Et3B- and et2Zn-mediated radical additions to glyoxylate imines, compared stereoinductions

Article abstract of DOI:10.1016/S0040-4020(00)00327-6

1,3-Stereoinduction in the addition of alkyl radicals to glyoxylic imines derived from various chiral amines has been investigated. New synthetic methodologies involving Et₃B and Et₂Zn as mediators have been compared. Dihydro-1,4-oxazin-2-one (2b) gave the highest d.e. but no chemoselectivity. Open chain analogues derived from β-alkoxyamines led to good stereoinduction when the reaction was performed with Et₂Zn which is a bidentate complexing reagent. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00327-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3951±3961
Et3B- and Et2Zn-Mediated Radical Additions to Glyoxylate
Imines, Compared Stereoinductions
*
Michele P. Bertrand, Stephanie Coantic, Laurence Feray, Robert Nouguier and Patricia Perfetti
Á
Â
   à Â
Laboratoire de Chimie Moleculaire Organique, UMR 6517, Boite 562, Faculte des Sciences St-Jerome, Universite d'Aix-Marseille III,
Avenue Normandie-Niemen, 13397 Marseille, Cedex 20, France
Received 20 January 2000; accepted 25 April 2000
AbstractÐ1,3-Stereoinduction in the addition of alkyl radicals to glyoxylic imines derived from various chiral amines has been investi-
gated. New synthetic methodologies involving Et3B and Et2Zn as mediators have been compared. Dihydro-1,4-oxazin-2-one (2b) gave the
highest d.e. but no chemoselectivity. Open chain analogues derived from b-alkoxyamines led to good stereoinduction when the reaction was
performed with Et2Zn which is a bidentate complexing reagent. q 2000 Elsevier Science Ltd. All rights reserved.
Radical additions to CvN bonds have been far less dev-
eloped than their ionic counterparts. The latter reactions
involve mainly organometallic species,1 or enolates2,3 and
suffer some limitations inherent to the low reactivity of the
CvN bond and to the basicity of most organometallic
reagents. Radical additions performed under strictly non
basic conditions offer an alternative to the above mentioned
nucleophilic reactions. The studies devoted to intermolecu-
lar additions to CvN bonds are few compared to those
dealing with intramolecular processes.4 It can be inferred
from literature data that intermolecular radical additions to
CvN bonds are successful when either the carbon atom is
not sterically hindered,5 or the carbon is rendered more
electrophilic by a substituent.6 The third possibility is to
activate the substrate through complexation with a Lewis
acid.7
conditions, is still a challenging problem. The results of
experiments conducted on a series of glyoxylate imines
(1, 2, Figs. 1 and 2), prepared from various chiral amines,
are reported in Tables 1±3. The structures of the products
are shown in Figs. 3 and 4. The comparison of triethyl-
borane- with diethylzinc-mediated reactions gives an insight
Scheme 1.
We have recently reported that triethylborane,8a and diethyl-
zinc8b were particularly well suited to achieve radical
additions onto the imino group (Scheme 1). Both reagents
are able to initiate radical processes by reacting with oxygen
(step a).9 This results in the production of ethyl radicals
which can either add to the imine (step c) or transfer an
iodine atom from an alkyl iodide10 (step b) thus generating
an alkyl radical which adds to the CvN bond (step c).
During this step, ethyl radical which is the chain carrier is
regenerated. Therefore, both Et3B and Et2Zn play simul-
taneously the role of initiator, the role of chain transfer
agent and the role of activating complexing reagent.
Figure 1.
Performing stereoselective addition to imines, under mild
Keywords: radical additions; glyoxylate imines; triethylborane diethylzinc.
* Corresponding author. Tel.: 133-491-288597; fax: 133-491-670944;
e-mail: michele.bertrand@LCMO.u-3mrs.fr
Figure 2.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00327-6

3952
M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
Table 1. Et3B- and Et2Zn-mediated radical additions to 1a±d: (i) Et3B (3 equiv.), RI (none or 6 equiv.), substrate (0.2 M solution in CH2Cl2), air (5 mL); (ii)
Et2Zn (2 equiv.), RI (none or 6 equiv.), substrate (0.2 M solution in CH2Cl2), air (5 mL); (iii) Et2Zn (2 equiv.), RI (none or 6 equiv.), substrate (0.2 M solution
in CH2Cl2 degassed, 4 cycles); (iv) Et2Zn (2 equiv.), RI (none or 6 equiv.), substrate (0.2 M solution in CH2Cl2), air (20 mL)
Entry
Substrate
RI
Conditions
T8C
Products
Relative ratio
Yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
1d
1d
None
t-BuI
None
t-BuI
None
None
c-HexI
t-BuI
t-BuI
None
t-BuI
None
None
t-BuI
t-BuI
None
t-BuI
None
None
c-HexI
t-BuI
t-BuI
None
t-BuI
None
None
c-HexI
t-BuI
t-BuI
(i)
(i)
(i)
(i)
(ii)
(iii)
(ii)
(ii)
(ii)
(i)
278
278
240
20
20
20
20
20
240
20
20
20
240
20
240
20
20
20
240
240
20
240
20
20
20
20
3a: 4a
7a: 8a
3a: 4a
7a: 8a
3a: 4a: 11a
3a: 4a: 11a
5a: 6a
7a: 8a
7a: 8a
3b: 4b
7b: 8b
3b: 4b
3b: 4b
7b: 8b
7b: 8b
3c: 4c
7c: 8c
3c: 4c
3c: 4c
5c: 6c
7c: 8c
7c: 8c
3d: 4d
7d: 8d
11d
60: 40
70: 30
58: 42
60
48
56
41
57
55
48
41
66
72
48
40
62
43
66
39
42
40
70
66
41
67
40
42
35
45
6212
39
69
69: 31
42.5: 42.5: 15
30.5: 30.5: 39
47: 53
40: 60
40: 60
59: 41
58: 42
38: 62
31: 69
30: 70
23: 77
56: 44
55: 45
80: 20
85: 15
87: 13
87: 13
92: 8
58: 42
65: 35
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
(i)
(ii)
(ii)
(ii)
(ii)
(i)
(i)
(ii)
(ii)
(ii)
(ii)
(ii)
(i)
(i)
(ii)
(iv)
(ii)
(ii)
(ii)
3d: 4d
5d: 6d
7d: 8d
7d: 8d
34: 66
13: 87
22: 78
7: 93
240
20
240
into the factors controlling the diastereoselectivity in these
reactions.
reactions. Further experiments, conducted in the presence of
triethylborane, were performed only at room temperature.
As expected, the diastereomeric ratio increased with the
steric bulk of the attacking radical. The difference between
the two modes of initiation is not important as regard to the
diastereomeric excess which is only slightly better under
conditions (i). However it is worth noting that the stereo-
selectivity is reversed going from boron- to zinc-mediated
reactions.
Results and Discussion
The reactions were carried out by adding Et3B or Et2Zn
(1 M solutions in hexane) to a solution containing the
imine and an alkyl iodide (if needed) under inert
atmosphere. Air was then injected throughout the solution
(generally over 1 h). The initial experiments were
conducted with imine 1a (Table 1; entries 1±9). The reac-
tion products were assigned respectively the like (3a, 5a, 7a)
and the unlike (4a, 6a, 8a) structures. These assignments
follow from literature data11 according to which, the proton
a to both the amino group and the carboxylate is more
shielded (0.2±0.3 ppm) in the like isomers.
Assuming a substrate controlled stereoinduction, it seems
obvious that the origin of the reversal of selectivity resides
into the nature of the preferred conformation of the substrate
depending upon whether it is associated with triethylborane
or with diethylzinc (Scheme 2). Et3B is a monodentate
complexing agent, whereas Et2Zn is bidentate.
It is noteworthy that the selectivity observed for Et3B-
mediated reactions is similar to that observed using tin
methodology,8a as if Et3B does not change the preferred
It can be noted that lowering the temperature improved the
overall yield signi®cantly in the case of the zinc-promoted
Table 3. Et3B- and Et2Zn-mediated additions to 1e: Reactions of 1e (0.2 M
solution in CH2Cl2) with RI (none or 6 equiv.), air (5 mL), 2408C; (i) Et3B
(3 equiv.), (ii) Et2Zn (2 equiv.)
Table 2. Et3B-mediated radical additions to 2b. Reactions of 2b (0.2 M
solution in CH2Cl2) with Et3B (3 equiv.), RI (6 equiv.), air (5 mL), 2408C
Entry
RI
Products
(diastereomeric ratio,
yield)
Entry
RI
Conditions Products Diastereomeric ratio Yield (%)
1
2
3
4
5
6
None
None
i-PrI
i-PrI
t-BuI
t-BuI
(i)
(ii)
(i)
(ii)
(i)
3e:4e
3e:4e
9e:10e
9e:10e
7e:8e
7e:8e
55:45
42:58
57:43
44:56
62:38
30:70
80
95
72
82
84
87
1
2
c-HexI
t-BuI
12:13 (75:25, 27%);
14:15 (90:10, 25%)
12:13 (75:25, 25%);
16:17 (.99:,1), 25%)
(ii)

M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
3953
Compound 11a was formed in variable amounts depending
on the reaction conditions when diethylzinc was the source
of ethyl radical (entries 5 and 6). In the absence of alkyl
iodide, low stationary concentrations of ethyl radical allows
the nucleophilic pathway to compete with the radical
pathway leading to 3a and 4a.
Experiments conducted with triethylborane preceded those
involving diethylzinc. The rather poor level of diastereo-
selectivity, that was accounted for by the conformational
¯exibility of the starting material, led us to prepare a series
of cyclic imines (2). The mono-substituted imine (2a) did
not bring a signi®cant improvement of the diastereomeric
ratio. The most interesting results were obtained with imine
2b, for which, whatever the conformation, one of the faces
is shielded either by the phenyl or by the methylgroup.8a
This substrate is more reactive than the acyclic imines.15
As reported in Table 2, the d.e reached 80% for the addition
of cyclo-hexyl radical, and only one diastereoisomer was
detected for the addition of tert-butyl radical. There is
however some drawback to increasing the reactivity: the
lack of chemoselectivity. The addition of ethyl radical
competes severely with the addition of the alkyl radical
issued from the alkyl iodide.
Figure 3.
Figure 4.
conformation with respect to the free imine.13 In this model,
due to the minimization of A1,3-strain, the C±H bond lies
close to the plane of the CvN bond, the relative shielding of
the two faces, respectively by the methyl and the phenyl
group, determines the selectivity. A slight preference for
approach syn to the phenyl group is observed (Scheme 2).
We have investigated the behaviour of imines 1b±d which
are open-chain analogues of imines 2. The guess was that
interesting selectivities could be observed with diethylzinc
owing to the possibility offered by these substrates to form
two types of chelates. For the sake of comparison, radical
additions initiated with triethylborane were studied in paral-
lel. The assignments follow from mechanistic analogy with
literature data concerning the addition of various organo-
metallics to closely related compounds,16 they were also
supported by NMR data correlations.17
In the case of diethylzinc, a chelate is formed with the
substrate which forces the imine to adopt a s-cis conforma-
tion. We tentatively suggest that the conformation around
the C±N bond of the amine moiety is reversed so that, in this
®rst generation model, the preferred attack now would take
place at the re-face. It must be recalled that previous work of
van Koten et al14 had shown that under inert atmosphere the
reaction of diethylzinc with glyoxylic imines led to zinc
enolates (Scheme 3). Chelation activates 1,4-nucleophilic
addition, the ethyl group migrates from zinc to nitrogen.
The structure of imine 1b is very close to that of imine 1a.
As regard to boron-mediated reactions, the selectivities
Scheme 2.
Scheme 3.

3954
M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
Scheme 4.
observed with these two substrates were very similar (Table
1: entries 10 and 11/3 and 4).
Imine 1d derived from (d,l)-norephedrine con®rmed the
mechanistic hypothesis. The triethylborane-mediated reac-
tions led to a low diastereoselectivity (Table 1: entries 23
and 24) which can be accounted for by the rather small
differentiation between the two diastereotopic faces in 18d
like in 18c (Scheme 6).
The reaction of 1b with diethylzinc exhibited a higher selec-
tivity (Table 1: entries 12±15). Again the selectivity was
reversed compared to the reactions involving triethylborane.
Two different chelates could result from interaction with the
metal (Scheme 4). Due to the greater basicity of the ether
oxygen atom, the equilibrium is likely to be shifted towards
20b, which would result in clean preferential attack at the
re-face. However, the phenyl group is not bulky enough to
shield completely the si-face, higher diastereomeric ratios
were obtained with the auxiliary derived from l-valinol (1c)
(Table 1: entries 18±22). In this case, it is to be noted that
there was no reversal of selectivity going from boron- to
zinc-mediated reactions (Table 1: entries 16 and 17/18±22).
Whichever complex was involved, preferential attack
occurred opposite to the iso-propyl group (Scheme 5). If
one refers to the selectivity observed in the additions of
organometallic compounds to related imines,1,16 the radical
additions exhibit a lower stereoinduction, although they are
easy to carry out and they allow the use of functional alkyl
iodides. This might be ascribed either to an earlier transition
state for the radical reaction, or more likely to the steric bulk
of the attacking species.
As expected, a reversal of selectivity was observed when the
radical additions were carried out in the presence of diethyl-
zinc (Table 1: entries 25±29). As shown in Scheme 6, due to
steric interactions between the phenyl and the methyl group
in chelate 20d, the equilibrium is shifted towards 19d.
This was con®rmed by adding variable amounts of air to the
reaction medium. Only the preferential formation of
complex 19d could activate 1,4-nucleophilic addition lead-
ing to 11d as the single product. No competitive radical
pathway was observed when 5 mL of air (conditions ii)
were introduced over 1 h (Table 1: entry 25). When the
volume of air was increased up to 20 mL (conditions iv),
even when diethylzinc was the source of ethyl radical, only
the products resulting from the radical reaction were
isolated (Table 1: entry 26).18 The introduction of a second-
ary or a tertiary alkyl iodide resulted in the production of the
corresponding radicals, the addition of which was faster
Scheme 5.
Scheme 6.

M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
3955
Scheme 7. Reactions of 1e (0.2 M solution in CH2Cl2) with RI (none or 6 equiv.), air (5 mL), 2408C; (i): Et3B (3 equiv.), (ii): Et2Zn (2 equiv.)
than the ionic pathway, even under conditions (ii) (Table 1:
entries 27±29).
from the added alkyl iodide). Imines derived from alkoxy-
amines lead to the highest diastereomeric ratios under
chelation controlled conditions i.e. when the reactions are
performed with diethylzinc as chain transfer agent.
The diastereomeric ratio observed for the addition of tert-
butyl radical is as high as that observed with 1c (Table 1:
entries 22/29). Either 19d or 20d could account for the
preferential attack at the re-face. Although disfavoured,
20d might react much faster than 19d with the alkyl radical
since there is no steric hindrance to approach the re-face in
this conformation.
Experimental
All chemicals and reagents were purchased from Aldrich
Chemical Co. NMR spectra (1H, 13C, and DEPT) were
registered in CDCl3; chemical shifts are relative to TMS
as internal reference. Coupling constants are reported in Hz.
It has been shown in the literature, that the alkoxyamines
derived from valinol or norephedrine, could be used as
`chiral source' of nitrogen atoms to prepare primary
amines,19 however benzylic amines look still more attrac-
tive owing to the formally easy removal of the benzyl group
via hydrogenolysis. We had a look at the behaviour of imine
1e that might be expected to lead to a six-membered chelate
(21) with diethylzinc (Scheme 7). Very good selectivities
were registered for the addition of organolithium to related
imines prepared from aromatic aldehydes.20
Starting materials were prepared as racemates unless other-
wise stated; 1a21 and 2a22 were prepared according to
known procedures, and spectral data were in accordance
with literature.
General procedures for radical addition
Method A (conditions i): The alkyl iodide (6 equiv.) was
added (when necessary), under argon at a given tempera-
ture, to a 0.2 M solution of substrate, in dichloromethane.
Triethylborane (3 equiv., 1 M solution in hexane) was then
introduced, and the reaction was stirred at the same
temperature while air (5 mL) was injected through a needle
into the solution over 1 h. The reaction was monitored by
TLC and GPC. After completion, the solvent was evapo-
rated under reduce pressure and the crude product was
puri®ed by FC.
Though this substrate resulted in particularly high yields of
adducts, the selectivity was rather low whatever the reaction
conditions (Table 3).
No reversal of the d.e. was registered going from boron- to
zinc-mediated reactions. If chelate 21 were to be involved,
one would have expected a clean preferential attack at the
re-face and what is more, no reversal of selectivity with
respect to boron. The results show that 19e is likely to be
preferred. This was not obvious on the ground of the close
basicities of the oxygen atoms. The size of the ring in the
chelate by no means can displace the equilibrium in the
expected direction. No further attempts to prepare more
hindered analogues of 1e were made.
Method B (conditions ii): The alkyl iodide (6 equiv.) was
added (when necessary), under argon at a given tempera-
ture, to a 0.2 M solution of substrate, in dichloromethane.
Diethylzinc (2 equiv., 1 M solution in hexane) was then
introduced, and the reaction was stirred at the same
temperature while air (5 mL) was injected through a needle
into the solution over 1 h. The reaction was monitored by
TLC and GPC. The reaction mixture was treated with satu-
rated NH4Cl (10 mL) and extracted with CH2Cl2 (£3). The
organic layer was dried (Na2SO4), ®ltered, and concen-
trated. The crude product was puri®ed by FC.
In conclusion, the screening of the reactivity of a series of
imines derived from chiral amines in triethylborane- and
diethylzinc-mediated radical additions led to the following
observations. Open-chain ¯exible substrates give poor
selectivity. Good stereoinductions are obtained with cyclic
imines, but the major drawback in these reactions is that
their greater reactivity results in a lack of chemoselectivity
(the addition of ethyl radical derived from the mediator
competes with the addition of the alkyl radical issued
Method C (conditions iii): The experimental conditions
were similar to method B except that the reaction was
degassed before introducing Et2Zn.

3956
M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
Method D (conditions iv): The experimental conditions
were similar to method B except that a higher volume of
oxygen was introduced in the solution (air: 20 mL/5 mL)
After stirring at 608C for 2 h, the mixture was cooled,
treated dropwise with methyl iodide (480 mL, 7.6 mmol,
1.05 equiv.), and then heated at re¯ux for 1 h. The reaction
mixture was cooled, and then methanol was added to
destroy the excess of NaH. The mixture was washed with
brine and the aqueous solution was extracted with diethyl
ether (£3). The combined extracts were dried and concen-
trated. The residue was dissolved in dichloromethane
Methyl 2-(1-phenylethylamino)butanoate (3a and 4a).8c
Treating 1a (222 mg, 1.16 mmol) according to method A, at
2408C, in the absence of any alkyl iodide, led to a mixture
of 3a and 4a (143 mg, 0.65 mmol, 56%), isolated as a color-
less oil after puri®cation by FC (5% EtOAc/pentane). The
diastereomeric ratio (58:42) was determined by 1H NMR on
the crude reaction mixture. When treated according to
method B, at 208C 1a (200 mg, 1.05 mmol) led to 3a, 4a,
and 11a (132 mg, 0.59 mmol, 57%) as an inseparable
mixture. The ratio 3a:4a:11a (42.5:42.5:15) was determined
by GPC and 1H NMR on the crude reaction mixture. When
treated according to method C, at 208C, 1a (100 mg,
0.52 mmol) led to 3a:4a:11a (64 mg, 0.28 mmol, 55%) in
a 30.5:30.5:39 ratio.
Ê
(10 mL). Molecular sieves (4 A) and methyl glyoxylate
(871 mg, 9.9 mmol, 1.5 equiv.) were added and the reaction
was stirred at room temperature for 1 h. After concentration,
puri®cation by FC (20% EtOAc/pentane) gave the desired
product 1b (705 mg, 3.2 mmol, 43%). [a]2D1ˆ232.5 (c 1.0,
CH2Cl2). 1H NMR (200 MHz): d 3.34 (s, 3H), 3.67 (dd, 1H,
Jˆ3.9 and 10.2 Hz), 3.82 (t, 1H, Jˆ9.0 Hz), 3.86 (s, 3H),
4.56 (dd, 1H, Jˆ3.9 and 8.8 Hz), 7.23±7.40 (m, 5H), 7.77
(s, 1H). 13C NMR (50 MHz): d 52.5 (CH3), 58.8 (CH3), 74.4
(CH), 76.1 (CH2), 127.2 (CH), 127.8 (CH), 128.6 (CH),
138.6 (C), 153.8 (CH), 163.3 (CvO). Anal. Calcd for
C12H15NO3: C, 65.14; H, 6.83. Found: C, 65.03; H, 6.59.
Methyl 2-cyclohexyl-2-(1-phenylethylamino)ethanoate (5a
and 6a). Treating 1a (200 mg, 1.05 mmol) according to
method B, at 208C, in the presence of cyclohexyl iodide,
led to a mixture of 5a and 6a (137 mg, 0.5 mmol, 48%),
isolated as a colorless oil after puri®cation by FC (5%
EtOAc/pentane). The diastereomeric ratio (47:53) was
Methyl 2-(2-methoxy-1-phenylethylamino)butanoate (3b
and 4b). Treating 1b (150 mg, 0.68 mmol) according to
method A, at 208C, led to a mixture of 3b and 4b
(120 mg, 0.48 mmol, 72%), isolated as a colorless oil after
puri®cation by FC (10% EtOAc/pentane). The diastereo-
1
1
determined from H NMR. H NMR (400 MHz): (major
isomer: 6a) d 0.90±1.85 (m, 12H), 1.29 (d, 3H,
Jˆ6.5 Hz), 3.09 (d, 1H, Jˆ6.5 Hz), 3.54 (s, 3H), 3.65 (q,
1H, Jˆ6.5 Hz), 7.16±7.31 (m, 5H); (minor isomer: 5a) d
0.90±1.85 (m, 11H), 1.30 (d, 3H, Jˆ6.5 Hz), 2.78 (d, 1H,
Jˆ6.5 Hz), 3.59 (q, 1H, Jˆ6.5 Hz), 3.68 (s, 3H), 7.16±7.31
(m, 5H). 13C NMR (50 MHz): (major isomer: 6a) d 22.5
(CH3), 26.2 (2£CH2), 29.03 (CH2), 29.4 (CH2), 29.8 (CH2),
41.5 (CH), 51.2 (CH3), 56.9 (CH), 64.6 (CH), 126.7 (CH),
126.8 (CH), 128.1 (CH),145.7 (C), 175.7 (CvO); (minor
isomer: 5a) d 25.6 (CH3), 26.1 (2£CH2), 29.03 (CH2), 29.5
(CH2), 29.8 (CH2), 41.4 (CH), 51.2 (CH3), 56.8 (CH), 64.2
(CH), 126.8 (CH), 126.9 (CH), 128.2 (CH),145.1 (C), 176.3
(C). Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15. Found:
C, 73.95; H, 9.15.
1
meric ratio (59:41) was determined from H NMR on the
crude reaction mixture. 1H NMR (200 MHz): (major
isomer: 3b): d 0.91 (t, 3H, Jˆ7.3 Hz), 1.57 (quint, 2H,
Jˆ7.1 Hz), 2.85 (br s, 1H), 2.91 (t, 1H, Jˆ6.8 Hz), 3.38
(s, 3H), 3.20±3.60 (m, 2H), 3.70 (s, 3H), 3.87 (dd, 1H,
Jˆ4.6 and 8.6 Hz), 7.24±7.36 (m, 5H); (minor isomer:
4b): d 0.88 (t, 3H, Jˆ7.3 Hz), 1.65 (quint, 2H, Jˆ7.1 Hz),
2.85 (br s, 1H), 3.28 (t, 1H, Jˆ6.8 Hz), 3.34 (s, 3H), 3.20±
3.60 (m, 2H), 3.53 (s, 3H), 3.92 (dd, 1H, Jˆ5.1 and 7.6 Hz),
7.24±7.36 (m, 5H). 13C NMR (50 MHz): (major isomer:
3b): d 10.3 (CH3), 27.0 (CH2), 51.4 (CH3), 58.4 (CH3),
59.5 (CH), 60.3 (CH), 77.7 (CH2), 127.6 (CH), 127.7
(CH), 128.3 (CH), 139.9 (C), 176.0 (CvO); (minor isomer:
4b): d 9.4 (CH3), 26.2 (CH2), 51.4 (CH3), 58.8 (CH3), 59.5
(CH), 60.7 (CH), 77.3 (CH2), 127.6 (CH), 127.7 (CH), 128.3
(CH), 139.9 (C), 175.9 (CvO). Anal. Calcd for C14H21NO3:
C, 66.91; H, 8.42. Found: C, 66.94; H, 8.47. When treated
according to method B, at 208C, 1b (150 mg, 0.68 mmol)
led to 3b and 4b (68 mg, 0.27 mmol, 40%) in a 38:62 ratio.
Treating 1b (150 mg, 0.68 mmol) according to method B, at
2408C, led to 3b and 4b (105 mg, 0.42 mmol, 62%) in a
31:69 ratio.
Methyl 3,3-dimethyl-2-(1-phenylethylamino)butanoate (7a
and 8a).8c Treating 1a (132 mg, 0.70 mmol) according to
method A, at 208C, in the presence of t-butyl iodide, led to a
mixture of 7a and 8a (71 mg, 0.28 mmol, 41%), isolated as a
colorless oil after puri®cation by FC (3% EtOAc/pentane).
1
The diastereomeric ratio (69:31) was determined from H
NMR on the crude reaction mixture. Treating 1a (160 mg,
0.84 mmol) according to method A, at 2788C, in the
presence of t-butyl iodide, led to 7a and 8a (93 mg,
0.38 mmol, 48%) in a 70:30 ratio. When treated according
to method B, at 208C, in the presence of t-butyl iodide, 1a
(136 mg, 0.71 mmol) led to 7a and 8a (72 mg, 0.29 mmol,
41%) in a 40:60 ratio. Treating 1a (100 mg, 0.52 mmol)
according to method B, at 2408C, in the presence of
t-butyl iodide, led to 7a and 8a (85 mg, 0.34 mmol, 66%)
in a 40:60 ratio.
Methyl 3,3-dimethyl-2-(2-methoxy-1-phenylethylamino)-
butanoate (7b and 8b). Treating 1b (150 mg, 0.68 mmol)
according to method A, at 208C, in the presence of t-butyl
iodide, led to a mixture of 7b and 8b (92 mg, 0.33 mmol,
48%), isolated as a colorless oil after puri®cation by FC
(10% EtOAc/pentane). The diastereomeric ratio (58:42)
was determined from 1H NMR on the crude reaction
1
mixture. H NMR (200 MHz): (major isomer: 7b): d 0.85
(s, 9H), 2.20 (br s, 1H), 2.66 (s, 1H), 3.29 (s, 3H), 3.20±3.70
(m, 3H), 3.62 (s, 3H), 7.17±7.26 (m, 5H); (minor isomer:
8b): d 0.88 (s, 9H), 2.20 (br s, 1H), 2.94 (s, 1H), 3.24 (s,
3H), 3.20±3.70 (m, 3H), 3.35 (s, 3H), 7.17±7.26 (m, 5H).
13C NMR (50 MHz): (major isomer: 7b): d 26.7 (3£CH3),
33.8 (C), 50.9 (CH3), 58.5 (CH3), 60.7 (CH), 67.1 (CH),
Methyl (2-methoxy-1-phenylethylimino)acetate (1b). A
solution of (R)-(2)-2-amino-2-phenylethanol (1 g,
7.3 mmol) in THF (2 mL) was added dropwise to a suspen-
sion of sodium hydride 60% in mineral oil (600 mg,
14.6 mmol, 2 equiv.) in THF (12 mL) at room temperature.

M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
3957
77.8 (CH2), 127.6 (CH), 127.9 (CH), 128.3 (CH), 141.4 (C),
175.6 (CvO); (minor isomer: 8b): d 26.6 (3£CH3), 34.5
(C), 50.9 (CH3), 58.9 (CH3), 63.1 (CH), 69.2 (CH), 77.3
(CH2), 127.4 (CH), 127.7 (CH), 128.2 (CH), 140.2 (C),
175.4 (CvO). Anal. Calcd for C16H25NO3: C, 68.79; H,
9.02. Found: C, 68.72; H, 9.13. When treated according to
method B, at 208C, in the presence of t-butyl iodide, 1b
(150 mg, 0.68 mmol) led to 7b and 8b (81 mg,
0.29 mmol, 43%) in a 30:70 ratio. Treating 1b (150 mg,
0.68 mmol) according to method B, at 2408C, in the
presence of t-butyl iodide, led to 7b and 8b (125 mg,
0.45 mmol, 66%) in a 23:77 ratio.
on the crude reaction mixture. 1H NMR (200 MHz):
(major isomer: 5c): d 0.91 (d, 6H, Jˆ6.8 Hz), 0.95±1.58
(m, 13H), 2.35 (q, 1H, Jˆ5.1 Hz), 3.18 (d, 1H, Jˆ6.3 Hz),
3.22±3.37 (m, 2H), 3.30 (s, 3H), 3.69 (s, 3H); (minor
isomer: 6c): d 0.89 (d, 6H, Jˆ6.8 Hz), 0.95±1.58 (m,
13H), 2.44 (q, 1H, Jˆ4.2 Hz), 3.05 (d, 1H, Jˆ6.3 Hz),
3.22±3.37 (m, 2H), 3.28 (s, 3H), 3.69 (s, 3H). 13C NMR
(50 MHz): (major isomer: 5c): d 18.1 (CH3), 18.8 (CH3),
26.1(2£CH2), 26.3 (CH2), 29.3 (CH2), 29.6 (CH2), 29.8
(CH), 41.4 (CH), 51.2 (CH3), 58.8 (CH3), 61.4 (CH), 65.3
(CH), 73.9 (CH2), 176.0 (CvO); (minor isomer: 6c): d 17.6
(CH3), 18.8 (CH3), 26.1 (2£CH2), 26.3 (CH2), 28.7 (CH),
29.3 (CH2), 29.8 (CH2), 41.9 (CH), 50.8 (CH3), 58.6 (CH3),
60.9 (CH), 65.3 (CH), 73.4 (CH2), 174.1 (CvO). Anal.
Calcd for C15H29NO3: C, 66.38; H, 10.77. Found: C,
66.51; H, 10.81.
Methyl (1-methoxymethyl-2-methylpropylimino)acetate
(1c). 1-Methoxymethyl-2-methylpropylamine23 (390 mg,
3.31 mmol) prepared from l-valinol was dissolved in
Ê
dichloromethane (15 mL). Molecular sieves (4 A) and
methyl glyoxylate (436 mg, 4.96 mmol, 1.5 equiv.) were
added and the reaction was stirred at room temperature for
1 h. After concentration, a puri®cation by FC (20% EtOAc/
pentane) gave the desired product 1c (464 mg, 2.48 mmol,
Methyl 3,3-dimethyl-2-(1-methoxymethyl-2-methylpro-
pylamino)butanoate (7c and 8c). Treating 1c (150 mg,
0.80 mmol) according to method A, at 208C, in the presence
of t-butyl iodide, led to a mixture of 7c and 8c (128 mg,
0.52 mmol, 42%), isolated as a colorless oil after puri®ca-
tion by FC (3% EtOAc/pentane). The diastereomeric ratio
(55:45) was determined from 1H NMR on the crude reaction
mixture. 1H NMR (400 MHz): (major isomer: 7c): d 0.87 (d,
3H, Jˆ6.8 Hz), 0.88 (d, 3H, Jˆ6.8 Hz), 0.91 (s, 9H), 1.61
(br s, 1H), 1.76 (dsept, 1H, Jˆ4.9 and 6.8 Hz), 2.27 (q, 1H,
Jˆ4.9 Hz), 3.05 (s, 1H), 3.23±3.32 (m, 2H), 3.28 (s, 3H),
3.66 (s, 3H); (minor isomer: 8c): d 2.36 (q, 1H, Jˆ4.1 Hz),
2.91 (s, 1H). 13C NMR (50 MHz): (major isomer: 7c): d
17.9 (CH3), 18.9 (CH3), 26.6 (3£CH3), 29.8 (CH), 34.1
(C), 51.0 (CH3), 58.8 (CH3), 61.6 (CH), 68.7 (CH), 74.2
(CH2), 175.9 (CvO); (minor isomer: 8c): d 17.9 (CH3),
18.8 (CH3), 26.7 (3£CH3), 29.0 (CH), 34.6 (C), 51.0
(CH3), 58.7 (CH3), 61.7 (CH), 68.3 (CH), 73.7 (CH2),
175.0 (CvO). Anal. Calcd for C13H27NO3: C, 63.64; H,
11.09. Found: C, 63.60; H, 11.00. When treated according
to method B, at 208C, in the presence of t-butyl iodide, 1c
(150 mg, 0.80 mmol) led to 7c and 8c (80 mg, 0.33 mmol,
41%) in a 87:13 ratio. Treating 1c (150 mg, 0.80 mmol)
according to method B, at 2408C, in the presence of
t-butyl iodide, led to 7c and 8c (130 mg, 0.53 mmol, 67%)
in a 92:8 ratio.
1
75%). [a]2D1ˆ231.3 (c 1.0, CH2Cl2). H NMR (200 MHz):
d 0.88 (d, 3H, Jˆ6.6 Hz), 0.94 (d, 3H, Jˆ6.6 Hz), 1.96 (oct,
1H, Jˆ6.6 Hz), 3.09 (ddd, 1H, Jˆ9.5, 6.6, and 3.7 Hz), 3.30
(s, 3H), 3.54 (t, 1H, Jˆ9.5 Hz), 3.62 (dd, 1H, Jˆ9.5 and
3.7 Hz), 7.64 (s, 1H). 13C NMR (50 MHz): d 18.9 (CH3),
19.3 (CH3), 29.7 (CH), 52.3 (CH3), 58.6 (CH3), 73.2 (CH2),
76.5 (CH), 153.1 (CH), 163.2 (CvO). Anal. Calcd for
C9H17NO3: C, 57.73; H, 9.15. Found: C, 57.65; H, 9.08.
Methyl
2-(1-methoxymethyl-2-methylpropylamino)-
butanoate (3c and 4c). Treating 1c (150 mg, 0.80 mmol)
according to method A, at 208C, led to a mixture of 3c and
4c (68 mg, 0.31 mmol, 39%), isolated as a colorless oil after
puri®cation by FC (5% EtOAc/pentane). The diastereomer-
ic ratio (56:44) was determined from 1H NMR on the crude
reaction mixture. 1H NMR (400 MHz): (major isomer: 3c):
d 0.91 (d, 3H, Jˆ6.8 Hz), 0.92 (t, 3H, Jˆ7.2 Hz), 0.93 (d,
3H, Jˆ6.8 Hz), 1.60±1.72 (m, 3H), 1.78 (dsept, 1H, Jˆ5.1
and 6.8 Hz), 2.43 (dt, 1H, Jˆ5.1 and 5.5 Hz), 3.28 (dd, 1H,
Jˆ5.8 and 9.8 Hz), 3.31 (s, 3H), 3.34±3.40 (m, 2H), 3.71 (s,
3H); (minor isomer: 4c): d 2.49 (dt, 1H, Jˆ4.1 and 8.1 Hz),
3.29 (s, 3H), 3.71 (s, 3H). 13C NMR (50 MHz): (major
isomer: 3c): d 10.2 (CH3), 18.5 (CH3), 18.7 (CH3), 27.0
(CH2), 29.7 (CH), 51.5 (CH3), 58.9 (CH3), 61.2 (2£CH),
73.8 (CH2), 176.3 (CvO); (minor isomer: 4c): d 10.4
(CH3), 17.8 (CH3), 18.5 (CH3), 28.8 (CH), 28.9 (CH2),
51.5 (CH3), 58.7 (CH3), 60.8 (CH), 61.3 (CH), 73.7
(CH2), 176.0 (CvO). Anal. Calcd for C11H23NO3: C,
60.80; H, 10.67. Found: C, 60.91; H, 10.70. When treated
according to method B, at 208C, 1c (144 mg, 0.77 mmol) led
to 3c and 4c (67 mg, 0.31 mmol, 40%) in a 80:20 ratio.
Treating 1c (150 mg, 0.80 mmol) according to method B,
at 2408C, led to 3c and 4c (120 mg, 0.55 mmol, 70%) in a
85:15 ratio.
Methyl (2-methoxy-1-methyl-2-phenylethylimino)acetate
(1d). A solution of (d,l)-norephedrine (1 g, 6.6 mmol)
(prepared from the commercially available hydrochloride
salt (Aldrich Chemical Co.) by neutralization and then
CH2Cl2 extraction) in THF (2 mL) was added dropwise to
a suspension of sodium hydride 60% in mineral oil (530 mg,
13.2 mmol, 2 equiv.) in THF (12 mL) at room temperature.
After stirring at 608C for 2 h, the mixture was cooled,
treated dropwise with methyliodide (430 mL, 6.9 mmol,
1.05 equiv.), and then heated at re¯ux for 1 h. The reaction
mixture was cooled, and then methanol was added to
destroy the excess of NaH. The mixture was washed with
brine and the aqueous solution was extracted with diethyl
ether (£3). The combined extracts were dried and concen-
trated. The residue was dissolved in dichloromethane
Methyl 2-cyclohexyl-2-(1-methoxymethyl-2-methylpro-
pylamino)ethanoate (5c and 6c). Treating 1c (150 mg,
0.80 mmol) according to method B, at 2408C, in the
presence of cyclohexyl iodide, led to a mixture of 5c and
6c (143 mg, 0.53 mmol, 66%), isolated as a colorless oil
after puri®cation by FC (5% EtOAc/pentane). The dia-
Ê
(10 mL). Molecular sieves (4 A) and methyl glyoxylate
(871 mg, 9.9 mmol, 1.5 equiv.) were added and the reaction
was stirred at room temperature for 1 h. After concentration,
puri®cation by FC (20% EtOAc/pentane) gave the desired
1
stereomeric ratio (87:13) was determined from H NMR

3958
M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
product 1d (620 mg, 2.6 mmol, 40%). 1H NMR (200 MHz):
d 1.35 (d, 3H, Jˆ6.4 Hz), 3.24 (s, 3H), 3.60 (q, 1H,
Jˆ6.4 Hz), 3.80 (s, 3H), 4.27 (d, 1H, Jˆ6.4 Hz), 7.17±
7.31 (m, 5H), 7.37 (s, 1H). 13C NMR (50 MHz): d 17.77
(CH3), 52.45 (CH3), 57.04 (CH3), 71.10 (CH), 86.09 (CH),
127.56 (CH), 127.82 (CH), 128.11 (CH), 138.76 (C), 152.74
(CH), 167.75 (CvO). Anal. Calcd for C13H17NO3: C, 66.36;
H, 7.28. Found: C, 66.19; H, 7.26.
Jˆ6.6 Hz), 3.21 (s, 3H), 3.61 (s, 3H), 3.95 (d, 1H,
Jˆ5.6 Hz), 7.25±7.38 (m, 5H). 13C NMR (50 MHz):
(major isomer: 6d): d 16.4 (CH3), 26.0 (CH2), 26.1 (CH2),
26.2 (CH2), 29.1 (CH2), 29.5 (CH2), 41.4 (CH), 51.4 (CH3),
57.2 (CH), 58.3 (CH3), 65.6 (CH), 86.8 (CH), 127.3 (CH),
127.4 (CH), 128.1 (CH), 140.1 (C), 176.2 (CvO); (minor
isomer: 5d): d 15.8 (CH3), 26.1 (CH2), 26.2 (CH2), 26.3
(CH2), 29.6 (CH2), 29.7 (CH2), 41.4 (CH), 51.2 (CH3),
56.4 (CH), 57.0 (CH3), 64.2 (CH), 87.6 (CH), 127.3 (CH),
127.8 (CH), 128.2 (CH), 140.1 (C), 175.9 (CvO). Anal.
Calcd for C19H29NO3: C, 71.44; H, 9.15. Found: C, 71.28;
H, 9.12.
Methyl
2-(2-methoxy-1-methyl-2-phenylethylamino)-
butanoate (3d and 4d). Treating 1d (150 mg, 0.63 mmol)
according to method A, at 208C, led to a mixture of 3d and
4d (65 mg, 0.25 mmol, 40%), isolated as a colorless oil after
puri®cation by FC (10% EtOAc/pentane). The diastereo-
Methyl 3,3-dimethyl-2-(2-methoxy-1-methyl-2-phenyl-
ethylamino)butanoate (7d and 8d). Treating 1d (100 mg,
0.42 mmol) according to method A, at 208C, in the presence
of t-butyl iodide, led to a mixture of 7d and 8d (53 mg,
0.18 mmol, 42%), isolated as a colorless oil after puri®ca-
tion by FC (5% EtOAc/pentane). The diastereomeric ratio
(65:35) was determined from 1H NMR on the crude reaction
mixture. 1H NMR (200 MHz): (major isomer: 7d): d 0.85 (s,
9H), 0.99 (d, 3H, Jˆ6.4 Hz), 1.56 (br s, 1H), 2.70 (dq, 1H,
Jˆ5.4 and 6.4 Hz), 2.96 (s, 1H), 3.21 (s, 3H), 3.60 (s, 3H),
3.92 (d, 1H, Jˆ5.4 Hz), 7.24±7.33 (m, 5H); (minor isomer:
8d): d 0.82 (s, 9H), 1.00 (d, 3H, Jˆ6.6 Hz), 1.56 (br s, 1H),
2.59 (dq, 1H, Jˆ5.1 and 6.6 Hz), 2.80 (s, 1H), 3.24 (s, 3H),
3.68 (s, 3H), 4.03 (d, 1H, Jˆ5.4 Hz), 7.24±7.33 (m, 5H). 13C
NMR (50 MHz): (major isomer: 7d): d 16.1 (CH3), 26.8
(3£CH3), 34.1 (C), 51.0 (CH3), 57.0 (CH3), 56.7 (CH),
67.6 (CH), 87.6 (CH), 127.8 (CH), 127.9 (CH), 128.2
(CH), 139.3 (C), 175.3 (CvO); (minor isomer: 8d): d
17.0 (CH3), 26.6 (3£CH3), 34.2 (C), 51.2 (CH3), 57.3
(CH3), 59.2 (CH), 69.5 (CH), 87.1 (CH), 127.4 (CH),
127.6 (CH), 128.1 (CH), 140.4 (C), 176.3 (CvO). Anal.
Calcd for C17H27NO3: C, 69.59; H, 9.28. Found: C, 69.39;
H, 9.25. When treated according to method B, at 208C, in
the presence of t-butyl iodide, 1d (100 mg, 0.42 mmol) led
to 7d and 8d (46 mg, 0.16 mmol, 39%) in a 22:78 ratio.
Treating 1d (200 mg, 0.85 mmol) according to method B,
at 2408C, in the presence of t-butyl iodide, led to 7d and 8d
(172 mg, 0.59 mmol, 69%) in a 7:93 ratio.
1
meric ratio (58:42) was determined from H NMR on the
crude reaction mixture. 1H NMR (400 MHz): (major
isomer: 3d): d 0.85 (t, 3H, Jˆ7.3 Hz), 1.06 (d, 3H,
Jˆ6.4 Hz), 1.58 (quint, 2H, Jˆ7.3 Hz), 2.80 (quint, 1H,
Jˆ6.4 Hz), 3.30 (t, 1H, Jˆ6.6 Hz), 3.22 (s, 3H), 3.57 (br
s, 1H), 3.64 (s, 3H), 4.01 (d, 1H, Jˆ5.9 Hz), 7.26±7.35 (m,
5H); (minor isomer: 4d): d 0.79 (t, 3H, Jˆ7.3 Hz), 1.04 (d,
3H, Jˆ6.6 Hz), 1.56 (quint, 2H, Jˆ7.3 Hz), 2.75 (quint, 1H,
Jˆ6.6 Hz), 3.13 (t, 1H, Jˆ6.4 Hz), 3.24 (s, 3H), 3.57 (br s,
1H), 3.70 (s, 3H), 4.10 (d, 1H, Jˆ5.1 Hz), 7.26±7.35 (m,
5H). 13C NMR (50 MHz): (major isomer: 3d): d 10.1 (CH3),
15.3 (CH3), 26.8 (CH2), 51.4 (CH3), 56.1 (CH3), 57.4 (CH),
60.7 (CH), 87.2 (CH), 127.4 (CH), 127.6 (CH), 128.2 (CH),
134.0 (C), 175.3 (CvO); (minor isomer: 4d): d 9.9 (CH3),
15.9 (CH3), 26.3 (CH2), 51.6 (CH3), 56.9 (CH3), 57.1 (CH),
59.8 (CH), 86.5 (CH), 127.3 (CH), 127.8 (CH), 128.1 (CH),
139.7 (C), 179.9 (CvO). Anal. Calcd for C15H23NO3: C,
67.90; H, 8.74. Found: C, 67.83; H, 8.71. Treating 1d
(300 mg, 1.27 mmol) according to method D, at 208C, led
to 3d and 4d (167 mg, 0.57 mmol, 45%) in a 34:66 ratio.
Methyl (ethyl-(2-methoxy-1-methyl-2-phenylethyl)ami-
no)acetate (11d). Treating 1d (150 mg, 0.64 mmol) accord-
ing to method B, at 208C, led to 11d (59 mg, 0.23 mmol,
35%), isolated as a colorless oil after puri®cation by FC
1
(10% EtOAc/pentane). H NMR (400 MHz): d 0.96 (d,
3H, Jˆ6.7 Hz), 1.01 (t, 3H, Jˆ7.1 Hz), 2.73 (q, 2H,
Jˆ7.1 Hz), 2.92 (dq, 1H, Jˆ3.3 and 6.7 Hz), 3.18 (s, 3H),
3.45 (AB, 2H, Jˆ17.3 Hz, Dnˆ50 Hz), 3.67 (s, 3H), 4.41
(d, 1H, Jˆ3.3 Hz), 7.18±7.35 (m, 5H). 13C NMR (50 MHz):
d 9.2 (CH3), 13.8 (CH3), 47.3 (CH2), 51.5 (CH2), 51.6
(CH3), 56.8 (CH3), 61.9 (CH), 85.4 (CH), 126.8 (CH),
127.1 (CH), 128.2 (CH), 141.0 (C), 173.6 (CvO). Anal.
Calcd for C15H23NO3: C, 67.90; H, 8.74. Found: C, 67.81;
H, 8.69.
5-Methyl-6-phenyl-5,6-dihydro-1,4-oxazin-2-one (2b). 2b
was prepared from 2,4-dimethyl-5-phenyl-4,5-dihydro-
oxazole according to a procedure described by Molinski
et al.22 H NMR (200 MHz): d 0.96 (d, 3H, Jˆ7.1 Hz),
4.27 (qdd, 1H, Jˆ1.2, 3.2 and 7.1 Hz), 5.58 (d, 1H,
Jˆ3.2 Hz), 7.31±7.48 (m, 5H), 7.93 (d, 1H, Jˆ1.2 Hz).
13C NMR (50 MHz): d 12.5 (CH3), 57.6 (CH), 79.8 (CH),
125.3 (CH), 128.4 (CH), 128.6 (CH), 134.9 (C), 151.6 (CH),
155.3 (CvO). Anal. Calcd for C11H11NO2: C, 69.83; H,
5.86. Found: C, 69.69; H, 5.54.
Methyl 2-cyclohexyl-2-(2-methoxy-1-methyl-2-phenyl-
ethylamino)ethanoate (5d and 6d). Treating 1d (70 mg,
0.30 mmol) according to method B, at 2408C, in the
presence of cyclohexyl iodide, led to a mixture of 5d and
6d (60 mg, 0.19 mmol, 62%), isolated as a colorless oil after
puri®cation by FC (5% EtOAc/pentane). The diastereomeric
3-Cyclohexyl-5-methyl-6-phenyl morpholin-2-one (14
and 15). Treating 2b (178 mg, 0.94 mmol) according to
method A, at 2408C, in the presence of cyclohexyl iodide,
led to a mixture of four products: 14, 15 (63 mg, 0.23 mmol,
27%) and 12, 13 (51 mg, 0.23 mmol, 25%), isolated as
colorless oils after puri®cation by FC (15% EtOAc/
pentane). The diastereomeric ratios (14:15: 90:10 and
12:13: 75:25) were determined from 1H NMR on the
crude reaction mixture. 1H NMR (200 MHz): (major
isomer: 14): d 0.92 (d, 2H, Jˆ6.6 Hz), 1.03±2.30 (m,
1
ratio (13:87) was determined from H NMR on the crude
reaction mixture. 1H NMR (200 MHz): (major isomer: 6d):
d 1.02 (d, 3H, Jˆ6.6 Hz), 0.76±1.75 (m, 12H), 2.62 (dq,
1H, Jˆ5.1 and 6.6 Hz), 2.92 (d, 1H, Jˆ6.1 Hz), 3.24 (s, 3H),
3.69 (s, 3H), 4.05 (d, 1H, Jˆ5.1 Hz), 7.25±7.38 (m, 5H);
(minor isomer: 5d): d 1.00 (d, 3H, Jˆ6.4 Hz), 0.76±1.75
(m, 12H), 2.75 (dq, 1H, Jˆ5.6 and 6.4 Hz), 3.07 (d, 1H,

M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
3959
12H), 3.46 (dq, 1H, Jˆ3.2 and 6.6 Hz), 3.74 (d, 1H,
Jˆ3.6 Hz), 5.59 (d, 1H, Jˆ3.2 Hz), 7.20±7.55 (m, 5H);
(minor isomer: 15): d 0.85 (d, 3H, Jˆ6.6 Hz), 1.03±2.30
(m, 12H), 3.46 (dq, 1H, Jˆ4.4 and 6.6 Hz), 3.63 (d, 1H,
Jˆ3.2 Hz), 5.35 (d, 1H, Jˆ4.4 Hz), 7.20±7.55 (m, 5H).
13C NMR (50 MHz): (major isomer: 14): d 13.1 (CH3),
26.0 (CH2), 26.1 (CH2), 26.4 (CH2), 27.6 (CH2), 29.6
(CH2), 42.0 (CH), 50.3 (CH), 58.6 (CH), 84.0 (CH), 125.5
(CH), 127.9 (CH), 128.4 (CH), 136.6 (C), 170.1 (CvO);
(minor isomer: 15): d 17.4 (CH3), 26.0 (CH2), 26.1 (CH2),
26.5 (CH2), 27.6 (CH2), 29.9 (CH2), 39.9 (CH), 52.0 (CH),
64.0 (CH), 84.1 (CH), 125.5 (CH), 127.6 (CH), 128.3 (CH),
136.6 (C), 169.9 (CvO). Anal. Calcd for C17H23NO2: C,
74.69; H, 8.48. Found: C, 74.64; H, 8.49.
method A, at 2408C, led to a mixture of 3e and 4e
(90 mg, 0.36 mmol, 90%), isolated as a colorless oil after
puri®cation by FC (10% EtOAc/pentane). The diastereo-
1
meric ratio (55:45) was determined from H NMR on the
crude reaction mixture. 1H NMR (400 MHz): (major
isomer: 3e): d 0.81 (t, 3H, Jˆ7.6 Hz), 1.23 (d, 3H,
Jˆ6.6 Hz), 1.44±1.64 (m, 2H), 1.95 (br s, 1H), 2.91 (t,
1H, Jˆ6.6 Hz), 3.59 (s, 3H), 3.69 (s, 3H), 4.05 (q, 1H,
Jˆ6.6 Hz), 6.72±6.88 (m, 2H), 7.05±7.39 (m, 2H); (minor
isomer: 4e): d 0.81 (t, 3H, Jˆ7.6 Hz), 1.27 (d, 3H,
Jˆ6.6 Hz), 1.44±1.64 (m, 2H), 1.95 (br s, 1H), 3.11 (t,
1H, Jˆ6.6 Hz), 3.41 (s, 3H), 3.73 (s, 3H), 4.03 (q, 1H,
Jˆ6.6 Hz), 6.72±6.88 (m, 2H), 7.05±7.39 (m, 2H). 13C
NMR (50 MHz): (major isomer: 3e): d 9.8 (CH3), 21.9
(CH3), 27.0 (CH2), 49.6 (CH), 51.3 (CH3), 55.1 (CH3),
60.2 (CH), 110.3 (CH), 120.4 (CH), 127.2 (CH), 127.6
(CH), 139.9 (C), 157.1 (C), 176.3 (CvO); (minor isomer:
4e): d 10.2 (CH3), 22.9 (CH3), 26.2 (CH2), 50.7 (CH), 51.2
(CH3), 55.1 (CH3), 60.4 (CH), 110.4 (CH), 120.5 (CH),
126.8 (CH), 127.4 (CH), 132.8 (C), 156.9 (C), 175.5
(CvO). Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42.
Found: C, 66.70; H, 8.31. Treating 1e (100 mg,
0.45 mmol) according to method B, at 2408C, led to 3e
and 4e (108 mg, 0.43 mmol, 95%) in a 42:58 ratio.
3-t-Butyl-5-methyl-6-phenyl morpholin-2-one (16 and
17). Treating 2b (184 mg, 0.97 mmol) according to method
A, at 2408C, in the presence of t-butyl iodide, led to a
mixture of four products: 16, 17 (60 mg, 0.24 mmol, 25%)
and 12, 13 (53 mg, 0.24 mmol, 25%), isolated as colorless
oils after puri®cation by FC (10% EtOAc/pentane). The
diastereomeric ratios (16:17: 99.1 and 12:13: 75:25)
were determined from 1H NMR on the crude reaction
1
mixture. H NMR (200 MHz): (major isomer: 16): d 0.85
(d, 3H, Jˆ6.8 Hz), 1.05 (s, 9H), 1.50 (br s, 1H), 3.41 (dq,
1H, Jˆ2.9 and 6.8 Hz), 3.50 (s, 1H), 5.59 (d, 1H, Jˆ2.9 Hz),
7.25±7.40 (m, 5H). 13C NMR (50 MHz): (major isomer:
16): d 13.7 (CH3), 26.8 (3£CH3), 36.1 (C), 50.9 (CH),
62.5 (CH), 83.5 (CH), 125.5 (CH), 127.6 (CH), 127.7
(CH), 137.3 (C), 169.7 (CvO). Anal. Calcd for
C15H21NO2: C, 72.84; H, 8.56. Found: C, 72.49; H, 8.35.
Methyl
3-methyl-2-(1-o-methoxyphenylethylamino)-
butanoate (9e and 10e). Treating 1e (100 mg, 0.45 mmol)
according to method A, at 2408C, in the presence of iso-
propyl iodide led to a mixture of 9e and 10e (86 mg,
0.32 mmol, 72%), isolated as a colorless oil after puri®ca-
tion by FC (5% EtOAc/pentane). The diastereomeric ratio
(57:43) was determined from 1H NMR on the crude reaction
mixture. 1H NMR (200 MHz): (major isomer: 9e): d 0.85 (d,
3H, Jˆ6.8 Hz), 0.88 (d, 3H, Jˆ6.8 Hz), 1.22 (d, 3H,
Jˆ6.6 Hz), 1.75 (oct, 1H, Jˆ6.8 Hz), 1.87 (br s, 1H), 2.76
(d, 1H, Jˆ6.6 Hz), 3.60 (s, 3H), 3.70 (s, 3H), 4.03 (q, 1H,
Jˆ6.6 Hz), 6.73±6.90 (m, 2H), 7.05±7.46 (m, 2H); (minor
isomer: 10e): d 0.80 (d, 3H, Jˆ6.8 Hz), 0.82 (d, 3H,
Jˆ6.8 Hz), 1.24 (d, 3H, Jˆ6.6 Hz), 1.75 (oct, 1H,
Jˆ6.8 Hz), 1.87 (br s, 1H), 2.92 (d, 1H, Jˆ6.6 Hz), 3.38
(s, 3H), 3.73 (s, 3H), 3.96 (q, 1H, Jˆ6.6 Hz), 6.73±6.90 (m,
2H), 7.05±7.46 (m, 2H). 13C NMR (50 MHz): (major
isomer: 9e): d 18.9 (CH3), 19.4 (CH3), 23.2 (CH3), 31.7
(CH), 51.0 (CH), 51.2 (CH3), 55.2 (CH3), 64.8 (CH),
110.3 (CH), 120.6 (CH), 127.1 (CH), 127.4 (CH), 132.9
(C), 157.3 (C), 176.3 (CvO); (minor isomer: 10e): d 18.6
(CH3), 18.9 (CH3), 21.7 (CH3), 31.9 (CH), 49.5 (CH), 51.5
(CH3), 55.2 (CH3), 65.4 (CH), 110.4 (CH), 120.5 (CH),
127.3 (CH), 127.6 (CH), 133.5 (C), 156.8 (C), 175.6
(CvO). Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74.
Found: C, 67.85; H, 8.72. Treating 1e (100 mg,
0.45 mmol) according to method B, at 2408C, in the
presence of isopropyl iodide, led to 9e and 10e (98 mg,
0.37 mmol, 82%) in a 44:56 ratio.
3-Ethyl-5-methyl-6-phenyl morpholin-2-one (12 and 13).
1H NMR (200 MHz): (major isomer: 12): d 0.91 (d, 3H,
Jˆ6.8 Hz), 1.12 (t, 3H, Jˆ7.1 Hz), 1.73±1.90 (m, 1H),
2.08±2.35 (m, 1H), 3.45±3.59 (m, 1H), 3.85 (ddd, 1H,
Jˆ4.9, 7.8 and 10.3 Hz), 4.98 (d, 1H, Jˆ4.9 Hz), 5.98 (d,
1H, Jˆ7.8 Hz, NH), 7.27±7.42 (m, 5H). 13C NMR
(50 MHz): (major isomer: 12): d 13.0 (CH3), 13.6 (CH3),
31.9 (CH2), 51.0 (CH), 61.9 (CH), 83.5 (CH), 125.6 (CH),
127.3 (CH), 127.9 (CH), 137.9 (C), 171.1 (CvO). Anal.
Calcd for C13H17NO2: C, 71.21; H, 7.81. Found: C, 71.38;
H, 7.78.
Methyl (1-o-methoxyphenylethylimino)acetate (1e).
1-(2-Methoxyphenyl)ethylamine (500 mg, 3.31 mmol)
prepared24 from 2-methoxyacetophenone was dissolved in
Ê
dichloromethane (6 mL). Molecular sieves (4 A) and
methyl glyoxylate (350 mg, 3.97 mmol, 1.5 equiv.) were
added and the reaction was stirred at room temperature for
1 h. After concentration, a puri®cation by FC (5% EtOAc/
pentane) gave the desired product 1e (326 mg, 1.47 mmol,
45%). 1H NMR (200 MHz): d 1.66 (d, 3H, Jˆ6.6 Hz), 3.88
(s, 3H), 3.92 (s, 3H), 5.15 (q, 1H, Jˆ6.6 Hz), 6.93 (d, 1H,
Jˆ8.0 Hz), 7.04 (t, 1H, Jˆ7.6 Hz), 7.32 (t, 1H, Jˆ7.6 Hz),
7.52 (d, 1H, Jˆ7.6 Hz), 7.80 (s, 1H). 13C NMR (50 MHz): d
21.6 (CH3), 52.3 (CH3), 55.1 (CH3), 61.8 (CH), 110.3 (CH),
120.6 (CH), 127.1 (CH), 128.2 (CH), 130.0 (C), 151.8 (CH),
156.3 (C), 163.8 (CvO). Anal. Calcd for C12H15NO3: C,
65.14; H, 6.83. Found: C, 65.09; H, 6.77.
Methyl 3,3-dimethyl-2-(1-o-methoxyphenylethylamino)-
butanoate (7e and 8e). Treating 1e (100 mg, 0.45 mmol)
according to method A, at 2408C, in the presence of t-butyl
iodide led to a mixture of 7e and 8e (106 mg, 0.38 mmol,
84%), isolated as a colorless oil after puri®cation by FC (5%
EtOAc/pentane). The diastereomeric ratio (62:38) was
1
Methyl 2-(1-o-methoxyphenylethylamino)butanoate (3e
and 4e). Treating 1e (100 mg, 0.45 mmol) according to
determined from H NMR on the crude reaction mixture.
1H NMR (200 MHz): (major isomer: 7e): d 0.84 (s, 9H),

3960
M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
Org. Lett. 1999, 1, 569±572. (g) Miyabe, H.; Ushiro, C.; Ueda, M.;
Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176±185.
7. (a) Russell, G. A.; Wang, L.; Rajaratnam, R. J. Org. Chem.
1996, 61, 8988±8991. (b) Miyabe, H.; Yamakawa, K.; Yoshioka,
N.; Naito, T. Tetrahedron 1999, 55, 11209±11218.
1.19 (d, 3H, Jˆ6.8 Hz), 1.92 (br s, 1H), 2.63 (s, 1H), 3.56 (s,
3H), 3.69 (s, 3H), 3.97 (q, 1H, Jˆ6.8 Hz), 6.68±6.90 (m,
2H), 7.02±7.42 (m, 2H); (minor isomer: 8e): d 0.85 (s, 9H),
1.24 (d, 3H, Jˆ6.6 Hz), 1.92 (br s, 1H), 2.82 (s, 1H), 3.30 (s,
3H), 3.72 (s, 3H), 3.88 (q, 1H, Jˆ6.6 Hz), 6.68±6.90 (m,
2H), 7.02±7.42 (m, 2H). 13C NMR (50 MHz): (major
isomer: 7e): d 23.3 (CH3), 26.7 (3£CH3), 34.2 (C), 49.1
(CH), 50.7 (CH3), 55.3 (CH3), 67.7 (CH), 110.3 (CH),
120.5 (CH), 127.1 (CH), 127.3 (CH), 132.9 (C), 156.8
(C), 176.0 (CvO); (minor isomer: 8e): d 21.6 (CH3), 26.4
(3£CH3), 34.2 (C), 50.6 (CH), 52.5 (CH3), 55.2 (CH3), 68.5
(CH), 110.4 (CH), 120.3 (CH), 127.3 (CH), 127.5 (CH),
133.6 (C), 156.8 (C), 175.4 (CvO). Anal. Calcd for
C16H25NO3: C, 68.79; H, 9.02. Found: C, 68.77; H,
8.97.Treating 1e (100 mg, 0.45 mmol) according to method
B, at 2408C, in the presence of t-butyl iodide, led to 7e and
8e (110 mg, 0.39 mmol, 87%) in a 30:70 ratio.
8. (a) Bertrand M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett
1998, 780±782. (b) Bertrand, M. P.; Feray, L.; Nouguier, R.;
Perfetti, P. Synlett 1999, 1148±1150. (c) Bertrand, M. P.; Feray,
L.; Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189±9193.
9. (a) Brown, H. C.; Midland, M. M. Angew. Chem. Int. Ed. Engl.
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(b) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron
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3157±3160.
10. Even in the presence of 10 equiv. of a primary alkyl iodide, the
addition of Etz was overwhelming compared to the addition of the
corresponding primary alkyl radical. The reaction is limited to
secondary and tertiary alkyl iodides.
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17. In the case of 1b, the structure of which is very close to that of
1a, the assignments were based on the relative shielding of the
proton a to the amino group and to the carboxylate in the diastereo-
meric products. With regard to 1c and 1d, correlations can be
established between the relative chemical shift of the proton a to
nitrogen in the chiral auxiliary in the diastereomeric adducts and

M. P. Bertrand et al. / Tetrahedron 56 (2000) 3951±3961
3961
their sterochemistry. Similar trends are observed in literature data,
see Refs. 16f±h.
20. Hashimoto, Y.; Kobayashi, N.; Kai, A.; Saigo, K. Synlett 1995,
961±962.
Â
21. Abraham, H.; Theus, E.; Stella, L. Bull. Soc. Chim. Belg. 1994,
18. As the reactions are conducted on 0.5 mmol or 1 mmol, the
injection of 5 mL of air corresponds to 10% or 5% molar O2; the
injection of 20 mL of air corresponds approximately to 35 or 20%
molar quantities of oxygen.
103, 361±366.
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43, 892±898.
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10320.