Synthesis of enantiomerically pure 3-amino-2-methylenealkanoates (Aza-Morita-Baylis-Hillman adducts) mediated by cinchona alkaloids

Article abstract of DOI:10.1002/ejoc.201101244

3-Substituted (Z)-2-(bromomethyl)propenoates reacted with (S)-1-(4-methoxyphenyl)ethylamine in the presence of astoichiometric amount of quinidine to yield (R)-3-[(tert-butoxycarbonyl)amino]-2-methylenealkanoates (aza-Morita-Baylis-Hillman adducts) in ena

Full text of DOI:10.1002/ejoc.201101244

FULL PAPER
DOI: 10.1002/ejoc.201101244
Synthesis of Enantiomerically Pure 3-Amino-2-methylenealkanoates
(Aza-Morita–Baylis–Hillman Adducts) Mediated by Cinchona Alkaloids
Gianluca Martelli,[a] Mario Orena,*[a] and Samuele Rinaldi*[a]
Keywords: Synthetic methods / Amino esters / Nucleophilic substitution / Enantioselectivity
3-Substituted (Z)-2-(bromomethyl)propenoates reacted with
(S)-1-(4-methoxyphenyl)ethylamine in the presence of a
stoichiometric amount of quinidine to yield (R)-3-[(tert-but-
oxycarbonyl)amino]-2-methylenealkanoates
Baylis–Hillman adducts) in enantiomerically pure form.
(aza-Morita–
Introduction
3-Amino-2-methylenealkanoic acids have become an at-
tractive class of organic compounds displaying high func-
tional density. In recent years they have also gained popu-
larity as substrates and building blocks in synthesis. The
S enantiomers have recently been prepared by a multistep
synthesis[1] and incorporated into peptides owing to the
conformational restriction arising from the conjugated
double bond, but stable secondary structures were not evi-
denced either in solution or in the solid state.[2] Moreover,
3-amino-2-methylenealkanoic acids and their derivatives
are key precursors to many natural products that have been
reported to display interesting biological activities.[3] Much
effort has been devoted to the stereoselective synthesis of
these compounds, especially by the aza-Morita–Baylis–Hill-
man (AMBH) reaction.[4] However, despite recent attempts,
most of these routes suffer from several drawbacks such as
moderate enantioselectivity and yields, poor substrate gen-
erality, expensive catalysts and the poor availability of acryl-
ates and imines. Finally, they cannot be readily scaled up
to provide a really useful amount of product.[5] This is also
true for the few alternative asymmetric strategies to these
compounds that do not exploit the AMBH methodology.[6]
Scheme 1. Stereoselective iodocyclization of 3-acylamino-2-methyl-
enealkanoates.
Owing to the interest in compounds such as 3, which are
isosteres of the C-13 side-chain of paclitaxel (Taxol®),[8] to
complement our work we herein disclose the preparation of
enantiopure N-protected 3-amino-2-methylenealkanoates.
Treatment of derivatives of MBH adducts 4 with an
amine converts the hydroxy group into a leaving group, giv-
ing mainly 2-aminomethyl derivatives by an SN2Ј path-
way.[9] Thus, we devised a double SN2Ј process exploiting
(S)-1-(4-methoxyphenyl)ethylamine (5) as chiral inducer.
First the racemic MBH adducts 4a–e were treated with LiBr
and H2SO4 to give with very high stereoselectivity[10] and
in quantitative yield the corresponding (Z)-bromomethyl
derivatives 6a–e (Table 1).
Table 1. Preparation of (Z)-2-(bromomethyl)-2-alkenoates 6.
Results and Discussion
We have previously reported a procedure for the prepara-
tion of racemic 3-acylamino-2-methylenealkanoates 1 start-
ing from the N-acylcarbamates of MBH adducts,[7] which
allowed analogues of bioactive 3-amino-2-hydroxy acids 3
to be obtained by totally stereoselective cyclofunctionaliza- Entry
R1
R2
Yield [%][a]
tion reactions (Scheme 1).[8]
a
b
c
d
e
Me
Me
Et
Et
Me
Ph
quantitative
quantitative
quantitative
quantitative
90
4-O2N-C6H4
4-Cl-C6H4
2-naphthyl
iBu
[a] Di.S.V.A.-CHEMISTRY, Polytechnic University of Marche,
via Brecce Bianche, 60131 Ancona, Italy
Fax: +39-071-2204714
E-mail: m.orena@univpm.it
[a] Yield of the pure isolated product, measured relative to 0.1 mol
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101244.
of 4a–e.
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Then compound 6a was treated first with triethylamine
We envisioned that higher levels of diastereoselectivity
in various solvents, rapidly followed by 5, to give the dia- could be obtained by a double asymmetric induction and
stereomeric amines 7a and 8a in moderate yields with al- for this purpose the latter SN2Ј reaction was performed with
most no diastereoselectivity. Moreover, the simultaneous the quaternary ammonium salt prepared starting from 6a
formation of substantial amounts of the aminomethyl de- and tertiary chiral amines bearing an additional hydroxy
rivative 9 due to direct substitution at the carbon atom group. In fact, a hydrogen bond formed with the incoming
bearing the leaving group strongly affects the yields of the nucleophile could give rise to restriction of the conforma-
desired diastereomers 7 and 8 (Table 2, entries a–c).
tional freedom in the transition state and consequent in-
creased stereoselectivity.
Thus, we treated compound 6a with quinidine, quinine,
cinchonine and cinchonidine to prepare the corresponding
salts A (see the Supporting Information). The subsequent
SN2Ј reaction was carried out by using either (S)- or (R)-1-
(4-methoxyphenyl)ethylamine (5). We observed that match/
mismatch effects take place and that the side-product 9 was
completely suppressed (see Tables 3 and 4).
Table 2. Reactions of 6a with (S)-1-(4-methoxyphenyl)ethylamine
(5) under different conditions.
Table 3. Reactions of (S)-5 with quaternary ammonium salts of
Cinchona alkaloids obtained from 6a.
Entry Base (t1)
Solvent (t2)
Overall
Ratio[b]
7a/8a/9
yield [%][a]
a
b
c
d
e
f
g
h
i
Et3N (1 min)
DCM (1 h)
MeOH (9 h)
DMSO (1 h)
CHCl3 (2 h)
DCM (1.5 h)
DCM (2 h)
DCM (4 d)
88
91
90
82
79
73
92
89
91
37:35:28
31:34:35
17:15:68
72:28:0
66:33:1
74:24:2
83:17:0
76:22:2
75:24:1
Et3N (1 min)
Et3N (1 min)
Et3N (2 h)[c]
EPIP[d] (5 h)
TMEDA (1 h)
Ph3P (40 min)[e]
Entry Base (t1 [h])
Overall yield [%][a]
Ratio[b] 7a/8a
a
b
c
quinidine (3)
94
85
90
86
94:6
41:59
85:15
65:35
3-HQD[d] (20 min) DCM (1 h)
DABCO (20 min) DCM (1 h)
quinine (3)
cinchonine (24)[c]
cinchonidine (3)
d
[a] Yield of the pure isolated product. [b] Determined for the crude
reaction mixture by 1H NMR spectroscopy. [c] Reflux temperature
was required for the intermediate formation. [d] Abbreviations:
EPIP = N-ethylpiperidine, 3-HQD = 3-quinuclidinol. [e] Et3N
(1 equiv.) was also added.
[a] Yield of pure isolated products, measured relative to 1 mmol of
6a. [b] Determined for the crude reaction mixture by 1H NMR
spectroscopy. [c] A 1:1 mixture of DCM/MeOH was required for
the formation of quaternary ammonium salt A.
Table 4. Reactions of (R)-ent-5 with quaternary ammonium salts
of Cinchona alkaloids obtained from 6a.
This side-reaction was especially significant when DMSO
was used as solvent and it is worth mentioning that this
solvent also promotes the slow rearrangement of dia-
stereomers 7 and 8 into the aminomethyl derivative 9 (see
the Supporting Information for the necessary cautions).
Thus, with the aim of obtaining compounds 7 and 8 ex-
clusively by an SN2Ј process, we carried out the reaction on
the corresponding quaternary ammonium salt.
In fact, when the reaction mixture was heated at reflux
for 2 h in chloroform before adding 5, or bases more nucleo-
philic than Et3N were used, we observed increased dia-
stereoselectivity together with an almost negligible forma-
tion of 9 (Table 2, entries d–i).[11] Note that all the reaction
mixtures were easily separable by silica gel chromatography.
The configurations reported for 7a and 8a were assigned by
conversion into derivatives, the configurations of which
Entry Base (t1 [h])
Overall yield [%][a] Ratio[b] ent-7a/ent-8a
a
b
c
quinidine (3)
89
93
87
88
29:71
90:10
37:63
64:36
quinine (3)
cinchonine (24)[c]
cinchonidine (3)
d
[a] Yield of pure isolated products, measured relative to 1 mmol of
6a. [b] Determined for the crude reaction mixture by 1H NMR
spectroscopy. [c] A 1:1 mixture of DCM/MeOH was required for
the formation of quaternary ammonium salt A.
1
were determined by H NMR spectroscopy and confirmed
by comparison of the optical rotation of the final product
10a with literature data (see the Supporting Information).
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Synthesis of 3-Amino-2-methylenealkanoates
In fact, the Si diastereofacial preference of (S)-5 signifi-
With the optimal reaction conditions identified, a series
cantly increased (Table 3, entries a and c) when quinidine of enantiomerically pure 3-amino-2-methylenealkanoates 7
or cinchonine were used to generate the intermediate am- and ent-7 were synthesized to establish the generality of this
monium salt A. It is apparent that (S)-5 and quinidine or methodology (Table 5). The reaction was seen to be general,
cinchonine are well-matched pairs leading predominantly offering yields of 72–89% and dr values ranging from 82:18
to 7a, whereas (S)-5 with quinine or cinchonidine are mis- to 94:6 for reactions carried out with quinidine and (S)-5
matched (Table 3, entries b and d).
(conditions i.). On the other hand, slightly lower yields (60–
On the other hand, (R)-ent-5 displayed good Re dia- 89%) and dr values (from 68:32 to 93:7) were obtained
stereofacial preference when quinine was used to generate when quinine and (R)-ent-5 were used (conditions ii.).
the ammonium salt A. Thus, (R)-ent-5 and quinine are a Moreover, all the reaction mixtures were easily purified by
well-matched pair leading to ent-7a (Table 4, entry b). Thus, FC and the reactions carried out using the recovered chiral
either 7a or ent-7a are easily accessible by simply exploiting base furnished products 7a and ent-7a with only very slight
the chirality of 5 or ent-5 with the appropriate chiral terti- decreases in yield and stereoselectivity (entries a and f). Fi-
ary base. In fact, by only changing the reagents, both com- nally, by using conditions i., compound 7a was prepared on
pounds 7a and ent-7a can be obtained pure and in high a large scale (100 mmol) starting from 6a with almost iden-
yields owing to the high stereoselectivity of the reaction and tical stereoselectivity and yield (entry a).
the easy separation from the minor diastereomers 8a and
ent-8a by silica gel chromatography.
The chiral inducer was removed from compounds 7 and
ent-7 at reflux in TFA. The intermediate salts B were di-
rectly converted, without isolation, into the corresponding
tBoc derivatives 10a–e in good-to-excellent yields consider-
ing that the overall process involves two steps (Table 6). The
configurations of compounds 10a,c,e were confirmed by
comparison with reported optical rotations, whereas the re-
maining ones were assigned by similarity to 10a,c,e (see the
Supporting Information).[1,6c,6d] Moreover, as evidenced by
HPLC analysis, the ee values of the products were invaria-
bly the same or even greater than those of the chiral in-
ducers employed (S)-5 and (R)-ent-5 (see the Supporting
Information).
Table 5. Preparation of amino derivatives 7a–e and ent-7a–e.
Table 6. Preparation of (R)- and (S)-3-[(tert-butoxycarbonyl)-
amino]-2-methylenealkanoates 10 and ent-10.
Conditions i.
Entry R1
R2
Yield of 7 [%][a]
Ratio[b] 7/8
a
b
c
d
e
Me
Me
Et
Et
Me
Ph
89 (82)[c] (85)[d]
94:6 (91:9)[c]
82:18
Entry
R1
R2
Yield [%][a]
4-O2N-C6H4
4-Cl-C6H4
2-naphthyl
iBu
78
86
89
72
a
b
c
d
e
Me
Me
Et
Et
Me
Ph
85[b]
72
94:6
90:10
85:15
4-O2N-C6H4
4-Cl-C6H4
2-naphthyl
iBu
80[b]
93
Conditions ii.
Entry R1
63[b,c]
R2
Yield of ent-7 [%][a] Ratio[b] ent-7/ent-8
[a] Average yield of the pure product after isolation, measured rela-
tive to 5 mmol of 7 (or ent-7). [b] The absolute configuration was
assigned by comparison of the optical rotation with a known value
(see the Supporting Information). [c] Heating carried out at reflux
for 72 h.
f
Me
Me
Et
Et
Me
Ph
84 (80)[c]
90:10 (88:12)[c]
86:14
g
h
i
4-O2N-C6H4
4-Cl-C6H4
2-naphthyl
iBu
81
89
84
60
93:7
89:11
68:32
l
[a] Yield of pure isolated 7a–e (or ent-7a–e), measured relative to
10 mmol of 6a–e. [b] Determined on the crude reaction mixture
Conclusions
1
by H NMR spectroscopy. [c] Reaction with recycled quinidine or
Starting from racemic Morita–Baylis–Hillman adducts 4
quinine. [d] Yield of the pure product from the reaction carried out
with 100 mmol of 6a.
we have developed a straightforward and easily scalable
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G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
using Kieselgel 60 Merck (230–400 mesh ASTM) unless specified
otherwise. TLC was performed by using Fluka silica gel TLC-PET
foils unless specified otherwise.
synthesis of N-protected 3-amino-2-methylenealkanoates 10
(aza-Morita–Baylis–Hillman adducts) in both enantiomer-
ically pure forms simply by changing quinidine for quinine
and (R)-ent-5 for (S)-5. In addition, Cinchona alkaloids
were recovered and used again without significant loss of
yield and stereoselectivity. Reactions aimed at preparing en-
antiomerically pure analogues of 3-amino-2-hydroxy acids
3 from these compounds are currently underway and the
results will be reported in due course. Moreover, we are
carrying out a computational investigation aimed at ob-
taining a better insight into the mechanistic effect of the
chiral tertiary base on the stereoselectivity.
Finally, with the aim of achieving results similar to those
presented here, but by using an achiral and cheaper tertiary
base than Cinchona alkaloids, further studies exploring the
influence of different anions of the quaternary ammonium
salts A on the diastereoselectivity of the SN2Ј reaction are
underway.
General Procedure for the Preparation of Morita–Baylis–Hillman
Adducts 4: The appropriate aldehyde (220 mmol), acrylate
(200 mmol), formamide (20 mmol, 0.8 mL) and DABCO
(60 mmol, 6.73 g) were mixed at room temperature (additional
40 mL of DMSO were added in the cases of p-nitro- and p-chloro-
benzaldehyde). After the conversion had reached at least 95%
(from 8 h to 15 d, depending on the reactants, calculated by 1H
NMR analysis of a 5 μL sample of the reaction mixture diluted in
CDCl3), the reaction was directly submitted to chromatographic
purification (c-hexane/ethyl acetate). The Morita–Baylis–Hillman
adducts 4a–e were obtained with high purity and in excellent yields
(91, 88, 94, 86 and 90% for 4a, 4b, 4c, 4d and 4e, respectively).
Compounds 4a, 4b, 4c and 4e are known compounds.[13]
Ethyl 2-[Hydroxy(naphthalen-2-yl)methyl]acrylate (4d): The title
compound was obtained in 86% yield as a pale-yellow oil. Rf =
1
0.20 (c-hexane/ethyl acetate = 8:2). H NMR (400 MHz, CDCl3):
δ = 1.24 (t, J = 7.0 Hz, 3 H), 3.18 (br. d, J = 4.7 Hz, 1 H), 4.18 (q,
J = 7.0 Hz, 2 H), 5.74 (br. d, J = 4.7 Hz, 1 H), 5.85 (s, 1 H), 6.38
(s, 1 H), 7.45–7.50 (m, 3 H), 7.81–7.87 (m, 4 H) ppm. 13C NMR
(100 MHz CDCl3): δ = 14.0, 61.0, 73.2, 124.7, 125.6, 125.9, 126.0,
126.1, 127.7, 128.1, 128.2, 133.0, 133.2, 138.8, 142.3, 166.4 ppm.
MS (ESI): m/z = 277 [M + Na]+. C16H16O3 (256.30): calcd. C 74.98,
H 6.29; found C 74.88, H 6.17.
Experimental Section
General Methods: Melting points were measured with an Electro-
thermal IA 9000 apparatus. Rf values refer to elution on silica gel
TLC-PET foils with the specified eluent. 1H and 13C NMR spectra
were recorded at 400 and 100 MHz, respectively, with a Varian
MR-400 spectrometer in CDCl3 at 25 °C. Chemical shifts are re-
ported in ppm relative to residual solvent signals (δ =7.26 and
77.16 ppm for 1H and 13C NMR, respectively[12]) and coupling con-
stants (J) are given in Hz. Mass spectra were recorded using elec-
trospray (ES) ionization. Specific rotation measurements, [α]2D0,
were recorded at room temperature with a Perkin–Elmer Model
241 polarimeter at the sodium D line (concentration in g/100 mL).
The enantiomeric purity of products 10a–e and ent-10a–e was con-
firmed by HPLC analysis using a Hewlett–Packard 1100 chromato-
graph equipped with a Daicel Chiralcel® OD-H column and a di-
ode array UV detector (210, 230 and 250 nm). The absolute config-
urations of some of the final products (10a, 10c and 10e) were
determined by comparison of the optical rotations with literature
values. The absolute configurations of the remaining final products
were assigned on the basis that the same chiral tertiary base/chiral
inducer couple [quinidine/(S)-(–)-1-(4-methoxyphenyl)ethylamine
or quinine/(R)-(–)-1-(4-methoxyphenyl)ethylamine] always fur-
nished good diastereoselectivities with very similar ratios of the
diastereomers 7a–e/8a–e or ent-7a–e/ent-8a–e, which indicates that
the diastereoselective addition of the chiral inducer occurs prefer-
entially at the same face of the double bond in the various quater-
nary ammonium salt intermediates. Moreover, the Rf values of 8a–
e (or ent-8a–e) are always greater than those of 7a–e (or ent-7a–e).
General Procedure for the Preparation of (Z)-2-Bromomethyl-2-alk-
enoates 6: Anhydrous LiBr (150 mmol, 13.3 g) was added to a solu-
tion of the appropriate Morita–Baylis–Hillman adduct
4
(100 mmol) in anhydrous DCM (40 mL) at room temperature. Af-
ter cooling to 0 °C, 98% H2SO4 (4 mL) was rapidly added, the
reaction vessel was tightly capped and then the reaction was al-
lowed to warm to room temperature under vigorous stirring for
1.5 h. In the case of 4e the entire reaction was performed at 0 °C.
After dilution with diethyl ether (200 mL), the organic phase was
washed with water (3ϫ50 mL), dried (Na2SO4) and evaporated un-
der reduced pressure at room temperature (Caution: Derivative 6a
and, to a much greater extent 6e, are volatile. In these cases the
evaporation was carried out only with a rotary evaporator at room
temp. In particular for 6e it was necessary to absolutely avoid the
use of the bath and to stop the evaporation before the flask had
reached room temperature.) The products 6a–d were obtained ne-
arly pure and in almost quantitative yield. On the other hand, 6e
required purification on a short column of silica gel (petroleum
ether/Et2O, 95:5) and careful evaporation with the cautions men-
tioned above. Compound 6e was stored at –18 °C. The E isomers,
sometimes present in up to 3%, were not characterized.
Methyl (Z)-2-Bromomethyl-3-phenylpropenoate (6a): The title com-
pound was obtained in quantitative yield as a pale-green oil. Rf =
1
0.26 (petroleum ether/Et2O = 9:1). H NMR (400 MHz, CDCl3): δ
Materials: Analytical-grade solvents and commercially available
reagents were used as received. Anhydrous DCM was obtained by
distillation over CaH2 and stored over 4 Å molecular sieves. The
petroleum ether 30–50 or 35–60 °C boiling-point fractions were
used. (S)-(–)-1-(4-Methoxyphenyl)ethylamine was purchased from
various suppliers with variable enantiomeric purities, namely with
an ee ranging from Ն95 to Ն98.5%, whereas for (R)-(+)-1-(4-meth-
oxyphenyl)ethylamine the ee ranged from Ն98 to Ն99%. In any
case, the residual quantities of the minor enantiomer in the com-
mercially available chiral inducers gave very small amounts of the
minor enantiomer in the products 10a–e (or ent-10a–e; see main
text and below). HPLC-grade 2-propanol and n-hexane were used
as the eluting solvents. Column chromatography was performed by
= 3.90 (s, 3 H), 4.41 (s, 2 H), 7.40–7.50 (m, 3 H), 7.57–7.60 (m, 2
H), 7.84 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.9,
52.6, 128.8, 129.0, 129.8, 134.4, 143.1, 166.8 ppm. MS (ESI): m/z
277 [M(79Br) + Na]+, 279 [M(81Br) + Na]+. C11H11BrO2 (255.11):
calcd. C 51.79, H 4.35; found C 51.44, H 4.19.
Methyl (Z)-2-Bromomethyl-3-(4-nitrophenyl)propenoate (6b): The
title compound was obtained in quantitative yield as pale-yellow
crystals. Rf = 0.22 (petroleum ether/Et2O = 7:3); m.p. 125–127 °C.
1H NMR (400 MHz, CDCl3): δ = 3.92 (s, 3 H), 4.31 (s, 2 H), 7.71–
7.74 (m, 2 H), 7.83 (s, 1 H), 8.31–8.34 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.4, 53.0, 124.2, 130.3, 132.1, 140.0, 140.7,
148.0, 166.0 ppm. MS (ESI): m/z 322 [M(79Br) + Na]+, 324
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Synthesis of 3-Amino-2-methylenealkanoates
[M(81Br) + Na]+. C11H10BrNO4 (300.11): calcd. C 44.02, H 3.36;
found C 43.84, H 3.18.
Compounds ent-7a–e were obtained as the predominant isomers by
performing the reaction with quinine and (R)-1-(4-methoxyphen-
yl)ethylamine (ent-5; Conditions ii. in the text), whereas com-
pounds ent-8a–e were obtained as the predominant isomers by
using quinidine and (R)-1-(4-methoxyphenyl)ethylamine (ent-5; en-
try a, Table 4).
Ethyl (Z)-2-Bromomethyl-3-(4-chlorophenyl)propenoate (6c): The
title compound was obtained in quantitative yield as a white pow-
der. Recrystallization from Et2O furnished white crystals. Rf = 0.33
1
(petroleum ether/Et2O = 9:1); m.p. 56–58 °C. H NMR (400 MHz,
CDCl3): δ = 1.38 (t, J = 7.2 Hz, 3 H), 4.30 (q, J = 7.2 Hz, 2 H),
4.35 (s, 2 H), 7.42–7.45 (m, 2 H), 7.50–7.53 (m, 2 H), 7.75 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.4, 26.5, 61.7, 129.3,
129.7, 131.1, 132.9, 135.8, 141.4, 166.0 ppm. MS (ESI): m/z 325
[M(79Br,35Cl) + Na]+, 327 [M(81Br,35Cl) + Na]+. C12H12BrClO2
(303.58): calcd. C 47.48, H 3.98; found C 47.24, H 3.78.
The experimental conditions were optimized on a 1 mmol scale of
6a following the general procedure but by using the conditions (sol-
vent, tertiary base and time) reported in Tables 2–4. When cincho-
nine was used as the tertiary base, a mixture of DCM (1 mL) and
MeOH (1 mL) was used as solvent. Then the solvent was elimin-
ated under vacuum at room temperature and only DCM (2 mL)
was added before the addition of (S)-1-(4-methoxyphenyl)ethyl-
amine (5) at 0 °C.
Ethyl (Z)-2-Bromomethyl-3-(2-naphthyl)propenoate (6d): The title
compound was obtained in quantitative yield as a pale-yellow vis-
cous oil. Rf = 0.23 (petroleum ether/Et2O = 9:1). 1H NMR
(400 MHz, CDCl3): δ = 1.41 (t, J = 7.0 Hz, 3 H), 4.37 (q, J =
7.0 Hz, 2 H), 4.49 (s, 2 H), 7.52–7.58 (m, 2 H), 7.64–7.66 (m, 1 H),
7.85–7.88 (m, 1 H), 7.90–7.93 (m, 2 H), 7.98 (s, 1 H), 8.12 (br. s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.4, 27.2, 61.6, 126.5,
126.8, 127.5, 127.8, 128.7, 128.8, 129.1, 130.0, 131.9, 133.2, 133.5,
142.9, 166.3 ppm. MS (ESI): m/z 341 [M(79Br) + Na]+, 343
[M(81Br) + Na]+. C16H15BrO2 (319.20): calcd. C 45.98, H 6.43;
found C 60.04, H 4.58.
Quinidine and quinine (for the reaction carried out on a 10 mmol
scale) were recycled by carefully washing the precipitate with ad-
ditional petroleum ether (30 mL) and cold water (20 mL), and then
drying at 80 °C overnight. In general, 75–90% of the bases were
recovered.
The reaction carried out on a 100 mmol scale of 6a under Condi-
tions i. was performed with the same proportion of reagents and
solvents as indicated above in the general procedure.
Methyl 2-[(R)-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}(phenyl)meth-
yl]acrylate (7a) and Methyl 2-[(S)-{[(R)-1-(4-Methoxyphenyl)-
ethyl]amino}(phenyl)methyl]acrylate (ent-7a): Compounds 7a and
ent-7a were obtained, respectively, in 89 (Conditions i.) and 84%
yields (Conditions ii.) as pale-yellow viscous oils. In the case of the
reaction performed on a 100 mmol scale of 6a under Conditions i.,
7a was obtained in 85% yield. In the case of the reaction of 6a
with recovered quinidine and (S)-(–)-1-(4-methoxyphenyl)ethyl-
amine (5), 7a was obtained in 82% yield, whereas the reaction of 6a
with recovered quinine and (R)-(–)-1-(4-methoxyphenyl)ethylamine
(ent-5) gave ent-7a in 80% yield. Rf = 0.36 (petroleum ether/Et2O
= 1:1). [α]2D0 (7a) = –75 (c = 1.00, CHCl3). [α]2D0 (ent-7a) = +77 (c
= 1.10, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.29 (d, J =
6.6 Hz, 3 H), 1.88 (br. s, 1 H), 3.57 (q, J = 6.6 Hz, 1 H), 3.63 (s, 3
H), 3.81 (s, 3 H), 4.46 (s, 1 H), 5.77–5.78 (m, 1 H), 6.23 (s, 1 H),
6.84–6.88 (m, 2 H), 7.14–7.18 (m, 2 H), 7.23–7.27 (m, 3 H), 7.23–
7.27 (m, 3 H), 7.29–7.34 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.8, 51.8, 54.5, 55.3, 60.1, 113.8, 125.4, 127.3, 127.9,
128.0, 128.4, 137.3, 141.6, 143.2, 158.7, 167.0 ppm. MS (ESI): m/z
348 [M + Na]+. C20H23NO3 (325.41): calcd. C 73.82, H 7.12, N
4.30; found C 73.66, H 6.99, N 4.43.
Methyl (Z)-2-Bromomethyl-5-methyl-2-hexenoate (6e): The title
compound was obtained in 90% yield as a colourless oil. Rf = 0.28
(petroleum ether/Et2O = 98:2). H NMR (400 MHz, CDCl3): δ =
0.97 (d, J = 6.6 Hz, 6 H), 1.77–1.90 (m, 1 H), 2.19 (dd, J = 6.6,
7.8 Hz, 2 H), 3.80 (s, 3 H), 4.23 (s, 2 H), 7.00 (t, J = 7.8 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.7, 24.5, 28.2, 38.0,
52.3, 129.8, 147.6, 166.2 ppm. MS (ESI): m/z 257 [M(79Br) +
Na]+, 259 [M(81Br) + Na]+. C9H15BrO2 (235.12): calcd. C 45.98, H
6.43; found C 45.76, H 6.29.
1
General Procedure for the Formation of Amino Esters 7a–e, ent-7a–
e, 8a–e and ent-8a–e: The following procedure refers to the condi-
tions optimized to obtain predominantly 7a–e (Conditions i. in the
text). See below for the modifications used to obtain predominantly
ent-7a–e (Conditions ii. in the text), 8a–e or ent-8a–e, for the reac-
tions performed during the optimization of the experimental condi-
tions and for the recycling of quinine or quinidine. Quinidine (3.6 g,
11 mmol) was added to a solution of compound 6a–e (10 mmol) in
dry DCM (20 mL) at room temp. After stirring for 3 h, the reaction
was cooled in an ice bath and then (S)-1-(4-methoxyphenyl)ethyl-
amine (5; 1.63 mL, 11 mmol) was added. The reaction mixture was
stirred for 1 h (2 h in the case of 6d) at 0 °C and then poured into
a mixture of petroleum ether (150 mL) and NaOH 1 m (15 mL)
under vigorous stirring. The precipitate was filtered and washed
with petroleum ether (3ϫ30 mL) and then the organic phase was
separated, dried with anhydrous Na2SO4 and the solvents evapo-
rated under vacuum [Caution: the presence of other bases, i.e., re-
sidual quantities of quinidine and (S)-1-(4-methoxyphenyl)ethyl-
amine, catalyses the rearrangement of products to the unwanted
aminomethyl derivatives. Then, to slightly improve the yields, it was
useful to avoid completely the use of the warming bath and to
stop the evaporation before the flask reached room temperature].
Compounds 7a–e were obtained pure after chromatographic purifi-
cation (petroleum ether/Et2O) and careful concentration, avoiding
the use of any warming [Caution: at room temp. the neat pure prod-
ucts undergo slow rearrangement to aminomethyl derivatives (up
to 5% in a day) and must then be stored at –18 °C].
Methyl 2-[(S)-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}(phenyl)meth-
yl]acrylate (8a) and Methyl 2-[(R)-{[(R)-1-(4-Methoxyphenyl)ethyl]-
amino}(phenyl)methyl]acrylate (ent-8a): Compounds 8a and ent-8a
were obtained, respectively, in 51 [reaction with quinine and (S)-
(–)-1-(4-methoxyphenyl)ethylamine (5)] and 67% yields [reaction
with quinidine and (R)-(+)-1-(4-methoxyphenyl)ethylamine (ent-5)]
as pale-yellow viscous oils. Rf = 0.47 (petroleum ether/Et2O = 1:1).
[α]2D0 (8a) = +51 (c = 1.00, CHCl3). [α]2D0 (ent-8a) = –50 (c = 0.95,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.34 (d, J = 6.6 Hz, 3
H), 1.95 (br. s, 1 H), 3.64 (s, 3 H), 3.72 (q, J = 6.6 Hz, 1 H), 3.80
(s, 3 H), 4.43 (s, 1 H), 5.88–5.89 (m, 1 H), 6.39–6.40 (m, 1 H),
6.84–6.87 (m, 2 H), 7.18–7.31 (m, 7 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.7, 51.8, 54.7, 55.4, 60.6, 114.0, 126.2, 127.1, 127.2,
127.8, 128.4, 137.7, 141.1, 142.2, 158.7, 166.9 ppm. MS (ESI): m/z
348 [M + Na]+. C20H23NO3 (325.41): calcd. C 73.82, H 7.12, N
4.30; found C 73.68, H 7.02, N 4.46.
Compounds 8a–e were obtained as the predominant isomers by
following the same procedure, but by using quinine and (S)-1-(4-
methoxyphenyl)ethylamine (5; entry b, Table 3).
Methyl 2-[(R)-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}(4-nitrophen-
yl)methyl]acrylate (7b) and Methyl 2-[(S)-{[(R)-1-(4-Meth-
Eur. J. Org. Chem. 2011, 7199–7206
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7203

G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
oxyphenyl)ethyl]amino}(4-nitrophenyl)methyl]acrylate
(ent-7b):
0.9 H), 4.12 (q, J = 7.0 Hz, 0.1 H), 4.36 (s, 1 H), 5.80–5.81 (m, 1
H), 6.39–6.40 (m, 1 H), 6.83–6.87 (m, 2 H), 7.20–7.27 (m, 6 H) ppm
[CO2CH2CH3 signal shows 2 major and 2 minor resonances due
to the presence of rotamers]. 13C NMR (100 MHz, CDCl3): δ =
14.2, 24.8, 54.7, 55.4, 60.3, 60.8, 114.0, 126.5, 127.8, 128.4, 128.6,
132.7, 137.4, 140.8, 141.0, 158.8, 166.3 ppm. MS (ESI): m/z 396
[M(35Cl)+Na]+. C21H24ClNO3 (373.88): calcd. C 67.46, H 6.47, N
3.75; found C 67.36, H 6.32, N 3.59.
Compounds 7b and ent-7b were obtained, respectively, in 78 (Con-
ditions i.) and 81% yields (Conditions ii.) as colourless waxes that
solidified on standing to form colourless needles; m.p. 59–61 °C.
Rf = 0.14 (petroleum ether/Et2O = 7:3). [α]2D0 (7b) = –101 (c = 0.55,
DCM). [α]2D0 (ent-7b) = +102 (c = 0.70, DCM). 1H NMR
(400 MHz, CDCl3): δ = 1.30 (d, J = 6.6 Hz, 3 H), 1.73 (br. s, 1 H),
3.51 (q, J = 6.6 Hz, 1 H), 3.63 (s, 3 H), 3.81 (s, 3 H), 4.55 (s, 1 H),
5.89 (m, 1 H), 6.32 (s, 1 H), 6.85–6.89 (m, 2 H), 7.10–7.13 (m, 2 H),
7.44–7.48 (m, 2 H), 8.16–8.19 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.6, 52.0, 54.7, 55.4, 59.6, 114.1, 123.7, 126.4, 127.8,
128.8, 136.7, 142.0, 147.3, 149.6, 158.9, 166.4 ppm. MS (ESI): m/z
393 [M + Na]+. C20H22N2O5 (370.40): calcd. C 64.85, H 5.99, N
7.56; found C 68.71, H 5.82, N 7.43.
Ethyl 2-[(R)-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}(naphthalen-2-
yl)methyl]acrylate (7d) and Ethyl 2-[(S)-{[(R)-1-(4-Methoxyphen-
yl)ethyl]amino}(naphthalen-2-yl)methyl]acrylate (ent-7d): Com-
pounds 7d and ent-7d were obtained, respectively, in 89 (Conditions
i.) and 84% yields (Conditions ii.) as colourless oils. Rf = 0.25 (pe-
troleum ether/Et2O = 1:1). [α]2D0 (7d) = –185 (c = 2.00, DCM).
Methyl 2-[(S)-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}(4-nitrophen- [α]2D0 (ent-7d) = +187 (c = 2.15, DCM). 1H NMR (400 MHz,
yl)methyl]acrylate (8b) and Methyl 2-[(R)-{[(R)-1-(4-Methoxy- CDCl3): δ = 1.17 (t, J = 7.0 Hz, 3 H), 1.32 (d, J = 6.6 Hz, 3 H),
phenyl)ethyl]amino}(4-nitrophenyl)methyl]acrylate (ent-8b): Com-
pounds 8b and ent-8b were obtained, respectively, in 47 [reaction
with quinine and (S)(–)-1-(4-methoxyphenyl)ethylamine (5)] and
65% yields [reaction with quinidine and (R)-(+)-1-(4-meth-
oxyphenyl)ethylamine (ent-5)] as pale-yellow waxes. Rf = 0.34 (pe-
troleum ether/Et2O = 7:3). [α]2D0 (8b) = +39 (c = 2.00, DCM).
[α]2D0 (ent-8b) = –40 (c = 1.83, DCM). 1H NMR (400 MHz, CDCl3):
δ = 1.36 (d, J = 6.6 Hz, 3 H), 2.07 (br. s, 1 H), 3.66 (s, 3 H), 3.75
1.99 (br. s, 1 H), 3.63 (q, J = 6.6 Hz, 1 H), 3.83 (s, 3 H), 4.05 (q, J
= 7.0 Hz, 0.1 H), 4.07 (q, J = 7.0 Hz, 0.9 H), 4.10 (q, J = 7.0 Hz,
0.9 H), 4.13 (q, J = 7.0 Hz, 0.1 H), 4.66 (s, 1 H), 5.85 (s, 1 H), 6.39
(s, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 7.19 (d, J = 8.6 Hz, 2 H), 7.41–
7.50 (m, 3 H), 7.71 (s, 1 H), 7.81–7.85 (m, 3 H) ppm [CO2CH2CH3
signal shows 2 major and 2 minor resonances due to the presence
of rotamers]. 13C NMR (100 MHz CDCl3): δ = 14.2, 24.8, 54.5,
55.4, 60.1, 60.7, 113.9, 125.3, 125.8, 126.0, 126.1, 126.9, 127.7,
(q, J = 6.6 Hz, 1 H), 3.79 (s, 3 H), 4.40 (s, 1 H), 5.84 (m, 1 H), 127.9, 128.0, 128.1, 132.9, 133.4, 137.3, 139.1, 143.4, 158.7,
6.48 (s, 1 H), 6.83–6.87 (m, 2 H), 7.20–7.24 (m, 2 H), 7.51–7.54 (m,
166.6 ppm. MS (ESI): m/z 412 [M + Na]+. C25H27NO3 (389.49):
2 H), 8.10–8.14 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = calcd. C 77.09, H 6.99, N 3.60; found C 76.86, H 6.92, N 3.47.
25.0, 52.0, 54.9, 55.4, 60.8, 114.1, 123.5, 127.8, 128.0, 136.9, 139.6,
Ethyl 2-[(S)-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}(naphthalen-2-
147.0, 150.0, 158.9, 166.3 ppm. MS (ESI): m/z 393 [M + Na]+.
yl)methyl]acrylate (8d) and Ethyl 2-[(R)-{[(R)-1-(4-Methoxyphen-
yl)ethyl]amino}(naphthalen-2-yl)methyl]acrylate (ent-8d): Com-
pounds 8d and ent-8d were obtained, respectively, in 53 [reaction
C20H22N2O5 (370.40): calcd. C 64.85, H 5.99, N 7.56; found C
68.68, H 5.85, N 7.46.
Ethyl
2-[(R)-(4-Chlorophenyl){[(S)-1-(4-methoxyphenyl)ethyl]- with quinine and (S)-(–)-1-(4-methoxyphenyl)ethylamine (5)] and
60% yields [reaction with quinidine and (R)-(+)-1-(4-meth-
amino}methyl]acrylate (7c) and Ethyl 2-[(S)-(4-Chlorophenyl){[(R)-
1-(4-methoxyphenyl)ethyl]amino}methyl]acrylate (ent-7c): Com- oxyphenyl)ethylamine (ent-5)] as pale-yellow oils. Rf = 0.42 (petro-
pounds 7c and ent-7c were obtained, respectively, in 86 (Conditions
i.) and 89% yields (Conditions ii.) as pale-yellow oils. Rf = 0.12
(petroleum ether/Et2O = 7:3). [α]2D0 (7c) = –92 (c = 1.50, CHCl3).
[α]2D0 (ent-7c) = +90 (c = 1.28, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.18 (t, J = 7.1 Hz, 3 H), 1.30 (d, J = 6.6 Hz, 3 H),
1.60 (br. s, 1 H), 3.54 (q, J = 6.6 Hz, 1 H), 3.81 (s, 3 H), 4.04 (q, J
= 7.1 Hz, 0.2 H), 4.07 (q, J = 7.1 Hz, 0.8 H), 4.09 (q, J = 7.1 Hz,
0.8 H), 4.12 (q, J = 7.1 Hz, 0.2 H), 4.43 (s, 1 H), 5.78–5.79 (m, 1
H), 6.25 (s, 1 H), 6.84–6.88 (m, 2 H), 7.12–7.16 (m, 2 H), 7.18–7.21
leum ether/Et2O = 1:1). [α]2D0 (8d) = +80 (c = 2.00, DCM). [α]2D0
(ent-8d) = –78 (c = 1.45, DCM). H NMR (400 MHz, CDCl3): δ
1
= 1.17 (t, J = 7.0 Hz, 3 H), 1.39 (d, J = 6.6 Hz, 3 H), 1.98 (br. s, 1
H), 3.79 (q, J = 6.6 Hz, 1 H), 3.80 (s, 3 H), 4.05 (q, J = 7.0 Hz, 0.1
H), 4.08 (q, J = 7.0 Hz, 0.9 H), 4.08 (q, J = 7.0 Hz, 0.9 H), 4.11
(q, J = 7.0 Hz, 0.1 H), 4.63 (s, 1 H), 5.93 (s, 1 H), 6.45 (d, J =
1.6 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H),
7.41–7.47 (m, 3 H), 7.75–7.81 (m, 4 H) ppm [CO2CH2CH3 signal
shows 2 major and 2 minor resonances due to the presence of rota-
(m, 2 H), 7.26–7.30 (m, 2 H) ppm [CO2CH2CH3 signal shows 2 mers]. 13C NMR (100 MHz, CDCl3): δ = 14.2, 24.6, 54.8, 55.4,
major and 2 minor resonances due to the presence of rotamers].
13C NMR (100 MHz, CDCl3): δ = 14.1, 24.6, 54.5, 55.3, 59.4, 60.8,
113.9, 125.3, 127.8, 128.5, 129.3, 132.9, 137.0, 140.3, 143.0, 158.7,
60.6, 60.7, 114.0, 125.7, 125.8, 125.9, 126.0, 126.1, 127.7, 127.9,
128.0, 128.1, 132.8, 133.5, 137.7, 139.8, 141.4, 158.7, 166.5 ppm.
MS (ESI): m/z 412 [M + Na]+. C25H27NO3 (389.49): calcd. C 77.09,
166.3 ppm. MS (ESI): m/z 396 [M(35Cl)+Na]+. C21H24ClNO3 H 6.99, N 3.60; found C 76.94, H 6.89, N 3.49.
(373.88): calcd. C 67.46, H 6.47, N 3.75; found C 67.31, H 6.35, N
3.56.
Methyl (R)-3-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}-5-methyl-2-
methylenehexanoate (7e) and Methyl (S)-3-{[(R)-1-(4-Methoxy-
phenyl)ethyl]amino}-5-methyl-2-methylenehexanoate (ent-7e): Com-
pounds 7e and ent-7e were obtained, respectively, in 72 (Conditions
i.) and 60% yields (Conditions ii.) as colourless oils. Rf = 0.04 (pe-
troleum ether/Et2O = 6:4). [α]2D0 (7e) = –46 (c = 0.67, DCM). [α]2D0
Ethyl
2-[(S)-(4-Chlorophenyl){[(S)-1-(4-methoxyphenyl)ethyl]-
amino}methyl]acrylate (8c) and Ethyl 2-[(R)-(4-Chlorophenyl){[(R)-
1-(4-methoxyphenyl)ethyl]amino}methyl]acrylate (ent-8c): Com-
pounds 8c and ent-8c were obtained, respectively, in 62 [reaction
with quinine and (S)-(–)-1-(4-methoxyphenyl)ethylamine (5)] and
65% yields [reaction with quinidine and (R)-(+)-1-(4-meth-
oxyphenyl)ethylamine (ent-5)] as pale-yellow oils. Rf = 0.26 (petro-
leum ether/Et2O = 7:3). [α]2D0 (8c) = +61 (c = = 1.50, CHCl3).
[α]2D0 = (ent-8c) = –62 (c = 1.40, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.18 (t, J = 7.0 Hz, 3 H), 1.35 (d, J = 6.6 Hz, 3 H),
1.95 (br. s, 1 H), 3.72 (q, J = 7.0 Hz, 1 H), 3.80 (s, 3 H), 4.06 (q, J
= 7.0 Hz, 0.1 H), 4.09 (q, J = 7.0 Hz, 0.9 H), 4.10 (q, J = 7.0 Hz,
1
(ent-7e) = +46 (c = 0.85, DCM). H NMR (400 MHz, CDCl3): δ
= 0.84 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H), 1.26 (d, J =
6.2 Hz, 3 H), 1.45 (t, J = 7.0 Hz, 2 H), 1.57–1.70 (br. s + m, 2 H),
3.56 (t, J = 7.0 Hz, 1 H), 3.68 (q, J = 6.2 Hz, 1 H), 3.72 (s, 3 H),
3.79 (s, 3 H), 5.58–5.59 (m, 1 H), 6.18–6.19 (s, 1 H), 6.81–6.85 (m,
2 H), 7.20–7.23 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
22.6, 22.7, 22.9, 25.2, 44.6, 51.7, 54.2, 55.4, 56.3, 113.8, 125.6,
127.9, 138.6, 142.4, 158.6, 167.4 ppm. MS (ESI): m/z 328 [M +
7204
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7199–7206

Synthesis of 3-Amino-2-methylenealkanoates
Na]+. C18H27NO3 (305.42): calcd. C 70.79, H 8.91, N 4.59; found
C 70.64, H 8.81, N 4.43.
from c-hexane/ethyl acetate furnished colourless crystals; m.p. 76–
78 °C. Rf = 0.23 (DCM). The ee values of the products were deter-
mined by HPLC using a Chiralcel OD-H column [n-hexane/iPrOH,
Methyl
methylenehexanoate (8e) and Methyl (R)-3-{[(R)-1-(4-Methoxy-
phenyl)eth-yl]amino}-5-methyl-2-methylenehexanoate (ent-8e):
(S)-3-{[(S)-1-(4-Methoxyphenyl)ethyl]amino}-5-methyl-2-
99:1, flow rate 0.3 mL/min, λ = 210 nm, tent-10a = 27.8 min, t10a
=
29.0 min, ee Ն 99% when (S)-(–)-1-(4-methoxyphenyl)ethylamine
(5) with Ն98.5% ee and (R)-(–)-1-(4-methoxyphenyl)ethylamine
(ent-5) with Ն99% ee were used, see the Materials section]. [α]2D0
(10a) = –23 (c = 1.05, CHCl3). [α]2D0 (ent-10a) = +22 (c = 0.75,
CHCl3). The absolute configurations of compounds 10a and ent-
10a were determined by comparison with the literature values:
[α]2D0 (10a) = –15.1 (c = 0.15, CHCl3), 77% ee.[6d] [α]2D0 (ent-10a) =
+21 (c = 0.68, CHCl3), 91% ee.[6c] 1H NMR (400 MHz, CDCl3): δ
= 1.45 (s, 9 H), 3.67 (s, 3 H), 5.48 (br. s, 1 H), 5.68 (br. d, J =
8.2 Hz, 1 H), 5.92 (s, 1 H), 6.37 (s, 1 H), 7.23–7.34 (m, 5 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 28.5, 52.0, 56.3, 80.0, 126.7,
127.6, 128.7, 140.0, 155.1, 166.3 ppm. MS (ESI): m/z 314 [M +
Na]+. C16H21NO4 (291.35): calcd. C 65.96, H 7.27, N 4.81; found
C 65.79, H 7.14, N 4.67.
Compounds 8e and ent-8e were obtained, respectively, in 45 [reac-
tion with quinine and (S)-(–)-1-(4-methoxyphenyl)ethylamine (5)]
and 50% yields [reaction with quinidine and (R)-(+)-1-(4-meth-
oxyphenyl)ethylamine (ent-5)] as colourless oils. Rf = 0.15 (petro-
leum ether/Et2O = 6:4). [α]2D0 (8e) = –28 (c = 2.00, DCM). [α]2D0
1
(ent-8e) = +29 (c = 1.65, DCM). H NMR (400 MHz, CDCl3): δ
= 0.71 (d, J = 6.2 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H), 1.24 (d, J =
6.6 Hz, 3 H), 1.30–1.37 (m, 1 H), 1.41–1.48 (m, 1 H), 1.55–1.70 (br.
s + m, 2 H), 3.09 (dd, J = 6.4, 8.0 Hz, 1 H), 3.61 (q, J = 6.6 Hz, 1
H), 3.75 (s, 3 H), 3.80 (s, 3 H), 5.41–5.42 (m, 1 H), 6.16–6.17 (m,
1 H), 6.83–6.86 (m, 2 H), 7.18–7.22 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.4, 23.0, 25.0, 25.6, 45.0, 51.7, 54.3, 55.3,
56.8, 113.8, 125.9, 128.0, 137.7, 141.9, 158.6, 167.3 ppm. MS (ESI):
m/z = 328 [M + Na]+. C18H27NO3 (305.42): calcd. C 70.79, H 8.91,
N 4.59; found C 70.59, H 8.78, N 4.46.
Methyl
(R)-2-{[(tert-Butoxycarbonyl)amino](4-nitrophenyl)meth-
yl}acrylate (10b) and Methyl (S)-2-{[(tert-Butoxycarbonyl)amino](4-
nitrophenyl)methyl}acrylate (ent-10b): The title compounds were
obtained in 72% yields from 7b and ent-7b, respectively, as pale-
yellow waxes. Rf = 0.17 (DCM). The ee values of the products were
determined by HPLC using a Chiralcel OD-H column [n-hexane/
iPrOH, 95:5, flow rate 0.3 mL/min, λ = 210 nm, tent-10b = 34.6 min,
t10b = 36.5 min, ee 99% when (S)-(–)-1-(4-methoxyphenyl)ethyl-
amine (5) with Ն98.5% ee and (R)-(–)-1-(4-methoxyphenyl)ethyl-
amine (ent-5) with Ն99% ee were used, see Materials section].
[α]2D0 (10b) = +26 (c = 1.75, DCM). [α]2D0 (ent-10b) = –27 (c = 1.88,
Methyl (S,E)-2-({[1-(4-Methoxyphenyl)ethyl]amino}methyl)-3-phen-
ylacrylate (9): The title compound was obtained in 79% yield as a
pale-yellow viscous oil (reaction with Et3N in DMSO, as in Table 2,
but with a reaction time of 3 d at room temperature). Rf = 0.11 (c-
hexane/ethyl acetate = 2:8). [α]2D0 = –107 (c = 1.50, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.35 (d, J = 7.0 Hz, 3 H), 1.74 (br.
s, 1 H), 3.41 (d, J = 11.7 Hz, 1 H), 3.46 (d, J = 11.7 Hz, 1 H), 3.74
(q, J = 7.0 Hz, 1 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 6.82–6.86 (m, 2
H), 7.21–7.31 (m, 5 H), 7.35–7.37 (m, 2 H), 7.76 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.4, 44.4, 52.2, 55.4, 58.0, 113.8,
128.1, 128.5, 128.9, 129.7, 130.7, 135.1, 137.4, 141.9, 158.7,
168.8 ppm. MS (ESI): m/z 348 [M + Na]+. C20H23NO3 (325.41):
calcd. C 73.82, H 7.12, N 4.30; found C 73.69, H 7.03, N 4.16.
1
DCM). H NMR (400 MHz, CDCl3): δ = 1.46 (s, 9 H), 3.70 (s, 3
H), 5.68–5.76 (m, 2 H), 6.00 (s, 1 H), 6.43 (s, 1 H), 7.46–7.49 (m,
2 H), 8.16–8.20 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
28.4, 52.2, 56.2, 80.4, 123.8, 127.3, 128.6, 138.9, 147.3, 147.7, 155.0,
165.8 ppm. MS (ESI): m/z = 359 [M + Na]+. C16H20N2O6 (336.34):
calcd. C 57.14, H 5.99, N 8.33; found C 57.02, H 5.78, N 8.12.
General Procedure for the Synthesis of Enantiomerically Pure Pro-
tected 2-Methylene-3-amino Esters 10 and ent-10: Compounds 7a–
e or ent-7a–e (5 mmol), were dissolved in trifluoroacetic acid
(10 mL) and the reactions were heated at reflux for 8 h (72 h in the
case of 7e) using a condenser equipped with an anhydrous CaCl2
trap. After elimination of the trifluoroacetic acid under vacuum
(bath temperature of 60 °C), the residue was dissolved in DCM
(3 mL) and THF (5 mL), and the solvent was carefully evaporated.
The procedure was repeated five times and then di-tert-butyl dicar-
bonate (7.5 mmol, 1.64 g) and 1 m NaOH (15 mL) were sequen-
tially added to the residue dissolved in DCM (10 mL) at room tem-
perature. The pH of the aqueous phase was verified to be Ն13; if
it was not, additional aliquots of 1 mL of 1 m NaOH were added
until the pH was above this value. The reaction mixture was stirred
for 2 h, diluted with DCM (20 mL) and water (10 mL) and, after
separation, the aqueous phase was extracted again with DCM
(2ϫ10 mL). The unified organic phases were dried with anhydrous
Na2SO4, the solvent was eliminated under vacuum and the residue
was submitted to silica gel chromatographic purification (from c-
hexane/DCM to DCM/methanol) to obtain the pure products 10a–
e or ent-10a–e. The ee values of the enantiomers 10a–e were Ն96
or Ն98%, whereas those of ent-10a–e were Ն98 or Ն99%, de-
pending on the enantiomeric purity of the chiral inducer used (see
Materials section).
Ethyl (R)-2-{[(tert-Butoxycarbonyl)amino](4-chlorophenyl)methyl}-
acrylate (10c) and Ethyl (S)-2-{[(tert-Butoxycarbonyl)amino](4-chlo-
rophenyl)methyl}acrylate (ent-10c): The title compounds were ob-
tained in 80% yields from 7c and ent-7c, respectively, as white
waxes. Recrystallization from c-hexane/ethyl acetate furnished
white crystals; m.p. 75–79 °C. Rf = 0.34 (DCM). The ee values of
the products were determined by HPLC using a Chiralcel OD-H
column [n-hexane/iPrOH, 99:1, flow rate 0.3 mL/min, λ = 220 nm,
tent-10c = 24.9 min, t10c = 26.0 min, ee Ն 99% when (S)-(–)-1-(4-
methoxyphenyl)ethylamine (5) with Ն98.5% ee and (R)-(–)-1-(4-
methoxyphenyl)ethylamine (ent-5) with Ն99% ee were used, see
Materials section]. [α]2D0 (10c) = –8 (c = 2.00, CHCl3). [α]2D0 (ent-
10c) = +7 (c = 1.40, CHCl3). The absolute configuration of com-
pound 10c was determined by comparison with the literature value:
[α]2D0 (10c) = –5.3 (c = 0.51, CHCl3), 90% ee.[3] 1H NMR (400 MHz,
CDCl3): δ = 1.19 (t, J = 7.0 Hz, 3 H), 1.45 (s, 9 H), 4.09 (q, J =
7.0 Hz, 0.1 H), 4.12 (q, J = 7.0 Hz, 0.9 H), 4.13 (q, J = 7.0 Hz, 0.9
H), 4.15 (q, J = 7.0 Hz, 0.1 H), 5.49 (br. s, 1 H), 5.64 (d, J = 8.2 Hz,
1 H), 5.89 (s, 1 H), 6.37 (s, 1 H), 7.20–7.24 (m, 2 H), 7.27–7.30
(m, 2 H) ppm [CO2CH2CH3 signal shows 2 major and 2 minor
resonances due to the presence of rotamers]. 13C NMR (100 MHz,
CDCl3): δ = 14.1, 28.5, 55.8, 61.1, 80.1, 126.9, 128.0, 128.8, 133.3,
138.8, 140.0, 155.0, 165.6 ppm. MS (ESI): m/z = 362 [M(35Cl) +
Na]+. C17H22ClNO4 (339.82): calcd. C 60.09, H 6.53, N 4.12; found
C 59.93, H 6.38, N 4.01.
Methyl (R)-2-{[(tert-Butoxycarbonyl)amino](phenyl)methyl}acrylate
(10a) and Methyl (S)-2-{[(tert-Butoxycarbonyl)amino](phenyl)-
methyl}acrylate (ent-10a): The title compounds were obtained in
85% yields from 7a and ent-7a, respectively, as colourless waxes
that solidified on standing to form white crystals. Recrystallization
Ethyl (R)-2-{[(tert-Butoxycarbonyl)amino](naphthalen-2-yl)methyl}-
acrylate (10d) and Ethyl (S)-2-{[(tert-Butoxycarbonyl)amino]-
Eur. J. Org. Chem. 2011, 7199–7206
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7205

G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
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(naphthalen-2-yl)methyl}acrylate (ent-10d): The title compounds
were obtained in 93% yields from 7d and ent-7d, respectively, as
pale-yellow waxes. Recrystallization from c-hexane furnished pale-
yellow crystals; m.p. 98–101 °C. Rf = 0.36 (DCM). The ee values
of the products were determined by HPLC using a Chiralcel OD-
H column [n-hexane/iPrOH, 99:1, flow rate 1.0 mL/min, λ =
210 nm, tent-10d = 12.9 min, t10d = 14.5 min, ee 99% when (S)-(–)-
1-(4-methoxyphenyl)ethylamine (5) with Ն98.5% ee and (R)-(–)-1-
(4-methoxyphenyl)ethylamine (ent-5) with Ն99% ee were used, see
Materials section]. [α]2D0 (10d) = –40 (c = 2.00, DCM). [α]2D0 (ent-
10d) = +41 (c = 1.53, DCM). 1H NMR (400 MHz, CDCl3): δ =
1.17 (t, J = 7.0 Hz, 3 H), 1.47 (s, 9 H), 4.07 (q, J = 7.0 Hz, 0.1 H),
4.09 (q, J = 7.0 Hz, 0.9 H), 4.10 (q, J = 7.0 Hz, 0.9 H), 4.13 (q, J
= 7.0 Hz, 0.1 H), 5.55 (br. s, 1 H), 5.86 (d, J = 8.2 Hz, 1 H), 5.96
(s, 1 H), 6.43 (s, 1 H), 7.41–7.49 (m, 3 H), 7.73 (s, 1 H), 7.79–7.81
(m, 3 H) ppm [CO2CH2CH3 signal shows 2 major and 2 minor
resonances due to the presence of rotamers]. 13C NMR (100 MHz,
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126.4, 127.7, 128.1, 128.4, 132.8, 133.4, 137.6, 140.4, 155.1,
165.8 ppm. MS (ESI): m/z = 378 [M + Na]+. C21H25NO4 (355.43):
calcd. C 70.96, H 7.09, N 3.94; found C 70.77, H 6.92, N 4.01.
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Methyl (R)-3-[(tert-Butoxycarbonyl)amino]-5-methyl-2-methylene-
hexanoate (10e) and Methyl (S)-3-[(tert-Butoxycarbonyl)amino]-5-
methyl-2-methylenehexanoate (ent-10e): The title compounds were
obtained in 63% yields from 7e and ent-7e, respectively, as colour-
less waxes. Rf = 0.30 (DCM). The ee values of the products were
determined by HPLC using a Chiralcel OD-H column [n-hexane/
iPrOH, 99.5:0.5, flow rate 1.0 mL/min, λ = 210 nm, t10e = 24.2 min,
tent-10e = 30.4 min, ee 99% when (S)-(–)-1-(4-methoxyphenyl)ethyl-
amine (5) with Ն98.5% ee and (R)-(–)-1-(4-methoxyphenyl)ethyl-
amine (ent-5) with Ն99% ee were used, see Materials section].
[α]2D0 (10e) = +11 (c = 1.22, CHCl3). [α]2D0 (ent-10e) = –11 (c = 1.39,
CHCl3). The absolute configuration of compound ent-10e was
determined by comparison with the literature value:
[α]2D0 (ent-10e) = –10.6 (c = 1.00, CHCl3).[1] 1H NMR (400 MHz,
CDCl3): δ = 0.90 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H),
1.42 (s, 9 H), 1.46–1.50 (m, 2 H), 1.53–1.63 (m, 1 H), 3.76 (s, 3 H),
4.39 (br. s, 0.2 H), 4.47 (dd, J = 7.8, 16.0 Hz, 0.8 H), 4.68 (br. s,
0.2 H), 5.12 (br. d, J = 8.6 Hz, 0.8 H), 5.67 (br. s, 0.2 H), 5.73 (s,
0.8 H), 6.16 (m, 1 H) ppm [some signals show multiple resonances
due to the presence of rotamers]. 13C NMR (100 MHz, CDCl3): δ
= 22.4, 22.7, 25.2, 28.5, 44.0, 51.9, 79.4, 126.1, 140.9, 155.2,
166.6 ppm. MS (ESI): m/z = 294 [M + Na]+. C14H25NO4 (271.36):
calcd. C 61.97, H 9.29, N 5.16; found C 61.76, H 8.98, N 5.02.
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Supporting Information (see footnote on the first page of this arti-
cle): Determination of the isomer ratio of quaternary ammonium
salt intermediates, preliminary assignment of the configuration at
C-3 in diastereomers 8a and 9a and NMR spectra of all new com-
pounds.
[10] The amount of (E)-bromomethyl derivatives was Յ3% in all
1
cases, as evidenced by the H NMR spectra.
[11] In these cases, the intermediate quaternary ammonium salts
were formed and characterized (see the Supporting Infor-
mation).
[12] H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997,
Acknowledgments
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We thank the Polytechnic University of Marche (Ancona, Italy) for
financial support.
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Received: August 25, 2011
Published Online: October 17, 2011
7206
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7199–7206