Aza-Reformatsky reaction promoted by catalytic samarium diiodide: Synthesis of β-amino esters or amides

Article abstract of DOI:10.1055/s-0034-1378229

The synthesis of β-amino esters or amides has been achieved from moderate to high yields from the reaction of imines and α-halo esters or amides promoted by catalytic amounts of samarium diiodide in the presence of magnesium turnings as co-reductant. A me

Full text of DOI:10.1055/s-0034-1378229

LETTER
▌1709
lAettzera-Reformatsky Reaction Promoted by Catalytic Samarium Diiodide:
Synthesis of β-Amino Esters or Amides
Synthesis of β-Amino Esters or Amides
Humberto Rodríguez-Solla,* Ainhoa Díaz-Pardo, Carmen Concellón, Vicente del Amo
Dpto. Química Orgánica e Inorgánica, Universidad de Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain
E-mail: hrsolla@uniovi.es
Received: 31.03.2014; Accepted after revision: 05.05.2014
In this communication, we report a new and easy access
to β-amino esters or amides by treatment of α-halo esters
or amides with our previously developed SmI2
cat./Mg/ZnCl2 system. A mechanism to explain this cata-
Abstract: The synthesis of β-amino esters or amides has been
achieved from moderate to high yields from the reaction of imines
and α-halo esters or amides promoted by catalytic amounts of
samarium diiodide in the presence of magnesium turnings as co-
reductant. A mechanism is proposed to explain this catalytic samar- lytic samarium(II)-promoted aza-Reformatsky process is
ium(II)-promoted aza-Reformatsky reaction.
also proposed.
Key words: amino esters, catalytic reactions, enolates,
Reformatsky reaction, samarium
Imines 1, derived from p-toluenesulfonamide and used as
starting materials, were prepared in high yields according
to a method previously reported in the literature.18,19
Initially, we studied the addition reaction of ethyl bromo-
Several syntheses of β-amino acids and their derivatives
acetate 2a to the N-tosylimine 1a derived from octanal ac-
have been reported to date.1 β-Amino acid derivatives2 are
cording to the same reaction conditions, previously
relevant starting materials in organic synthesis,3 as this
reported by our group for the SmI2-catalyzed β-elimina-
functionality is present in compounds with biological4 or
tion reaction.16 So, when 0.4 equivalents of SmI2 and six
pharmacological5 activity. In addition, their peptides6 are
equivalents of the mixture Mg/ZnCl2 were added to 1a
also featured in several active drugs.7
and 2a in THF, β-amino ester 3a was isolated in 83% yield
after chromatography.20
Previously, we have reported a synthetic protocol to carry
out aza-Reformatsky reactions using samarium enolates,
derived from different α-amino esters or amides, and a
number of imines.8 In those cases, stoichiometric amounts
of samarium diiodide were required for the samarium eno-
late generation.
Samarium diiodide9 is a very important reagent as it can
mediate reactions that other reagents cannot, however,
one of the main drawbacks of SmI2 chemistry is its rela-
tively high cost, moreover when it has been generally em-
ployed in stoichiometric amounts. For this reason,
methods to carry out transformations using this salt in cat-
alytic amounts would be desirable.
We have also tested different amounts of SmI2 (0.05, 0.1
equiv) and reaction times. In all cases, the yields of the
isolated products were lower than when the reaction was
performed with 0.4 equivalents used in our previous con-
tribution.16 When the reaction was carried out in the ab-
sence of SmI2 no reaction took place and compound 1a
was isolated unaltered.
After several tests, we found that ideal reaction conditions
utilizing a mixture composed of one equivalent of N-tosyl
imine 1a, one equivalent of α-halo ester 2, 0.4 equivalents
of SmI2, 6.0 equivalents of magnesium turnings,21 and 6.0
equivalents of ZnCl2, for 3.5 hours at room temperature.22
With this set of conditions in hand, we performed the aza-
Reformatsky reaction with a range of imines 1 as it is
shown in Table 1.
Several systems for the regeneration of Sm(II) from
Sm(III) species have been reported to date: the use of cat-
alytic amounts of samarium diiodide and different core-
ductants such as Zn(Hg) amalgams,10 Ce-mischmetal,11
and magnesium turnings (with different additives: 1,2-di-
bromoethane,12 trimethylsilyl chloride,13 dimethylsilyl di-
chloride),14 or electrochemical techniques employing
magnesium15 or samarium16 cathodes. As part of our re-
search program concerned with the use catalytic amounts
of samarium diiodide in organic synthesis, we have also
reported the use of a mixture of catalytic SmI2/Mg/ZnCl2
in β-elimination reactions of α-halo-β-hydroxy esters af-
fording (E)-α,β-unsaturated esters in a totally stereoselec-
tive manner.17
Table 1 reveals that, according to our methodology, the
synthesis of β-amino esters is general. It has been possible
to use linear, cyclic, branched, or aromatic N-tosyl imines
1. Moreover, this reaction has been also carried out using
imines containing readily enolizable protons, such as 1d
(Table 1, entry 5). It is noteworthy that other protecting
group such as tert-butoxycarbonyl23 can be used in this
process (Table 1, entry 8). Also, no differences were ob-
served on the reaction outcome when this process was car-
ried out on bromo or chloro derivatives 2 (Table 1, entries
1 and 2).
As a logical extension, we have also studied the synthesis
of β-amino amides. So, the reaction of imines 1c with the
samarium enolate generated from N,N-diethyl chloroacet-
SYNLETT 2014, 25, 1709–1712
Advanced online publication: 24.06.2014
DOI: 10.1055/s-0034-1378229; Art ID: st-2014-d0273-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1710
H. Rodríguez-Solla et al.
LETTER
The structure of β-amino esters 3 and amide 5 were estab-
lished by comparison with the NMR data of these com-
pounds previously reported in the literature (3b–d,8 3f,8
3g,24 3h,22 and 58b). The structure of compounds 3a19 and
Table 1 Synthesis of β-Amino Esters 3 by Using Catalytic SmI2
NHR2
O
R2
R3
SmI2 (0.4 equiv), ZnCl2
Mg, I2, THF
N
CO2Et
R1
+
OEt
1
13
3e25 were assigned by H NMR, C NMR, and IR spec-
R1
R3
Hal
1
2
3
troscopy, and HRMS.
R1
R2
R3
Hal Yield (%)a
A mechanistic proposal is described in Scheme 2. Thus,
the formation of β-amino esters 3 or amides 5 might be ex-
plained assuming the generation of the samarium enolate
6 after metalation, by SmI2, of the C–Hal bond in esters 2
or amides 4.
Entry 1
2
3
1
2
3
4
5
6
7
8
1a
2a 3a n-C7H15
2b 3b n-C7H15
2a 3c s-Bu
2a 3d Cy
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Boc
H
Br
Cl
Br
Br
Br
Br
Br
Br
83
64
68
71
54
60
66
74
1a
1b
1c
1d
1e
1f
Me
H
Reaction between the enolate 6 and imines 1 would afford
the samarium(III) amide 7 which, after transmetalation
with ZnCl2, would generate a Zn(II) amide 8. The use of
ZnCl2 allowed the release of the samarium(III) species
from the amide group. Samarium(III) is further reduced
by magnesium turnings to generate samarium(II) species,
which are again involved in the catalytic cycle to promote
the formation of enolates 6 from esters 2 or amides 4. Fi-
nally, hydrolysis of Zn(II) amides 8 would afford β-amino
esters or amides 3, and 5, respectively.
H
2a 3e Bn
H
2a 3f BnCH2
2a 3g Ph
H
H
1g
2a 3h Ph
H
a Isolated yield of pure compounds 3 after column chromatography
based on compounds 1.
In conclusion, an efficient, general, and very cheap meth-
odology has been developed for the synthesis of β-amino
esters from easily available N-tosyl or N-Boc imines and
commercial α-halo esters or amides with catalytic
amounts of SmI2. Attempts to carry out other processes
with catalytic samarium diiodide, including an asymmet-
ric version of the aza-Reformatsky reaction, are currently
under investigation within our laboratory.
amide (4) afforded the corresponding β-amino amide 5 in
similar yield to that obtained when ester functionalities
were used (Scheme 1).
Ts
O
NHTs
N
SmI2 (0.4 equiv), ZnCl2
Cl
CONEt2
+
NEt2
Cy
Cy
Mg, I2, THF
61%
Acknowledgment
1c
4
5
We thank to Ministerio de Economía y Competitividad for financial
support. V.d A. and A. D. -P. thank MINECO (Spain), and Univer-
sity of Oviedo, for a Ramón y Cajal contract and a predoctoral fel-
lowship, respectively.
Scheme 1 Synthesis of β-amino amide 5
H
ClZn
NR2
O
NR2
O
Y
H3O+
R1
Y
R1
R3
3 or 5
R3
Mg0
2 SmX3
8
X = Cl, Br, I
MgII
ZnCl2
SmIII
NR2
O
R1
Y
2 SmX2
R3
7
O
R3
OSmIII
Y
NR2
R3
Hal
Y
R1
1
6
2 or 4
Scheme 2 Mechanistic proposal for the conversion of 1 into 3 or 5
Synlett 2014, 25, 1709–1712
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of β-Amino Esters or Amides
1711
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(19) Procedure for the Synthesis of N-Tosyloctan-1-imine (1a)
A mixture of n-octanal (10 mmol), p-toluenesulfonamide
(10 mmol), sodium p-toluenesulfinate (10 mmol) in H2O (15
mL), and formic acid (15 mL) was stirred for 24 h at r.t. The
resulting white precipitate was collected by filtration,
washed with H2O (3 × 10 mL) and hexane (2 × 10 mL), then
dissolved in CH2Cl2 (100 mL), followed by addition of H2O
(35 mL) and sat. aq NaHCO3 (35 mL). The solution was well
stirred for 10 min at r.t. The organic phase was collected, the
aqueous phase was extracted with CH2Cl2 (3 × 70 mL).
The combined organic layers were dried over Na2SO4 and
concentrated in vacuo to yield N-tosyloctan-1-imine (1a) as
a colorless oil (1.84 g, 65%). This material was used without
further purification. 1H NMR (300 MHz, CDCl3): δ = 8.60 (t,
J = 4.6 Hz, 1 H), 7.81 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2
Hz, 2 H), 2.51 (dt, J = 7.4, 4.6 Hz, 2 H), 2.40 (s, 3 H), 1.66–
1.57 (m, 2 H), 1.39–1.14 (m, 8 H), 0.86 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 178.4 (CH), 144.4 (C),
134.4 (C), 129.5 (2 × CH), 127.8 (2 × CH), 35.6 (CH2), 31.2
(CH2), 28.7 (CH2), 28.5 (CH2), 24.3 (CH2), 22.2 (CH2), 21.3
(CH3), 13.7 (CH3). IR (neat): ν = 3292, 1629, 1020, 737 cm–1.
(20) Please note that a minimum of 2.0 equiv of SmI2 are required
to carry out this transformation in a stoichiometric manner.
(21) Since magnesium is normally coated with a layer of MgO,
we have previously treated the magnesium turnings with a
few crystals of iodine to activate its surface.
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(22) Procedure for the Synthesis of Ethyl 3-(Tosylamino)-
decanoate (3a)
(7) Krauthäuser, S.; Christianson, L. A.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1997, 119, 11719.
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(9) For recent reviews of SmI2, see: (a) Edmons, D. J.; Johnston,
D.; Procter, D. J. Chem. Rev. 2004, 104, 3371.
A solution of N-tosyloctan-1-imine (1a, 0.2 mmol) and ethyl
bromoacetate (2a, 0.2 mmol) in THF (2.5 mL) was added
dropwise at r.t. and vigorous stirring to a mixture of SmI2
(0.1 M in THF, 0.8 mL) and activated Mg (1.2 mmol) with
iodine and ZnCl2 (1.2 mmol) in THF (2.5 mL). After stirring
at the same temperature 3.5 h, the mixture was hydrolyzed
with an aq solution of HCl (0.1 M, 10 mL). The aqueous
phase was filtered through a pad of Celite® and extracted
(b) Concellón, J. M.; Rodríguez-Solla, H. Chem. Soc. Rev.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1709–1712

1712
H. Rodríguez-Solla et al.
LETTER
(23) For the synthesis of N-Boc imine 1g, see: Wenzel, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
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6660.
with CH2Cl2 (3 × 10 mL). The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo. Flash
column chromatography on silica gel (hexane–EtOAc, 5:1)
provided pure ethyl 3-(tosylamino)decanoate (3a) as a
yellow oil (62 mg, 83%). 1H NMR (300 MHz, CDCl3): δ =
7.69 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 5.22 (d,
J = 9.0 Hz, 1 H), 4.09–3.92 (m, 2 H), 3.50–3.38 (m, 1 H),
2.51 (ddd, J = 3.0, 15.0, 30.0 Hz, 2 H), 2.35 (s, 3 H), 1.47–
1.06 (m, 12 H), 1.15 (t, J = 7.0 Hz, 3 H), 0.79 (t, J = 7.0 Hz,
3 H). 13C NMR (75 MHz, CDCl3): δ = 171.3 (C), 143.1 (C),
138.1 (C), 129.5 (2 × CH), 126.8 (2 × CH), 60.5 (CH2), 50.6
(CH), 41.2 (CH2), 38.8 (CH2), 34.6 (CH2), 31.6 (CH2), 29.1
(CH2), 28.9 (CH2), 25.6 (CH2), 22.5 (CH3), 21.4 (CH3), 13.9
(CH3). IR (neat): ν = 1747, 1331, 1160, 1094 cm–1. HRMS:
m/z calcd for C19H32NO4S [M + H]+: 370.2052; found:
370.2049.
(25) Spectroscopic Data of Compound 3e
1H NMR (300 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2 H),
7.14–7.10 (m, 5 H), 6.93 (d, J = 8.2 Hz, 2 H), 5.21 (d, J = 8.2
Hz, 1 H), 4.08–3.92 (m, 2 H), 3.74–3.63 (m, 1 H), 2.72 ( d,
J = 6.0 Hz, 1 H), 2.71 (d, J = 6.0 Hz, 1 H), 2.37 (d, J = 5.2
Hz, 2 H), 2.32 (s, 3 H), 1.15 (t, J = 7.1 Hz, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 171.6 (C), 143.5 (C), 137.8 (C), 137.1
(C), 129.9 (2 × CH), 129.6 (2 × CH), 128.9 (2 × CH), 127.3
(2 × CH), 127.0 (CH), 61.0 (CH2), 52.2 (CH), 41.0 (CH2),
38.3 (CH2), 21.8 (CH3), 14.4 (CH3). IR (neat): ν = 2929,
1740, 1265, 1160, 738 cm–1. HRMS: m/z calcd for
C19H24NO4S [M + H]+: 362.1426; found: 362.1428.
Synlett 2014, 25, 1709–1712
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