Intermolecular addition of alkyl radicals to imines in the absence and in the presence of a Lewis acid

Article abstract of DOI:10.1039/b101762o

The metal-catalyzed, and metal-catalyzed enantioselective, intermolecular additions of alkyl radicals to imines have been investigated. The reaction proceeds well for imines having both activating and deactivating nitrogen substituents, and can be controlled and accelerated to a high extent by the use of Lewis acids. For imines having different carbon substituents, it has been observed that those derived from glyoxylate react much faster than those derived from 3-oxopropionate or benzaldehyde. The intermolecular radical addition can be carried out for different types of imines with alkyl and alkoxyalkyl radicals and it is demonstrated that it is possible to perform the radical addition in a catalytic enantioselective fashion with moderate yield and enantioselectivity. On the basis of the experimental results and theoretical calculations the mechanism for the radical addition to imines is discussed.

Full text of DOI:10.1039/b101762o

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Intermolecular addition of alkyl radicals to imines in the absence
and in the presence of a Lewis acid
Nis Halland and Karl Anker Jørgensen*
1
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University, DK-8000,
Aarhus C, Denmark. E-mail: kaj@kemi.aau.dk; Fax: 45-86-19-61-99
Received (in Cambridge, UK) 23rd February 2001, Accepted 6th April 2001
First published as an Advance Article on the web 2nd May 2001
The metal-catalyzed, and metal-catalyzed enantioselective, intermolecular additions of alkyl radicals to imines
have been investigated. The reaction proceeds well for imines having both activating and deactivating nitrogen
substituents, and can be controlled and accelerated to a high extent by the use of Lewis acids. For imines having
different carbon substituents, it has been observed that those derived from glyoxylate react much faster than those
derived from 3-oxopropionate or benzaldehyde. The intermolecular radical addition can be carried out for different
types of imines with alkyl and alkoxyalkyl radicals and it is demonstrated that it is possible to perform the radical
addition in a catalytic enantioselective fashion with moderate yield and enantioselectivity. On the basis of the
experimental results and theoretical calculations the mechanism for the radical addition to imines is discussed.
Table 1 The reaction of different imines 1a–i with i-PrI in the presence
of Et3B–O2 as radical initiator, in the absence or presence of BF3ؒOEt2
Introduction
The catalysis and control of intermolecular radical addition to
alkenes, carbonyl compounds and imines are a challenge and
only recently have the first examples of diastereo- and enantio-
selective control in these transformations appeared.1
as a Lewis acid catalyst
Entry
Substrate
Reaction time/h
Yield (%)
Yield (%)
1
2a
3
1a
1a
1b
1b
1c
1d
1e
1e
1f
2
0.5
20
0.5
0.5
1
20
2
20
20
0.5
20
3a 69
3a 91
3b 50
3b 87
3c 45
3d 59
3e 8
3e 78
3f 0
3g 72
5a 32c
3i 0
4a 17
4a 0
4b 0
4b 0
4c 25
4d 40
4e 0
4e 0
4f 0
4g 0
5b 64c
4i 0
Intermolecular radical addition to C᎐N bonds catalyzed by
᎐
Lewis-acid complexes is a rarely studied reaction, although it is
a powerful method for the formation of C–C bonds. Naito et al.
have shown, in a series of papers, that BF3 in particular can be
used to promote radical addition to oxime ethers and they used
this approach e.g. in diastereoselective reactions, employing
mainly Oppolzer’s camphorsultam as the chiral auxiliary, and
in solid-phase reactions.2 Addition of alkyl radicals to chiral
glyoxylate imines has been studied in the presence of ZnEt2 and
depending on the reaction conditions addition to both the
4a
5
6
7
8a
9
10
11
12
1g
1h
1i
carbon atom and the nitrogen atom of the C᎐N bond was
᎐
a One equiv. BF3ؒOEt2 added. b 1.5 : 1 mixture of E- and Z-isomers.
observed.3 However, it should be noted that the addition to the
nitrogen atom is not a radical process. More recently it has been
shown that Lewis acids can catalyze the diastereoselective
radical addition to chiral hydrazones giving N-acylhydrazines
in moderate yield and with high stereocontrol.4
c Cyclised products 5a and 5b are obtained (see text).
(1)
This paper presents an investigation of the metal-catalyzed,
and the metal-catalyzed, enantioselective intermolecular
radical addition to C᎐N bonds of various alkyl halides. The
᎐
influence of different Lewis acids on the reaction course is
investigated and it is shown that it is possible to perform
catalytic enantioselective radical addition to C᎐N bonds using
᎐
chiral Lewis acids as the catalyst.
Results and discussion
A challenge for the Et3B-mediated intermolecular tin-free
radical addition to C᎐N bonds is to control the reactivity and
᎐
selectivity of the radical attack as addition of both isopropyl
and ethyl (from Et3B) radicals can take place [eqn. (1)]. In Table
1 are shown the results for the reaction of different imines
in eqn. (1) with i-PrI in the presence of Et3B–O2 as a radical
initiator under various reaction conditions.
It appears from the results in Table 1 that the range of imines
(1a–i) that can be used in the radical addition is large and that
the imine substituents have an influence on which radical
attacks the imine carbon atom, leading to products 3 or 4. The
nitrogen substituent (R2) can be varied from the deactivating
benzyloxy group (e.g. 1a) to the strongly activating tosyl group
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J. Chem. Soc., Perkin Trans. 1, 2001, 1290–1295
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101762o

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(e.g. 1c) to give 3a and 3c as the major products, respectively,
and the ethylated compounds 4a and 4c as the minor products
(entries 1 and 5). The carbon substituent (R1) has, on the other
hand, a strong influence on the reactivity of the imine. In
general, imines derived from glyoxylate (R1 = COOEt), 1a,c,d,
react much faster than the substrates derived from 3-oxo-
propionate (R1 = CH2COOEt), 1b, or benzaldehyde, 1g,h.
The latter substrates often require activation by Lewis acids
to give reasonable yields as seen in entry 3 vs. 4 and entry 7 vs.
8. The activation and selectivity by the Lewis acid are also
pronounced for the activated imine 1a (entry 1 vs. 2). It is
notable that 1f and 1i do not react under these conditions. The
results in Table 1 show that the addition of the isopropyl radical
to the various types of imine proceeds well in several cases,
as up to 91% yield of the radical addition product is isolated.
For the reaction using 1h as the imine, the cyclised products 5a
and 5b are formed in 32 and 64% yield, respectively.
(2)
Table
2
Metal-catalyzed radical addition to imines 1a,b,d,e by
reaction of alkyl and alkoxyalkyl halides in the presence of Et3B–O2 as
radical initiator
Entry
Imine
Alkyl halide
Yield (%)
The mechanism for the formation of 3 and 4 in eqn. (1) is
outlined in Scheme 1.5 The first step is generation of the ethyl
1
1a
1b
1d
1a
1b
1e
1a
1a
2b
2b
2b
2c
2c
2c
2d
2e
3j 85
3k 60
3l 80
3m 84
3n 62
3o <5
3p <5
3a 25
2a
3a
4c
5ac
6ac
7
8b
a One equiv. BF3ؒOEt2 added. b One equiv. of Bu3SnH added. c The
reactions of methoxymethyl iodide were performed at Ϫ78 ЊC.
the ethylated by-product 4, while unactivated imines, or imines
substituted with an electron-donating substituent produce
none, or only a small amount, of 4 (entries 1–4, 7, 8, 10).
A series of other alkyl halides 2b–e also reacts with the differ-
ent imines 1a,b,d,e [eqn. (2)] with various degrees of success
under the present reaction conditions and the results are
presented in Table 2.
The results in Table 2 show that metal-catalyzed radical
addition to the various types of imine proceeds well for nucleo-
philic alkyl and alkoxyalkyl radicals (entries 1–5). Furthermore,
alkyl bromides can also be used instead of alkyl iodides,
however, in this case the addition of Bu3SnH is necessary for
the generation of the alkyl radical (entry 8), since the atom-
transfer process to the ethyl radical (Scheme 1) is only effective
for iodine. It has been observed that the methoxymethyl radical
gives the fastest and cleanest reaction due to the higher nucleo-
philicity of this radical compared to the alkyl radicals.
The difference in reactivity of the imines can be accounted
for by an FMO approach as outlined in Fig. 1. The reaction
takes place by an interaction of the SOMO of the radical with
the LUMO of the imine and this explains why the ethyl gly-
oxylate derived imine 1a (R1 = COOEt, Table 1, entry 1) is
more reactive than the 3-oxopropionate derived imine 1b (R1 =
CH2COOEt, Table 1, entry 3). The LUMO of 1a is located
lower in energy than that of 1b and therefore the interaction
with the SOMO of the radical is more favourable for compound
1a than for 1b. However, both imines have the ability to
coordinate in a mono- or bidentate fashion to a Lewis acid,
depending on the type of Lewis acid. The coordination of the
imine to the Lewis acid causes a further lowering of the LUMO
energy, which will enhance the imine’s reactivity towards the
Scheme 1
radical by reaction of O2 with Et3B. The amount of ethylated
product (4) is dependent on the efficiency of the iodine atom-
transfer step. At low temperature the iodine atom-transfer step
is slow and the concentration of the isopropyl radical is low
leading to formation of 4 as the major product, although the
isopropyl radical is more reactive due to its higher nucleo-
philicity. At the temperature of the present reactions, the con-
centration of the isopropyl radical is increased and, due to its
higher reactivity, the formation of 3 is now favoured. It appears
also from the results in Table 1 that the distribution between 3
and 4 is dependent on the reactivity of the imine; imines activ-
ated by electron-withdrawing groups give a higher amount of
J. Chem. Soc., Perkin Trans. 1, 2001, 1290–1295
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The activation of the imines by Lewis acids leads us to
investigate the possibility of performing enantioselective
addition reactions of radicals to the various types of imines
1a–i with i-PrI (2a) using Et3B–O2 as a radical initiator and in
the presence of chiral Lewis acids. A variety of different com-
binations of Lewis acids and chiral ligands have been screened
for their ability to induce enantioselectivity in these reactions.
Among the different combinations, it was found that Cu()–Tol-
BINAP† catalyzed a reaction with enantioselectivity and the
most promising results are outlined in eqn. (3).
(3)
Fig. 1 Calculated LUMO energies of 1a and 1b. The lines show the
interaction with the SOMO of the alkyl radical.
The chiral copper Lewis acids tested for the radical addition
to imines have very recently been found to be very enantio-
selective catalysts for other addition reactions to similar, related
imines.6 In the present catalytic, enantioselective reactions the
radical-addition proceeds in moderate yield for imines 1a,c with
i-PrI (2a) and an enantioselectivity of up to 33% ee is obtained
for imine 1d. It should also be mentioned that t-BuI also can be
used and similar enantioselectivities are obtained to those for
i-PrI.
In an attempt to account for the moderate enantioselectivity
obtained for the present Cu()–Tol-BINAP-catalyzed enantio-
selective addition of e.g. the isopropyl radical to the imines
a series of theoretical investigations have been performed [eqn.
(4)].
Fig. 2 Conversion as a function of time for the reaction of imine 1b
with i-PrI in the presence of Et3B–O2 as a radical initiator in the
absence and presence of Lewis acid activation BF3ؒOEt2 and
CuPF6ؒ4MeCN.
(4)
radical, leading to a smaller LUMO–SOMO energy gap com-
pared to the reaction in the absence of a Lewis acid.
The catalytic effect of coordination of the imine to the Lewis
acid is also apparent from Table 1. A graphical representation,
as a function of time, of the addition of two different Lewis
acids to the reaction of the 3-oxopropionate derived imine 1b
with i-PrI in the presence of Et3B–O2 as a radical initiator is
shown in Fig. 2. It is obvious that the presence of a Lewis acid
in the radical-addition reaction has a rate-accelerating effect.
For the reaction activated by BF3ؒOEt2, to which the imine
can coordinate in a monodentate fashion, full conversion is
accomplished within 30 min, while in the presence of
CuPF6ؒ4MeCN a slower reaction seems to take place. The
imine 1b exists in an approximately 2 : 3 ratio of the E- and Z-
isomers at room temperature and only the E-isomer can
Calculations have been performed using DFT7 with an
unrestricted B3LYP/6-31G** basis set to obtain information
about the transition-state structure for the reaction and the
influence of the Lewis acid on the transition-state structure.
According to our knowledge, no theoretical calculations have
been reported for radical addition to imines, while several
investigations have been performed for radical-addition reac-
tions to alkenes.8 The calculated transition state for the reaction
of the glyoxylate oxime ether 1e with the isopropyl radical [eqn.
(4)] is shown in Fig. 3. The calculated transition-state structure
is very similar to the calculated transition-state structures for
radical addition to alkenes.8 The C–C bond being formed is
2.39 Å in the transition state and the approaching carbon atom
is in the C–N plane (Fig. 3, top). The ЄC–C–N angle for the
incoming radical is 104.4Њ. The calculated transition-state
energy is very low, as the energy barrier for the reaction is only
1.6 kcal molϪ1 relative to the total energy for the imine 1e and
isopropyl radical (Ϫ555.4905 Eh). This transition-state energy is
slightly lower than those calculated for radical addition to
1
coordinate in a bidentate fashion to the Cu()-Lewis acid. H
NMR spectroscopy shows that the E-isomer of 1b has been
consumed after a reaction time of 30 min in the presence of
Cu() as the catalyst. The Z-isomer of 1b cannot coordinate in a
bidentate fashion to Cu() and no activation of 1b is therefore
observed. The remaining part of the reaction takes place by the
uncatalyzed addition of the isopropyl radical to the Z-isomer
of 1b and it appears from Fig. 2 that the conversion of 1b, after
all the E-isomer has been consumed, follows the conversion of
the uncatalyzed reaction.
† Tol-BINAP = 2,2Ј-bis(ditolylphosphino)-1,1Ј-binaphthyl.
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J. Chem. Soc., Perkin Trans. 1, 2001, 1290–1295

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used in Lewis-acid catalyzed reactions were flame-dried before
use. 1H and 13C NMR spectra were recorded on a Varian Mer-
cury 400 at 400 and 100 MHz, respectively. Chemical shifts for
1H and 13C NMR were recorded in CDCl3 and measured in
ppm downfield from tetramethylsilane (TMS). Enantiomers
were separated by HPLC on a Waters instrument, or by GC/
GC-MS on an HP 6890 instrument, using a chiral column as
indicated in the respective entries.
Materials
All substrates were prepared according to literature procedures.
Et3B (1.0 M solution in hexanes) and CuPF6ؒ4MeCN were pur-
chased from Aldrich and used as received. (R)-Tol-BINAP was
purchased from Strem.
General procedure for Lewis-acid catalyzed and enantioselective
Lewis-acid catalyzed radical-addition reactions
CuPF6ؒ4MeCN (14.9 mg, 0.04 mmol) and (R)-Tol-BINAP
(29.0 mg, 0.042 mmol) were added to a flame-dried Schlenk
flask and dried for 1 h under vacuum. Dry CH2Cl2 (2 ml) was
added and the solution was stirred for 1 h at room temperature,
which was followed by addition of compound 1d (47.5 mg, 0.23
mmol) and 2-iodopropane (200 µl, 2.0 mmol). Et3B (1.0 ml, 1.0
M solution in hexanes, 1.0 mmol) was added followed by O2
(5 ml) and the mixture was stirred for 2 h at room temperature.
The reaction mixture was quenched with brine and extracted
with CH2Cl2 and the solvent was removed in vacuo. The prod-
uct was isolated by flash column chromatography on silica gel
using 12% Et2O–pentane to yield 4d (48.4 mg, 89%) as a color-
less oil, and 3d (2.9 mg, 5%) as a colorless oil in 30% ee as
measured by GC/GC-MS using an Astec B-DM column.
Fig. 3 Calculated transition state for the reaction of the glyoxylate
oxime ether 1a with isopropyl radical from DFT calculations with the
B3LYP/6-31G** basis set.
1
alkenes using a smaller basis set.8 The total energy of the rad-
ical product (6) is calculated to be Ϫ555.5300 Eh. We have also
tried to locate a transition state for the Lewis-acid catalyzed
[e.g. B() and Cu()] addition of the isopropyl radical to imine
1e. However, in all the cases investigated, no transition state
could be located, and the calculations show that the radical
product was formed without any transition state. These results
for the transition state (in the absence of a Lewis-acid catalyst)
show that the reaction proceeds through an early transition
state. We have used this transition-state structure to model the
catalytic enantioselective reaction in the presence of a chiral
Lewis acid and found that the face-shielding of the imine is
very small in agreement with the moderate enantioselectivity
obtained for these reactions.
In summary, it has been shown that different radicals can be
added to various types of imines in the presence of Lewis acids
as the catalyst. The reaction proceeds well for imines having
both activating and deactivating nitrogen substituents, and the
reaction can be controlled and accelerated to a large extent by
the use of Lewis acids. For imines having different carbon sub-
stituents it has been observed that those derived from glyoxylate
react much faster than substrates derived from 3-oxopropionate
or benzaldehyde. The intermolecular Lewis-acid catalyzed
radical addition can occur for different types of imines with
both alkyl and alkoxyalkyl radicals and it is demonstrated that
it is possible to perform the radical addition in a catalytic,
enantioselective fashion in moderate yield and with enantio-
selectivities of up to 33% ee. DFT calculations show that the
radical attack in the uncatalyzed reaction has a very low
transition-state energy and an early transition state with bond
length of 2.39 Å for the carbon–carbon bond being formed.
2-Benzyloxyamino-3-methylbutyric acid ethyl ester (3a). H
NMR δ 0.82 (d, J = 6.8 Hz, 3H, CH3), 0.83 (d, J = 6.8 Hz, 3H,
CH3), 1.21 (t, J = 7.6 Hz, 3H, CH3), 1.70 (octet, J = 6.8 Hz, 1H,
CH), 3.26 (dd, J = 6.8, 10.8 Hz, 1H, CH), 4.16 (q, J = 7.6 Hz,
2H, OCH2), 4.60 (s, 2H, OCH2), 5.94 (d, J = 10.8 Hz, 1H, NH),
7.19–7.32 (m, 5H, ArH); 13C NMR δ 14.3, 19.3, 29.2, 60.7, 69.5,
75.9, 127.7, 128.2, 128.6, 137.9, 174.0; HRMS m/z 274.1421
(M + Na)+, calc. for C14H21NO3Na 274.1419; m/z (EI) 178
(27%), 91 (100), 77 (23). Enantiomers were separated by HPLC
using a Chiralcel OJ column with 99 : 1 v/v hexane–i-PrOH.
1
2-Benzyloxyaminobutyric acid ethyl ester (4a). H NMR δ
0.85 (t, J = 7.2 Hz, 3H, CH3), 1.21 (t, J = 7.2 Hz, 3H, CH3), 1.52
(m, 2H, CH2), 3.43 (dt, J = 10.0, 6.8 Hz, 1H, CH), 4.18 (q,
J = 7.2 Hz, 2H, OCH2), 4.61 (s, 2H, OCH2), 5.89 (d, J = 10.0
Hz, 1H, NH), 7.19–7.32 (m, 5H, ArH); 13C NMR δ 10.4, 14.3,
22.9, 60.8, 65.1, 76.0, 127.7, 128.2, 128.4, 137.8, 174.0; HRMS
m/z 260.1260 (M + Na)+, calc. for C13H19NO3Na 260.1263; m/z
(EI) 164 (21%), 91 (100), 77 (25).
3-Benzyloxyamino-4-methylpentanoic acid ethyl ester (3b). 1H
NMR δ 0.84 (d, J = 7.2 Hz, 3H, CH3), 0.87 (d, J = 7.2 Hz, 3H,
CH3), 1.19 (t, J = 6.8 Hz, 3H, CH3), 1.83 (octet, J = 7.2 Hz, 1H,
CH), 2.35 (m, 2H, CH2), 3.08 (m, 1H, CH), 4.02 (q, J = 6.8 Hz,
2H, OCH2), 4.60 (s, 2H, OCH2), 5.78 (br s, 1H, NH), 7.19–7.32
(m, 5H, ArH); 13C NMR δ 14.2, 18.2, 19.2, 29.0, 34.0, 60.4,
62.7, 76.3, 127.7, 128.3, 128.4, 137.9, 173.0; HRMS m/z
288.1571 (M + Na)+, calc. for C15H23NO3Na 288.1576; m/z (EI)
222 (37%), 91 (100). Enantiomers were separated by HPLC
using a Chiralcel OJ column with 99.5 : 0.5 v/v hexane–i-PrOH.
3-Methyl-2-(4-tolylsulfonylamino)butyric acid ethyl ester (3c).
1H NMR δ 0.79 (d, J = 7.4 Hz, 3H, CH3), 0.92 (d, J = 7.4 Hz,
3H, CH3), 1.02 (t, J = 7.6 Hz, 3H, CH3), 1.95 (octet, J = 7.4 Hz,
1H, CH), 2.35 (s, 3H, ArCH3), 3.63 (dd, J = 11.0, 7.4 Hz, 1H,
CH), 3.81 (q, J = 7.6 Hz, 2H, OCH2), 4.99 (d, J = 11.0 Hz, 1H,
NH), 7.21 (d, J = 8.0 Hz, 2H, ArH), 7.63 (d, J = 8.0 Hz, 2H,
Experimental
General
Solvents were dried using standard procedures. All glassware
J. Chem. Soc., Perkin Trans. 1, 2001, 1290–1295
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ArH); 13C NMR δ 12.9, 16.3, 17.9, 20.5, 30.7, 60.0, 60.4, 126.4,
128.5, 135.7, 142.5, 170.3; HRMS m/z 322.1090 (M + Na)+,
calc. for C14H21NO4SNa 322.1090; m/z (EI) 226 (100%), 155
(64), 91 (64).
J = 7.6 Hz, 1H, CH), 6.30–7.35 (m, 9H, ArH); 13C NMR δ 8.9,
9.0, 11.9, 26.3, 58.9, 111.2, 112.0, 119.6, 121.4, 127.4, 128.1,
128.6, 137.4, 141.9, 149.8; m/z 265 (EI) (M+, 31%), 236 (100), 91
(34).
2-(4-Tolylsulfonylamino)butyric acid ethyl ester (4c). 1H
NMR δ 0.84 (t, J = 7.6 Hz, 3H, CH3), 1.03 (t, J = 7.2 Hz, 3H,
CH3), 1.56–1.75 (m, 2H, CH2), 2.35 (s, 3H, ArCH3), 3.76 (m,
1H, CH), 3.85 (q, J = 7.2 Hz, 2H, OCH2), 5.08 (d, J = 9.2 Hz,
1H, NH), 7.21 (d, J = 8.4 Hz, 2H, ArH), 7.65 (d, J = 8.4 Hz,
2H, ArH); 13C NMR δ 9.5, 14.2, 21.8, 27.0, 57.0, 61.8, 127.5,
129.8, 136.9, 143.8, 171.9; HRMS m/z 308.0937 (M + Na)+,
calc. for C13H19NO4SNa 308.0933; m/z (EI) 212 (60%), 171 (29),
155 (53), 91 (100).
2-Benzyloxyamino-3,3-dimethylbutyric acid ethyl ester (3j).
1H NMR δ 0.96 (s, 9H, 3 CH3), 1.23 (t, J = 8.4 Hz, 3H, CH3),
3.28 (d, J = 10.3 Hz, 1H, CH), 4.21 (q, J = 8.4 Hz, 2H, OCH2),
4.63 (s, 2H, OCH2), 6.11 (d, J = 10.3 Hz, 1H, NH), 7.25–7.37
(m, 5H, ArH); 13C NMR δ 13.3, 26.0, 32.0, 59.5, 71.0, 74.7,
126.6, 127.1, 127.6, 137.0, 172.9; HRMS m/z 288.1577
(M + Na)+, calc. for C15H23NO3Na 288.1576; m/z (EI) 208
(21%), 192 (36), 91 (100).
3-Benzyloxyamino-4,4-dimethylpentanoic acid ethyl ester
(3k). H NMR δ 0.96 (s, 9H, 3 CH3), 1.22 (t, J = 7.2 Hz, 3H,
1
2-(4-Methoxyphenylamino)-3-methylbutyric acid ethyl ester
(3d). 1H NMR δ 0.95 (d, J = 7.2 Hz, 3H, CH3), 0.97 (d, J = 7.2
Hz, 3H, CH3), 1.18 (t, J = 7.0 Hz, 3H, CH3), 2.01 (octet, J = 7.2
Hz, 1H, CH), 3.65 (s, 3H, OCH3), 3.70 (m, 1H, CH), 3.81 (br,
1H, NH), 4.10 (q, J = 7.0 Hz, 2H, OCH2), 6.55 (d, J = 8.4 Hz,
2H, ArH), 6.70 (d, J = 8.4 Hz, 2H, ArH); 13C NMR δ 14.3, 18.7,
19.1, 31.5, 55.7, 60.7, 63.8, 114.8, 115.3, 141.5, 152.7, 174.0;
HRMS m/z 274.1419 (M + Na)+, calc. for C14H21NO3Na
274.1419; m/z (EI) 251 (M+, 19%), 208 (15), 178 (100), 134 (56),
122 (21). Enantiomers were separated by GC/GC-MS using a
Chrompack chirasil-Dex CB column.
CH3), 2.49 (d, J = 6.0 Hz, 2H, CH2), 3.18 (t, J = 6.0 Hz, 1H,
CH), 4.12 (m, 2H, OCH2), 4.65 (s, 2H, OCH2), 5.80 (br, 1H,
NH), 7.25–7.36 (m, 5H, ArH); 13C NMR δ 14.4, 27.3, 33.8,
34.7, 60.6, 65.9, 76.1, 127.9, 128.5, 128.6, 138.1, 173.7; HRMS
m/z 302.1734 (M + Na)+, calc. for C16H25NO3Na 302.1732; m/z
(EI) 222 (85%), 148 (14), 91 (100).
2-(4-Methoxyphenylamino)-3,3-dimethylbutyric acid ethyl
1
ester (3l). H NMR δ 1.05 (s, 9H, 3 CH3), 1.22 (t, J = 7.2 Hz,
3H, CH3), 3.75 (s, 3H, OCH3), 3.89 (br, 1H, NH), 3.92 (br, 1H,
CH), 4.15 (q, J = 7.2 Hz, 2H, OCH2), 6.63 (d, J = 9.2 Hz, 2H,
ArH), 6.76 (d, J = 9.2 Hz, 2H, ArH); 13C NMR δ 14.3, 26.8,
34.3, 55.7, 60.5, 67.0, 114.8, 115.6, 141.8, 152.7, 173.6; HRMS
m/z 288.1573 (M + Na)+, calc. for C15H23NO3Na 288.1576; m/z
(EI) 265 (M+, 21%), 208 (48), 192 (50), 134 (100).
2-(4-Methoxyphenylamino)butyric acid ethyl ester (4d). 1H
NMR δ 0.92 (t, J = 7.6 Hz, 3H, CH3), 1.18 (t, J = 6.4 Hz, 3H,
CH3), 1.65–1.85 (m, 2H, CH2), 3.65 (s, 3H, OCH3), 3.80 (br, 1H,
NH), 3.86 (m, 1H, CH), 4.11 (q, J = 6.4 Hz, 2H, OCH2), 6.55
(d, J = 6.8 Hz, 2H, ArH), 6.70 (d, J = 6.8 Hz, 2H, ArH); 13C
NMR δ 9.0, 13.3, 25.2, 54.7, 58.0, 59.9, 113.8, 114.1, 140.0,
151.6, 173.3; HRMS m/z 260.1261 (M + Na)+, calc. for
C13H19NO3Na 260.1263; m/z (EI) 237 (M+, 16%), 164 (100), 134
(17), 122 (7).
2-Benzyloxyamino-3-methoxypropionic acid ethyl ester (3m).
1H NMR δ 1.22 (t, J = 7.6 Hz, 3H, CH3), 3.33 (s, 3H, OCH3),
3.59 (d, J = 5.6 Hz, 2H, OCH2), 3.78 (m, 1H, CH), 4.22 (q,
J = 7.6 Hz, 2H, OCH2), 4.73 (s, 2H, OCH2), 6.04 (d, J = 8.4 Hz,
1H, NH), 7.25–7.37 (m, 5H, ArH); 13C NMR δ 14.4, 59.5, 61.5,
64.0, 70.5, 76.6, 128.1, 128.5, 128.6, 137.9, 171.4; HRMS m/z
276.1210 (M + Na)+, calc. for C13H19NO4Na 276.1212; m/z (EI)
208 (10%), 180 (16), 108 (12), 91 (100), 77 (17).
O-Benzyl-N-[1-(2-methoxyphenyl)-2-methylpropyl]hydroxyl-
1
amine (3e). H NMR δ 0.64 (d, J = 6.8 Hz, 3H, CH3), 0.91 (d,
J = 6.8 Hz, 3H, CH3), 1.85–2.05 (octet, J = 6.8 Hz, 1H, CH),
3.72 (s, 3H, OCH3), 3.98 (d, J = 8.0 Hz, 1H, CH), 4.57 (s, 2H,
OCH2), 6.00 (br s, 1H, NH), 6.75–6.91 (m, 2H, ArH), 7.11–7.22
(m, 7H, ArH); 13C NMR δ 20.8, 21.6, 30.5, 57.3, 61.3, 76.1,
110.5, 120.3, 127.4, 127.9, 128.0, 128.2, 128.4, 129.3, 138.0,
157.3; HRMS m/z 308.1629 (M + Na)+, calc. for C18H23NO2Na
308.1626; m/z (EI) 242 (100%), 136 (40), 121 (48), 91 (86), 77
(23).
1
3-Benzyloxyamino-4-methoxybutyric acid ethyl ester (3n). H
NMR δ 1.22 (t, J = 7.2 Hz, 3H, CH3), 2.43 (dd, J = 15.6, 5.6 Hz,
1H, CH), 2.58 (dd, J = 15.6, 5.6 Hz, 1H, CH), 3.35 (s, 3H,
OCH3), 3.42 (d, J = 5.6 Hz, 2H, OCH2), 3.55 (sextet, J = 5.6 Hz,
1H, CH), 4.12 (q, J = 7.2 Hz, 2H, OCH2), 4.70 (s, 2H, OCH2),
6.06 (d, J = 5.6 Hz, 1H, NH), 7.25–7.37 (m, 5H, ArH); 13C
NMR δ 14.4, 34.6, 57.4, 59.3, 60.7, 72.0, 76.8, 128.0, 128.5,
128.6, 138.0, 172.2; HRMS m/z 290.1369 (M + Na)+, calc. for
C14H21NO4Na 290.1368; m/z 222 (42%), 91 (100).
(2-Methoxyphenyl)(2-methyl-1-phenylpropyl)amine (3g). 1H
NMR δ 0.84 (d, J = 6.4 Hz, 3H, CH3), 0.95 (d, J = 6.4 Hz, 3H,
CH3), 2.00 (octet, J = 6.4 Hz, 1H, CH), 3.81 (s, 3H, OCH3), 4.04
(d, J = 5.6 Hz, 1H, CH), 4.71 (br s, 1H, NH), 6.23 (dd, J = 7.6,
1.6 Hz, 1H, ArH), 6.49 (dt, J = 1.6, 7.6 Hz, 1H, ArH), 6.59 (dt,
J =1.6, 7.6 Hz, 1H, ArH), 6.68 (dd, J = 7.6, 1.6 Hz, 1H, ArH),
7.10–7.26 (m, 5H, ArH); 13C NMR δ 18.9, 20.1, 35.2, 55.8, 63.9,
109.4, 110.9, 116.1, 121.4, 126.9, 127.4, 128.4, 137.9, 143.1,
146.9; HRMS m/z 278.1520 (M + Na)+, calc. for C17H21NONa
278.1521; m/z (EI) 255 (M+, 6%), 212 (100), 196 (12), 120 (15),
91 (11).
Acknowledgements
We are indebted to The Danish National Research Foundation
for financial support. Thanks are expressed to Dr Mark
Roberson for performing the theoretical calculations.
References
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1
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