Lewis Acid Catalyzed Cyclization Reactions of Ethenetricarboxylates via Intramolecular Hydride Transfer

Article abstract of DOI:10.1021/acs.joc.7b00895

Catalytic cyclization of amides of ethenetricarboxylate bearing ether and acetal groups has been examined. The reaction of the amides bearing cyclic ether and acetal groups in the presence of Lewis acid such as Sc(OTf)₃ gave spirocyclic piperidine derivatives as major products. The cyclized products may be formed via intramolecular hydride transfer. The reaction mechanism was examined by the DFT calculations. The scope and limitations of the hydride transfer/cyclization reactions of amides of ethenetricarboxylates was investigated, and morpholine formation by intramolecular oxy-Michael addition was also found.

Full text of DOI:10.1021/acs.joc.7b00895

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Article
Lewis Acid-Catalyzed Cyclization Reactions of
Ethenetricarboxylates via Intramolecular Hydride Transfer
Shoko Yamazaki, Taku Naito, Mamiko Niina, and Kiyomi Kakiuchi
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Jun 2017
Downloaded from http://pubs.acs.org on June 11, 2017
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Lewis Acid-Catalyzed Cyclization Reactions of Ethenetricarboxylates via
Intramolecular Hydride Transfer
a
a
a
b
Shoko Yamazaki,* Taku Naito, Mamiko Niina, and Kiyomi Kakiuchi
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a
Department of Chemistry, Nara University of Education, Department of Chemistry, Nara
b
University of Education, Takabatake-cho, Nara 630-8528, Japan, Graduate School of
Materials Science, Nara Institute of Science and Technology (NAIST), Takayama, Ikoma,
Nara 630-0192, Japan
yamazaks@naraꢀedu.ac.jp
Graphical Abstract
H
EtO C CO
Et
2
CO Et
2
2
cat. Lewis Acid
O
R
CO Et
2
O
Y
H
Y
N
N
O
n
n
R
O
n = 1,2, Y = CH , O
2
Abstract: Catalytic cyclization of amides of ethenetricarboxylate bearing ether and acetal
groups has been examined. The reaction of the amides bearing cyclic ether and acetal groups
3
in the presence of Lewis acid such as Sc(OTf) gave spirocyclic piperidine derivatives as
major products. The cyclized products may be formed via intramolecular hydride transfer.
The reaction mechanism was examined by the DFT calculations. The scope and limitations
of the hydride transfer/cyclization reactions of amides of ethenetricarboxylates was
investigated and morpholine formation by intramolecular oxyꢀMichael addition was also
found.
Introduction
Nitrogenꢀcontaining sixꢀmembered heterocyclic systems, such as piperidines and
morpholines (1,4ꢀoxazines), are important structures in organic chemistry because they are
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
5
5
5
5
5
5
6
1
,2
present in a large number of biologically active compounds. The development of new
efficient synthetic strategies for the construction of these heterocycles has attracted
3
,4
considerable interest.
Recently, various cyclization methods involving intramolecular hydride transfer of
0
1
2
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9
0
1
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3
4
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
5
ethers, amines and acetals as hydride donors have been developed. Among the methods
developed, alkylidene or arylidenemalonates have been effectively utilized as hydride
6
acceptors (Scheme 1). However, the structures of substrates for cyclization are still limited.
While many of these reactions including various substrates are effective for the formation of
6b,6g,7
benzoꢀannulated cyclic compounds,
few general methods have been reported for the
8
formation of monocyclic sixꢀmembered nitrogen heterocycles such as piperidines.
MeO C CO
Me
H
2
2
cat.
Sc(OTf)3
CO Me
2
CO Me
2
H
ref. 6a
O
O
H
O
MeO C CO
Me
2
2
CO Me
cat.
2
Lewis acid
CO Me
2
FG
H
O
FG
R
ref. 6c,d
R
MeO C CO
Me
H
N
2
2
CO Me
2
cat.
Gd(OTf)3
CO Me
2
H
ref. 6b
N
EtO C CO
Et
2
2
H
cat.
Sc(OTf)3
H
O
CO Et
2
CO Et
2
H
CO Et
2
CO Et
2
O
O
O
O
ref. 6e
6
Scheme 1
We have developed various ring formation reactions utilizing ethenetricarboxylates as
9
highly electrophilic C=C components. In order to develop general synthetic methodology for
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the construction of the heterocycles, we have investigated the use of more reactive
electrophilic substrates than alkylidene and arylidenemalonates, ethenetricarboxylates.
H
EtO C CO
Et
CO Et
2
2
2
cat. Lewis Acid
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O
R
CO Et
2
O
Y
H
Y
N
N
O
n
n
R
O
n = 1,2, Y = CH , O
2
1
2
Scheme 2
In this study, catalytic cyclization of amides of ethenetricarboxylate bearing ether and
acetal groups 1 has been examined (Scheme 2). The reaction of the amides 1 in the presence
of Lewis acid gave piperidine derivatives as major products. The cyclized products may be
formed via intramolecular hydride transfer. The scope and limitations of the hydride
transfer/cyclization reactions of amides of ethenetricarboxylates have been studied.
Results and Discussion
Amide precursors 1 for cyclization in this study were prepared by the condensation
reaction of 1,1ꢀdiethyl 2ꢀhydrogen ethenetricarboxylate 3 with the corresponding amines 4 in
3
the presence of HOBT, EDCI and Et N in 49ꢀ80% yields (Scheme 3). Use of
ethenetricarboxylate 3 is beneficial for ready introduction of various functional groups into 2ꢀ
carboxyl position.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
6
EtO C CO
Et
2
2
HOBT, EDCI
+
HNRR'
O
4
Et N, THF
3
OH
3
EtO C CO
Et
EtO C CO
Et
EtO
O
C
CO Et
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
N
O
R
N
Ph
N
R
O
O
O
1
1
1
a:R = CH Ph (72%)
1d:R = CH Ph (57%)
2
2
1
f (68%)
b:R = CH Cyclohexyl (58%) 1e:R = CH Cyclohexyl
2
2
c:R = nBu (64%)
(67%)
EtO C CO
Et
EtO C CO
Et
2
2
2
EtO C CO Et
2
2
2
For eqs 1ꢀ6
O
O
Ph
O
O
Ph
N
N
Ph
N
O
O
1g (63%)
1i (78%)
1h (63%)
EtO C CO
Et
2
EtO C CO Et
2
2
2
R1
R1
O
O
O
O
N
N
Ph
R
O
O
1
1
1
j:R = CH Ph (80%)
1l:R = Me (62%)
2
1
k:R = CH Cyclohexyl (49%) 1m:R = H (52%)
2
EtO C CO
Et
EtO C CO Et
2
2
2
2
O
N
O
N
O
1n (72%)
1o:(79%)
For Scheme 8
EtO C CO Et
2
2
EtO C CO
Et
2
2
O
R
O
O
O
N
Ph
N
O
1r (53%)
1
1
p:R = CH CH CH (64%)
2 2 3
q:R = CH Cyclohexyl (66%)
2
EtO C CO Et
2
EtO C CO
Et
2
2
2
R2
O
O
R
O
O
O
R2
For Scheme 9
N
Ph
N
O
2
1s (61%)
1t:R = R = Me (65%)
u:R = CH CH=CH , R = Me (76%)
2 2
2
1
1
2
v:R = CH CH=CH , R = Et (61%)
2
2
Scheme 3
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Catalytic cyclization of amides of ethenetricarboxylate bearing ether groups 1 has been
examined. The reaction of the amides bearing 5ꢀ and 6ꢀmembered cyclic ethers 1a-e in the
3
presence of Lewis acid such as Sc(OTf) gave spirocyclic piperidine products 2a-e
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selectively (eqs 1ꢀ2). The cyclized products may be formed via intramolecular hydride
transfer.
H
EtO C CO
Et
0.2 equiv.
CO
Et
2
2
2
Lewis Acid
O
R
CO Et
2
(
eq 1)
O
H
80 °C
N
ClCH CH Cl
2
2
N
O
R
O
2
a:R = CH Ph; Sc(OTf) (72%)
2 3
1
1
1
a:R = CH Ph
2
2a:R = CH Ph; AlCl (64%)
2 3
b:R = CH Cyclohexyl
2
2b:R = CH Cyclohexyl; Sc(OTf) (52%)
2
3
c:R = nBu
2
c:R = nBu; Sc(OTf) (76%)
3
H
0
.2 equiv.
EtO C CO Et
CO Et
2
2
2
Sc(OTf)3
O
CO Et
2
O
R
(eq 2)
H
80 °C
ClCH CH Cl
0 h
N
R
2
2
N
O
2
O
2
2
d:R = CH Ph; (75%)
2
1d:R = CH Ph
2
e:R = CH Cyclohexyl (67%)
2
1
e:R = CH Cyclohexyl
2
Activation of an electronꢀdeficient alkene by a Lewis acid triggers a 1,5ꢀhydride transfer and
formation of a zwitterionic intermediate, which is followed by cyclization via ionic CꢀC bond
formation (Scheme 4).
(
Sc
OTf)3
(OTf)
Sc
3
O
H
O
O
O
1
,5ꢀH
EtO
O
OEt
O
shift
EtO
O
OEt
O
H
N
N
R
R
EtO
O
Sc(OTf)3
ring
closure
H
O
O
OEt
O
N
R
Scheme 4
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
3
3
3
4
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4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
The scope and generality of the reaction were investigated using variously substituted
1
0
tetrahydrofuranꢀbased substrates. The reaction of 1f,g,h with Lewis acids such as Sc(OTf)
3
4
and SnCl gave the cyclized products 2f,g,h efficiently (eq 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
2
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0
1
2
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9
0
EtO C CO
Et
H
2
2
CO Et
Lewis Acid
2
O
R2
CO Et
2
O
H
(eq 3)
R2
R1
80 °C
R2
R2
Ph
N
ClCH CH Cl
2
2
Ph
N
O
O
R1
R1
R1
1f,g,h
CO Et
2
CO Et
CO Et
2
2
O
CO Et
O
O
2
CO Et
CO Et
2
2
Ph
N
Ph
N
Ph
N
O
O
O
2
g
2h
2f
0
.2 equiv. Sc(OTf) (69%) 0.2 equiv. Sc(OTf)
.2 equiv. Sc(OTf) (64%) 0.5 equiv. SnCl (95%)
3
(59%)
0.5 equiv. SnCl (72%)
4
3
0
3
4
0.2 equiv. AlCl (61%)
3
0.2 equiv. SnCl (67%)
4
However, the reaction of 1i with Lewis acids gave a small amount of cyclized product
2i along with byproduct 5 (eq 4). The byproduct 5 may be formed via intramolecular hydride
transfer and the subsequent deprotonation to form alkene from the resulting zwitterion
intermediate (Scheme 5). Probably 3,3ꢀdimethyl groups of tetrahydrofuran ring interfere with
cyclization sterically.
EtO C CO
Et
2
H
2
CO Et
EtO C
CO Et
2
2
Lewis Acid
2
O
CO Et
2
(eq 4)
O
H
O
O
80 °C
O
O
Ph
N
ClCH CH Cl
Ph
N
2
2
N
Ph
18 h
2i
5
1i
0.2 equiv. Sc(OTf) (a)
.2 equiv. AlCl (a)
.5 equiv. SnCl (30%)
(30%)
(54%)
(16%)
3
0
0
3
4
a. A small amount of 2i produced but
could not isolated.
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LA
LA
LA
O
O
O
O
N
O
O
N
1
,5ꢀH
ꢀH+
EtO
O
OEt
O
EtO
O
OEt
EtO
O
OEt
O
shift
H
H
+H+
O
H
Ph
N
R
R
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H
5
ꢀLA
1iꢀLA
Scheme 5
The reaction of the amides bearing cyclic acetal, dioxolane derivatives 1j,k in the
presence of Sc(OTf) gave piperidine derivatives 2j,k similarly (eq 5). Reaction of 5,5ꢀ
dimethylꢀ1,3ꢀdioxolane derivative 1l gave a cyclic compound as a major product upon
heating in CH Cl (eq 6). However, upon heating in 1,2ꢀdichloroethane the byproduct 6 was
3
2
2
also formed. The byproduct 6 may be formed via intramolecular hydride transfer and the
subsequent reaction of the resulting zwitterion intermediate with water in situ (Scheme 6).
Reaction of 1,3ꢀdioxane derivative 1m gave a complex mixture. This is probably because the
deacetalization (hydrolysis by water in situ) competes with hydride transfer and/or
cyclization.
H
0
.2 equiv.
EtO C CO Et
CO Et
2
2
2
Sc(OTf)3
O
R
CO Et
2
(
eq 5)
O
O
H
80 °C
O
N
ClCH CH Cl
2
2
N
O
2
1 h
R
O
2j:R = CH Ph (88%)
1
j:R = CH Ph
2
2
2k:R = CH Cyclohexyl (75%)
1
k:R = CH Cyclohexyl
2
2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H
EtO C CO
Et
CO
Et
2
2
2
0
.2 equiv
O
CO Et
2
Sc(OTf)3
O
O
H
(eq 6)
O
R1
R1
N
Ph
R1
R1
80 °C
CH Cl2
or
O
N
Ph
O
2
1
1
1
1
l:R = Me
2l:R = Me (63%, CH Cl )
2l:R = Me (40%, ClCH CH Cl, 3h)
m:R = H (0%)
ClCH CH Cl
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
m:R = H
2
2
1
2
EtO C
CO Et
2
2
OH
H
O
O
N
Ph
O
6
(
26%,ClCH CH Cl, 3h)
2
2
(OTf)3
Sc
(OTf)3
Sc
(
OTf)3
Sc
O
O
O
O
O
O
+
H O
2
1,5ꢀH
shift
OEt
OH
OEt
EtO
O
OEt
H
O
EtO
O
EtO
O
H
H
N
H
H
HO
O
O
Ph
N
N
Ph
Ph
O
O
O
1
lꢀSc(OTf)3
6ꢀSc(OTf)3
(
OTf)3
(
OTf)3
(OTf)3
Sc
Sc
Sc
O
O
O
O
O
O
+H O
1
,5ꢀH
2
OEt
OH
OEt
EtO
O
OEt
shift
H
O
EtO
O
EtO
O
H
H
N
H
H
HO
O
O
Ph
N
N
Ph
Ph
O
O
O
1lꢀSc(OTf)3
6ꢀSc(OTf)3
Scheme 6
Product elaboration was next investigated. The acetal/malonate derivatives 2j,l underwent
1
1
monodecarboxylation in wet DMSO in the presence of LiCl under Krapcho conditions to
afford monoester derivatives 7j,l (eq 7). Further selective transformation is under
investigation.
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CO Et
2
CO Et
DMSO
H O
2
2
O
O
CO Et
2
(eq 7)
O
O
Ph
N
Ph
N
LiCl
O
O
Z
Z
160 °C
2
2
j: Z = CH2
7j: Z = CH (51%)
2
l: Z = CH ꢀCMe
7l: Z = CH ꢀCMe (77%)
2
2
2 2
10
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60
Next, the stereoselectivity of the cyclization reaction was studied. Reaction of
enantiomeric cyclic ethers (ꢀ)ꢀ(R)ꢀ1a and (+)ꢀ(S)ꢀ1a gave products (ꢀ)ꢀ2a and (+)ꢀ2a in 42ꢀ
1
2
4
6% ee, respectively (eq 8). The chiral information remained partially.
H
EtO C CO Et
0.2ꢀ0.5 equiv.
Lewis Acid
CO2Et
CO Et
2
2
O
2
O
∗
H
∗
80 °C
Ph
N
(eq 8)
ClCH CH Cl
2
2
O
Ph
ꢀ)ꢀ(R)ꢀ1a ee% >98%
+)ꢀ(S)ꢀ1a ee% >98%
N
O
0
.2 eq. Sc(OTf) (78%) (ꢀ)ꢀ2a 42% ee
3
(
0.5 eq. SnCl (68%)
(ꢀ)ꢀ2a 46% ee
4
0
.2 eq. Sc(OTf) (82%) (+)ꢀ2a 43% ee
3
(
0.2 eq. SnCl (71%)
(+)ꢀ2a 46% ee
4
In order to elucidate the proposed mechanism in Scheme 4 and explain the
13,14
15
stereochemical course, B3LYP/6ꢀ31G*
calculations including the PCM solvent effect
(
solvent=CH
2
Cl
2
) were carried out. TS geometry was characterized by vibrational analysis,
‡
which checked whether the obtained geometry has single imaginary frequencies (ν ). From
1
6
TSs, reaction paths were traced by the intrinsic reaction coordinate (IRC) method to obtain
the energyꢀminimum geometries. Relative Gibbs free energies are of RB3LYP/6ꢀ31G* SCRF
1
2
= (PCM, solvent = CH Cl ) (T = 353.15 K, P = 1 atm). The model compounds (R = R = Me
2
2
and Lewis acid = AlCl
3
) with (R)ꢀconfiguration originally were used for the DFT calculations
and the result is shown in Scheme 7 and Figure 1. The hydride transfer transition state TS1A
leads to the zwitterion intermediate Int1A. A small conformational change to retain the
original configuration gives Int2A, the precursor for ring closure. Int2A via transition state
TS2A leads to (S)ꢀ2A with retention of configuration. However, Int1A may partially change
to Int1B/cyclization with inversion of configuration. Moreover, the racemization of Int1A by
the major conformational change could also result in the loss of chirality. For example, CꢀN
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
bond rotation via TS3A from Int1A leads to Int1B. The energy barrier for CꢀN rotation
(19.21 kcal/mol) is only slightly higher than that of hydride transfer of TS1A. Although
7b,17
6g
Reinhoudt
and Akiyama reported high retention of chirality of their benzoꢀannulated
substrates, in this case the chirality remained only partially. This is probably because the
ethenetricarboxlates are less rigid.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OR1
O
O
O
OR1
O
1
R O
hydride
transfer
O
AlCl3
[
AlCl3
1
2.871 Å
OR1
1
R O
R O
O
TS1A
4.831 Å
O AlCl3
O
O
O
H
O
O
N
H
R2
+19.05
kcal/mol]
N
N
R2
R2
Int2A
[+8.76
kcal/mol]
Int1A
+10.86
(
R)ꢀ1AꢀAlCl3
[
[
ꢀG = 0
kcal/mol]
R =R =Me
kcal/mol]
1
2
1
R O
O
OR1
ring closure
O
AlCl3
TS2A
+9.89
ꢀAlCl3
O
O
(S)ꢀ2A
N
[
R2
kcal/mol]
2AꢀAlCl3
[
ꢀ7.53
kcal/mol]
O
OR1
O
O
1
OR1
R O
O
N
CꢀN
AlCl3
2
.760 Å
OR1
bond
1
1
AlCl3
R O
O
R O
O
rotation
5
.353 Å
O AlCl3
O
O
TS3A
N
R2
O
N
O
[+19.21
kcal/mol]
R2
R2
O
Int2B
[+6.07
kcal/mol]
Int1B
+10.23
kcal/mol]
Int1A
[
1
R O
O
OR1
ring closure
TS2B
O
AlCl3
O
N
R2
ꢀAlCl3
[
+7.80
O
(R)ꢀ2A
kcal/mol]
2
BꢀAlCl3
[
ꢀ3.95
kcal/mol]
enantiomer ꢀAlCl
3
of 2AꢀAlCl3
enantiomer
of Int1A
enantiomer
of Int2A
Int1A
(R)ꢀ2A
CꢀC,
CꢀN
bond
rotations
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6
7
8
9
1
2
Scheme 7. Reaction paths of the model compounds (R = R = Me; Lewis acid = AlCl
3
).
Gibbs free energies (T = 353.15 K, P = 1 atm) were obtained at the RB3LYP/6ꢀ31G* SCRF
=
(PCM, solvent = CH Cl ) level and are relative to (R)ꢀ1AꢀAlCl .
2
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
.570 Å
1.281 Å
1.369 Å
ν‡ = 632.65i cmꢀ1
TS1A
ν‡ = 112.96i cmꢀ1
TS2A
2
.639 Å
5
.799 Å
ν‡ = 73.46i cmꢀ1
ν‡ = 72.95i cmꢀ1
TS3A
TS2B
Figure 1. B3LYP/6ꢀ31G*ꢀoptimized structures of the transition states in Scheme 7.
The reactions of various substrates were also examined. As shown in Scheme 8, the
1
8
cyclization reaction of diisobutylamide 1n did not proceed. The reaction of 1n with TiCl
4
gave nonꢀcyclized water and chlorine adducts as major products. The reaction of acyclic
primary and secondary ethers 1o,p,q also did not proceed under the reaction conditions. The
reaction of 1,4ꢀbenzodioxane substrate 1r (the structure is shown in Scheme 3) gave a
complex mixture. Furthermore, the cyclization reaction of tetrahydropyranꢀ2ꢀmethyl ester 10
1
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
did not proceed efficiently. An isolable product is a reduced compound of C=C double bond
11. This product 11 may be formed via intermolecular hydride transfer, although the detailed
mechanism is not clear yet. The difference on reactivity between oxygen and nitrogen
analogues can be explained, similar to the cyclization of other ethenetricarboxylate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
derivatives. Triester 10 may be more stable in sꢀcis conformation, probably because of the
steric repulsion. For intramolecular hydride transfer and cyclization, this must have sꢀtrans
conformation. In diester amides, the energy differences of sꢀcis and sꢀtrans conformations
may be small. The facile intramolecular reactions of amides probably originates from higher
ratio of the reactive sꢀtrans conformer.
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9
H
EtO C CO Et
CO Et
2
2
2
Lewis Acid
O
CO Et
2
O
H
N
N
1n
EtO C CO
Et EtO C CO
Et
2
2
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
Cl
O
O
+
N
N
(1 equiv. TiCl , r.t.) 8 (48%)
9 (34%)
4
EtO C CO Et
2
2
0.2 equiv.
Sc(OTf)3
H
CO Et
2
O
O
CO Et
H
2
R2
N
N
80 °C/ClCH CH Cl
R1
2
2
R1
O
O
R2
or 110 °C/toluene
1
2
1
1
1
o:R = Me, R = H
1
2
p:R = CH CH CH , R = Ph
2
2
3
1
2
q:R = CH Cyclohexyl, R = Ph
2
H
0.2 equiv.
Sc(OTf)3
H
EtO C CO Et
EtO C CO
Et
CO Et
2
2
2
2
2
O
CO Et
H
2
O
H
O
H
8
0 °C
O
ClCH CH Cl
2
2
O
O
O
O
O
10
11 (21%)
EtO C CO Et
EtO C
CO Et
2
2
2
2
O
O
O
>
H
O
O
O
(
OTf)3
Sc
(
OTf)3
Sc
intermolecular
Hꢀtransfer
O
O
+
O
O
H
10 + 10
EtO
O
OEt
EtO
O
OEt
O
O
O
O
+H O
2
decomposition?
11
Scheme 8
On the other hand, reaction of the amides bearing acetonide and acyclic acetals
s,1t,1u in the presence of Sc(OTf) (0.2 equiv.) gave morpholine derivatives 12 and 13t,u
via nucleophilic attack of oxygen (Scheme 9). For the reaction of 1s-u, facile CꢀO cleavage
1
3
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
occurs because of formation of tertiary carbocations (for 1s) or demethylation (1t,u). Similar
oxonium ion intermediates for the substrates 1a-l may be formed reversibly, and
intramolecular hydride transfer and cyclization reaction lead to 2a-l.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Sc
OTf)3
+H O
EtO C
CO Et
2
2
2
EtO C CO Et
2
2
0.2 equiv
Sc(OTf)3
ꢀ
(CH ) C=O
3 2
O
O
O
2
ꢀSc(OTf)3
3
O
O1
O
O
EtO
O
OEt
18 h
4
OH
Ph
N
Ph
N
O
6
5
12
1s
O
Ph
N
8
0 °C/ClCH CH Cl
2 2
(65%; trans:cis = 3:7)
r.t. CH Cl2
2
(80%; trans:cis = 1:9)
(
Sc
OTf)3
EtO C CO
Et
+H
O
EtO
O
C
CO Et
2
2
2
2
2
0
.2 equiv
+
ꢀ
CH (CH OH)
3 3
Sc(OTf)3
O
O
O
2
3
O
O
ꢀSc(OTf)3
O1
r.t.
CH Cl
EtO
O
OEt
4N
N
O
6
O
2
2
R
R
5
1
t: R = Me
13t: R = Me
(44%; trans:cis = 5:1)
3u: R = CH CH=CH2
N
1u: R = CH CH=CH
2
2
O
R
1
(
2
56%; trans:cis = 1:0)
(
Sc
OTf)3
(OTf)3
Sc
O
N
O
H
1,5ꢀH
ring
O
O
shift closure
2
a-c
EtO
OEt
EtO
O
OEt
(and 2d-l)
O
O
O
N
R
R
1a-c
and 1d-l)
(
Scheme 9
Acid catalyzed hydrolysis reaction of acetal amides 1v and 1j was also examined. The
reaction of acyclic and cyclic acetals gave the cyclic hemiacetals 14 and 15, respectively, as
shown in Scheme 10. The formation of the products 14 and 15 demonstrates high
electrophilicity of the ethenetricarboxylates.
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8
9
EtO C CO
Et
EtO C
CO Et
2
2
2
2
6
0 °C
3
CH CO H/
H O
2
O
O
O
N
2
O
N
OH
O
1
4
1v
(
87%; trans:cis = 2.5:1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EtO C CO Et
80 °C
EtO C
CO Et
2
2
2
2
1M HCl aq
THF
O
O
O
O
Ph
N
Ph
N
OH
O
1
j
15
(49%; trans:cis = 2.7:1)
EtO C CO Et
2
2
O
R
H
O
O
H
N
H
Scheme 10
In summary, Lewis Acidꢀcatalyzed cyclization reactions of ethenetricarboxylates
bearing cyclic acetal and ether groups via intramolecular hydride transfer have been studied.
The scope of the substrate for intramolecular hydride transfer/cyclization was expanded. The
hydride transfer mechanism was examined by the DFT calculations. Reaction of
enantiomeric cyclic ethers gave products with partial chirality, probably because the
ethenetricaboxylates are not rigid enough. Reaction of the amides bearing acetonide and
3
acyclic acetals in the presence of catalytic Sc(OTf) gave morpholine derivatives via
nucleophilic attack of oxygen. Further investigation on expansion of the substrate scope and
improvement of the selectivity is underway.
Experimental Section
1
13
General Methods. H Chemical shifts are reported in ppm relative to Me
4
Si. C Chemical
1
3
shifts are reported in ppm relative to CDCl
3
(77.1 ppm). C mutiplicities were determined by
DEPT and HSQC. Peak assignments are made by 2D COSY, HSQC, NOESY, and HMBC
spectra. Mass spectra were recorded at an ionizing voltage of 70 eV by EI, FAB, CI or ESI.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Mass analyzer type used for EI, FAB and CI is doubleꢀfocusing and that for ESI is TOF in
the HRMS measurements. HPLC analysis was performed with a UV detecter (detection, 254
nm light) and flow rate of 1.0 mL/min using a CHIRALPAK ASꢀH (0.46 cm × 250 mm)
column at 30 °C. Optical rotations were measured with a 1 cm i.d. × 10 cm cell.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Amines 4a-c were prepared from the aldehydes (benzaldehyde, cyclohexanecarboxaldehyde,
and butanal) and tetrahydrofurfurylamine by reductive amination in methanol according to
19
the literature procedure.
N-Benzyltetrahydrofurfurylamine (4a): (8.9 mmol scale, 1.04 g, 61%) R = 0.2 (ether);
f
1
pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.51ꢀ1.60 (m, 1H), 1.83ꢀ1.99 (m, 4H),
2.65 (dd, J = 11.9, 7.5 Hz, 1H), 2.71 (dd, J = 11.9, 3.9 Hz, 1H), 3.71ꢀ3.76 (m, 1H), 3.81ꢀ3.86
(m, 1H), 3.82 (s, 2H), 4.03 (dddd, J = 7.5, 7.2, 7.2, 3.9 Hz, 1H), 7.21ꢀ7.26 (m, 1H), 7.29ꢀ7.35
1
3
(m, 4H); C NMR (100.6 MHz, CDCl
3 2 2 2
) δ (ppm) 25.8 (CH ), 29.3 (CH ), 53.7 (CH ), 54.0
(CH ), 67.9 (CH ), 78.4 (CH), 126.9 (CH), 128.1 (CH), 128.4 (CH), 140.3 (C); IR (neat)
2
2
ꢀ1
+
3325, 2971, 2867, 1604, 1495, 1453, 1361, 1132, 1072, 1028 cm ; MS (EI) m/z 191 (M ,
+
5.7), 120 (75), 91 (100%); HRMS (EI) m/z: M Calcd for C12
H17NO 191.1310; Found
191.1311.
N-Cyclohexylmethyltetrahydrofurfurylamine (4b): (8.9 mmol scale, 1.06 g, 60%) R = 0.2
f
1
(
MeOH); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.857ꢀ0.943 (m, 2H), 1.10ꢀ
1
6
1
1
.29 (m, 4H), 1.41ꢀ1.58 (m, 2H), 1.64ꢀ1.82 (m, 5H), 1.83ꢀ2.00 (m, 3H), 2.43 (dd, J = 11.5,
.6 Hz, 1H), 2.46 (dd, J = 11.5, 6.7 Hz, 1H), 2.63 (dd, J = 11.9, 7.2 Hz, 1H), 2.64 (dd, J =
1.9, 4.3 Hz, 1H), 3.70ꢀ3.78 (m, 1H), 3.81ꢀ3.87 (m, 1H), 4.00 (dddd, J = 7.4, 7.2, 4.3, 4.3 Hz,
13
H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 25.6 (CH
2
), 26.0 (CH
2
), 26.6 (CH
2
), 29.2
(
CH ), 31.3 (CH ), 37.9 (CH), 54.6 (CH ), 56.9 (CH ), 67.7 (CH ), 78.3 (CH); IR (neat)
2 2 2 2 2
ꢀ1
+
3
336, 2925, 2850, 1449, 1362, 1137, 1072 cm ; MS (FAB) m/z 198 ([M + H] ); HRMS
+
+
(
FAB) m/z: [M + H] Calcd for C12
H24NO 198.1858; Found 198.1859, [M − H] Calcd for
C H NO 196.1701; Found 196.1702.
12
22
f
N-Butyltetrahydrofurfurylamine (4c): (8.9 mmol scale, 0.48 g, 31%) R = 0.1 (ether);
1
colorless oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.912 (t, J = 7.2 Hz, 3H), 1.27 (bs, 1H),
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1
.30ꢀ1.39 (m, 2H), 1.43ꢀ1.58 (m, 3H), 1.83ꢀ2.01 (m, 3H), 2.57ꢀ2.71 (m, 4H), 3.74 (ddd, J =
.4, 6.8, 6.8 Hz, 1H), 3.85 (ddd, J = 8.4, 6.8, 6.8 Hz, 1H), 4.00 (tdd, J = 7.2, 7.2, 4.1 Hz, 1H);
C NMR (100.6 MHz, CDCl ) δ (ppm) 14.1 (CH ), 20.6 (CH ), 25.8 (CH ), 29.4 (CH ), 32.4
8
1
3
3
3
2
2
2
(
CH
137, 1072 cm ; MS (CI) m/z 158 ([M + H] ); HRMS (CI) m/z: [M + H] Calcd for
C H NO 158.1545; Found 158.1538.
2 2 2 2
), 50.0 (CH ), 54.7 (CH ), 67.9 (CH ), 78.5 (CH); IR (neat) 3326, 2956, 1458, 1377,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1
+
+
1
9
20
Amines 4d-m,4r,s were prepared by reaction of benzylamine or cyclohexylamine (2 equiv.
to an excess amount) with alkyl bromides or iodides (1 equiv.) at 60ꢀ80 °C according to the
2
0
literature procedure. Amines 4u,v were prepared by reaction of aminoacetaldehyde
dimethyl/diethyl acetal (2 equiv.) with allyl bromide in ether at room temperature according
2
1
to the literature procedure.
2ꢀ(Bromomethyl)tetrahydroꢀ2Hꢀpyran for 4d,e and 2ꢀ
bromomethylꢀ1,3ꢀdioxolane for 4j were purchased. The alkyl iodides for 4f,g were prepared
2
2
according to the literature. 2ꢀ(Iodomethyl)ꢀ4,4ꢀdimethyltetrahydrofuran for 4h and 2ꢀ
(iodomethyl)ꢀ3,3ꢀdimethyltetrahydrofuran for 4i were prepared according to the literature
2
2
method. 2ꢀ(Bromomethyl)ꢀ5,5ꢀdimethylꢀ1,3ꢀdioxane for 4l and 2ꢀ(bromomethyl)ꢀ1,3ꢀ
2
3
dioxane for 4m were prepared according to the literature. 4ꢀ(Bromomethyl)ꢀ2,2ꢀdimethylꢀ
2
4
1,3ꢀdioxolane for 4s was prepared according to the literature.
2
-(Iodomethyl)-4,4-dimethyltetrahydrofuran: (17.5 mmol scale, 1.370 g, 33%); pale
1
yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.10 (s, 3H), 1.12 (s, 3H), 1.46 (dd, J =
12.5, 8.8 Hz, 1H), 1.94 (ddd, J = 12.5, 6.6, 0.8 Hz, 1H), 3.23 (dd, J = 9.9, 6.5 Hz, 1H), 3.27
(dd, J = 9.9, 5.4 Hz, 1H), 3.55 (dd, J = 8.0, 0.8 Hz, 1H), 3.62 (d, J = 8.0 Hz, 1H), 4.15 (dddd,
13
J = 8.8, 6.6, 6.5, 5.4 Hz, 1H); C NMR (100.6 MHz, CDCl
3
2
) δ (ppm) 11.0 (CH ), 26.0
(CH ), 26.6 (CH ), 40.5 (C), 47.2 (CH ), 78.6 (CH), 80.7 (CH ); IR (neat) 2958, 2867, 1465,
3 3 2 2
ꢀ1
+
+
1368, 1168, 1047 cm ; MS (CI) m/z 241 ([M + H] ); HRMS (CI) m/z: [M + H] Calcd for
7
C H14IO 241.0089; Found 241.0080.
2-(Iodomethyl)-3,3-dimethyltetrahydrofuran: (6.76 mmol scale, 1.622 g, quantitative
1
yield) R
f
= 0.5 (hexaneꢀether = 4 : 1); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm)
0.946 (s, 3H), 1.12 (s, 3H), 1.80ꢀ1.91 (m, 2H), 3.10 (dd, J = 10.3, 9.6 Hz, 1H), 3.20 (dd, J =
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
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5
5
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5
5
5
5
5
5
5
6
1
3
1
0.3, 3.3 Hz, 1H), 3.72 (dd, J = 9.6, 3.3 Hz, 1H), 3.83ꢀ3.94 (m, 2H); C NMR (100.6 MHz,
CDCl
3
) δ (ppm) 4.8 (CH
2
), 21.1 (CH
3
), 26.1 (CH
3
2 2
), 41.6 (C), 41.8 (CH ), 65.3 (CH ), 87.3
ꢀ1
(
CH); IR (neat) 2958, 2871, 1464, 1414, 1389, 1369, 1183, 1109, 1021 cm ; MS (EI) m/z
+
+
2
40 (M , 1.2), 113 (59), 99 (100%); HRMS (EI) m/z: M Calcd for C
7
H13IO 240.0011;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Found 240.0015.
N-Benzyl(tetrahydropyran-2-methyl)amine (4d): (10 mmol scale, 1.816 g, 86%) R = 0.1
f
1
(ether); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.25ꢀ1.35 (m, 1H), 1.43ꢀ1.62
(
m, 4H), 1.80ꢀ1.85 (m, 2H), 2.60 (dd, J = 12.1, 3.5 Hz, 1H), 2.65 (dd, J = 12.1, 8.1 Hz, 1H),
3
.39ꢀ3.49 (m, 2H), 3.79 (s, 2H), 3.97 (bd, J = 11.3 Hz, 1H), 7.21ꢀ7.26 (m, 1H), 7.29ꢀ7.33 (m,
1
3
4
3 2 2 2
H); C NMR (100.6 MHz, CDCl ) δ (ppm) 23.3 (CH ), 26.2 (CH ), 29.8 (CH ), 54.2
(CH
2 2 2
), 54.9 (CH ), 68.4 (CH ), 77.2 (CH), 126.9 (CH), 128.2 (CH), 128.4 (CH), 140.5 (C);
ꢀ1
IR (neat) 3327, 2935, 2844, 1604, 1495, 1453, 1378, 1353, 1200, 1089, 1048 cm ; MS (EI)
+
+
m/z 205 (M , 8.4), 120 (88), 91 (100%); HRMS (EI) m/z: M Calcd for C13
H19NO 205.1467;
Found 205.1468.
N-(Cyclohexylmethyl)(tetrahydropyran-2-methyl)amine (4e): (10 mmol scale, 1.582 g,
1
75%) R
f
= 0.4 (MeOH); colorless oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.831ꢀ0.945 (m,
2
H), 1.09ꢀ1.34 (m, 5H), 1.40ꢀ1.59 (m, 5H), 1.61ꢀ1.76 (m, 4H), 1.80ꢀ1.84 (m, 1H), 2.40 (dd, J
=
11.5, 6.8 Hz, 1H), 2.43 (dd, J = 11.5, 6.6 Hz, 1H), 2.54 (dd, J = 12.1, 3.3 Hz, 1H), 2.62 (dd,
1
3
J = 12.1, 8.4 Hz, 1H), 3.40ꢀ3.47 (m, 2H), 3.97 (bd, J = 11.1 Hz, 1H); C NMR (100.6 MHz,
CDCl
3
) δ (ppm) 23.3 (CH
2
), 26.10 (CH
2
), 26.12 (CH
2
), 26.2 (CH
2
2 2
), 26.7 (CH ), 29.9 (CH ),
3
1.48 (CH ), 31.54 (CH ), 38.0 (CH), 55.7 (CH ), 57.0 (CH ), 68.4 (CH ), 77.2 (CH); IR
2
2
2
2
2
ꢀ1
(
neat) 3339, 2929, 1449, 1376, 1345, 1262, 1202, 1178, 1089, 1047 cm ; MS (CI) m/z 212
+
+
(
[M + H] ); HRMS (CI) m/z: [M + H] Calcd for C13H26NO 212.2014; Found 212.2013.
N-Benzyl-(1-oxaspiro[4.5]decan-2-ylmethyl)amine (4f): (3.5 mmol scale, 924 mg, 97%) Rf
1
=
0.5 (ether); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.31ꢀ1.56 (m, 8H), 1.61ꢀ
1
1
7
.71 (m, 5H), 1.78 (bs, 1H), 1.90ꢀ1.96 (m, 1H), 2.62 (dd, J = 11.7, 7.0 Hz, 1H), 2.69 (dd, J =
1.7, 4.1 Hz, 1H), 3.80 (d, J = 13.4 Hz, 1H), 3.83 (d, J = 13.4 Hz, 1H), 4.08ꢀ4.14 (m, 1H),
1
3
.20ꢀ7.25 (m, 1H), 7.28ꢀ7.35 (m, 4H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 23.8 (CH
2
),
24.1 (CH
2
), 25.7 (CH ), 29.3 (CH ), 35.9 (CH ), 37.4 (CH ), 38.6 (CH
2
2
2
2
2
), 54.0 (CH ), 54.5
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(
CH
2
), 77.1 (CH), 82.8 (C), 126.7 (CH), 128.0 (CH), 128.3 (CH), 140.6 (C); IR (neat) 3327,
ꢀ1
+
2
928, 1495, 1454, 1359, 1314, 1131, 1074, 1028 cm ; MS (EI) m/z 259 (M , 51), 120 (100),
+
9
1 (71%); HRMS (EI) m/z: M Calcd for C H NO 259.1936; Found 259.1943.
1
7
25
N-Benzyl-(2-oxaspiro[4.5]decan-3-ylmethyl)amine (4g): (16.1 mmol scale, 2.896 g, 68%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
R
f
= 0.5 (hexaneꢀether = 1 : 8); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.34
(
dd, J = 12.4, 8.9 Hz, 1H), 1.40ꢀ1.45 (m, 10H), 1.74 (bs, 1H), 1.82 (dd, J = 12.4, 6.6 Hz, 1H),
2
.65ꢀ2.72 (m, 2H), 3.53 (d, J = 8.4 Hz, 1H), 3.56 (d, J = 8.4 Hz, 1H), 3.82 (s, 2H), 4.10
13
(
dddd, J = 8.9, 6.6, 6.6, 4.9 Hz, 1H), 7.21ꢀ7.26 (m, 1H), 7.29ꢀ7.34 (m, 4H); C NMR (100.6
MHz, CDCl ) δ (ppm) 23.6 (CH ), 24.1 (CH ), 26.1 (CH ), 35.6 (CH ), 36.8 (CH ), 42.2
3
2
2
2
2
2
(CH
2
), 43.8 (C), 54.1 (CH
2
2 2
), 54.2 (CH ), 78.1 (CH), 78.4 (CH ), 126.9 (CH), 128.2 (CH),
1
28.4 (CH), 140.4 (C); IR (neat) 3327, 3027, 2925, 1660, 1604, 1495, 1451, 1358, 1121,
ꢀ1
+
+
1
050 cm ; MS (CI) m/z 260 ([M + H] ); HRMS (CI) m/z: [M + H] Calcd for C H NO
17 26
260.2014; Found 260.2011.
N-Benzyl(tetrahydro-4,4-dimethylfuran-2-yl)methylamine (4h): (3.6 mmol scale, 664 mg,
1
68%) R = 0.3 (hexaneꢀether = 1 : 5); pale yellow oil; H NMR (400 MHz, CDCl ) δ (ppm)
f
3
1.08 (s, 3H), 1.09 (s, 3H), 1.41 (dd, J = 12.3, 8.9 Hz, 1H), 1.74 (dd, J = 12.3, 6.8 Hz, 1H),
1
.80 (bs, 1H), 2.69 (d, J = 5.7 Hz, 2H), 3.45 (d, J = 8.1 Hz, 1H), 3.48 (d, J = 8.1 Hz, 1H),
13
3
.82 (s, 2H), 4.19 (ddt, J = 8.9, 6.8, 5.7 Hz, 1H), 7.21ꢀ7.26 (m, 1H), 7.29ꢀ7.35 (m, 4H); C
) δ (ppm) 26.57 (CH ), 26.60 (CH ), 39.6 (C), 44.6 (CH ), 54.1
NMR (100.6 MHz, CDCl
3
3
3
2
(CH
2 2 2
), 54.3 (CH ), 78.7 (CH), 80.0 (CH ), 126.9 (CH), 128.1 (CH), 128.4 (CH), 140.4 (C);
ꢀ1
IR (neat) 3327, 3027, 2952, 1604, 1495, 1454, 1367, 1200, 1128, 1060, 1028 cm ; MS (CI)
+
+
m/z 220 ([M + H] ); HRMS (CI) m/z: [M + H] Calcd for C14
H22NO 220.1701; Found
220.1704.
N-Benzyl(tetrahydro-3,3-dimethylfuran-2-yl)methylamine (4i): (19.0 mmol scale, 474
1
mg, 34%) R
f
= 0.3 (hexaneꢀether = 1 : 4); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ
(
ppm) 0.905 (s, 3H), 1.07 (s, 3H), 1.65 (bs, 1H), 1.63ꢀ1.83 (m, 2H), 2.59ꢀ2.66 (m, 2H), 3.55
(
dd, J = 7.5, 4.6 Hz, 1H), 3.76ꢀ3.90 (m, 2H), 3.82 (s, 2H), 7.21ꢀ7.26 (m, 1H), 7.29ꢀ7.35 (m,
1
3
4H); C NMR (100.6 MHz, CDCl
3 3 3 2
) δ (ppm) 21.8 (CH ), 26.0 (CH ), 40.1 (C), 41.5 (CH ),
50.0 (CH
2
), 54.4 (CH ), 65.7 (CH ), 86.2 (CH), 126.9 (CH), 128.1 (CH), 128.4 (CH), 140.4
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3
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3
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3
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ
1
(
C); IR (neat) 3326, 3027, 2956, 2871, 1495, 1453, 1386, 1368, 1102, 1026 cm ; MS (EI)
+
+
m/z 219 (M , 3.3), 176 (3.5), 120 (98), 91 (100%); HRMS (EI) m/z: M Calcd for C14
H21NO
2
19.1623; Found 219.1618.
f
N-Benzyl(1,3-dioxolan-2-yl)methylamine (4j): (10.7 mmol scale, 1.670 g, 81%) R = 0.9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(MeOHꢀether = 1 : 10); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.83 (bs, 1H),
2
.83 (d, J = 4.3 Hz, 2H), 3.84ꢀ4.02 (m, 4H), 3.85 (s, 2H), 5.02 (t, J = 4.3 Hz, 1H), 7.22ꢀ7.27
13
(m, 1H), 7.29ꢀ7.34 (m, 4H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 51.4 (CH
2 2
), 54.0 (CH ),
6
5.1 (CH
027, 2358, 1603, 1495, 1454, 1411, 1362, 1201, 1122, 1029 cm ; MS (EI) m/z 194 ([M +
2
), 103.4 (CH), 127.0 (CH), 128.2 (CH), 128.5 (CH), 140.0 (C); IR (neat) 3330,
ꢀ1
3
+
+
+
H] , 3.8), 193 (M , 2.8), 120 (52), 91 (100%); HRMS (EI) m/z: M Calcd for C11
H15NO
2
1
93.1103; Found 193.1102.
N-Cyclohexyl(1,3-dioxolan-2-yl)methylamine (4k): (10 mmol scale, 1.172 g, 59%) R = 0.2
f
1
(ether); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.843ꢀ0.937 (m, 2H), 1.09ꢀ1.31
(m, 3H), 1.31 (bs, 1H), 1.41ꢀ1.52 (m, 1H), 1.65ꢀ1.73 (m, 5H), 2.48 (d, J = 6.6 Hz, 2H), 2.79
1
3
(d, J = 4.3 Hz, 2H), 3.83ꢀ3.92 (m, 2H), 3.94ꢀ4.02 (m, 2H), 4.99 (t, J = 4.3 Hz, 1H); C NMR
(100.6 MHz, CDCl ) δ (ppm) 26.0 (CH ), 26.7 (CH ), 31.3 (CH ), 37.9 (CH), 52.5 (CH ),
3
2
2
2
2
ꢀ1
5
7.0 (CH
FAB) m/z 222 ([M + Na] ), 200 ([M + H] ); HRMS (FAB) m/z: [M + H] Calcd for
200.1651; Found 200.1653.
2 2
), 65.0 (CH ), 103.4 (CH); IR (neat) 2921, 2851, 1449, 1129, 1039 cm ; MS
+
+
+
(
11 2
C H22NO
N-Benzyl(5,5-dimethyl-1,3-dioxan-2-yl)methylamine (4l): (10 mmol scale, 2.961 g, 66%)
1
R = 0.2 (ether); colorless crystals; mp 37ꢀ39 °C; H NMR (400 MHz, CDCl ) δ (ppm) 0.707
f
3
(
s, 3H), 1.18 (s, 3H), 1.66 (bs, 1H), 2.80 (d, J = 4.9 Hz, 2H), 3.42 (d, J = 10.7 Hz, 2H), 3.60
(
d, J = 10.7 Hz, 2H), 3.81 (s, 2H), 4.57 (t, J = 4.9 Hz, 1H), 7.20ꢀ7.26 (m, 1H), 7.28ꢀ7.31 (m,
13
4
H); C NMR (100.6 MHz, CDCl ) δ (ppm) 21.8 (CH ), 23.0 (CH ), 30.4 (C), 52.4 (CH ),
3
3
3
2
5
2 2
4.0 (CH ), 77.1 (CH ), 100.8 (CH), 126.9 (CH), 128.2 (CH), 128.4 (CH), 140.1 (C); IR
ꢀ1
(
KBr) 3326, 2953, 2839, 1468, 1453, 1412, 1398, 1144, 1123, 1097, 1025, 1011, 986 cm ;
+
+
MS (EI) m/z 235 (M , 6.8), 115 (100), 91 (76%); HRMS (EI) m/z: M Calcd for C H NO
2
1
4
21
2
35.1572; Found 235.1576.
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f
N-Benzyl(1,3-dioxan-2-yl)methylamine (4m): (10 mmol scale, 1.444 g, 70%) R = 0.1
1
(
ether); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.32 (bd, J = 12.5 Hz, 1H),
1
1
7
5
.71 (bs, 1H), 2.07 (dtt, J = 12.5, 12.5, 5.0 Hz, 1H), 2.75 (d, J = 4.9 Hz, 2H), 3.75 (ddd, J =
2.5, 11.1, 2.4 Hz, 2H), 3.79 (s, 2H), 4.09 (dd, J = 11.1, 5.0 Hz, 2H), 4.67 (t, J = 4.9 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
.20ꢀ7.25 (m, 1H), 7.27ꢀ7.33 (m, 4H); C NMR (100.6 MHz, CDCl
3 2
) δ (ppm) 25.8 (CH ),
2.5 (CH ), 53.9 (CH ), 66.7 (CH ), 100.7 (CH), 126.9 (CH), 128.1 (CH), 128.3 (CH), 140.0
2
2
2
ꢀ1
(
C); IR (neat) 3331, 2958, 2850, 1603, 1495, 1454, 1377, 1242, 1145, 1087, 1005 cm ; MS
+
+
(
EI) m/z 207 (M , 7.8), 120 (44), 91 (97), 87 (100%); HRMS (EI) m/z: M Calcd for
C H NO 207.1259; Found 207.1254.
12
17
2
N-Benzyl-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methylamine (4r): (10 mmol scale, 1.582
1
g, 62%) R
f
= 0.4 (hexaneꢀether = 1 : 1); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm)
1.76 (bs, 1H), 2.86 (dd, J = 12.5, 4.7 Hz, 1H), 2.91 (dd, J = 12.5, 6.6 Hz, 1H), 3.84 (s, 2H),
4.02 (dd, J = 11.1, 7.4 Hz, 1H), 4.23ꢀ4.31 (m, 2H), 6.81ꢀ6.88 (m, 4H), 7.23ꢀ7.28 (m, 1H),
13
3 2 2
7.30ꢀ7.36 (m, 4H); C NMR (100.6 MHz, CDCl ) δ (ppm) 49.3 (CH ), 54.0 (CH ), 66.6
(CH ), 72.7 (CH), 117.2 (CH), 117.4 (CH), 121.4 (CH), 121.6 (CH), 127.2 (CH), 128.2
2
(CH), 128.5 (CH), 140.0 (C), 143.2 (C), 143.3 (C); IR (neat) 3343, 3027, 2882, 1592, 1494,
ꢀ1
+
1
454, 1350, 1305, 1263, 1199, 1114, 1042 cm ; MS (EI) m/z 255 (M , 17), 120 (88), 91
+
(
100%); HRMS (EI) m/z: M Calcd for C H NO 255.1259; Found 255.1257.
16 17
2
N-Benzyl-(2,2-dimethyl-1,3-dioxolan-4-yl)methylamine (4s): (10 mmol scale, 1.274 g,
1
6
1
1
6%) R
f
= 0.3 (hexaneꢀether = 1 : 2); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm)
.35 (s, 3H), 1.41 (s, 3H), 1.69 (bs, 1H), 2.74 (d, J = 5.7 Hz, 2H), 3.69 (dd, J = 8.0, 6.6 Hz,
H), 3.83 (d, J = 13.4 Hz, 1H), 3.84 (d, J = 13.4 Hz, 1H), 4.04 (dd, J = 8.0, 6.4 Hz, 1H), 4.26
13
(
ddt, J = 6.6, 6.4, 5.7 Hz, 1H), 7.23ꢀ7.28 (m, 1H), 7.29ꢀ7.34 (m, 4H); C NMR (100.6 MHz,
CDCl ) δ (ppm) 25.5 (CH ), 27.0 (CH ), 51.8 (CH ), 54.0 (CH ), 67.6 (CH ), 75.5 (CH),
3
3
3
2
2
2
109.2 (C), 127.1 (CH), 128.2 (CH), 128.5 (CH), 140.1 (C); IR (neat) 3327, 2986, 2934, 2881,
ꢀ1
+
1
604, 1495, 1454, 1379, 1370, 1254, 1213, 1159, 1055 cm ; MS (EI) m/z 221 (M , 2.6), 206
+
(
7.8), 163 (10), 120 (83), 91 (100%); HRMS (EI) m/z: M Calcd for C H NO 221.1416;
13
19
2
Found 221.1407.
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3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
f
N-(2,2-Dimethoxyethyl)-1-prop-2-enylamine (4u): (11.8 mmol scale, 789 mg, 46%) R =
1
0
1
5
.5 (MeOHꢀether = 1 : 1); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.68 (bs,
H), 2.75 (d, J = 5.5 Hz, 2H), 3.28 (ddd, J = 6.0, 1.6, 1.2 Hz, 2H), 3.39 (s, 6H), 4.49 (t, J =
.5 Hz, 1H), 5.11 (dddd, J = 10.3, 1.6, 1.2, 1.2 Hz, 1H), 5.19 (dddd, J = 17.2, 1.6, 1.6, 1.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
Hz, 1H), 5.89 (ddt, J = 17.2, 10.3, 6.0 Hz, 1H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 50.5
(
CH ), 52.4 (CH ), 54.2 (CH ), 104.0 (CH), 116.4 (CH ), 136.5 (CH); IR (neat) 3329, 2935,
2
2
3
2
ꢀ1
+
2
831, 1644, 1461, 1195, 1132, 1059, 996 cm ; MS (EI) m/z 145 (M , 2.4), 134 (11.9), 114
+
(
19), 75 (100%); HRMS (EI) m/z: M Calcd for C
7
H
15NO
2
145.1103; Found 145.1084.
N-(2,2-Diethoxyethyl)-1-prop-2-enylamine (4v): (10.6 mmol scale, 1.583 g, 86%) R = 0.7
f
1
(
MeOHꢀether = 1 : 1); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.22 (t, J = 7.0
Hz, 6H), 1.94 (bs, 1H), 2.75 (d, J = 5.5 Hz, 2H), 3.29 (ddd, J = 6.1, 1.6, 1.2 Hz, 2H), 3.55
dq, J = 9.4, 7.0 Hz, 2H), 3.71 (dq, J = 9.4, 7.0 Hz, 2H), 4.63 (t, J = 5.5 Hz, 1H), 5.11 (dddd,
J = 10.4, 1.4, 1.2, 1.2 Hz, 1H), 5.20 (dddd, J = 17.2, 1.6, 1.6, 1.4 Hz, 1H), 5.90 (ddt, J = 17.2,
(
1
3
10.4, 6.1 Hz, 1H); C NMR (100.6 MHz, CDCl
3 3 2
) δ (ppm) 15.5 (CH ), 51.5 (CH ), 52.3
(CH ), 62.6 (CH ), 102.2 (CH), 116.5 (CH ), 136.4 (CH); IR (neat) 3407, 2977, 2899, 1644,
2
2
2
ꢀ1
+
1456, 1374, 1125, 1062, 1007 cm ; MS (EI) m/z 173 (M , 1.3), 128 (30), 103 (100%);
+
HRMS (EI) m/z: M Calcd for C
9
H
19NO
2
173.1416; Found 173.1395.
Diisopropylamine (4n), Nꢀ(2ꢀmethoxyethyl)methylamine (4o), and Nꢀ(2,2ꢀdimethoxyethyl)ꢀ
methylamine (4t) were purchased.
4
Amines 4p,q were prepared by the reduction of the corresponding amides with LiAlH . The
amides, 2ꢀmethoxyꢀ2ꢀphenylꢀNꢀpropylacetamide and Nꢀ(cyclohexylmethyl)ꢀ2ꢀmethoxyꢀ2ꢀ
phenylacetamide for 4p,q were prepared by the reaction of DLꢀαꢀmethoxyphenylacetic acid
and propylamine or cyclohexylmethylamine with EDCI/HOBt/Et
3
N.
2-Methoxy-2-phenyl-N-propylacetamide: (10 mmol scale, 2.038 g, 98%); pale yellow oil;
1
H NMR (400 MHz, CDCl
6.6 Hz, 2H), 3.36 (s, 3H), 4.61 (s, 1H), 6.77 (bs, 1H), 7.28ꢀ7.41 (m, 5H); C NMR (100.6
MHz, CDCl ) δ (ppm) 11.4 (CH ), 22.9 (CH ), 40.7 (CH ), 57.3 (CH ), 83.9 (CH), 127.0
3
) δ (ppm) 0.916 (t, J = 7.4 Hz, 3H), 1.50ꢀ1.59 (m, 2H), 3.24 (q, J
13
=
3
3
2
2
3
(CH), 128.4 (CH), 128.6 (CH), 137.3 (C), 170.5 (C); IR (neat) 3314, 2964, 2934, 1668, 1455,
2
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ꢀ
1
+
1
255, 1198, 1102 cm ; MS (EI) m/z 207 (M , 0.1), 177 (2.4), 121 (100%); HRMS (EI) m/z:
+
M Calcd for C12
H
17NO
2
207.1259; Found 207.1248.
N-(Cyclohexylmethyl)-2-methoxy-2-phenylacetamide: (10 mmol scale, 2.618 g, 100%);
1
colorless crystals; mp 60ꢀ61 °C; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.868ꢀ0.967 (m, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
.08ꢀ1.27 (m, 3H), 1.42ꢀ1.53 (m, 1H), 1.63ꢀ1.73 (m, 5H), 3.11 (dd, J = 6.5, 6.5 Hz, 2H), 3.36
13
(s, 3H), 4.61 (broad t, 1H), 7.28ꢀ7.40 (m, 5H); C NMR (100.6 MHz, CDCl ) δ (ppm) 25.8
3
(CH
2
), 26.4 (CH
2
), 30.77 (CH
2
), 30.81 (CH
2
), 37.9 (CH), 45.1 (CH
2
), 57.2 (CH
3
), 83.9 (CH),
1
27.0 (CH), 128.3 (CH), 128.5 (CH), 137.2 (C), 170.5 (C); IR (KBr) 3328, 2917, 2849, 1654,
ꢀ1
+
+
1
539, 1449, 1197, 1098, 992 cm ; MS (FAB) m/z 284 ([M + Na] ), 262 ([M + H] ); HRMS
+
(FAB) m/z: [M + H] Calcd for C16
H
24NO
2
262.1807; Found 262.1810; Anal. Calcd for
C
16 2
H23NO : C, 73.53; H, 8.87; N, 5.36. Found: C, 73.26; H, 8.86; N, 5.38.
N-(2-methoxy-2-phenylethyl)-1-propylamine (4p): (2.56 mmol scale, 199 mg, 40%) R =
f
1
0.3 (MeOHꢀether = 1 : 4); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.909 (t, J =
7.4 Hz, 3H), 1.46ꢀ1.56 (m, 2H), 2.02 (bs, 1H), 2.56ꢀ2.60 (m, 2H), 2.69 (dd, J = 12.3, 3.7 Hz,
1H), 2.86 (dd, J = 12.3, 9.2 Hz, 1H), 3.25 (s, 3H), 4.33 (dd, J = 9.2, 3.7 Hz, 1H), 7.27ꢀ7.38
1
3
3 3 2 2
(m, 5H); C NMR (100.6 MHz, CDCl ) δ (ppm) 11.8 (CH ), 23.2 (CH ), 51.8 (CH ), 56.87
(CH
2
), 56.89 (CH
3
), 83.2 (CH), 126.8 (CH), 127.9 (CH), 128.5 (CH), 140.5 (C); IR (neat)
ꢀ1
+
3
1
327, 2933, 2822, 1674, 1493, 1454, 1356, 1103 cm ; MS (EI) m/z 193 (M , 1.1), 132 (6.0),
+
21 (12), 72 (100%); HRMS (EI) m/z: M Calcd for C12H19NO 193.1467; Found 193.1475.
N-(Cyclohexylmethyl)-2-methoxy-2-phenylethylamine (4q): (5 mmol scale, 992 mg, 80%)
1
R = 0.4 (hexaneꢀether = 1 : 4); pale yellow oil; H NMR (400 MHz, CDCl ) δ (ppm) 0.835ꢀ
f
3
0
6
1
.935 (m, 2H), 1.09ꢀ1.29 (m, 3H), 1.41ꢀ1.51 (m, 1H), 1.65ꢀ1.75 (m, 5H), 2.44 (dd, J = 11.6,
.6 Hz, 1H), 2.46 (dd, J = 11.6, 6.6 Hz, 1H), 2.66 (dd, J = 12.3, 3.7 Hz, 1H), 2.85 (dd, J =
13
2.3, 9.2 Hz, 1H), 3.25 (s, 3H), 4.34 (dd, J = 9.2, 3.7 Hz, 1H), 7.27ꢀ7.38 (m, 5H); C NMR
(
100.6 MHz, CDCl
CH ), 38.0 (CH), 56.7 (CH
28.5 (CH), 140.6 (C); IR (neat) 3338, 2922, 2850, 1680, 1450, 1109 cm ; MS (EI) m/z 247
3
) δ (ppm) 26.11 (CH
2
), 26.12 (CH
2 2 2
), 26.7 (CH ), 31.48 (CH ), 31.51
(
2
2
), 56.9 (CH ), 57.2 (CH
3
2
), 83.2 (CH), 126.7 (CH), 127.8 (CH),
ꢀ1
1
+
+
(M , 2.9), 126 (100%); HRMS (EI) m/z: M Calcd for C16H25NO 247.1936; Found 247.1931.
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Preparation of Substrates 1a-v. To
a
solution of 1,1ꢀdiethyl 2ꢀhydrogen
ethenetricarboxylate (238 mg, 1.1 mmol) (prepared from 1,1ꢀdiethyl 2ꢀtertꢀbutyl
ethenetricarboxylate upon treatment with CF CO H) in THF (1 mL) were added Nꢀbenzyl
3
2
(
(tetrahydrofuranꢀ2ꢀyl)methyl)amine 4a (192 mg, 1 mmol) in THF (0.5 mL), Et
01 mg, 1 mmol), HOBt (1ꢀhydroxybenzotriazole) (280 mg, 2.1 mmol) and EDCI (1ꢀ[3ꢀ
dimethylamino)propyl]ꢀ3ꢀethylcarbodiimide hydrochloride) (210 mg, 1.1 mmol) at 0 °C.
3
N (0.14 mL,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
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0
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2
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7
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0
1
(
The reaction mixture was stirred for 1 h at 0 °C, and was allowed to warm to room
temperature and stirred overnight. The reaction mixture was concentrated under reduced
pressure and the residue was diluted with CH Cl . The organic phase was washed with
2
2
saturated aqueous NaHCO
3 3
solution, 2M aqueous citric acid, saturated aqueous NaHCO and
water, dried (Na SO ), and evaporated in vacuo. The residue was purified by column
2
4
chromatography over silica gel eluting with hexaneꢀether to give 1a (300 mg, 72%).
1
1a: R
f
= 0.6 (ether); pale yellow oil; H NMR (400 MHz, CDCl
3
) (2 rotamers, ratio 1.2:1) δ
(ppm) 1.26ꢀ1.36 (m, 6H), 1.40ꢀ1.53 (m, 1H), 1.80ꢀ2.03 (m, 3H), 3.07 (dd, J = 14.0, 8.1 Hz,
1H×0.55, major rotamer), 3.24 (dd, J = 15.4, 3.3 Hz, 1H×0.45, minor rotamer), 3.33 (dd, J =
15.4, 8.3 Hz, 1H×0.45), 3.72ꢀ3.87 (m, 2H+1H×0.45), 4.04 (ddd, J = 8.3, 7.0, 3.2 Hz,
1
H×0.45), 4.15 (ddd, J = 8.1, 7.4, 3.1 Hz, 1H×0.55), 4.22ꢀ4.38 (m, 4H), 4.62 (d, J = 15.0 Hz,
H×0.45), 4.75 (d, J = 16.6 Hz, 1H×0.55), 4.79 (d, J = 16.6 Hz, 1H×0.55), 4.89 (d, J = 15.0
1
1
3
Hz, 1H×0.45), 7.20ꢀ7.38 (m, 5H), 7.35 (s, 1H×0.55), 7.53 (s, 1H×0.45); C NMR (100.6
MHz, CDCl
3
) δ (ppm) 13.96 (CH
3
), 14.00 (CH
3
), 14.1 (CH
3
), 25.5 (CH
2
), 25.7 (CH
2
), 29.29
(
CH ), 29.30 (CH ), 48.7 (CH ), 48.9 (CH ), 51.4 (CH ), 52.7 (CH ), 61.8 (CH ), 61.9 (CH ),
2
2
2
2
2
2
2
2
2 2 2 2
62.07 (CH ), 62.13 (CH ), 67.97 (CH ), 68.04 (CH ), 77.0 (CH), 78.0 (CH), 127.0 (CH),
127.5 (CH), 127.9 (CH), 128.2 (CH), 128.6 (CH), 129.0 (CH), 134.0 (C), 134.4 (CH), 135.2
(
(
(
C), 135.6 (CH), 136.3 (C), 136.7 (C), 163.0 (C), 163.2 (C), 164.58 (C), 164.64 (C), 164.9
ꢀ1
C); IR (neat) 2980, 1728, 1652, 1465, 1445, 1374, 1256, 1209, 1069 cm ; MS (EI) m/z 389
+
+
M , 1.0), 343 (39), 200 (70), 190 (97), 91 (100%); HRMS (EI) m/z: M Calcd for
C H NO 389.1838; Found 389.1843.
21
27
6
1
1b: (3 mmol scale, 690 mg, 58%) R
f
= 0.6 (ether); pale yellow oil; H NMR (400 MHz,
CDCl
3
) (2 rotamers, ratio 1.3:1) δ (ppm) 0.823ꢀ0.989 (m, 2H), 1.19ꢀ1.28 (m, 3H), 1.311 (t, J
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=
7.1 Hz, 3H×0.43, minor rotamer), 1.312 (t, J = 7.1 Hz, 3H×0.43), 1.317 (t, J = 7.1 Hz,
3
6
1
3
7
H×0.57, major rotamer), 1.319 (t, J = 7.1 Hz, 3H×0.57), 1.43ꢀ1.55 (m, 1H), 1.59ꢀ1.76 (m,
H), 1.80ꢀ2.05 (m, 3H), 3.10 (dd, J = 13.8, 7.7 Hz, 1H×0.57), 3.21 (dd, J = 13.4, 7.1 Hz,
H×0.43), 3.29ꢀ3.34 (m, 2H×0.57+1H×0.43), 3.39ꢀ3.45 (m, 2H×0.43), 3.69ꢀ3.79 (m, 1H),
.82ꢀ3.88 (m, 1H+1H×0.57), 4.03 (dddd, J = 7.3, 7.3, 7.3, 3.3 Hz, 1H×0.43), 4.09 (dddd, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
.3, 7.3, 7.3, 3.3 Hz, 1H×0.57), 4.26ꢀ4.36 (m, 4H), 7.36 (s, 1H×0.57), 7.47 (s, 1H×0.43); C
NMR (100.6 MHz, CDCl
3
) δ (ppm) 13.9 (CH
3
), 14.01 (CH
3
), 14.03 (CH
3
), 25.4 (CH
2
), 25.7
(CH
2
), 25.8 (CH
2
), 25.85 (CH ), 25.89 (CH
2
2
), 26.3 (CH
2
), 26.4 (CH ), 29.3 (CH
2
2
), 29.4
(CH ), 30.68 (CH ), 30.74 (CH ), 30.8 (CH ), 30.9 (CH ), 36.1 (CH), 37.5 (CH), 50.0 (CH ),
2
2
2
2
2
2
52.4 (CH
2
), 53.1 (CH
2
), 55.7 (CH
2
), 61.7 (CH
2
), 62.0 (CH
2
), 62.1 (CH
2
), 67.9 (CH
2
), 68.0
(CH
2
), 77.2 (CH), 77.7 (CH), 133.3 (C), 134.1 (CH), 134.7 (C), 135.9 (CH), 163.2 (C), 163.3
(C), 164.2 (C), 164.7 (C), 164.77 (C), 164.79 (C); IR (neat) 2926, 2853, 1735, 1653, 1629,
ꢀ1
+
1449, 1373, 1257, 1207, 1071, 1029 cm ; MS (EI) m/z 395 (M , 2.7), 350 (56), 349 (88),
+
200 (94), 199 (76), 143 (66), 126 (71), 84 (100%); HRMS (EI) m/z: M Calcd for C21
H33NO
6
395.2308; Found 395.2309.
1
1c: (2 mmol scale, 456 mg, 64%) R
f
= 0.4 (ether); colorless oil; H NMR (400 MHz, CDCl
3
)
(2 rotamers, ratio 1.5:1) δ (ppm) 0.919 (t, J = 7.2 Hz, 3H×0.4, minor rotamer), 0.937 (t, J =
7
3
4
4
.2 Hz, 3H×0.6, major rotamer), 1.26ꢀ1.36 (m, 8H), 1.43ꢀ1.62 (m, 3H), 1.81ꢀ2.05 (m, 3H),
.12 (dd, J = 13.9, 7.6 Hz, 1H×0.6), 3.29ꢀ3.55 (m, 2H+2H×0.4), 3.69ꢀ3.89 (m, 2H+1H×0.6),
.04 (dddd, J = 7.2, 7.2, 7.2, 3.5 Hz, 1H×0.4), 4.08 (dddd, J = 7.3, 7.3, 7.3, 3.4 Hz, 1H×0.6),
1
3
.26ꢀ4.36 (m, 4H), 7.35 (s, 1H×0.6), 7.44 (s, 1H×0.4); C NMR (100.6 MHz, CDCl ) δ
3
(
(
(
(
ppm) 13.8 (CH
3
), 13.9 (CH
3
), 13.99 (CH
3
), 14.01 (CH ), 19.9 (CH
3
), 14.1 (CH
3
2
2
), 20.2
), 46.4
CH ), 25.5 (CH
2
2
), 25.8 (CH
2
), 29.3 (CH ), 29.35 (CH
2
2
), 29.42 (CH ), 31.2 (CH
2
CH ), 49.2 (CH ), 49.4 (CH ), 52.5 (CH ), 61.77 (CH ), 61.79 (CH ), 62.0 (CH ), 62.2
2
2
2
2
2
2
2
CH
2
2 2
), 68.0 (CH ), 68.1 (CH ), 77.3 (CH), 78.0 (CH), 133.4 (C), 134.1 (CH), 134.9 (C),
136.0 (CH), 163.2 (C), 163.3 (C), 164.0 (C), 164.4 (C), 164.7 (C); IR (neat) 2964, 1732,
ꢀ1
+
1652, 1455, 1373, 1343, 1255, 1067, 1029 cm ; MS (EI) m/z 355 (M , 0.4), 354 (0.5), 326
+
(1.9), 310 (43), 309 (42), 200 (100%); HRMS (EI) m/z: M Calcd for C18
H
29NO
6
355.1995;
Found 355.1990.
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1
d: (2 mmol scale, 456 mg, 57%) R
f
= 0.5 (ether); pale yellow oil; H NMR (400 MHz,
CDCl ) (2 rotamers, ratio 1:1) δ (ppm) 1.14ꢀ1.24 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H×0.5), 1.30
3
(
t, J = 7.1 Hz, 3H×0.5), 1.32 (t, J = 7.1 Hz, 3H×0.5), 1.35 (t, J = 7.1 Hz, 3H×0.5), 1.39ꢀ1.61
m, 4H), 1.78ꢀ1.85 (m, 1H), 3.04 (dd, J = 13.9, 8.3 Hz, 1H×0.5), 3.08ꢀ3.15 (m, 1H×0.5),
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
.25ꢀ3.42 (m, 1H+1H×0.5+1H×0.5), 3.63 (dddd, J = 10.9, 8.3, 2.7, 2.5 Hz, 1H×0.5), 3.70
(
dd, J = 13.9, 2.7 Hz, 1H×0.5), 3.92ꢀ3.98 (m, 1H), 4.22ꢀ4.41 (m, 4H), 4.63 (d, J = 15.0 Hz,
1
1
1
2
5
H×0.5), 4.70 (d, J = 16.7 Hz, 1H×0.5), 4.79 (d, J = 16.7 Hz, 1H×0.5), 4.82 (d, J = 15.0 Hz,
H×0.5), 7.19ꢀ7.21 (m, 2H×0.5), 7.24ꢀ7.37 (m, 3H+2H×0.5), 7.33 (s, 1H×0.5), 7.57 (s,
13
H×0.5); C NMR (100.6 MHz, CDCl ) δ (ppm) 13.98 (CH ), 14.02 (CH ), 14.1 (CH ),
3
3
3
3
3.06 (CH
2
), 23.10 (CH
2
), 25.7 (CH
2
), 25.9 (CH
2
), 29.39 (CH
2
), 29.42 (CH
2
), 49.1 (CH
2
),
0.7 (CH ), 52.5 (CH
2
2
), 53.4 (CH
2
), 61.8 (CH
2
), 61.9 (CH
2
), 62.1 (CH
2
2
), 62.2 (CH ), 68.3
(
CH ), 68.4 (CH ), 75.7 (CH), 76.9 (CH), 126.9 (CH), 127.5 (CH), 127.8 (CH), 128.2 (CH),
2 2
128.6 (CH), 128.9 (CH), 134.1 (CH), 134.2 (C), 135.4 (C), 135.8 (CH), 136.5 (C), 136.9 (C),
163.0 (C), 163.3 (C), 164.5 (C), 164.7 (C), 164.8 (C), 165.1 (C); IR (neat) 2938, 2850, 1731,
ꢀ1
1651, 1496, 1465, 1444, 1373, 1347, 1254, 1205, 1133, 1093, 1071, 1048, 1027 cm ; MS
+
(EI) m/z 403 (M , 0.65), 395 (3.8), 358 (14), 204 (67), 200 (59), 120 (88), 84 (100%); HRMS
+
(EI) m/z: M Calcd for C22
H29NO
6
403.1995; Found 403.1976.
1
1
e: (2.4 mmol scale, 650 mg, 67%) R = 0.3 (hexaneꢀether = 1 : 1); pale yellow oil; H NMR
f
(400 MHz, CDCl
3
) (2 rotamers, ratio 1.5:1) δ (ppm) 0.805ꢀ0.976 (m, 2H), 1.09ꢀ1.28 (m, 4H),
1
.31 (t, J = 7.1 Hz, 6H×0.4, minor rotamer), 1.32 (t, J = 7.1 Hz, 3H×0.6, major rotamer), 1.33
(
t, J = 7.1 Hz, 3H×0.6), 1.42ꢀ1.87 (m, 12H), 3.01 (dd, J = 13.8, 8.2 Hz, 1H×0.6), 3.17ꢀ3.23
m, 2H×0.4), 3.29 (d, J = 7.2 Hz, 2H×0.6), 3.32ꢀ3.44 (m, 1H+3H×0.4), 3.59 (dddd, J = 10.9,
(
8
.2, 2.5, 2.5 Hz, 1H×0.6), 3.72 (dd, J = 13.8, 2.8 Hz, 1H×0.6), 3.89ꢀ3.97 (m, 1H), 4.25ꢀ4.37
13
(
m, 4H), 7.36 (s, 1H×0.6), 7.49 (s, 1H×0.4); C NMR (100.6 MHz, CDCl ) δ (ppm) 14.01
3
(CH
3
2
), 14.03 (CH
3
), 14.1 (CH
3
), 23.1 (CH
2
), 23.2 (CH
2
), 25.8 (CH
2
), 25.87 (CH ), 25.91
2
(CH
), 25.94 (CH
2
), 26.3 (CH
2
), 26.5 (CH
2
), 29.5 (CH
2
), 30.7 (CH
2
), 30.8 (CH ), 30.85
2
(
CH ), 30.87 (CH ), 36.1 (CH), 37.6 (CH), 51.9 (CH ), 52.7 (CH ), 54.1 (CH ), 56.5 (CH ),
2
2
2
2
2
2
61.7 (CH
2
), 62.0 (CH
2
), 62.2 (CH
2
), 68.3 (CH
2
2
), 68.5 (CH ), 76.2 (CH), 76.7 (CH), 133.6
(C), 134.1 (CH), 134.8 (C), 136.0 (CH), 163.3 (C), 163.4 (C), 164.1 (C), 164.8 (C), 164.9
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(
C); IR (neat) 2930, 2852, 1733, 1652, 1447, 1372, 1345, 1252, 1206, 1145, 1093, 1069,
ꢀ1
+
1
047, 1028 cm ; MS (EI) m/z 409 (M , 0.06), 363 (1.3), 309 (0.8), 308 (0.5), 224 (47), 83
+
(100%); HRMS (EI) m/z: M Calcd for C H NO 409.2464; Found 409.2454.
2
2
35
6
1
1
f: (2 mmol scale, 638 mg, 68%) R
f
= 0.3 (hexaneꢀether = 1 : 1); pale yellow oil; H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
400 MHz, CDCl
3
) (2 rotamers, ratio 1.2:1) δ (ppm) 1.28 (t, J = 7.2 Hz, 3H×0.45, minor
rotamer), 1.30 (t, J = 7.1 Hz, 3H×0.55, major rotamer), 1.31 (t, J = 7.0 Hz, 3H×0.55), 1.34 (t,
J = 7.1 Hz, 3H×0.45), 1.27ꢀ1.76 (m, 13H), 1.88ꢀ2.04 (m, 1H), 3.02 (dd, J = 13.8, 7.7 Hz,
1
H×0.45), 3.28 (dd, J = 15.2, 3.1 Hz, 1H×0.55), 3.35 (dd, J = 15.2, 8.1 Hz, 1H×0.55), 3.88
(dd, J = 13.8, 3.0 Hz, 1H×0.45), 4.06 (dddd, J = 8.4, 8.1, 6.3, 3.1 Hz, 1H×0.55), 4.18ꢀ4.38
(m, 4H+1H×0.45), 4.69 (d, J = 15.0 Hz, 1H×0.55), 4.82 (s, 2H×0.45), 4.85 (d, J = 15.0 Hz,
1
3
1
3
H×0.55), 7.21ꢀ7.38 (m, 5H+1H×0.45), 7.66 (s, 1H×0.55); C NMR (100.6 MHz, CDCl ) δ
(ppm) 13.96 (CH ), 13.99 (CH ), 14.1 (CH ), 23.5 (CH ), 23.7 (CH ), 23.9 (CH ), 24.0
3
3
3
2
2
2
(CH
2
), 25.6 (CH
2
), 25.7 (CH
2
), 29.3 (CH
2
), 35.9 (CH
2
), 36.2 (CH
2
), 37.1 (CH
2
2
), 37.4 (CH ),
38.5 (CH
2 2 2 2 2 2 2
), 38.7 (CH ), 48.9 (CH ), 50.0 (CH ), 52.5 (CH ), 52.7 (CH ), 61.78 (CH ), 61.83
(CH ), 62.0 (CH ), 62.1 (CH ), 75.8 (CH), 77.1 (CH), 83.4 (C), 83.6 (C), 127.0 (CH), 127.4
2
2
2
(CH), 127.8 (CH), 128.1 (CH), 128.6 (CH), 128.9 (CH), 134.0 (C), 134.4 (CH), 135.2 (C),
1
35.9 (CH), 136.5 (C), 136.9 (C), 163.0 (C), 163.2 (C), 164.5 (C), 164.6 (C), 164.8 (C),
ꢀ1
1
65.0 (C); IR (neat) 2931, 2857, 1730, 1496, 1447, 1374, 1257, 1209, 1063, 1027 cm ; MS
+
(EI) m/z 457 (M , 2.0), 412 (24), 411 (20), 258 (34), 200 (62), 139 (81), 120 (99), 91
+
(100%); HRMS (EI) m/z: M Calcd for C26
H35NO
6
457.2464; Found 457.2457.
1
1
g: (2 mmol scale, 861 mg, 63%) R = 0.6 (hexaneꢀether = 1 : 3); pale yellow oil; H NMR
f
(400 MHz, CDCl
3
) (2 rotamers, ratio 1.1:1) δ (ppm) 1.18ꢀ1.43 (m, 11H), 1.28 (t, J = 7.1 Hz,
3
3
1
1
H×0.52, major rotamer), 1.29 (t, J = 7.1 Hz, 3H×0.48, minor rotamer), 1.32 (t, J = 7.2 Hz,
H×0.48), 1.34 (t, J = 7.1 Hz, 3H×0.52), 1.81 (dd, J = 12.5, 6.8 Hz, 1H×0.48), 1.89 (dd, J =
2.7, 6.6 Hz, 1H×0.52), 3.04 (dd, J = 13.9, 8.2 Hz, 1H×0.52), 3.22 (dd, J = 15.6, 2.9 Hz,
H×0.48), 3.36 (dd, J = 15.6, 8.5 Hz, 1H×0.48), 3.51ꢀ3.58 (m, 2H), 3.84 (dd, J = 13.9, 2.6
Hz, 1H×0.52), 4.12 (dddd, J = 8.7, 8.5, 6.8, 2.9 Hz, 1H×0.48), 4.20ꢀ4.38 (m, 4H+1H×0.48),
.59 (d, J = 14.8 Hz, 1H×0.48), 4.76 (d, J = 16.6 Hz, 1H×0.52), 4.79 (d, J = 16.6 Hz,
1H×0.52), 4.91 (d, J = 14.8 Hz, 1H×0.48), 7.20ꢀ7.38 (m, 5H), 7.34 (s, 1H×0.52), 7.55 (s,
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
2
3
5
H×0.48); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 13.97 (CH
3
), 14.00 (CH
3
), 14.1 (CH
3
2
),
),
3.5 (CH ), 24.0 (CH ), 24.1 (CH ), 25.95 (CH
2
2
2
2
), 26.00 (CH ), 35.25 (CH
2
2
), 35.33 (CH
6.5 (CH ), 36.6 (CH ), 41.9 (CH ), 43.6 (C), 43.9 (C), 48.7 (CH ), 49.4 (CH ), 51.7 (CH ),
2
2
2
2
2
2
2.8 (CH
2
), 61.8 (CH
2
), 61.9 (CH
2 2 2
), 62.05 (CH ), 62.13 (CH ), 76.7 (CH), 77.8 (CH), 78.1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(CH
2
), 78.4 (CH
2
), 127.0 (CH), 127.5 (CH), 127.8 (CH), 128.3 (CH), 128.6 (CH), 128.9
(
CH), 134.0 (C), 134.3 (CH), 135.3 (C), 135.7 (CH), 136.3 (C), 136.8 (C), 163.0 (C), 163.2
(
C), 164.57 (C), 164.64 (C), 164.9 (C); IR (neat) 2926, 2853, 1732, 1652, 1496, 1455, 1373,
ꢀ1
+
+
1
258, 1069, 1027 cm ; MS (CI) m/z 458 ([M + H] ); HRMS (CI) m/z: [M + H] Calcd for
C H NO 458.2543; Found 458.2545.
26
36
6
1
1
h: (2 mmol scale, 517 mg, 63%) R
400 MHz, CDCl ) (2 rotamers, ratio 1.1:1) δ (ppm) 1.06 (s), 1.080 (s), 1.084 (s), (6H), 1.25ꢀ
.36 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H×0.52, major rotamer), 1.30 (t, J = 7.1 Hz, 3H×0.48,
f
= 0.6 (hexaneꢀether = 1 : 7); pale yellow oil; H NMR
(
3
1
minor rotamer), 1.32 (t, J = 7.1 Hz, 3H×0.48), 1.34 (t, J = 7.1 Hz, 3H×0.52), 1.74 (dd, J =
12.3, 7.0 Hz, 1H×0.48), 1.80 (dd, J = 12.4, 6.7 Hz, 1H×0.52), 3.06 (dd, J = 13.9, 8.2 Hz,
1H×0.52), 3.22 (dd, J = 15.4, 2.7 Hz, 1H×0.48), 3.38 (dd, J = 15.4, 8.3 Hz, 1H×0.48), 3.43ꢀ
3.51 (m, 2H), 3.83 (dd, J = 13.9, 2.7 Hz, 1H×0.52), 4.17ꢀ4.37 (m, 5H), 4.58 (d, J = 14.9 Hz,
1
H×0.48), 4.77 (d, J = 16.6 Hz, 1H×0.52), 4.80 (d, J = 16.6 Hz, 1H×0.52), 4.93 (d, J = 14.9
1
3
Hz, 1H×0.48), 7.21ꢀ7.38 (m, 5H), 7.35 (s, 1H×0.52), 7.56 (s, 1H×0.48); C NMR (100.6
MHz, CDCl ) δ (ppm) 13.95 (CH ), 13.99 (CH ), 14.1 (CH ), 26.2 (CH ), 26.4 (CH ), 39.4
3
3
3
3
3
3
(
C), 39.8 (C), 44.1 (CH
2 2 2 2 2 2
), 44.4 (CH ), 48.6 (CH ), 49.4 (CH ), 51.7 (CH ), 52.8 (CH ), 61.81
(
CH ), 61.84 (CH ), 62.0 (CH ), 62.1 (CH ), 77.2 (CH), 78.3 (CH), 79.7 (CH), 79.9 (CH),
2
2
2
2
1
27.0 (CH), 127.5 (CH), 127.8 (CH), 128.2 (CH), 128.6 (CH), 128.9 (CH), 134.0 (C), 134.3
(
CH), 135.2 (C), 135.7 (CH), 136.3 (C), 136.7 (C), 162.9 (C), 163.2 (C), 164.5 (C), 164.58
(
C), 164.62 (C), 164.9 (C); IR (neat) 2961, 2871, 1732, 1649, 1496, 1466, 1372, 1254, 1070,
ꢀ1
+
+
1
4
1
027 cm ; MS (CI) m/z 418 ([M + H] ); HRMS (CI) m/z: [M + H] Calcd for C23H32NO
6
18.2230; Found 418.2234.
1
i: (2 mmol scale, 686 mg, 78%) R = 0.3 (hexaneꢀether = 1 : 1); pale yellow oil; H NMR
f
(
400 MHz, CDCl
3
) (2 rotamers, ratio 1.1:1) δ (ppm) 0.853 (s, 3H×0.52, major rotamer),
0.868 (s, 3H×0.48, minor rotamer), 1.03 (s, 3H×0.52), 1.11 (s, 3H×0.48), 1.28 (t, J = 7.1 Hz,
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H×0.48), 1.305 (t, J = 7.1 Hz, 3H×0.52), 1.308 (t, J = 7.1 Hz, 3H×0.52), 1.34 (t, J = 7.1 Hz,
H×0.48), 1.64ꢀ1.81 (m, 2H), 2.77 (dd, J = 13.8, 9.6 Hz, 1H×0.48), 3.19 (dd, J = 15.4, 2.3
3
Hz, 1H×0.52), 3.24 (dd, J = 15.4, 9.0 Hz, 1H×0.52), 3.52 (dd, J = 9.0, 2.3 Hz, 1H×0.52),
3
4
1
7
.64 (dd, J = 9.6, 1.6 Hz, 1H×0.48), 3.76ꢀ3.95 (m, 2H), 4.00 (d, J = 13.8 Hz, 1H×0.48), 4.24ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
.39 (m, 4H), 4.69 (d, J = 14.8 Hz, 1H×0.52), 4.72 (d, J = 16.6 Hz, 1H×0.48), 4.76 (d, J =
6.6 Hz, 1H×0.48), 4.79 (d, J = 14.8 Hz, 1H×0.52), 7.21ꢀ7.38 (m, 5H), 7.34 (s, 1H×0.48),
13
.56 (s, 1H×0.52); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 13.96 (CH
3 3
), 13.97 (CH ), 14.02
(CH
3
), 14.1 (CH
3
), 21.2 (CH
3
), 21.4 (CH
3
), 25.0 (CH ), 25.4 (CH ), 40.4 (C), 40.8 (C), 41.95
3
3
(CH ), 41.04 (CH ), 46.0 (CH ), 47.9 (CH ), 48.5 (CH ), 52.5 (CH ), 61.9 (CH ), 62.0 (CH ),
2
2
2
2
2
2
2
2
62.1 (CH
2
), 65.8 (CH
2
2
), 65.9 (CH ), 85.1 (CH), 85.5 (CH), 127.0 (CH), 127.5 (CH), 127.8
(CH), 128.4 (CH), 128.6 (CH), 128.9 (CH), 134.0 (C), 134.6 (CH), 135.0 (C), 135.7 (CH),
1
36.5 (C), 136.8 (C), 163.0 (C), 163.1 (C), 164.4 (C), 164.6 (C), 164.7 (C); IR (neat) 2961,
ꢀ1
2874, 1728, 1652, 1496, 1466, 1453, 1371, 1255, 1208, 1069, 1025 cm ; MS (EI) m/z 417
+
+
(M , 0.8), 371 (43), 218 (75), 99 (100%); HRMS (EI) m/z: M Calcd for C23H31NO
6
417.2151; Found 417.2137.
1
1j: (3.11 mmol scale, 1.035 g, 80%) R
400 MHz, CDCl
f
= 0.4 (hexaneꢀether = 1 : 4); pale yellow oil; H NMR
(
3
) (2 rotamers, ratio 1.8:1) δ (ppm) 1.28 (t, J = 7.0 Hz, 3H×0.36, minor
rotamer), 1.29 (t, J = 7.1 Hz, 3H×0.64, major rotamer), 1.32 (t, J = 7.0 Hz, 3H×0.64), 1.34 (t,
J = 7.1 Hz, 3H×0.36), 3.45 (d, J = 3.1 Hz, 2H×0.64), 3.54 (d, J = 4.5 Hz, 2H×0.36), 3.84ꢀ
4
1
1
4
.00 (m, 4H), 4.23ꢀ4.38 (m, 4H), 4.73 (s, 2H×0.36), 4.79 (s, 2H×0.64), 4.99 (t, J = 3.1 Hz,
H×0.64), 5.10 (t, J = 4.5 Hz, 1H×0.36), 7.20ꢀ7.38 (m, 5H), 7.33 (s, 1H×0.36), 7.55 (s,
13
H×0.64); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 13.99 (CH
3
), 14.04 (CH
3
), 14.1 (CH
3
),
7.5 (CH
2
), 48.6 (CH
2
), 49.7 (CH
2
), 52.7 (CH ), 61.9 (CH ), 62.0 (CH
2
2
2
), 62.1 (CH
2
), 62.2
(CH ), 64.9 (CH ), 65.3 (CH ), 101.9 (CH), 102.3 (CH), 127.1 (CH), 127.6 (CH), 128.0
2 2 2
(CH), 128.5 (CH), 128.7 (CH), 129.0 (CH), 134.3 (CH), 134.5 (C), 135.3 (CH), 136.0 (C),
1
2
3
36.7 (C), 162.9 (C), 163.2 (C), 164.5 (C), 164.8 (C), 165.0 (C), 165.4 (C); IR (neat) 2983,
ꢀ1
895, 1728, 1652, 1496, 1465, 1444, 1374, 1256, 1203, 1134, 1068, 1022 cm ; MS (EI) m/z
+
+
91 (M , 2.1), 346 (9.9), 192 (35), 91 (58), 73 (100%); HRMS (EI) m/z: M Calcd for
20 7
C H25NO
391.1631; Found 391.1631.
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