The addition reaction of samarium enolates and 2-haloenolates derived from esters, and amides to imines. totally stereoselective synthesis of enantiopure 3,4-diamino esters or amides

Article abstract of DOI:10.1002/adsc.200900534

The addition reaction of samarium enolates and 2-haloenolates derived from esters and amides to imines takes place in an efficient manner. A novel protocol to perform the addition reaction of samarium enolates derived from esters or amides to chiral 2-ami

Full text of DOI:10.1002/adsc.200900534

FULL PAPERS
DOI: 10.1002/adsc.200900534
The Addition Reaction of Samarium Enolates and 2-Haloenolates
Derived from Esters, and Amides to Imines. Totally Stereoselec-
tive Synthesis of Enantiopure 3,4-Diamino Esters or Amides
Josꢀ M. Concellꢁn,a,* Humberto Rodrꢂguez-Solla,a Carmen Simal,a
Vicente del Amo,a Santiago Garcꢂa-Granda,a and M. Rosario Dꢂaza
a
Departamento de Quꢂmica Orgꢃnica e Inorgꢃnica and Quꢂmica Fꢂsica y Analꢂtica, Facultad de Quꢂmica, Universidad de
Oviedo, 33071 Oviedo, Spain
Fax : (+34)-98-510-3446; e-mail: jmcg@uniovi.es
Received: July 30, 2009; Published online: November 18, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900534.
Abstract: The addition reaction of samarium eno- enolates (lithium, magnesium, etc.) could be a valua-
lates and 2-haloenolates derived from esters and ble alternative to obtain enantiopure 3,4-diamino
amides to imines takes place in an efficient manner. esters or amides, when enolates of low basicity are
A novel protocol to perform the addition reaction of necessary.
samarium enolates derived from esters or amides to
chiral 2-aminoimines, with total stereoselectivity and
without racemization, is also reported. The use of sa- Keywords: addition to carbonyl compounds; eno-
marium enolates in place of other classic metallic lates; imines; Mannich reaction; samarium
Introduction
In this sense, samarium enolates[8] could be a valuable
alternative to the use of lithium enolates due to their
3-Amino acid derivatives[1] are important starting ma- lower basicity.
terials in organic synthesis,[2] and their functionality is
Recently, we have communicated the first protocol
present in compounds with biological[3] or pharmaco- to carry out the Mannich reaction with samarium eno-
logical[4] activity. In addition, their peptides[5] are pres- lates.[9] Here, a range of various 3-amino esters or
ent in several drugs.[6]
amides were prepared by the reaction of samarium
For this reason, many syntheses of 3-amino acids enolates with imines derived from p-toluenesulfona-
and their derivatives have been reported.[7] In particu- mide. In the same communication, we also reported
lar, the Mannich-type reaction (the addition reaction the reaction of samarium enolate of ethyl acetate
of enolates of acid derivatives to imines) constitutes a with the chiral 2-aminoimine readily available from
method of choice in many cases due to its generality phenylalaninal and (R)-2-methyl-2-propanesulfinam-
and versatility. Generally, the Mannich reaction is per-
ACHTUNGTRENiNGNU de. Here, the corresponding enantiopure 3,4-diamino
formed using activated aldimines (for example, de- ester was obtained with total stereoselectivity and
rived from tosylamides or alkanesulfonamides) and without racemization.
lithium enolates. In recent years, much effort has
Now, in this paper, our objective is to report the
been focused on the development of novel reagents generalization of those previous results and to de-
to perform this transformation under milder reaction scribe novel addition reactions of samarium enolates
conditions and to enhance the generality of the reac- to imines. The study of the reaction of samarium eno-
tion. Thus, alternative, more reactive imines or eno- lates with prochiral imines has been completed, and
lates derived from other metals, without the draw- the stereoselective synthesis of enantiopure 3,4-diami-
backs of lithium enolates have been reported. Hence, no esters has been generalized by preparing two addi-
to overcome the limitations derived from the high ba- tional examples. The hitherto unreported Mannich re-
sicity, other alternative, less basic enolates derived action of samarium 2-haloenolates of esters or amides
from metals other than lithium have been developed. and the totally stereoselective synthesis of enantio-
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pure 3,4-diamino amides by reaction of samarium aldimine 1) by treating the corresponding 2-halo ester
enolates from amides with chiral 2-aminoimines is 2 with SmI2 at ꢀ208C for 30 min. Then, the corre-
also described.
sponding imine 1e or 1f was added dropwise, and the
Firstly, the results obtained from the addition reac- mixture was stirred for 30 min at the same tempera-
tion of samarium enolates from esters and amides, or ture and for an additional 3.5 h at ambient tempera-
from 2-halo esters and amides to prochiral imines will ture. The amino esters 3e, f were then obtained in
be described. The chiral version of this samarium- good yields, as shown in Table 1. A similar protocol
Mannich reaction will additionally be discussed.
was followed in the synthesis of products 4h, i derived
from p-chloro- and p-methoxybenzaldimine.
In general terms, as can be seen in Table 1, it is pos-
sible to conclude that: (1) the addition reaction of sa-
marium enolates derived from esters or amides is gen-
Results and Discussion
We have previously developed the addition reaction eral thus, aliphatic (linear, cyclic, or branched) and ar-
of samarium enolates derived from esters or amides omatic (differently substituted) aldimines 1 can be
to a range of imines 1 derived from p-toluenesulfon- employed as starting materials. When the starting
A
pared following a method previously reported in the diastereoisomeric mixture, the dr ranged between 1:1
literature[10] and samarium enolates were prepared and 3:1. (2) The 3-amino acids were obtained in good
under Barbier-type conditions. Thus, the treatment of to high yields and, as can be observed in Table 1,
a solution of the corresponding imine 1 and the 2- higher yields (~10–20% higher) were obtained from
halo ester or amide 2 (1 equiv.) in THF at ambient amides (entries 7–17) than from esters (entries 1–6).
temperature with a solution of 2.5 equiv. of SmI2 in (3) Bromo or chloro derivatives 2 can be utilized as
THF (0.1M)[11] afforded, after 3.5 h, the 3-amino starting materials (Table 1, entries 1–3, and 4–17). (4)
esters 3 or amides 4 shown in Table 1.
The reaction has also been carried out on N-benzene-
In the case of aldimines derived from benzaldehyde sulfonylimines (Table 1, entries 13, and 14) and no dif-
1e or phenylacetaldehyde 1f, by-products derived ferences were observed when compared with the reac-
from the pinacol coupling of the starting aldimines tion of N-tosylimines 1.
were obtained. To overcome this problem, the samari-
Taking into account the fact that amides derived
um enolate was pre-generated (in the absence of the from morpholine can be readily transformed into ke-
Table 1. Synthesis of 3-amino esters and amides 3 and 4.
Entry
1
3/4
R1
R2
Hal
Pg
Y
Yield [%][a]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1d
1a
1a
1c
1c
1e
1g
1h
1f
1b
1d
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
4g
4h
4i
PhCH2CH2
s-Bu
c-C6H11
n-C7H15
Ph
PhCH2
n-C7H15
PhCH2CH2
PhCH2CH2
c-C6H11
c-C6H11
Ph
p-ClC6H4
p-MeOC6H4
PhCH2
s-Bu
H
H
H
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
PhSO2
PhSO2
Ts
Ts
Ts
OEt[c]
OEt[c]
OEt[c]
OEt
69
63
67
67
60
61
84
81
80
84
85
80
56
51
74
73
73
Me
Me
n-C5H11
H
H
H
H
H
H
H
OEt
OEt
[b]
–
NEt2
[b]
9
–
10
11
12
13
14
15
16
17
NEt2
[b]
–
NEt2
[b]
[b]
H
–
–
–
–
[b]
Me
Me
Ph
[b]
4j
4k
[b]
n-C7H15
[a]
Isolated yield after column chromatography based on compounds 1.
From morpholine amide.
[b]
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The Addition Reaction of Samarium Enolates and 2-Haloenolates
FULL PAPERS
tones by reaction with organolithium reagents,[12] a se- Synthesis of 3-Amino-2-Halo Acid Derivatives 7 and
quential synthesis of n-butyl ketones 5 was carried
out from 1c and 1e. Thus, the successive treatment of
8
N-tosylimines 1c and 1e with the samarium enolate Due to the synthetic possibilities of a C-halogen
derived from 2-chloro-1-morpholinoethanone and placed on the a-carbon of a carbonyl group and to
subsequently, with n-butyllithium at ꢀ788C for 1 h af- generalize the reaction, efforts were next directed to-
forded 3-amino ketones 5a, b in 43 and 41% yield, re- wards the synthesis of 3-amino-2-halo esters 7 or
spectively. When the same reaction was performed amides 8.
from the isolated product 4e (Scheme 1), a similar
Thus, under similar conditions to those developed
for the addition of samarium enolates derived from
esters or amides we performed the addition of the
corresponding samarium haloenolates. The results are
summarized in Table 2.
In a similar manner to the synthesis of compounds
3 and 4, the addition of haloenolates was general, and
no differences were observed in their addition reac-
tions to linear, branched, cyclic aliphatic and aromatic
imines. In all these cases, the corresponding 3-amino-
2-halo esters or amides were obtained in good to high
yields (>51%, after purification by column chroma-
tography). The synthesis of compounds 7b and 7c
demonstrated that the process was also tolerant to the
presence of halogens other than chlorine. As was ob-
served in compounds 3d–f, and 4i, k, the 3-amino-2-
Scheme 1. Synthesis of 3-amino ketones 5.
yield of n-butyl ketone 5a was obtained (63% yield). halo esters 7 and amides 8 were obtained with the dr
Furthermore, the N-substituent on the 3-amino ranging between 1:1 and 3:1.
amide 4e could be easily removed by using sodium
naphthalenide, following a method previously report-
ed,[13] furnishing deprotected 3-amino amide 6 in 49% Synthesis of Enantiopure (3R,4S)-3,4-Diamino Esters
isolated yield after purification (Scheme 2).
and Amides 10 and 11
3,4-Diamino acids[14] are important compounds due to
their pharmacological activity[15] and since they can
modify the biological properties of small peptides.[16]
From a synthetic point of view, 3,4-diamino acid de-
rivatives are precursors to various interesting organic
compounds, such as 2-aminopyrrolidinones or 3-ami-
Scheme 2. Deprotection of N-tosyl-3-amino amide 4e.
Table 2. Synthesis of 3-amino-2-halo esters 7 and amides 8.
Entry
1
7/8
R1
Hal
Pg
Y
Yield [%][a]
1
2
3
4
5
6
7
8
9
1c
1c
1e
1d
1b
1c
1a
1g
1h
7a
7b
7c
8a
8b
8c
8d
8e
8f
c-C6H11
c-C6H11
Ph
n-C7H15
sBu
c-C6H11
PhCH2CH2
p-ClC6H4
p-MeOC6H4
Cl
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Ts
Ts
Ts
Ts
Ts
Ts
Ts
PhSO2
PhSO2
OMe
OEt
OEt
56
65
68
64
63
66
60
54
51
[b]
–
NEt2
NEt2
[b]
–
–
–
[b]
[b]
[a]
Isolated yield after column chromatography based on compounds 1.
From morpholine amide.
[b]
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nopyrrolidines.[17] Despite these applications, only a
few preparative methods have been reported,[17,18] and
most of these employ multi-step reactions that afford
the desired compounds in low overall yields.
Table 4. Synthesis of enantiopure 3,4-diamino amides 11
We initially performed the synthesis of the enantio-
pure 3,4-diamino esters by reaction of the samarium
ester enolate with the tosylimine derived from N,N-
dibenzylphenylalaninal.[19] Unfortunately, the addition
reaction of the ester samarium enolate afforded the
expected 3,4-diamino ester in only 5% yield. In order
to improve the yields, we changed the protecting
group on the iminic nitrogen. Thus, two changes in
the reaction were made: we prepared the imine 9c by
reaction of phenylalaninal with (R)-2-methyl-2-pro-
panesulfinamide[20] and the samarium diiodide was
generated in situ, from a mixture of Sm/CH2I2.[21]
Thus, the addition of diiodomethane to a mixture of
Entry
9
11
R1
Yield [%][a]
1
2
3
9a
9b
9c
11a
11b
11c
Me
i-PrCH2
PhCH2
53
52
62
[a]
Isolated yield after column chromatography based on
imine 9.
imine 9c [derived from phenylalaninal, and (R)-2- reoisomer in good yields. The obtained results are
methyl-2-propanesulfinamide], ethyl chloroacetate summarized in Table 4.
and samarium powder in THF at 08C, and further stir-
The method for the synthesis of 3,4-diamino acid
ring at ambient temperature for 6 h, afforded the cor- derivatives 10 and 11 is general and similar results
responding diamino ester 10c in 55% yield and as a were observed during the synthesis of 3,4-amino ester
single diastereoisomer (dr>98/2) (Table 3). The scope or amino amide derivatives.
of this process was subsequently studied by carrying
The total stereoselectivity (dr>98/2) of the addi-
1
out the reaction with the tosylimines derived from tion reaction was established on the basis of H NMR
alaninal and leucinal. The entries in Table 3 demon- data of crude reaction products 10 or 11, which re-
strate that, in all cases, similar results were obtained. vealed the presence of only one stereoisomer. The ab-
Based on the results of the synthesis of 3,4-diamino sence of the other stereoisomer also proved that no
esters 10, we tested the synthesis of enantiopure 3,4- racemization took place in the reaction.
diamino amides 11. Using the same reaction condi-
The absolute configuration of the 3,4-diamino
tions as those used to prepare compounds 10, enantio- esters 10 was established after transformation of 10c
pure compounds 11 were obtained as a single diaste- into ethyl (3R,4S)-5-phenyl-4-(N,N-dibenzylamino)-3-
(tosylamino)pentanoate 13, following the synthetic
pathway described (Scheme 3). The spectroscopic
Table 3. Synthesis of enantiopure 3,4-diamino esters 10
data of 13 were identical to those reported for the
same product, previously prepared and characterized
(X-ray analysis) by Reetz.[22]
In the case of 3,4-diamino amides 11 the absolute
configuration was determined after a deprotection
protocol. Hence, after bubbling a stream of HCl to a
solution of (3R,4S)-4-(dibenzylamino)-N,N-diethyl-3-
Entry
9
10
R1
Yield[%][a]
[(R)-tertbutanesulfinamide]pentanamide 11a in di-
chloromethane, (3R,4S)-3-amino-4-(dibenzylamino)-
N,N-diethylpentanamide 14 was isolated as the hydro-
chloride salt after recrystallization (Scheme 4).
1
2
3
9a
9b
9c
10a
10b
10c
Me
i-PrCH2
PhCH2
51
50
55
The single-crystal X-ray analysis of compound 14[23]
unambiguously confirmed the absolute configuration
of amide 11a. The absolute configurations of the
[a]
Isolated yield after column chromatography based on
imine 9.
Scheme 3. Synthesis of enantiopure 3,4-diamino esters 12 and 13.
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The Addition Reaction of Samarium Enolates and 2-Haloenolates
FULL PAPERS
Experimental Section
General Procedure for the Synthesis of Compounds 1
Imines 1 were synthesized following the method reported in
ref.[10] Imine 1a displayed analytical data in accordance with
the published values in ref.[9] Imines 1b–h displayed analyti-
cal data in accordance with the published values.[27]
Scheme 4. Deprotection of 3,4-diamino amide 11a
General Procedure for the Synthesis of Compounds 3
and 4
other 3,4-diamino amides 11b and 11c were assigned
by correlation.
To a stirred solution of the requisite imine 1 (0.4 mmol) and
2-halo ester or amide 2 (0.4 mmol) in THF (2 mL), a solu-
tion of SmI2 in THF (10 mL, 2.5 equiv., 1.0 mmol) was
added at ambient temperature. After stirring at the same
temperature for 3.5 h, the excess of SmI2 was removed by
bubbling a stream of air through the solution. An aqueous
solution of 0.1N HCl (10 mL) was then added and the aque-
ous phase was extracted with diethyl ether (3ꢅ10 mL). The
combined organic layers were dried over anhydrous Na2SO4,
filtered and concentrated under vacuum. Flash column chro-
matography on silica gel (hexane/EtOAc, 3:1) provided
pure compounds 3 or 4.
In the case of compounds 3e and 3f, the samarium enolate
was pre-formed at ꢀ208C and the imine 1e or 1f was added
subsequently. The reaction mixture was stirred at the same
temperature for 30 min and then it was left to warm to am-
bient temperature for 3 h. After the corresponding hydroly-
sis and the purification, the products 3e and 3f were isolated
pure.
The absolute configuration of 3,4-diamino esters or
amides 10 and 11 is in agreement with that obtained
in the previously reported addition of organometallic
reagents to 2-dibenzylamino aldehydes,[24] chloro-
methyl ketones[24] and the reduction of chloromethyl-
ketimines.[25] Thus, the stereochemical course of the
addition reaction of the samarium enolate 15 could
be controlled by the bulky dibenzylamino group. In
this case, the addition of samarium enolate to imine 9
could take place under non-chelation control in which
the most favoured transition state has the larger sub-
stituent (dibenzylamino group) anti to the attack of
the samarium enolate (Scheme 5). A similar stereo-
chemical course was observed in the addition of other
anions to N-(3-phenyl-2-dibenzylaminopropylidene)-
tert-butanesulfilamide.[20,26]
For amino esters 3a–f and amino amides 4b, 4e, 4f, 4i–k
spectroscopic data have been reported in ref.[9]
Conclusions
1-Morpholino-3-(tosylamino)decan-1-one (4a): 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=8.2 Hz, 2H), 7.28 (d, J=
8.2 Hz, 2H), 5.77 (d, J=8.6 Hz, 1H), 3.64–3.51 (m, 8H),
3.35–3.30 (m, 1H), 2.49 (dd, J=16.1, 4.0 Hz, 1H), 2.41 (s,
3H), 2.38 (dd, J=16.1, 6.0 Hz, 1H), 1.55–1.45 (m, 2H),
1.42–0.75 (m, 10H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=169.2 (C), 143.0 (C), 138.1 (C), 129.4
(2CH), 127.0 (2CH), 66.6 (CH2), 66.3 (CH2), 51.1 (CH),
45.7 (CH2), 41.5 (CH2), 36.6 (CH2), 34.5 (CH2), 31.5 (CH2),
29.0 (CH2), 28.9 (CH2), 25.9 (CH2), 22.5 (CH2), 21.3 (CH3),
13.9 (CH3); MS (70 eV, EI): m/z (%)=410 (M+, <1), 311
(17), 255 (100), 155 (25), 114 (57), 91 (71); HR-MS (70 eV);
m/z=311.1060, calcd. for C14H19N2O4S (M+ꢀC7H15):
In conclusion, the use of samarium enolates as a val-
uable alternative to lithium enolates in the Mannich
reaction, in special using enantiopure aldimines with
high proclivity to racemize, has been proved.
Thus, the addition reaction of samarium enolates
(derived from esters, amides, 2-bromo or 2-chloro
esters and 2-chloro amides) to prochiral aldimines
was carried out in an efficient manner. In addition,
enantiopure (3R,4S)-diamino esters or amides were
obtained without racemization and with total stereo-
selectivity from enolizable chiral 2-aminoaldimines.
The addition reaction of samarium enolates to
other compounds with high proclivity to enolize are
currently under study in our laboratory.
311.1065, IR (neat): n=1614, 1442, 1266, 1160, 738 cmꢀ1
Rf =0.75 (hexane/EtOAc 1:1).
;
1-Morpholino-5-phenyl-3-(tosylamino)pentan-1-one (4c):
1H NMR (400 MHz, CDCl3): d=7.75 (d, J=8.3 Hz, 2H),
Scheme 5. Mechanism of the addition to aminoaldimines 9.
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7.31–7.14 (m, 5H), 7.03 (d, J=8.3 Hz, 2H), 5.88 (d, J=
6.8 Hz, 1H), 3.58–3.44 (m, 7H), 3.27–3.16 (m, 2H), 2.65–
2.58 (m, 1H), 2.49–2.41 (m, 1H), 2.43 (s, 3H), 2.40–2.38 (m,
2H), 2.02–1.93 (m, 1H), 1.84–1.75 (m, 1H); 13C NMR
(75 MHz, CDCl3): d=169.0 (C), 143.1 (C), 141.0 (C), 138.2
(C), 129.5 (2CH), 128.2 (4CH), 127.0 (2CH), 125.8 (CH),
66.5 (CH2), 66.2 (CH2), 50.7 (CH), 45.6 (CH2), 41.5 (CH2),
36.4 (CH2), 36.0 (CH2), 32.1 (CH2), 21.4 (CH3); MS (ESI+):
m/z (%)=439 ([M+Na]+, 22), 417 ([M+H]+, 100); HR-MS
a solution of SmI2 in THF (10 mL, 2.5 equiv., 1.0 mmol) was
added at ambient temperature. After stirring at the same
temperature for 3.5 h, the reaction mixture was cooled at
ꢀ788C and n-BuLi (1.6 mmol) was added dropwise. After
stirring for an additional hour at ꢀ788C, the reaction mix-
ture was quenched with an aqueous solution of 0.1N HCl
(10 mL) and the aqueous phase was extracted with diethyl
ether (3ꢅ10 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and concentrated under
vacuum. Flash column chromatography on silica gel
(hexane/EtOAc, 3:1) provided pure compounds 5.
(70 eV):
m/z=311.1059,
calcd.
for
C14H19N2O4S
(M+ꢀPhCH2CH2): 311.1065; IR (neat): n=2923, 1628, 1456,
1159, 736 cmꢀ1; Rf =0.15 (hexane/EtOAc, 1:1).
Spectroscopic data for amino ketone 5a have been report-
3-Cyclohexyl-N,N-diethyl-3-(tosylamino)propanamide
(4d): 1H NMR (300 MHz, CDCl3): d=7.74 (d, J=8.0 Hz,
2H), 7.26 (d, J=8.0 Hz, 2H), 6.21 (d, J=8.9 Hz, 1H), 3.29–
3.10 (m, 5H), 2.48–2.40 (m, 1H), 2.40 (s, 3H), 2.19 (dd, J=
16.3, 5.3 Hz, 1H), 1.86–1.49 (m, 6H), 1.08–0.69 (m, 5H),
1.06 (t, J=7.1 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=170.1 (C), 142.7 (C), 138.5 (C), 129.4
(2CH), 127.0 (2CH), 56.2 (CH), 41.9 (CH2), 40.5 (CH), 40.0
(CH2), 32.4 (CH2), 29.7 (CH2), 29.6 (CH2), 26.1 (CH2), 25.9
(CH2), 25.8 (CH2), 21.4 (CH3), 14.0 (CH3), 12.8 (CH3); MS
(70 eV, EI): m/z (%)=380 (M+, <1), 297 (52), 225 (37), 100
(100), 91 (36), 72 (38); HR-MS (70 eV): m/z=380.2146,
calcd. for C20H32N2O3S: 380.2134; IR (neat): n=2931, 1624,
1266, 1162, 738 cmꢀ1; Rf =0.22 (hexane/EtOAc, 2:1).
ed in ref.[9]
1-Phenyl-1-(tosylamino)heptan-3-one
(5b):
1H NMR
(300 MHz, CDCl3): d=7.59 (d, J=8.2 Hz, 2H), 7.18–7.07
(m, 7H), 5.75 (d, J=7.2 Hz, 1H), 4.67–4.60 (m, 1H), 2.98
(dd, J=17.0, 5.6 Hz, 1H), 2.84 (dd, J=17.0, 6.2 Hz, 1H),
2.37 (s, 3H), 2.22 (t, J=7.3 Hz, 2H), 1.39 (quintuplet, J=
7.3 Hz, 2H), 1.16 (sixtuplet, J=7.3 Hz, 2H), 0.80 (t, J=
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=209.1 (C),
143.1 (C), 139.7 (C), 137.2 (C), 129.3 (2CH), 128.4 (2CH),
127.5 (CH), 127.1 (2CH), 126.5 (2CH), 54.1 (CH), 48.5
(CH2), 43.3 (CH2), 25.3 (CH2), 22.0 (CH2), 21.4 (CH3), 13.6
(CH3); MS (70 eV, EI): m/z (%)=359 (M+, <1), 260 (37),
204 (87), 155 (44), 120 (40), 91 (100); HR-MS (70 eV):
m/z=359.1565, calcd. for C20H25NO3S: 359.1555; IR (neat):
n=2950, 1713, 1456, 1160, 738 cmꢀ1; Rf =0.25 (hexane/
EtOAc, 3:1).
3-(Benzenesulfonylamino)-3-(4-chlorophenyl)-1-morpholi-
1
nopropan-1-one (4g): H NMR (300 MHz, CDCl3): d=7.68
(d, J=7.3 Hz, 2H), 7.48 (t, J=7.3 Hz, 1H), 7.36 (t, J=
7.3 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.06 (d, J=8.5 Hz,
2H), 6.73 (d, J=7.3 Hz, 1H), 4.72 (q, J=5.6 Hz, 1H), 3.56–
3.34 (m, 6H), 3.28–3.14 (m, 2H), 2.82 (dd, J=15.7, 5.6 Hz,
1H), 2.67 (dd, J=15.7, 5.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=168.4 (C), 140.3 (C), 138.2 (C), 133.3 (C), 132.3
(CH), 128.7 (2CH), 128.4 (2CH), 128.1 (2CH); 126.9
Synthesis of 6 from 4e
Deprotection of compound 4e was carried out by using the
conditions described in ref.[13] Spectra and analytical data of
compound 6 have been reported in ref.[9]
(2CH), 66.5 (CH2), 66.1 (CH2), 54.1 (CH), 45.9 (CH2), 41.7 General Procedure for the Synthesis of Compounds 7
(CH2), 38.5 (CH2); MS (ESI+): m/z (%)=433 ([M
(37Cl)+
ACHTUNGTRENNUNG
and 8
Na]+, 17), 431 ([M(35Cl)+Na]+, 19), 411 ([M(37Cl)+H]+,
A
ACHTUNGTRENNUNG
39), 409 ([MACHTUNGTRENNUNG
(35Cl)+H]+, 100); HR-MS (70 eV): m/z=
To a stirred solution of the requisite imine 1 (0.4 mmol) and
2,2-dihalo ester or amide 2 (0.4 mmol) in THF (2 mL), a so-
lution of SmI2 in THF (10 mL, 2.5 equiv., 1.0 mmol) was
added at 08C. After stirring at the same temperature for
2 h, the excess of SmI2 was removed by bubbling a stream of
air through the solution. An aqueous solution of 0.1
N HCl (10 mL) was then added, and the aqueous phase was
extracted with diethyl ether (3ꢅ10 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4, filtered and
concentrated under vacuum. Flash column chromatography
on silica gel (hexane/EtOAc, 3:1) provided pure compounds
7 or 8.
In the case of compound 7c, the samarium enolate was
pre-formed at ꢀ208C, and the imine 1e was added subse-
quently. The reaction mixture was stirred at the same tem-
perature for 30 min, and then it was left at 08C for 2 h.
After the corresponding hydrolysis and purification by flash
column chromatography, the product 7c was isolated in the
pure state.
280.0209, calcd. for C13H11ClNO2S (M+ꢀC6H10NO2):
280.0199; IR (neat): n=2860, 1622, 1447, 1266, 1162 cmꢀ1
Rf =0.40 (EtOAc).
;
3-(Benzenesulfonylamino)-3-(4-methoxyphenyl)-1-mor-
1
pholinopropan-1-one (4h): H NMR (300 MHz, CDCl3): d=
7.69 (d, J=7.4 Hz, 2H), 7.46 (t, J=7.4 Hz, 1H), 7.35 (t, J=
7.4 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.67 (d, J=8.7 Hz,
2H), 6.59 (d, J=6.9 Hz, 1H), 4.68 (q, J=5.9 Hz, 1H), 3.72
(s, 3H), 3.59–3.09 (m, 8H), 2.83 (dd, J=15.3, 5.9 Hz, 1H),
2.64 (dd, J=15.3, 5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=168.7 (C), 158.9 (C), 140.5 (C), 132.1 (CH), 131.6 (C),
128.6 (2CH), 127.7 (2CH), 127.0 (2CH); 113.7 (2CH), 66.4
(CH2), 66.1 (CH2), 55.1 (CH3), 54.3 (CH), 45.9 (CH2), 41.6
(CH2), 38.7 (CH2); MS (ESI+): m/z (%)=427 ([M+Na]+,
10), 405 ([M+H]+, 21), 248 (100); HR-MS (70 eV): m/z=
276.0692, calcd. for C14H14NO3S (M+ꢀC6H10NO2): 276.0694;
IR (neat): n=2962, 1616, 1515, 1446, 1265 cmꢀ1; Rf =0.35
(EtOAc).
Methyl 2-chloro-3-cyclohexyl-3-(tosylamino)propanoate
(7a): 1H NMR (400 MHz, CDCl3): d=7.76 (d, J=8.1 Hz,
2H), 7.72 (d, J=8.3 Hz, 2H), 7.29–7.26 (m, 4H), 5.36 (d, J=
9.3 Hz, 1H), 5.08 (d, J=9.8 Hz, 1H), 4.56 (d, J=2.7 Hz,
1H), 4.41 (d, J=4.4 Hz, 1H), 3.82–3.71 (m, 2H), 3.70 (s,
3H), 3.56 (s, 3H), 2.40 (s, 6H), 1.78–1.47 (m, 10H), 1.14–
General Procedure for the Synthesis of Compounds 5
To a stirred solution of the requisite imine 1 (0.4 mmol) and
2-chloro-1-morpholinoethanone (0.4 mmol) in THF (2 mL),
2996
asc.wiley-vch.de
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2991 – 3000

The Addition Reaction of Samarium Enolates and 2-Haloenolates
FULL PAPERS
0.99 (m, 8H), 0.91–0.75 (m, 4H); 13C NMR (75 MHz,
CDCl3): d=168.4 (C), 167.9 (C), 143.2 (C), 143.1 (C), 138.4
(C), 138.0 (C), 129.4 (2CH), 129.3 (2CH), 126.9 (2CH),
126.8 (2CH), 60.8 (CH), 60.7 (CH), 59.9 (CH), 58.7 (CH),
53.0 (2CH2), 40.1 (CH), 39.9 (CH), 29.7 (CH2), 29.4 (CH2),
29.0 (CH2), 28.5 (CH2), 25.8 (CH2), 25.7 (5CH2), 21.3
(2CH3); HR-MS (ESI+): m/z=374.1187, calcd. for
C17H25ClNO4S (M+H)+: 374.1193; IR (neat): n=1756, 1449,
1332, 1160, 738 cmꢀ1; Rf =0.32 (hexane/EtOAc, 3:1).
2-Chloro-N,N-diethyl-4-methyl-3-(tosylamino)hexanamide
(8b): 1H NMR (300 MHz, CDCl3): d=7.73 (d, J=8.4 Hz,
4H), 7.20 (d, J=8.4 Hz, 4H), 7.14 (d, J=8.6 Hz, 1H), 6.97
(d, J=8.8 Hz, 1H), 4.46 (d, J=3.5 Hz, 1H), 4.43 (d, J=
3.6 Hz, 1H), 3.73–3.60 (m, 2H), 3.47–3.16 (m, 8H), 2.36 (s,
6H), 1.72–1.52 (m, 2H), 1.50–1.35 (m, 1H), 1.25–0.98 (m,
15H), 0.95–0.81 (m, 12H); 13C NMR (75 MHz, CDCl3): d=
167.7 (2C), 142.3 (2C), 139.3 (2C), 128.9 (4CH), 126.9
(4CH), 62.9 (CH), 62.0 (CH), 51.0 (CH), 50.0 (CH), 42.3
(2CH2), 40.8 (2CH2), 39.2 (CH), 38.8 (CH), 26.5 (CH2), 26.1
(CH2), 21.3 (2CH3), 15.6 (CH3), 15.5 (CH3), 14.3 (CH3), 14.2
(CH3), 12.1 (2CH3), 11.3 (2CH3); MS (APCI+): m/z (%)=
Ethyl
2-bromo-3-cyclohexyl-3-(tosylamino)propanoate
(7b): 1H NMR (300 MHz, CDCl3): d=7.77 (d, J=8.4 Hz,
2H), 7.74 (d, J=8.4 Hz, 2H), 7.29–7.26 (m, 4H), 5.51 (d, J=
9.5 Hz, 1H), 4.92 (d, J=9.8 Hz, 1H), 4.51 (d, J=3.6 Hz,
1H), 4.39 (d, J=4.3 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 4.07–
3.94 (m, 2H), 3.74–3.65 (m, 2H), 2.41 (s, 6H), 1.81–1.45 (m,
10H), 1.26 (t, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.23–
0.71 (m, 12H); 13C NMR (75 MHz, CDCl3): d=168.5 (C),
167.3 (C), 143.0 (2C), 138.5 (C), 138.4 (C), 129.2 (4CH),
127.0 (2CH), 126.9 (2CH), 62.6 (CH2), 62.3 (CH2), 61.0
(CH), 60.4 (CH), 51.7 (CH), 46.9 (CH), 41.5 (CH), 41.1
(CH), 30.0 (CH2), 29.6 (CH2), 28.9 (CH2), 28.6 (CH2), 25.9
(2CH2), 25.7 (2CH2), 25.6 (2CH2), 21.4 (2CH3), 13.7 (CH3),
389 ([M+H]+ 30), 353 (98), 283 (46), 197 (36), 182 (100);
,
HR-MS (ESI+): m/z=389.1660, calcd. for C18H30ClN2O3S
(M+H)+: 389.1666; IR (neat): n=1637, 1456, 1330, 1159,
667 cmꢀ1; Rf =0.25, 0.20 (hexane/EtOAc, 3:1).
2-Chloro-3-cyclohexyl-N,N-diethyl-3-(tosylamino)propan-
AHCTUNGTRENNUNG
amide (8c): 1H NMR (300 MHz, CDCl3): d=7.83 (d, J=
8.2 Hz, 2H), 7.77 (d, J=7.6 Hz, 2H), 7.31 (d, J=8.2 Hz,
2H), 7.26 (d, J=7.6 Hz, 2H), 5.08 (d, J=9.2 Hz, 2H), 4.50
(d, J=7.9 Hz, 2H), 3.85–3.78 (m, 2H), 3.41–3.15 (m, 8H),
2.43 (s, 3H), 2.40 (s, 3H), 1.82–1.50 (m, 12H), 1.21–1.07 (m,
22H); 13C NMR (75 MHz, CDCl3): d=166.1 (C), 163.5 (C),
144.2 (C), 142.9 (C), 138.3 (C), 136.6 (C), 129.4 (2CH),
129.2 (2CH), 127.8 (2CH), 127.3 (2CH), 60.8 (2CH), 55.1
(CH), 52.1 (CH), 44.5 (CH2), 42.2 (CH2), 42.8 (CH2), 40.9
(CH2), 40.1 (CH), 37.8 (CH), 31.3 (CH2), 30.6 (CH2), 30.2.
(CH2), 27.6 (CH2), 26.1 (CH2), 26.0 (CH2), 25.9 (CH2), 25.4
(CH2), 25.2 (CH2), 24.9 (CH2), 21.5 (CH3), 21.4 (CH3), 14.4
(CH3), 14.3. (CH3), 12.4 (CH3), 12.3 (CH3); MS (ESI+): m/z
13.6 (CH3); MS (ESI+): m/z (%)=456 ([M
454 ([M
(79Br)+Na]+, 32), 434 ([M(81Br)+H]+, 100), 432
([M
(79Br)+H]+, 99), 352 (12), 181 (9); HR-MS (ES): m/z=
(81Br)+Na]+, 30),
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
432.0838, calcd. for C18H27BrNO4S (M+H)+: 432.0844; IR
(neat): n=1735, 1449, 1333, 1160, 738 cmꢀ1
; Rf =0.25
(hexane/EtOAc, 3:1).
Ethyl 2-bromo-3-phenyl-3-(tosylamino)propanoate (7c):
1H NMR (300 MHz, CDCl3): d=7.57 (d, J=8.4 Hz, 2H),
7.53 (d, J=8.4 Hz, 2H), 7.19–7.08 (m, 14H), 6.30 (d, J=
9.1 Hz, 1H), 5.70 (d, J=7.1 Hz, 1H), 4.90–4.84 (m, 2H),
4.45 (d, J=2.9 Hz, 1H), 4.43 (d, J=4.7 Hz,1H), 4.15–4.04
(m, 2H), 4.03–3.94 (m, 2H), 2.33 (s, 6H), 1.15 (t, J=7.1 Hz,
3H), 1.08 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=168.2 (C), 166.7 (C), 143.3 (C), 143.1 (C), 137.4 (C),
137.0 (C), 136.4 (C), 136.0 (C), 129.2 (2CH), 129.1 (2CH),
128.5 (2CH), 128.3 (2CH), 128.2 (2CH), 127.4 (2CH), 127.1
(2CH), 127.0 (2CH), 126.9 (2CH), 62.4 (CH2), 62.3 (CH2),
60.0 (CH), 59.7 (CH), 50.7 (CH), 46.5 (CH), 21.3 (2CH3),
(%)=439 ([M
N
(35Cl)+Na]+, 21),
ACHTUNGTRENNUNG
417 ([M ACHTNUGTRENNUNG
N
(70 eV): m/z=414.1742, calcd. for C20H31ClN2O3S: 414.1744;
IR (neat): n=1636, 1450, 1331, 1158, 667 cmꢀ1; Rf =0.25,
0.18 (hexane/EtOAc, 3:1).
2-Chloro-1-morpholino-5-phenyl-3-(tosylamino)pentan-1-
one (8d): 1H NMR (300 MHz, CDCl3): d=7.78 (d, J=
7.6 Hz, 2H), 7.30–7.14 (m, 5H), 6.93 (d, J=7.6 Hz, 2H),
6.10 (d, J=8.6 Hz, 1H), 4.66 (d, J=2.9 Hz, 1H), 3.69–3.32
(m, 9H), 2.65–2.55 (m, 1H), 2.45–2.39 (m, 1H), 2.41 (s, 3H),
2.07–1.81 (m, 2H); 13C NMR (75 MHz, CDCl3): d=165.5
(C), 143.3 (C), 140.6 (C), 138.1 (C), 129.4 (2CH), 128.2
(2CH), 128.1 (2CH), 126.9 (2CH), 125.9 (CH), 66.3 (CH2),
66.1 (CH2), 56.7 (CH), 56.2 (CH), 46.2 (CH2), 42.4 (CH2),
33.0 (CH2), 31.8 (CH2), 21.4 (CH3); MS (70 eV, EI): m/z
13.6 (2CH3); MS (ESI+): m/z (%)=450 ([M
34), 448 ([M
(79Br)+Na]+, 35), 428 ([M(81Br)+H]+, 96), 426
([M
(79Br)+H]+, 100), 255 (26), 257 (25); HR-MS (ESI+):
(81Br)+Na]+,
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
m/z=448.0189, calcd. for C18H20BrNNaO4S (M+Na)+:
448.0194; IR (neat): n=3056, 1733, 1265, 1162, 738 cmꢀ1
Rf =0.28 (hexane/EtOAc, 3:1).
;
(%)=450 (M+ 30), 415 (18), 327 (22), 224 (37), 191 (59),
,
2-Chloro-1-morpholino-3-(tosylamino)decan-1-one (8a):
1H NMR (300 MHz, CDCl3): d=7.76 (d, J=8.2 Hz, 4H),
7.28 (d, J=8.2 Hz, 4H), 6.04 (d, J=8.5 Hz , 1H), 5.79 (d,
J=8.5 Hz, 1H), 4.80 (d, J=3.5 Hz, 1H), 4.68 (d, J=3.5 Hz,
1H), 3.72–3.50 (m, 18H), 2.42 (s, 6H), 1.71–1.45 (m, 4H),
1.32–0.92 (m, 20H), 0.86 (t, J=7.1 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d=166.0 (2C), 143.2 (2C), 138.1 (2C),
129.5 (4CH), 126.9 (4CH), 66.5 (2CH2), 66.4 (2CH2), 56.8
(2CH), 56.1 (2CH), 46.5 (2CH2), 42.5 (2CH2), 31.6 (2CH2),
31.5 (2CH2), 29.0 (2CH2), 28.9 (2CH2), 25.8 (2CH2), 22.4
(2CH2), 21.4 (2CH3), 13.9 (2CH3); MS (ESI+): m/z (%)=
155 (51), 114 (100); HR-MS (70 eV): m/z=450.1378, calcd.
for C22H27ClN2O4S: 450.1380; IR (neat): n=2927, 1644,
1455, 1265, 1158 cmꢀ1; Rf =0.35 (hexane/EtOAc, 1:1).
3-(Benzenesulfonylamino)-2-chloro-3-(4-chlorophenyl)-1-
1
morpholinopropan-1-one (8e): H NMR (300 MHz, CDCl3):
d=7.72 (d, J=9.0 Hz, 2H), 7.39–7.18 (m, 8H), 4.94 (dd, J=
8.3, 4.4 Hz, 1H), 4.65 (d, J=4.4 Hz, 1H), 3.73–3.47 (m, 4H),
3.46–3.28 (m, 3H), 3.26–3.08 (m, 1H); 13C NMR (75 MHz,
CDCl3): d=165.7 (C), 140.9 (C), 139.4 (C), 135.2 (C), 132.2
(CH), 128.8 (2CH), 128.7 (2CH), 128.6 (2CH), 126.9
(2CH), 66.3 (CH2), 66.1 (CH2), 60.7 (CH), 52.2 (CH), 46.6
469 ([M
N
(35Cl)+Na]+, 25), 447
ACHTUNGTRENNUNG
(CH2), 42.5 (CH2); MS (ESI+): m/z (%)=467 ([M
Na]+, 31), 465 ([M(35Cl)+Na]+, 46), 445 ([M
70), 443 ([M
(35Cl)+H]+, 100), 288 (19), 286 (31), 114 (3); H-
RMS (ESI+): m/z=465.0400, calcd. for C19H20Cl2N2NaO4S
ACHTUNGTRENNUNG
([M ACHTGNUTRENNUNG
R
A
ACHTUNGTRENNUNG
(70 eV): m/z=444.1849, calcd. for para C21H33ClN2O4S:
444.1850; IR (neat): n=1648, 1438, 1266, 1159, 738 cmꢀ1
Rf =0.55 (hexane/EtOAc, 1:1).
;
AHCTUNGTRENNUNG
Adv. Synth. Catal. 2009, 351, 2991 – 3000
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2997

Josꢀ M. Concellꢁn et al.
FULL PAPERS
(M+Na)+: 465.0419; IR (neat): n=2960, 1645, 1445, 1163,
735 cmꢀ1; Rf =0.28 (hexane/EtOAc, 3:1)
(2CH2), 37.7 (CH2), 35.9 (CH2), 25.6 (CH), 23.5 (CH3), 22.6
(3CH3), 22.0 (CH3), 14.1 (CH3); MS (ESI+): m/z (%)=509
([M+Na]+, 100), 487 ([M+H]+, 96); HR-MS (ESI+): m/z=
487.2988, calcd. for C28H43N2O3S (M+H)+: 487.2994; IR
(neat): n=2926, 1732, 1455, 1266, 1066 cmꢀ1; [a]D20: ꢀ8.9 (c
0.70, CHCl3); Rf =0.23 (hexane/EtOAc, 3:1).
3-(Benzenesulfonylamino)-2-chloro-3-(4-methoxyphenyl)-
1-morpholinopropan-1-one (8f): 1H NMR (300 MHz,
CDCl3): d=7.71 (d, J=8.7 Hz, 2H), 7.47–7.28 (m, 4H), 7.12
(d, J=8.4 Hz, 2H), 6.73 (d, J=8.7 Hz, 2H), 4.91 (dd, J=8.2,
4.4 Hz, 1H), 4.68 (d, J=4.4 Hz, 1H), 3.76 (s, 3H), 3.61–3.32
(m, 6H), 3.26–3.19 (m, 1H), 3.13–3.06 (m, 1H); 13C NMR
(75 MHz, CDCl3): d=166.1 (C), 159.4 (C), 141.0 (C), 132.0
(C), 128.5 (CH), 128.4 (2CH), 128.3 (2CH), 126.9 (2CH),
113.9 (2CH), 66.3 (CH2), 66.0 (CH2), 60.7 (CH), 55.2 (CH3),
52.2 (CH), 46.5 (CH2), 42.4 (CH2); MS (ESI+) m/z (%)=
AHCTUNGTERG(NNNU 3R,4S)-3-[(R)-tert-butanesulfinamide]-4-(dibenzyl-
1
AHCTUNGTREGaNNUN mino)-N,N-diethylpentanamide (11a): H NMR (400 MHz,
CDCl3): d=7.32–7.21 (m, 10H), 4.55 (d, J=5.9 Hz, 1H),
3.78 (d, J=13.6 Hz, 2H), 3.72–3.65 (m, 1H), 3.41 (d, J=
13.6 Hz, 2H), 3.37–3.21 (m, 3H), 3.20–3.09 (m, 2H), 2.99
(dd, J=16.6, 2.9 Hz, 1H), 2.56 (dd, J=16.6, 9.3 Hz, 1H),
1.21 (d, J=6.8 Hz, 3H), 1.15 (s, 9H), 1.15 (t, J=7.1 Hz,
3H), 1.09 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=171.0 (C), 139.7 (2C), 128.9 (4CH), 128.2 (4CH), 126.9
(2CH), 56.9 (CH), 56.0 (C), 55.3 (CH), 54.0 (2CH2), 41.9
(CH2), 40.3 (CH2), 36.8 (CH2), 22.6 (3CH3), 14.1 (CH3), 13.1
(CH3), 9.9 (CH3); MS (APCI+): m/z (%)=472 ([M+H]+,
99), 382 (15), 224 (100), 175 (33), 91 (11); HR-MS (ESI+):
m/z=472.2992, calcd. for C27H42N3O2S (M+H)+: 472.2998;
IR (neat): n=2979, 1636, 1266, 1100, 736 cmꢀ1; [a]D20: ꢀ18.2
(c 0.85, CHCl3); Rf =0.35 (hexane/EtOAc, 1:2).
463 ([M
([M
(37Cl)+H]+, 4), 439 ([M
(50); HR-MS
N
(35Cl)+Na]+, 100), 441
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
(ESI+): m/z=461.0897, calcd.
for
General Procedure for the Synthesis of Compounds
10 and 11
a-Aminoimines 9 were synthesized following the method re-
ported in ref.[20]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
To a stirred solution of Sm (0) (3 equiv., 1.2 mmol), previ-
ously activated by heating, in THF (2 mL), the imine 9
(0.4 mmol), 2-halo ester or amide (0.4 mmol) and THF
(10 mL) were added at ambient temperature. Then, CH2I2
(3 equiv., 1.2 mmol) was added, and the reaction mixture
was stirred at the same temperature for 6 h. The excess of
SmI2 was removed by bubbling a stream of air through the
solution and further treatment with an aqueous solution of
0.1N HCl (10 mL). The aqueous phase was extracted with
diethyl ether (3ꢅ10 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and concentrated
under vacuum. Flash column chromatography on silica gel
(hexane/EtOAc, 2:1) provided pure compounds 10 and 11.
For 3,4-diamino ester 10c spectroscopic data have been
previously reported in ref.[9]
(300 MHz, CDCl3): d=7.34–7.16 (m, 10H), 4.59 (d, J=
7.7 Hz, 1H), 3.90–3.78 (m, 1H), 3.80 (d, J=14.0 Hz, 2H),
3.70 (d, J=14.0 Hz, 2H), 3.34–3.27 (m, 3H), 3.20–3.00 (m,
2H), 2.57 (dd, J=15.3, 9.0 Hz, 1H), 2.44 (dd, J=15.3,
3.2 Hz, 1H), 1.88–1.73 (m, 1H), 1.57–1.48 (m, 1H), 1.35–
1.26 (m, 1H), 1.17 (s, 9H), 1.07 (t, J=7.1 Hz, 3H), 1.06 (t,
J=7.1 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.4 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=170.4 (C), 139.6 (2C),
129.0 (4CH), 128.2 (4CH), 126.9 (2CH), 59.7 (CH), 56.6
(CH), 55.6 (C), 54.7 (2CH2), 42.0 (CH2), 40.4 (CH2), 36.7
(CH2), 35.3 (CH2), 25.3 (CH), 23.1 (CH3), 22.6 (4CH3), 14.3
(CH3), 13.0 (CH3); MS (APCI+): m/z (%)=514 ([M+H]+,
100), 399 (13), 298 (11), 266 (26); HR-MS (ESI+): m/z=
514.3462, calcd. for C30H48N3O2S (M+H)+: 514.3467; IR
(neat): n=2960, 1635, 1455, 1266, 736 cmꢀ1; [a]D20: ꢀ21.0 (c 1,
CHCl3); Rf =0.25 (hexane/EtOAc, 1:1).
Ethyl (3R,4S)-3-[(R)-tertbutanesulfinamide]-4-(dibenzyl-
ACHTUNGTRENNUNG
amino)pentanoate (10a): 1H NMR (300 MHz, CDCl3): d=
AHCTUNGTRENNUNG
7.65–7.17 (m, 10H), 4.03 (q, J=7.0 Hz, 2H), 3.87–3.64 (m,
2H), 3.76 (d, J=13.6 Hz, 2H), 3.39 (d, J=13.6 Hz, 2H),
3.00 (dd, J=16.4, 3.3 Hz, 1H), 2.95–2.82 (m, 1H), 2.52 (dd,
J=16.4, 8.0 Hz, 1H), 1.48–1.03 (m, 15H); 13C NMR
(75 MHz, CDCl3): d=172.1 (C), 139.1 (2C), 128.8 (4CH),
128.2 (4CH), 126.9 (2CH), 60.2 (CH2), 57.9 (CH), 56.2
(CH), 55.9 (C), 53.8 (2CH2), 38.4 (CH2), 22.4 (3CH3), 14.0
(CH3), 9.4 (CH3); MS (ESI+): m/z (%)=467 ([M+Na]+,
100), 445 ([M+H]+, 98); HR-MS (ESI+): m/z=445.2519,
calcd. for C25H37N2O3S (M+H)+: 445.2525; IR (neat): n=
2981, 1728, 1454, 1266, 1061 cmꢀ1; [a]D20: ꢀ15.3 (c 1, CHCl3);
Rf =0.35 (hexane/EtOAc, 1:1).
AHCTUNGTRENNUNG
(300 MHz, CDCl3): d=7.36–7.17 (m, 15H), 4.62 (d, J=
6.3 Hz, 1H), 3.91–3.80 (m, 1H), 3.81 (d, J=13.7 Hz, 2H),
3.64–3.56 (m, 1H), 3.54 (d, J=13.7 Hz, 2H), 3.32 (q, J=
7.1 Hz, 2H), 3.27–3.05 (m, 3H), 2.94 (dd, J=14.5, 8.0 Hz,
1H), 2.87 (dd, J=16.1, 2.9 Hz, 1H), 2.54 (dd, J=16.1,
9.5 Hz, 1H), 1.15 (s, 9H), 1.10 (t, J=7.1 Hz, 3H), 1.09 (t,
J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=170.7 (C),
140.9 (C), 139.4 (2C), 129.5 (2CH), 129.0 (4CH), 128.5
(2CH), 128.1 (4CH), 126.9 (2CH), 126.0 (CH), 62.3 (CH),
56.3 (CH), 55.9 (C), 54.5 (2CH2), 41.9 (CH2), 40.3 (CH2),
36.8 (CH2), 33.5 (CH2), 22.5 (3CH3), 14.1 (CH3), 13.1
(CH3); MS (APCI+): m/z (%)=548 ([M+H]+, 100), 474 (9),
300 (13); HR-MS (ESI+): m/z=548.3305, calcd. for
C33H46N3O2S (M+H)+: 548.3311; IR (neat): n=2978, 1625,
1454, 1266, 737 cmꢀ1; [a]D20: ꢀ26.7 (c 1.08, CHCl3); Rf =0.25
(hexane/EtOAc, 1:1)
Ethyl (3R,4S)-3-[(R)-tertbutanesulfinamide]-4-(dibenzyl-
ACHTUNGTRENNUNG
amino)-6-methylheptanoate (10b): 1H NMR (300 MHz,
CDCl3): d=7.52–7.17 (m, 10H), 4.27 (d, J=8.3 Hz, 1H),
4.12–3.99 (m, 2H), 3.89–3.73 (m, 1H), 3.75 (d, J=14.0 Hz,
2H), 3.61 (d, J=14.0 Hz, 2H), 3.23–3.16 (m, 1H), 2.59 (dd,
J=15.1, 3.6 Hz, 1H), 2.48 (dd, J=15.1, 9.4 Hz, 1H), 1.46–
1.36 (m, 1H), 1.31–1.11 (m, 14H), 0.92 (d, J=6.6 Hz, 3H),
0.83 (d, J=6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
171.8 (C), 139.0 (2C), 129.1 (4CH), 128.3 (4CH), 127.0
(2CH), 60.4 (CH2), 60.0 (CH), 56.0 (CH), 55.7 (C), 54.4
2998
asc.wiley-vch.de
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2991 – 3000

The Addition Reaction of Samarium Enolates and 2-Haloenolates
FULL PAPERS
(CRL, University of Oxford) for his revision of the English.
We thank Prof. M. T. Reetz for his personal communication
concerning the spectroscopic data of compound 13.
General Procedure for the Synthesis of Compound 12
To a stirred solution of crude material 10c in CH2Cl2, was
bubbled a stream of HCl (g) for 15 min. The aqueous phase
was extracted with CH2Cl2, and the organic layer was
washed with NaHCO3 and dried over Na2SO4. After remov-
ing the solvents, the crude mixture was obtained and puri-
fied by flash chromatography on silica gel (hexane/EtOAc.
1:1) to yield analytically pure 12.
References
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General Procedure for the Synthesis of Compound 13
Triethylamine (1.1 equiv., 0.44 mmol) and tosyl chloride
(1.1 equiv., 0.44 mmol) were added to a stirred solution of
12 (0.4 mmol) in CH2Cl2 (10 mL) at 08C. The reaction mix-
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HCl (1M), dried over anhydrous Na2SO4, filtered and con-
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ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CD3OD): d=7.83–6.87 (m, 10H), 4.21–4.08 (m, 4H), 3.75–
3.59 (m, 1H), 3.39–3.17 (m, 3H), 3.16–3.00 (m, 3H), 2.52
(dd, J=9.7 Hz, 1H), 1.62 (d, J=6.5 Hz, 3H), 0.99 (t, J=
7.5 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=170.0 (C), 131.4 (2CH), 131.0 (2CH), 130.2
(2C), 129.5 (CH), 129.4 (CH), 129.1 (2CH), 128.9 (2CH),
61.0 (CH), 54.6 (CH2), 53.7 (CH2), 47.1 (CH), 42.6 (CH2),
40.5 (CH2), 37.9 (CH2), 13.3 (CH3), 12.6 (CH3), 10.5 (CH3);
MS (APCI+): m/z (%)=368 ([M+H - HCl]+, 100), 171
(12); HR-MS (ESI+): m/z=368.2699, calcd. for C23H34N3O
(M+HꢀHCl)+: 368.2696; IR (KBr): n=3423, 3054, 2984,
1609, 1457, 1387 cmꢀ1; [a]D20: ꢀ35.7 (c 1.30, CHCl3); Rf =0.48
(dichloromethane/EtOH, 9:1).
Acknowledgements
We acknowledge Ministerio de Ciencia
e Innovaciꢀn
(CTQ2007-61132 and MAT2006-01997) and Principado de
Asturias (FICYT IB08-028) for financial support. J.M.C.
thanks his wife Carmen Fernꢁndez-Flꢀrez for her time.
H.R.S. and C.S. thank MICINN for a Ramꢀn y Cajal Con-
tract (Fondo Social Europeo) and for a predoctoral fellow-
ship, respectively. Our thanks to Dr. Euan C. Goddard
Adv. Synth. Catal. 2009, 351, 2991 – 3000
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Adv. Synth. Catal. 2009, 351, 2991 – 3000