (3H, t, J = 7.5 Hz, Me), 1.23–1.42, 1.45–
1.66 (2H each, 2m, CH2CHCH2), 1.81 (2H, br s, NH2), 2.58–2.80
(3H, m, CH2Ph and CHN), 7.16–7.30 (5H, m, ArH); dC 10.3 (Me),
30.4, 32.5, 39.0 (3 ꢂ CH2), 52.3 (CN), 125.7 (2C), 128.2 (2C),

R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 2484–2491
2491
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Asymmetry 2008, 19, 603–606.
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Acknowledgements
This work was generously supported by the Spanish Ministerio
de Educación y Ciencia (MEC; Grant No. CONSOLIDER INGENIO
2010, CSD2007-00006 and CTQ200765218) and the Generalitat
Valenciana (GV/2007/036). R.A. thanks the Spanish Ministerio de
Educación y Ciencia for a predoctoral fellowship. We also thank
MEDALCHEMY S.L. for a gift of chemicals.
19. The low transfer ability of the methyl group from triorganozincates has been
shown in other addition reactions. For example, see Refs. 8d and 9b.
20. The determination of the relative proportion of 2 and 3 by HPLC using UV
detection is an estimate unless it has been proven that both diastereoisomers
have the same UV response. The fact that the enantiomeric ratios of the free
primary amines are equal to the corresponding 2:3 diastereomeric
ratios determined by HPLC indicates that the latter technique is
appropriate for estimating the diastereomeric ratios of this type of
sulfinamides.
21. (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999,
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22. This formula indicates only the composition of the organometallic mixture and
implies neither the molecular formula nor the dominant species in solution.
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