Inverse-electron-demand diels-alder reactions of N-(heteroarylsulfonyl)-1- aza-1,3-dienes catalyzed by chiral lewis acids

Article abstract of DOI:10.1055/s-0028-1083276

The feasibility of using chiral Lewis acids as catalysts to promote the inverse-electron-demand Diels-Alder reactions of 1-azadienes with vinyl ethers has been demonstrated. Two catalyst systems were identified for this reaction, both relying on the prese

Full text of DOI:10.1055/s-0028-1083276

PAPER
113
Inverse-Electron-Demand Diels–Alder Reactions of N-(Heteroarylsulfonyl)-1-
aza-1,3-dienes Catalyzed by Chiral Lewis Acids
I
nverse-El
o
ectron-Dem
a
r
ndDiels
g
–Alde
r
R
eac
e
tions Esquivias, Inés Alonso, Ramón Gómez Arrayás,* Juan Carlos Carretero*
Departamento de Química Orgánica, Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049 Madrid, Spain
Fax +34(91)4973966; E-mail: ramon.gomez@uam.es; E-mail: juancarlos.carretero@uam.es
Received 4 November 2008
OMe
R2
H
R2
R1
Abstract: The feasibility of using chiral Lewis acids as catalysts to
promote the inverse-electron-demand Diels–Alder reactions of 1-
azadienes with vinyl ethers has been demonstrated. Two catalyst
systems were identified for this reaction, both relying on the pres-
ence of a coordinating 2-pyridylsulfonyl or 8-quinolylsulfonyl
group at the imine nitrogen of the 1-azadiene. The combination of a
8-quinolylsulfonyl moiety and nickel(II)/DBFOX-Ph proved to be
highly efficient, allowing the synthesis of substituted piperidine de-
rivatives in good yields, excellent endo selectivity, and enantio-
selectivities typically in the range of 77 to 92% ee.
N
N
(A)
(B)
+
+
+
R1
O
TMSO
N
iminodienophile
R2
R2
N
2-azadiene
Key words: Diels–Alder reactions, N-sulfonyl-1-azadienes, vinyl
ethers, chiral Lewis acids, imines, asymmetric catalysis
R1
N
R2
N
R1
R2
(C)
1-azadiene
The catalytic asymmetric aza-Diels–Alder reaction
(ADAR) of imines, in which the imine component acts
either as azadienophile (strategy A, Scheme 1) or as aza-
diene (strategies B and C), is a convergent strategy for the
preparation of highly valuable optically active piperidine
derivatives.1 Remarkable progress has been achieved in
the ADAR of electron-rich dienes with imines, resulting
in the development of some very efficient chiral Lewis
acid catalyst systems2 based on zirconium,3 silver,4 cop-
per,5 zinc,6 scandium,7 and niobium,8 as well as organo-
catalytic versions.9 In sharp contrast, very few precedents
have been disclosed on the participation of azadienes in
catalytic asymmetric ADAR. Ghosez and co-worker10
first described the copper(II) triflate/BOX-catalyzed
ADAR of electron-rich 2-azadienes with N-alkenoyl-
oxazolidinones. The inverse-electron-demand ADAR of
benzylideneaniline as 2-azadiene with vinyl ethers in the
presence of chiral titanium11 and aluminum12 catalysts has
also been reported. The use of 1-azadienes is also a very
appealing strategy in the ADAR (strategy C, Scheme 1),13
even though it is well known that 1-azadienes are much
less reactive than 2-azadienes. In this field, Boger et al.
have found that N-phenylsulfonyl a,b-unsaturated imines
participate as dienes in inverse-electron-demand ADAR
with vinyl ethers under harsh thermal conditions (high
pressure or high temperature), albeit with high endo selec-
tivity.14 The smoother reaction conditions required when
the 1,3-azabutadiene system is activated with an electron-
withdrawing ester group at C-4 paved the way for the de-
velopment of the first asymmetric variant of this reaction,
Scheme 1 Intermolecular aza-Diels–Alder approaches to piperidine
derivatives
in which vinyl ethers bearing chiral auxiliaries are
used.15,16
In 2006, Bode and co-workers17 reported the first catalytic
asymmetric inverse-electron-demand ADAR between 1-
azadienes (N-sulfonyl a,b-unsaturated imines) and b-acti-
vated enals using chiral N-heterocyclic carbenes. The nu-
cleophilic catalyst reacts with the enal leading to a chiral
enolate that acts as reactive dienophile. More recently, the
group of Chen has reported an inverse-electron-demand
ADAR of N-tosyl-1-azadienes and enolizable aldehydes
catalyzed by a chiral secondary amine.18 In this case, the
chiral enamine generated in situ reacts as dienophile lead-
ing to an aminal that is subsequently hydrolyzed by the
water present in the reaction medium, thus enabling re-
lease of the catalyst and catalytic turnover.
With these precedents, the development of a chiral Lewis
acid catalyst capable of promoting the ADAR of 1-aza-
dienes with electron-rich olefins would significantly ex-
pand the scope of this process, providing a valuable
alternative route to optically active functionalized piperi-
dine derivatives. This task, however, represents a big
challenge, as it has to provide solutions to the low reactiv-
ity associated with 1-azadienes and the high propensity of
both azadiene and electron-rich dienophile to decompose
in the presence of Lewis acids. In fact, to the best of our
knowledge, no chiral Lewis acid has been reported to pro-
mote ADAR of 1-azadienes.19
SYNTHESIS 2009, No. 1, pp 0113–0126
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083276; Art ID: C05908SS
0
2
.
0
2
.2
0
0
9
The use of N-sulfonylimines bearing potentially coordi-
nating heteroaryl groups at sulfur has been demonstrated
© Georg Thieme Verlag Stuttgart · New York

114
J. Esquivias et al.
PAPER
Table 1 Substrate and Catalyst Optimizationa
sources catalyzed the reaction with similar good endo
selectivity (endo/exo = 80:20 to 87:13). Silver(I) triflate,
titanium(IV) isopropoxide, and zinc(II) triflate were less
effective than copper(II) triflate, all providing endo-6 in
yields £50% (Table 1, entries 5–7). However, nickel(II)
perchlorate hexahydrate was superior to copper(II) tri-
flate, providing endo-6 in good yield (80%) after 36 hours
(Table 1, entry 9). The higher reactivity of this Lewis acid
allowed for a reduction in the amount of dipolarophile 5
used, from 20 to 5 equivalents (Table 1, entry 10).
O
O
R
R
O
S
N
O
S
N
Ph
Ph
OEt
OEt
metal salt
exo-6
+
Ph
Ph
5
1–4
endo-6 (R = 2-pyridyl)
Entry R (imine)
Metal salt
Cu(OTf)2
Time Ratio
Yieldc,d
(h) endo/exob (%)
The asymmetric variant of this procedure was next inves-
tigated by use of copper(II) triflate or nickel(II) perchlor-
ate hexahydrate with a variety of P,P- and N,N-
coordinating chiral ligands (Table 2). The copper(II)-cat-
alyzed ADAR of imine 4 with 5 required 20 equivalents
of dienophile, while 5 equivalents of 5 were sufficient
when using the more reactive nickel(II) catalyst. The fol-
lowing conclusions are drawn from this study:
1
2
4-Tol (1)
120
120
120
72
–
n.r.
n.r.
n.r.
67
2-thienyl (2) Cu(OTf)2
–
3
NMe2 (3)
2-Py (4)
2-Py (4)
2-Py (4)
2-Py (4)
2-Py (4)
2-Py (4)
2-Py (4)
Cu(OTf)2
Cu(OTf)2
AgOTf
–
4
85:15
87:13
83:17
80:20
–
5
72
32
– While the reactivity of the copper(II)-catalyzed reaction
is not greatly influenced by the chiral ligand, the reaction
yields generally improved when nickel(II)–ligand cata-
lysts were used.
6
Ti(Oi-Pr)4
Zn(OTf)2
72
41
7
72
50
8
Mg(ClO4)2·6H2O 120
Ni(ClO4)2·6H2O 36
Ni(ClO4)2·6H2O 48
n.r.
80
– In both copper(II)- and nickel(II)-catalyzed reactions,
the presence of the chiral ligand resulted in excellent endo
selectivity (endo/exo typically 98:2).
9
80:20
84:16
10e
73
– The enantiocontrol is low with most of the ligands ex-
amined, with only the combinations copper(II) triflate/
BOX-V (65% ee, Table 2, entry 5) and nickel(II) perchlo-
rate hexahydrate/BOX-IV (54% ee, entry 4) providing
enantioselectivities higher than 50% ee. BOX ligands
gave the best results, although the amount of asymmetric
induction was strongly influenced by the nature of the
substitution at the bis-oxazoline core (entries 3–6).
a Reagents and conditions: imine (1 equiv), 5 (20 equiv), metal salt (10
mol%), CH2Cl2, r.t.
b Determined by 1H NMR from the crude reaction mixture.
c Yield of endo-product after chromatography.
d n.r. = no reaction.
e Ether 5 (5 equiv) was used.
by others20 and us21 to result in unique levels of reactivity
and/or selectivity not feasible with the traditional N-phe-
nylsulfonyl or N-tosyl groups. Herein we describe the suc-
cessful application of this strategy to bring about ADAR
of 1-azadienes with alkenyl ethers catalyzed by chiral
Lewis acids.22
We next examined the scope of the ADAR with regard to
both the azadiene and the vinyl ether in the presence of
this catalyst system. Table 3 (entries 1–6) summarizes the
evaluation of a series of N-(2-pyridylsulfonyl)imines 7–
1223 derived from substituted chalcones in the reaction
with 5 (R = Et) under the optimized conditions. In general,
very similar diastereoselectivities and enantioselectivities
were obtained, regardless of the electronic or the steric na-
ture of the aryl groups Ar1 and Ar2. Excellent endo selec-
tivity (endo/exo = 98:2 in all cases) and asymmetric
inductions in the range of 59–65% ee were obtained
(Table 3, entries 1–4 and 6), except for substrate 11
(Ar1 = 4-O2NC6H4, 30% ee; entry 5). With regard to reac-
tivity, the presence of electron-withdrawing groups on Ar1
(Table 3, entries 4 and 6) or Ar2 (entry 2) led to a signifi-
cant increase in the cycloaddition yield (typically from
55–60% to 71–93%). Much more limited was the structur-
al versatility in the dienophile counterpart. For example,
the reaction of the model imine 4 with the bulky tert-butyl
vinyl ether under identical reaction conditions gave ad-
duct 19 in low yield (20%), low endo selectivity (80:20),
and low enantioselectivity (25% ee; Table 3, entry 7). The
same reaction with a cyclic vinyl ether such as dihydrofu-
ran was completely unsuccessful owing to the rapid de-
On the basis of the good results obtained in copper-cata-
lyzed addition reactions to (heteroarylsulfonyl)imines,21
we initially evaluated the influence of the sulfonyl pro-
tecting group in the copper(II) triflate catalyzed (10
mol%) reaction of a set of ketimines 1–4 of chalcone23,24
with ethyl vinyl ether (5; 20 equiv)25 in dichloromethane26
at room temperature (Table 1, entries 1–4). The tosyl-, (2-
thienylsulfonyl)-, and (N,N-dimethylsulfamoyl)imine de-
rivatives 1–3 (Table 1, entries 1–3, respectively) were re-
covered unaltered after five days at room temperature. In
contrast, the N-(2-pyridylsulfonyl)imine 4 led to an 85:15
mixture of cycloadducts endo-6 and exo-6 after three
days, the major product endo-6 being isolated in 67%
yield (Table 1, entry 4).
After the superiority of the 2-pyridylsulfonyl group had
been identified, other metal salts (10 mol%) were ex-
plored in the model reaction between 4 and 5 (Table 1,
entries 5–9). With the exception of magnesium(II)
perchlorate hexahydrate (Table 1, entry 8), all metal
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

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Inverse-Electron-Demand Diels–Alder Reactions
115
Table 2 Enantioselective ADAR of Imine 4 with Ethyl Vinyl Ethera
O
O
O
N
2-Py
S
O
S
N
2-Py
Ph
Ph
OEt
OEt
MII/L*
+
Ph
Ph
4
5
endo-6
Entry
L*
Time (h)
CuII
Ratio endo/exob
Yieldc (%)
CuII
eeb (%)
CuII
NiII
48
48
48
48
24
48
48
CuII
98:2
98:2
98:2
98:2
98:2
98:2
97:3
NiII
NiII
89
85
73
84
91
74
68
NiII
0
1
2
3
4
5
6
7
I
72
72
72
72
72
72
72
98:2
98:2
98:2
98:2
98:2
98:2
98:2
60
52
57
50
62
61
49
26
21
43
20
65
15
7
II
0
BOX-III
BOX-IV
BOX-V
BOX-VI
0
54
20
35
0
PyBOX-VII
O
O
O
N
O
N
O
O
PR2
PR2
N
N
N
L* =
N
N
R
R
Ph
Ph
BOX-III, R = t-Bu
BOX-IV, R = Bn
BOX-V, R = Ph
PyBOX-VII
BOX-VI
Binap, R = Ph (I)
Tol-Binap, R = 4-Tol (II)
a Reagents and conditions: CuII: 4 (1 equiv), 5 (20 equiv), Cu(OTf)2 (10 mol%), L* (11 mol%), CH2Cl2, r.t.; NiII: 4 (1 equiv), 5 (5 equiv),
Ni(ClO4)2·6H2O (10 mol%), L* (11 mol%), CH2Cl2, r.t.
b Determined by chiral HPLC.
c Yield of endo-product after chromatography.
Table 3 Scope of the ADAR Catalyzed by Copper(II) Triflate/BOX-Va
O
O
O
2-Py
O
S
N
S
2-Py
Ar1
N
Ar1
OEt
OR
Cu(OTf)2/BOX-V
+
Ar2
4,7–12
Ar2
endo-13–19
Entry
Ar1
Ph
Ar2
Imine
7
R (vinyl ether)
Et (5)
Product
13d
Yieldb (%)
eec (%)
59
1
2
3
4
5
6
7b
Naph
4-FC6H4
Ph
55
71
59
80
93
87
20
Ph
8
Et (5)
14d
60
Naph
9
Et (5)
15d
60
4-ClC6H4
4-O2NC6H4
4-F3CC6H4
Ph
Ph
10
11
12
4
Et (5)
16d
62
Ph
Et (5)
17d
30
Ph
Et (5)
18d
65
Ph
t-Bu
19e
25
a Reagents and conditions: imine (1 equiv), vinyl ether (20 equiv), Cu(OTf)2 (10 mol%), BOX-V (11 mol%), CH2Cl2, r.t., 3 d.
b Isolated yield after chromatography.
c Determined by chiral HPLC.
d For 13–18: endo/exo = 98:2.
e For 19: endo/exo = 80:20.
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

116
J. Esquivias et al.
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Table 4 ADAR of (8-Quinolylsulfonyl)imine 20 with Vinyl Ether 5 Catalyzed by Different Lewis Acidsa
O
O
8-Q
O
O
S
N
S
N
Ph
OEt
N
Ph
OEt
MII/L*
+
Ph
Ph
endo-21
5
20
Entry
1d
Metal salt
Cu(OTf)2
L*
Time (d)
Ratio endo/exo
Yieldb (%)
eec (%)
–
5
5
5
3
3
3
3
3
3
3
3
–
–
–
2d
Zn(ClO4)2·6H2O
Mg(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
–
–
–
–
3d
–
–
–
–
4e
–
70:30
80:20
80:20
90:10
87:13
–
62
83
81
53
42
<10
52
55
–
5e
I
<5
<5
<5
<5
–
6e
II
7e
BOX-III
BOX-IV
BOX-V
BOX-VI
8e
9e
10e
11e
87:13
88:12
<5
<5
PyBOX-VII
a Reagents and conditions: 20 (1 equiv), 5 (5 or 20 equiv)d,e, MII (10 mol%), L* (11 mol%), CH2Cl2, r.t.
b Isolated yield after chromatography.
c Determined by chiral HPLC.
d Ether 5 (20 equiv) was used.
e Ether 5 (5 equiv) was used.
composition of the dienophile in the presence of the Lewis 20 with 5 in the presence of several Lewis acids (10
acid catalyst.
mol%) under the optimized reaction conditions (CH2Cl2,
r.t.) (Table 4, entries 1–4). We were surprised to find no
reaction under copper(II) triflate catalysis even after five
days (entry 1), and identical results were obtained with
zinc(II) and magnesium(II) perchlorates (entries 2 and 3,
respectively). In contrast, the reaction of 20 with 5 (5
equiv) catalyzed by nickel(II) perchlorate hexahydrate
(entry 4) led to the cycloadduct endo-21 in good yield
(62%) and moderate diastereocontrol (endo/exo = 70:30).
To summarize these initial studies: the catalyst system
composed of copper(II) triflate/BOX-V proved to be effi-
cient in promoting the asymmetric ADAR of N-(2-py-
ridylsulfonyl)-1-azadienes with ethyl vinyl ether, which
represents an important advance with regard to previously
described protocols based on thermal reaction condi-
tions.13–16 However, this procedure still has important lim-
itations: (a) necessity to use a large excess of dienophile
(20 equiv), (b) limited versatility in dienophile substitu- Encouraged by the results obtained with the nickel(II)
tion, and (c) insufficient enantiocontrol (typically 59– Lewis acid/8-quinolylsulfonyl group combination,
65% ee). With the aim of improving the levels of reactiv- ligands I–VII (see Table 2) were tested in the ADAR of
ity, versatility, and enantioselectivity, we revisited our 20 with 5 (5 equiv) under nickel(II) catalysis (10 mol%).
original N-sulfonyl substitution study with the expecta- The results are collected in Table 4, entries 5–11. As ex-
tion of finding a more efficient directing group. In partic- pected, the endo selectivity improved to acceptable levels
ular, we decided to replace the 2-pyridyl group by an 8- (80:20 to 90:10) in all cases. Unfortunately, and to our
quinolyl (8-Q) unit, with the sp2 nitrogen one position fur- surprise, all tested ligands provided almost racemic prod-
ther with respect to the sulfonyl group.
ucts (<5% ee). In terms of reactivity, only the diphosphine
ligands Binap (I) and Tol-Binap (II) led to complete con-
versions, providing endo-21 in yields above 80%
(Table 4, entries 5 and 6). The BOX-V ligand, which was
the best ligand in the case of the copper(II) triflate/2-py-
ridylsulfonyl combination, proved to be unproductive un-
der nickel(II) catalysis (<10% yield, entry 9). Modest
The N-(8-quinolylsulfonyl)imine 20 of chalcone
(Table 4) was readily prepared by direct condensation be-
tween 8-quinolylsulfonamide and chalcone under the con-
ditions typically used for the preparation of other N-
sulfonyl-1-azadienes.23 First we examined the ADAR of
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

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Inverse-Electron-Demand Diels–Alder Reactions
117
reactivity was observed with the rest of the BOX and Py-
BOX ligands (42–55% yield, entries 7, 8, 10, and 11).
Table 5 ADAR Catalyzed by Nickel(II) Perchlorate Hexahydrate/
DBFOX-Pha
O
O
In an attempt to generate a deeper chiral environment
around the nickel(II) aqua complex, the trans-chelating
DBFOX-Ph ligand27 was tested (Table 5). The chiral
nickel catalyst was preformed in situ by stirring of
equimolar amounts of nickel(II) perchlorate hexahydrate
and DBFOX-Ph in dichloromethane28 at room tempera-
ture for at least four to five hours, since lower catalyst-ag-
ing times result in a significant loss of enantioselectivity.
Fortunately, this ligand proved to be highly efficient in the
ADAR of imine 20 with 5 (Table 5, entry 2), leading to
the cycloaddition product 21 in good yield (73%), excel-
lent endo selectivity (>30:1) and high enantiocontrol
(88% ee). In contrast, this catalyst system was much less
efficient for the (2-pyridylsulfonyl)imine 4 (entry 1) in
terms of asymmetric induction (42% ee). The presence of
water seems to be crucial for achieving high enantiocon-
trol,29 as the reaction of 20 with 5 in the presence of acti-
vated 4-Å molecular sieves led to endo-21 in good yield
and diastereoselectivity, but in racemic form (entry 3).
S
N
Ar
Ni(ClO4)2⋅6H2O/
O
Ph
OEt
O
O
DBFOX-Ph
N
N
+
6, 21
Ph
Ph
Ph
5
DBFOX-Ph
(5 equiv)
4, Ar = 2-Py
20, Ar = 8-Q
endo-6, Ar = 2-Py
endo-21, Ar = 8-Q
Entry
Ar
Additive Ratio endo/exob Yieldc (%) eeb (%)
1
2
3
2-Py
8-Q
8-Q
–
98:2
97:3
90:10
80
73
68
42
88
0
–
4-Å MS
a Reagents and conditions: 4 or 20 (1 equiv), 5 (5 equiv),
Ni(ClO4)2·6H2O/DBFOX-Ph (10 mol%), CH2Cl2, r.t., 3 d.
b Determined by chiral HPLC.
c Isolated yield after chromatography.
The structural scope and limitations of the nickel(II)/
DBFOX-Ph/8-quinolylsulfonyl catalyst system was in-
vestigated by screening a set of alkenyl ethers in the reac- Table 6 Scope of the Dienophile in the ADAR with Imine 20 Cata-
lyzed by Nickel(II)/DBFOX-Pha
tion with imine 20 (Table 6, entries 1–5). This procedure
proved to be efficient with monosubstituted vinyl ethers
SO2(8-Q)
Ni(ClO4)2⋅6H2O/
R1
with primary or secondary alkyl substituents at oxygen
(88–91% ee, entries 1–2). Even the bulky tert-butyl vinyl
ether led to the corresponding adduct 24 with acceptable
diastereoselectivity (endo/exo = 80:20) and enantioselec-
tivity (68% ee), although with poor yield (35%, entry 3).
The asymmetric induction was found to be much more
sensitive to the substitution at the double bond of the alk-
ene. Thus, a 50:50 mixture of (E)- and (Z)-prop-1-enyl
ether (5 equiv) led exclusively to product 25, resulting
from the ADAR of the kinetically more reactive dipolaro-
phile of E-configuration (entry 4). However, despite the
good reactivity (68% yield) and high endo selectivity
(98:2), endo-25 was isolated with only 4% ee. Similarly,
dihydrofuran showed a particularly high reactivity, af-
fording the corresponding cycloadduct 26 in excellent
yield (93%) and endo selectivity (98:2) after 24 hours of
reaction, albeit also with low enantioselectivity (20% ee,
entry 5). The high reactivity displayed by this dienophile
allowed the temperature to be reduced to 0 °C, which re-
sulted in an increased asymmetric induction (58% ee),
while maintaining a high yield (91%, entry 5). Electron-
rich styrene derivatives such as p-methoxystyrene proved
also to be suitable, providing an acceptable chemical yield
(58%) and high endo selectivity (98:2), although with
very low enantiocontrol (5% ee, entry 6).
Ph
N
R1
DBFOX-Ph
2
3
20
+
4
R2
R2
(5 equiv)
Ph
22–27
Entry R1
R2 Product Ratio
Yield
ee (%)b
endo/exob
(%)c
1
2
3
4
5f
6
On-Pr
H
H
H
22
23
24
98:2
69
91
88
68
4
OCy
98:2
70
Ot-Bu
OEtd
80:20
98:2
35
Med 25e
67
OCH2CH2
PMP
26
98:2 (98:2)g 93 (91)g 20 (58)g
98:2 58
H
27
5
a Reagents and conditions: 20 (1 equiv), alkene (5 equiv),
Ni(ClO4)2·6H2O (10 mol%), DBFOX-Ph (11 mol%), CH2Cl2, r.t., 3 d.
b Determined by chiral HPLC.
c Isolated yield after chromatography.
d A 50:50 mixture of E- and Z-alkenes.
e Product with 2R,3S,4R configuration was exclusively formed.
f Reaction at r.t. for 24 h or at 0 °C for 3 d.
g Values in parentheses were obtained at 0 °C.
To evaluate the scope of this cycloaddition protocol with
regard to the 1-azadiene counterpart, a representative set
of N-sulfonyl a,b-unsaturated ketimines was surveyed in
the reaction with n-propyl vinyl ether under the optimal
experimental conditions. As shown in Table 7, good
yields (52–75%) and high levels of endo selectivity and
enantioselectivity (80–92% ee) were achieved in most
cases. Aryl substituents of varied electronic and steric na-
ture at the b-position of the azadiene (R2) are well tolerat-
ed (entries 1–4), although electron-rich groups led to a
slight decrease of enantioselectivity (entries 3 and 4).
Even substrate 32, with a tert-butyl group as R2 proved to
be suitable (entry 5, 84% ee). In contrast, a more limited
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118
J. Esquivias et al.
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Table 7 Scope of the Azadiene in the ADAR with a Vinyl Ether Catalyzed by Nickel(II)/DBFOX-Pha
SO2(8-Q)
SO2(8-Q)
Ni(ClO4)2⋅6H2O/
R1
N
R1
N
On-Pr
On-Pr
DBFOX-Ph
+
(5 equiv)
R2
R2
28–35
36–43
Entry
R1
R2
Imine
Product
36
Ratio endo/exob
98:2
Yieldc (%)
eeb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4-FC6H4
28
29
30
31
32
33
34
35
75
69
65
52
61
73
69
67
92
90
80
77
84
90
91
6
Naph
PMP
2-furyl
t-Bu
Ph
37
97:3
38
98:2
39
97:3
40
98:2
4-ClC6H4
4-F3CC6H4
Naph
41
97:3
Ph
42
97:3
Ph
43
98:2
a Reagents and conditions: imine (1 equiv), alkene (5 equiv), Ni(ClO4)2·6H2O/DBFOX-Ph (10 mol%), CH2Cl2, r.t., 3 d.
b Determined by chiral HPLC.
c Isolated yields after flash chromatography.
versatility was found with respect to the substitution at the
imine carbon (R1). para-Substituted aryl groups led to ex-
cellent results (90–91% ee, entries 6 and 7), whereas a
dramatic drop in enantioselectivity resulted with more
sterically demanding aryl groups such as 2-naphthyl (6%
ee, entry 8).
SO2(8-Q)
N
Ni(ClO4)2⋅6H2O/
SO2(8-Q)
N On-Pr
R1
DBFOX-Ph
R1
On-Pr
(10 mol%)
+
CH2Cl2, r.t., 3 d
(5 equiv)
Ph
Ph
The cycloaddition of imines 44 and 45 with an additional
double bond (part of a styryl substituent) conjugated with
the azadiene system (Scheme 2) deserves particular atten-
tion. In both cases studied, complete chemoselectivity in
favor of the hetero-Diels–Alder cycloaddition was ob-
served, the corresponding 4-alkenyl-substituted tetrahy-
dropyridine products 46 and 47 being isolated in good
yield and excellent diastereo- and enantioselectivities
(92% ee in both cases). Less satisfactory results were ob-
tained with the N-(8-quinolylsulfonyl)imine of diben-
zylidene acetone (48), whose ADAR with n-propyl vinyl
ether provided tetrahydropyridine 49 in good yield (68%)
and endo selectivity (90:10), but poor enantioselectivity
(20% ee, Scheme 2). This result highlights again the much
higher sensitivity of this reaction to the substitution at the
imine carbon of the azadiene than that at the b-position.
44, R1 = p-ClC6H4
45, R1 = p-NCC6H4
(endo/exo = 98:2)
(endo/exo = 98:2)
46, 63%, 92% ee
47, 70%, 92% ee
Ph
Ph
Ni(ClO4)2⋅6H2O/
SO2(8-Q)
SO2(8-Q)
DBFOX-Ph
(10 mol%)
N
On-Pr
N
On-Pr
+
CH2Cl2, r.t., 3 d
(5 equiv)
Ph
Ph
(endo/exo = 90:10)
48
49, 68%, 20% ee
Scheme 2 Nickel(II)/DBFOX-Ph-catalyzed ADAR of conjugated
azatrienes
mediate iminium ion by the quinoline moiety (Scheme 3).
Subsequent aqueous treatment of 50 produced the 2-hy-
droxy derivative 51 with complete stereoselectivity in
88% yield.
Regarding the potential synthetic interest in the obtained
cycloadducts, we tried first to effect the nucleophilic dis-
placement of the alkoxy group at C-2 with carbon nucleo-
philes such as allyltrimethylsilane in the presence of a
Lewis acid, which is known to occur with inversion of the
configuration.15 However, treatment of cycloadduct endo-
21 with boron trifluoride–diethyl ether (1.5 equiv) in
dichloromethane led quantitatively to the quinolinium salt
50 after two hours at 0 °C (TLC monitoring), likely
formed by intramolecular trapping of the resulting inter-
Alternatively, trapping of intermediate 50 with stronger
nucleophiles such as hydride or Grignard reagents result-
ed in selective attack at the 2-position of the bicyclic quin-
oline ring system, affording tetracyclic compounds 52–54
in good yields (Scheme 3). Product 52 (R = H) was isolat-
ed as the only diastereomer in 82% yield in the reaction of
50 with sodium cyanoborohydride (Scheme 3). The use of
phenylmagnesium bromide as nucleophile led to a 90:10
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

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Inverse-Electron-Demand Diels–Alder Reactions
119
firming by TLC its complete transformation into 50 after
two hours (Rf = 0, n-hexane–EtOAc, 1:1). When it was
quenched with ethanol, the instantaneous re-formation of
endo-21 resulted.
O
SO2(8-Q)
BF3⋅OEt2
O
S
N
Ph
N
OH
H2O
88%
CH2Cl2, 0 °C
Ph
N
endo-21
2 h
(overall)
Ph
O
Ph
50
SO2(8-Q)
51
O
BF3⋅OEt2
CH2Cl2, 0 °C
S
N
Ph
N
OEt
NaCNBH3
or RMgBr
EtOH
Ph
N
endo-21
2 h
88%
O
O
(overall)
Ph
O
O
S
N
S
N
Ph
50
endo-21
Ph
N
H
Ph
N
Scheme 4 Ethanolysis of quinolinium intermediate 50
H
R
R
Ph
Ph
52a–54a
52b–54b
The relative stereochemistry of tetracyclic compounds
52–54 (see Scheme 3) was determined by NMR spectros-
copy (HMBC, COSY, and NOESY) of diastereomers 54a
and 54b.33 This stereochemistry is in concordance with
the approach of the nucleophile from the less hindered
convex face of the molecule. The absolute configuration
of compound 54b was unambiguously established by X-
ray diffraction analysis of a single crystal from enan-
tiopure 54b, obtained by recrystallization of a 91% ee
sample (Figure 2).34
R = H, 52a = 52b; 82%
R = Ph, 53a/53b = 90:10; 53a 71%, 53b (not isolated)
R = Me, 54a/54b = 80:20; 54a 60%, 54b 15%
Scheme 3 Stereoselective transformations of the cycloadducts
diastereomeric mixture of 53a and 53b, the major product
53a being obtained in 71% isolated yield. An 80:20 mix-
ture of 54a and 54b (60% and 15% yield, respectively)
was produced with the less hindered Grignard reagent
methylmagnesium bromide. Products 52–54 are medical-
ly attractive, because they can be considered as chiral non-
racemic [1,2,4]benzothiadiazine-5,5-dioxide deriva-
tives,30 which have proven to be potential drugs for mem-
ory and learning disorders, as well as neurodegenerative
diseases.31
It is well known that the Diels–Alder reaction of N-tosyl-
1-aza-1,3-dienes takes place with very high endo selectiv-
ity.15 This relative stereochemistry in the 2-pyridylsulfo-
nyl- and 8-quinolylsulfonyl cycloadducts was confirmed
by comparison of their NMR data with those reported for
the corresponding tosyl derivatives, and further confirmed
by X-ray diffraction analysis of a single-crystal sample of
( )-endo-1832 (Figure 1).
Figure 2 X-ray crystal structure of compound 54b
To shed some light on the origin of the enantioselectivity
in the Ni/DBFOX-Ph-catalyzed ADAR of N-(8-quino-
linesulfonyl)-1-aza-1,3-dienes with vinyl ethers, the theo-
retical structures of different catalyst–imine complexes,
based on the previously reported X-ray crystal structure of
the DBFOX-Ph–Ni(ClO4)2·3H2O complex A,27a were
studied (Scheme 5). The 1-aza-1,3-diene in which
R1 = Ph and R2 = Me (see Table 7) and methyl vinyl ether
were used as model substrates. Several complexes were
first analyzed by using a semi-empirical PM3(tm) proce-
dure, as implemented in HyperChem 6.02,35 varying the
coordinated prochiral sulfonyl oxygen, the imine configu-
ration, the O–S–N–C dihedral angle and the mode of co-
ordination of the quinolinesulfonyl moiety (that can locate
the N atom either in the plane of the chiral ligand, desig-
nated as equatorial, or in a perpendicular arrangement,
designated as axial). This preliminary study showed that
complexes with the quinoline moiety in an axial arrange-
ment are much more stable, probably due to a p-stacking
interaction with the closest Ph group. These complexes
Figure 1 X-ray crystal structure of cycloadduct endo-18
To verify the overall retention of stereochemistry in the
transformation of endo-21 into 51 (Scheme 3), we de-
signed the experiment shown in Scheme 4. Adduct endo-
21 (Rf = 0.68, n-hexane–EtOAc, 1:1) was treated with
boron trifluoride–diethyl ether complex (1.2 equiv), con-
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

120
J. Esquivias et al.
PAPER
proR
O
proS
O
N
S
Ph
O
N
E
Ph
O
OH2
Ni
O
O
O
N
OH2
Ni
OH2
OH2
Ph
Me
OMe
O
N
H
N
OMe
Ph
N
H
H
N
H
S
O
Me
O
N
Ph
Ph
A
B
Scheme 5 Stereochemical model for the cycloaddition
were re-optimized at the DFT (B3LYP)36 level by using
the Gaussian03 program.37 The standard 6-31G(d)38 basis
set was used for S, O, and N atoms, 3-21G39 for C and H,
and the LANL2DZ40 was employed for the Ni atom. Har-
monic frequencies were calculated at the same level of
theory to characterize the stationary points and to deter-
mine the zero-point energies (ZPE).
All the reactions were carried out in anhydrous solvents and under
argon atmosphere. Melting points were taken in open-end capillary
tubes. NMR spectra were recorded at 300 MHz (1H) or 75 MHz
(13C) at room temperature in CDCl3 [calibrated at d = 7.26 (1H), and
d = 77.0 (13C)]. Optical rotations were obtained on a Perkin-Elmer
241 polarimeter. Mass spectra were recorded on a VG AutoSpec
mass spectrometer. HPLC experiments were conducted using
Daicel Chiralpak columns (AD, OD or AS). Flash column chroma-
tography was performed on silica gel (Merck-60, 230–400 mesh).
N-Heteroarylsulfonyl a,b-unsaturated imines were prepared ac-
cording to procedures previously described.23
Because the H2O ligand in the starting nickel salt
Ni(ClO4)2·6H2O has a key role in the reaction outcome
(addition of molecular sieves led to racemic mixtures) and
that electron-rich olefins different from vinyl ethers, such
as styrenes, afforded the product in almost racemic form,
we envisaged the possibility of the participation of both
azadiene and olefin in the reactive complex, the latter be-
ing stabilized by a hydrogen bond with water. Thus the
complex model B shown in Scheme 5, with the proS oxy-
gen coordinated to Ni and E-configuration at the imine,
could account for the fact that the main product of the re-
action comes from the endo approach of the olefin to the
re face of the imine. The equivalent proR-oxygen-coordi-
nated complex that would afford the other enantiomer was
shown to be only 0.2 kcal·mol–1 less stable. However, the
slightly longer distances between the carbons to be bond-
ed (4.62 and 5.62 Å, vs 4.57 and 5.36 Å in proS complex
Copper(II)-Catalyzed Asymmetric Inverse-Electron-Demand
ADAR; General Procedure
A soln of Cu(OTf)2 (7.2 mg, 0.02 mmol) and BOX-V (7.0 mg, 0.021
mmol) in CH2Cl2 (1.0 mL) was stirred for 30 min before a soln of
the N-(2-pyridylsulfonyl) ketimine (0.2 mmol) in CH2Cl2 (1.0 mL)
and the vinyl ether (20 equiv) were successively added. The reac-
tion mixture was stirred at r.t. until consumption of the starting imi-
ne, before it was quenched with sat. aq NH4Cl and extracted several
times with CH2Cl2. The combined organic phase was dried
(Na2SO4) and concentrated. The residue was purified by flash chro-
matography (deactivated silica gel, CH2Cl2).
Nickel(II)-Catalyzed Asymmetric Inverse-Electron-Demand
ADAR; General Procedure
A soln of Ni(ClO4)2 6 H2O (7.2 mg, 0.02 mmol) and (R,R)-DBFOX-
Ph (9.2 mg, 0.022 mmol) in CH2Cl2 (1 mL) was stirred at r.t. for 4
B), and between the centroids of the aromatic rings show- h before a soln of N-(8-quinolylsulfonyl) ketimine (0.2 mmol) in
CH2Cl2 (1.0 mL) and the vinyl ether (5 equiv) were successively
added. Isolation of the product was performed as in the previous
case.
ing the p-stacking interaction (4.38 Å vs 3.99 Å in proS
complex B) observed in proR complex, could result in a
higher energy difference in the transition state, favoring
the reaction from complex B.
2-Ethoxy-4,6-diphenyl-1-[(2-pyridyl)sulfonyl]-1,2,3,4-tetrahy-
dropyridine (endo-6)
In conclusion, we have demonstrated that the presence of
an appropriate heteroarylsulfonyl group at the imine nitro-
gen confers unique reactivity to the 1-aza-1,3-diene sys-
tem, allowing the development of a hetero-Diels–Alder
reaction with alkenyl ethers that is catalyzed by a chiral
Lewis acid. The performance of the combination of the 8-
quinolylsulfonyl moiety at the substrate and nickel(II)/
DBFOX-Ph as catalyst was very good, leading to func-
tionalized piperidine derivatives in good yields, excellent
endo selectivity, and enantioselectivities typically in the
range of 80–91% ee. A tentative model based on theoret-
ical DFT calculations is provided to explain the origin of
this high reactivity and selectivity.
Yield: 60%; white solid; mp 69–71 °C; [a]D20 –43 (c 0.65, CHCl3);
65% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
15.7 (minor), tR = 23.1 (major).
1H NMR (300 MHz, CDCl3): d = 8.80 (ddd, J = 4.6, 1.6, 0.8 Hz, 1
H), 7.80 (m, 1 H), 7.65 (m, 1 H), 7.53 (ddd, J = 7.5, 4.6, 1.1 Hz, 1
H), 7.34–7.05 (m, 10 H), 5.98 (dd, J = 6.1, 4.2 Hz, 1 H), 5.96 (d,
J = 3.4 Hz, 1 H), 4.19 (dq, J = 9.5, 7.0 Hz, 1 H), 3.83 (dq, J = 9.5,
7.0 Hz, 1 H), 2.87 (td, J = 7.3, 3.4 Hz, 1 H), 2.62 (ddd, J = 14.0, 7.1,
5.9 Hz, 1 H), 2.07 (ddd, J = 14.0, 7.8, 4.2 Hz, 1 H), 1.27 (t, J = 7.0
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 157.3, 150.0, 144.0, 138.6, 137.6,
136.6, 128.4, 127.9, 127.7, 127.5, 126.9, 126.6, 126.5, 123.6, 85.4,
63.9, 40.2, 37.6, 14.9.
MS–FAB: m/z (%) = 375.0 (100) [M+ – OEt].
HRMS–FAB: m/z [M + H]+ calcd for C24H25N2O3S: 421.15076;
found: 421.15104.
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Inverse-Electron-Demand Diels–Alder Reactions
121
(2R,4S)-2-Ethoxy-6-phenyl-4-(2-naphthyl)-1-[(2-pyridyl)sulfo-
nyl]-1,2,3,4-tetrahydropyridine (13)
1H NMR (300 MHz, CDCl3): d = 8.79 (ddd, J = 4.6, 1.6, 0.8 Hz, 1
H), 7.84 (m, 1 H), 7.69 (m, 1 H), 7.55 (ddd, J = 7.7, 4.6, 1.1 Hz, 1
H), 7.30–7.18 (m, 7 H), 7.11–7.06 (m, 2 H), 5.94 (dd, J = 5.9, 4.0
Hz, 1 H), 5.93 (d, J = 3.4 Hz, 1 H), 4.13 (dq, J = 9.7, 7.3 Hz, 1 H),
3.79 (dq, J = 9.7, 7.3 Hz, 1 H), 2.84 (td, J = 7.4, 3.4 Hz, 1 H), 2.60
(ddd, J = 14.0, 7.3, 6.1 Hz, 1 H), 2.05 (ddd, J = 14.0, 7.7, 4.0 Hz, 1
H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 157.3, 150.1, 143.9, 137.7, 137.2,
135.6, 133.8, 128.4, 128.2, 128.0, 127.9, 127.0, 126.6, 123.5, 85.5,
64.0, 40.1, 37.7, 14.9.
Yield: 55%; white solid; mp 60–62 °C; [a]D20 –33 (c 0.50, CHCl3);
59% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
19.7 (minor), tR = 33.2 (major).
1H NMR (300 MHz, CDCl3): d = 8.82 (ddd, J = 4.6, 1.6, 0.8 Hz, 1
H), 7.86–7.63 (m, 5 H), 7.58–7.52 (m, 2 H), 7.46–7.40 (m, 2 H),
7.38–7.21 (m, 6 H), 6.01 (d, J = 3.2 Hz, 1 H), 5.99 (dd, J = 5.6, 3.8
Hz, 1 H), 4.20 (dq, J = 9.7, 7.3 Hz, 1 H), 3.81 (dq, J = 9.7, 7.3 Hz,
1 H), 3.13 (td, J = 7.1, 3.2 Hz, 1 H), 2.69 (ddd, J = 13.7, 7.7, 5.9 Hz,
1 H), 2.27 (ddd, J = 13.9, 6.9, 3.8 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 157.4, 149.9, 138.6, 137.6, 133.3,
132.2, 128.0, 127.9, 127.6, 127.5, 127.0, 126.8, 126.7, 126.5, 126.4,
125.9, 125.5, 85.3, 64.0, 39.7, 37.6, 15.0.
MS–FAB: m/z (%) = 409.0 (100) [M+ – OEt].
HRMS–FAB: m/z [M + H]+ calcd for C24H24N2O3SCl: 455.1196;
found: 455.1193.
MS–FAB: m/z (%) = 425.1 (100) [M+ – OEt].
(2R,4S)-2-Ethoxy-4-phenyl-6-(4-nitrophenyl)-1-[(2-pyridyl)sul-
fonyl]-1,2,3,4-tetrahydropyridine (17)
Yield: 93%; white solid; mp 140–142 °C; [a]D –12 (c 0.46,
CHCl3); 30% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH,
90:10): tR = 12.3 (minor), tR = 20.5 (major).
HRMS–FAB: m/z [M + H]+ calcd for C28H27N2O3S: 471.1742;
found: 471.1740.
20
(2R,4S)-2-Ethoxy-4-(4-fluorophenyl)-6-phenyl)-1-[(2-py-
ridyl)sulfonyl]-1,2,3,4-tetrahydropyridine (14)
Yield: 71%; white solid; mp 116–118 °C; [a]D –40 (c 0.80,
CHCl3); 60% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH,
90:10): tR = 21.2 (minor), tR = 29.6 (major).
1H NMR (300 MHz, CDCl3): d = 8.77 (ddd, J = 4.6, 1.6, 0.8 Hz, 1
H), 7.78 (m, 1 H), 7.59 (m, 1 H), 7.51 (ddd, J = 7.7, 4.6, 1.2 Hz, 1
H), 7.30–7.19 (m, 7 H), 7.09 (d, J = 8.3 Hz, 2 H), 5.93 (dd, J = 5.2,
3.4 Hz, 1 H), 5.80 (d, J = 3.2 Hz, 1 H), 4.12 (dq, J = 9.5, 7.1 Hz, 1
H), 3.79 (dq, J = 9.5, 7.1 Hz, 1 H), 3.05 (td, J = 7.4, 3.4 Hz, 1 H),
2.58 (ddd, J = 14.0, 8.1, 5.3 Hz, 1 H), 2.07 (ddd, J = 14.0, 5.9, 3.4
Hz, 1 H), 1.26 (t, J = 6.9 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 8.83 (ddd, J = 4.2, 1.6, 0.7 Hz, 1
H), 8.18 (d, J = 8.9 Hz, 2 H), 7.91 (td, J = 7.4, 1.6 Hz, 1 H), 7.77 (dt,
J = 7.9, 0.7 Hz, 1 H), 7.60 (ddd, J = 7.7, 4.6, 1.0 Hz, 1 H), 7.54 (d,
J = 8.9 Hz, 2 H), 7.30–7.18 (m, 3 H), 7.11–7.06 (m, 2 H), 6.14 (d,
J = 3.4 Hz, 1 H), 5.90 (dd, J = 4.2, 6.1 Hz, 1 H), 4.11 (dq, J = 9.7,
7.3 Hz, 1 H), 3.81 (dq, J = 9.7, 7.3 Hz, 1 H), 2.84 (td, J = 7.5, 3.4
Hz, 1 H), 2.56 (ddd, J = 14.0, 7.3, 6.1 Hz, 1 H), 2.05 (ddd, J = 14.0,
7.7, 4.0 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H).
20
13C NMR (75 MHz, CDCl3): d = 156.9, 150.3, 147.2, 145.4, 143.2,
137.9, 134.9, 131.1, 128.5, 127.8, 127.0, 126.7, 123.4, 123.3, 85.4,
64.2, 39.5, 37.7, 14.9.
13C NMR (75 MHz, CDCl3): d = 157.4, 149.9, 143.0, 138.6, 137.6,
136.6, 132.2, 129.5, 128.4, 128.0, 127.9, 126.9, 126.8, 125.5, 123.4,
84.9, 64.0, 39.0, 36.8, 14.9.
MS–FAB: m/z (%) = 394.1 (100) [M+ – OEt].
HRMS–FAB: m/z [M + H]+ calcd for C24H24N2O3SF: 439.1413;
(2R,4S)-2-Ethoxy-4-phenyl-6-(4-trifluoromethylphenyl)-[(2-py-
ridyl)sulfonyl]-1,2,3,4-tetrahydropyridine (18)
Yield: 87%; white solid; mp 122–123 °C; [a]D –40 (c 0.52,
20
CHCl3); 65% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH,
90:10): tR = 16.9 (minor), tR = 27.4 (major).
1H NMR (300 MHz, CDCl3): d = 8.82 (ddd, J = 4.3, 1.6, 0.7 Hz, 1
H), 8.18 (d, J = 8.9 Hz, 2 H), 7.91 (td, J = 7.4, 1.6 Hz, 1 H), 7.77 (dt,
J = 7.8, 0.8 Hz, 1 H), 7.70 (d, J = 7.7, Hz, 1 H), 7.60–7.41 (m, 5 H),
7.31–7.13 (m, 3 H), 7.12–7.06 (m, 2 H), 6.06 (d, J = 3.4 Hz, 1 H),
5.94 (dd, J = 5.7, 4.0 Hz, 1 H), 4.15 (dq, J = 9.7, 7.3 Hz, 1 H), 3.80
(dq, J = 9.7, 7.3 Hz, 1 H), 2.87 (td, J = 7.5, 3.6 Hz, 1 H), 2.60 (ddd,
J = 14.0, 7.3, 6.1 Hz, 1 H), 2.05 (ddd, J = 14.0, 7.7, 4.0 Hz, 1 H),
1.28 (t, J = 7.1 Hz, 3 H).
found: 439.1410.
(2R,4S)-2-Ethoxy-4-phenyl-6-(2-naphthyl)-1-[(2-pyridyl)sulfo-
nyl]-1,2,3,4-tetrahydropyridine (15)
Yield: 59%; white solid; mp 59–60 °C; [a]D20 –33 (c 0.58, CHCl3);
60% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
29.5 (minor), tR = 41.0 (major).
1H NMR (300 MHz, CDCl3): d = 8.81 (ddd, J = 4.6, 1.6, 0.8 Hz, 1
H), 7.83–7.65 (m, 1 H), 7.61 (m, 1 H), 7.53–7.40 (m, 4 H), 7.30–
7.11 (m, 6 H), 6.09 (d, J = 3.4 Hz, 1 H), 6.02 (dd, J = 5.8, 4.2 Hz, 1
H), 4.24 (dq, J = 9.7, 7.3 Hz, 1 H), 3.85 (dq, J = 9.7, 7.3 Hz, 1 H),
2.95 (td, J = 7.7, 3.8 Hz, 1 H), 2.68 (ddd, J = 13.5, 7.3, 6.1 Hz, 1 H),
2.10 (ddd, J = 13.9, 7.7, 4.0 Hz, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 157.2, 150.2, 143.7, 142.4, 137.8,
135.2, 130.1, 129.6, 128.5, 127.9, 127.1, 126.8, 126.7, 125.1, 125.0,
123.4, 85.4, 64.2, 39.9, 37.7, 14.9.
(2R,4S)-2-tert-Butoxy-4,6-diphenyl-1-[(2-pyridyl)sulfonyl]-
13C NMR (75 MHz, CDCl3): d = 157.4, 149.9, 144.0, 137.5, 136.5,
136.0, 132.9, 128.4, 128.2, 128.1, 127.9, 127.6, 127.5, 126.8, 126.5,
125.9, 125.4, 124.7, 123.5, 85.5, 64.0, 40.2, 37.7, 14.9.
MS–FAB: m/z (%) = 425.1 (100) [M+ – OEt].
HRMS–FAB: m/z [M + H]+ calcd for C28H27N2O3S: 471.1742;
1,2,3,4-tetrahydropyridine (19)
20
Yield: 20%; white solid; mp 31–32 °C; [a]D –6 (c 0.5, CHCl3);
25% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
14.7 (minor), tR = 23.1 (major).
1H NMR (300 MHz, CDCl3): d = 8.68 (ddd, J = 4.1, 1.7, 0.8 Hz, 1
H), 7.92 (dt, J = 7.8, 1.8 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 7.41
(ddd, J = 7.7, 4.7, 1.1 Hz, 1 H), 7.30 (m, 2 H), 7.20–7.10 (m, 8 H),
6.02 (dd, J = 4.1, 2.6 Hz, 1 H), 5.71 (d, J = 3.2 Hz, 1 H), 3.05 (dt,
J = 9.2, 3.2 Hz, 1 H), 2.45 (ddd, J = 13.9, 9.3, 4.3 Hz, 1 H), 1.83 (dt,
J = 13.9, 2.6 Hz, 1 H), 1.26 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 156.7, 149.8, 145.4, 139.1, 137.5,
136.1, 128.6, 128.0, 127.9, 127.8, 127.2, 126.9, 126.7, 126.1, 125.3,
123.8, 79.3, 76.0, 39.0, 37.2, 28.5.
found: 471.1739.
(2R,4S)-6-(4-Chlorophenyl)-2-ethoxy-4-phenyl-1-[(2-py-
ridyl)sulfonyl]-1,2,3,4-tetrahydropyridine (16)
Yield: 80%; white solid; mp 150–151 °C; [a]D –38 (c 0.56,
20
CHCl3); 62% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH,
90:10): tR = 20.3 (minor), tR = 28.6 (major).
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

122
J. Esquivias et al.
PAPER
(2R,4S)-2-Ethoxy-4,6-diphenyl-1-[(8-quinolyl)sulfonyl]-1,2,3,4-
1H NMR (300 MHz, CDCl3): d = 9.07 (dd, J = 4.1, 1.7 Hz, 1 H),
8.18 (dd, J = 8.3, 1.7 Hz, 1 H), 8.01 (dd, J = 7.4, 1.3 Hz, 1 H), 7.92
(dd, J = 8.3, 1.3 Hz, 1 H), 7.49 (dd, J = 8.3, 4.3 Hz, 1 H), 7.36 (t,
J = 7.7 Hz, 1 H), 7.26 (m, 2 H), 7.15–6.93 (m, 8 H), 6.37 (dd,
J = 4.5, 3.0 Hz, 1 H), 5.65 (d, J = 3.4 Hz, 1 H), 2.76 (m, 1 H), 2.34
(ddd, J = 13.4, 8.5, 4.5 Hz, 1 H), 1.83 (ddd, J = 13.8, 4.3, 3.2 Hz, 1
H), 1.31 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 145.4, 139.6, 139.4, 136.4,
134.2, 133.7, 128.3, 127.9, 127.6, 127.5, 127.1, 125.9, 125.4, 124.6,
122.0, 78.8, 75.7, 40.8, 37.4, 28.7.
tetrahydropyridine (21)
Yield: 73%; white solid; mp 65–67 °C; [a]D –22 (c 0.4, CHCl3);
20
88% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
32.3 (minor), tR = 37.3 (major).
1H NMR (300 MHz, CDCl3): d = 9.20 (dd, J = 4.2, 1.7 Hz, 1 H),
8.32 (dd, J = 8.3, 1.7 Hz, 1 H), 8.11 (dd, J = 7.4, 1.4 Hz, 1 H), 8.06
(dd, J = 8.2, 1.3 Hz, 1 H), 7.63 (dd, J = 8.3, 4.2 Hz, 1 H), 7.47 (m,
1 H), 7.31–7.12 (m, 9 H), 6.89 (dd, J = 7.9, 1.7 Hz, 1 H), 6.55 (dd,
J = 5.7, 4.3 Hz, 1 H), 5.87 (d, J = 3.3 Hz, 1 H), 4.22 (dq, J = 9.6, 7.1
Hz, 1 H), 3.91 (dq, J = 9.6, 7.1 Hz, 1 H), 2.73–2.55 (m, 2 H), 2.08
(ddd, J = 13.2, 7.4, 3.4 Hz, 1 H), 1.27 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.3, 144.0, 139.0, 137.4,
136.7, 133.9, 133.8, 128.9, 128.2, 127.9, 127.7, 126.9, 126.8, 126.3,
125.4, 122.2, 85.1, 63.7, 41.3, 37.8, 15.2.
MS–FAB: m/z (%) = 425.1 (100) [M+ – Ot-Bu].
HRMS–FAB: m/z [M+] calcd for C26H21O2N2S: 425.1318; found:
425.1306.
(2R,3S,4R)-2-Ethoxy-4,6-diphenyl-3-methyl-1-[(8-quinolyl)sul-
fonyl]-1,2,3,4-tetrahydropyridine (25)
MS–FAB: m/z (%) = 425.1 (85) [M+ – OEt].
Yield: 67%; white solid; mp 139–140 °C; 4% ee; HPLC (AD) (0.8
mL/min; n-hexane–i-PrOH, 97:3): tR = 40.0 (minor), tR = 44.8 (ma-
jor).
HRMS–FAB: m/z [M+] calcd for C28H28O3N2S: 471.1742; found:
471.1758.
(2R,4S)-4,6-Diphenyl-2-propoxy-1-[(8-quinolyl)sulfonyl]-
1H NMR (300 MHz, CDCl3): d = 9.16 (dd, J = 4.1, 1.6 Hz, 1 H),
8.26 (dd, J = 8.2, 1.6 Hz, 1 H), 7.98 (dd, J = 7.3, 1.2 Hz, 1 H), 7.84
(dd, J = 8.2, 1.3 Hz, 1 H), 7.59 (dd, J = 8.3, 4.2 Hz, 1 H), 7.41–7.02
(m, 11 H), 5.96 (d, J = 2.6 Hz, 1 H), 5.63 (d, J = 3.2 Hz, 1 H), 4.10
(dq, J = 9.5, 6.7 Hz, 1 H), 3.83 (dq, J = 9.5, 6.7 Hz, 1 H), 3.49 (dd,
J = 8.9, 3.2 Hz, 1 H), 2.55 (m, 1 H), 1.21 (t, J = 7.0 Hz, 3 H), 0.86
(d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 151.0, 143.9, 141.3, 139.1, 137.8,
136.4, 135.7, 133.6, 133.4, 131.4, 128.7, 127.5, 127.4, 127.3, 127.2,
126.1, 125.3, 123.1, 122.1, 87.5, 64.3, 43.3, 37.6, 15.2, 15.1.
1,2,3,4-tetrahydropyridine (22)
20
Yield: 69%; white solid; mp 53–55 °C; [a]D –35 (c 0.4, CHCl3);
91% ee; HPLC (AD) 0.8 mL/min; n-hexane–i-PrOH, 97:3): tR
40.0 (minor), tR = 44.8 (major).
=
1H NMR (300 MHz, CDCl3): d = 9.09 (dd, J = 4.2, 1.7 Hz, 1 H),
8.22 (dd, J = 8.3, 1.7 Hz, 1 H), 7.98 (dd, J = 7.4, 1.3 Hz, 1 H), 7.94
(dd, J = 8.2, 1.3 Hz, 1 H), 7.53 (dd, J = 8.3, 4.2 Hz, 1 H), 7.37 (m,
1 H), 7.21–7.02 (m, 9 H), 6.83 (dd, J = 7.9, 1.7 Hz, 1 H), 6.39 (dd,
J = 5.6, 3.8 Hz, 1 H), 5.74 (d, J = 3.4 Hz, 1 H), 4.02 (dq, J = 9.5, 6.7
Hz, 1 H), 3.69 (dq, J = 9.5, 6.7 Hz, 1 H), 2.65 (td, J = 7.3, 3.4 Hz, 1
H), 2.48 (ddd, J = 15.0, 7.2, 1.4 Hz, 1 H), 1.98 (ddd, J = 13.9, 7.2,
3.8 Hz, 1 H), 1.56 (m, 2 H), 0.86 (t, J = 7.3 Hz, 3 H).
2,3,3a,4,7,7a-Hexahydro-4,6-diphenyl-7-[(8-quinolyl)sulfo-
nyl]furo[2,3-b]pyridine (26)
Yield: 83%; white solid; mp 65–67 °C; [a]D20 –15 (c 0.26, CHCl3);
58% ee; HPLC (AD) (1.0 mL/min; n-hexane–i-PrOH, 70:30): tR =
26.9 (major), tR = 38.8 (minor).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.6, 144.0, 139.0, 137.4,
137.3, 136.6, 133.9, 133.7, 128.9, 128.2, 127.9, 127.7, 127.6, 126.9,
126.4, 126.2, 125.4, 122.2, 85.2, 70.1, 40.8, 37.7, 22.9, 10.9.
1H NMR (300 MHz, CDCL3): d = 9.25 (dd, J = 4.2, 1.8 Hz, 1 H),
8.31 (dd, J = 8.3, 1.7 Hz, 1 H), 8.06 (dd, J = 7.5, 1.4 Hz, 1 H), 8.03
(dd, J = 8.1, 1.4 Hz, 1 H), 7.65 (dd, J = 8.3, 4.1 Hz, 1 H), 7.44 (t,
J = 7.8 Hz, 1 H), 7.31–7.15 (m, 9 H), 6.95 (m, 2 H), 6.09 (dd,
J = 3.9, 0.8 Hz, 1 H), 3.96 (m, 1 H), 3.63 (m, 1 H), 3.22 (m, 2 H),
1.89 (m, 1 H), 1.55 (m, 1 H).
MS–FAB: m/z (%) = 425.1 (75) [M+ – OPr].
HRMS–FAB: m/z [M+] calcd for C26H21O2N2S: 425.1318; found:
425.1312.
Anal. Calcd for C29H28O3N2S: C 71.87, H 5.82, N 5.78, S 6.62;
found: C 71.57, H 6.13, N 5.53, S 6.24.
13C NMR (75 MHz, CDCL3): d = 151.1, 143.8, 141.0, 138.0, 137.6,
136.5, 133.6, 133.3, 128.9, 128.6, 128.0, 127.7, 127.6, 126.7, 126.6,
125.3, 125.2, 122.2, 90.3, 67.3, 52.4, 41.2, 26.8.
MS–FAB: m/z (%) = 469.0 (7) [M+ + H].
HRMS–FAB: m/z [M+] calcd for C28H25O3N2S: 469.1585; found:
(2R,4S)-2-Cyclohexyloxy-4,6-diphenyl-1-[(8-quinolyl)sulfonyl]-
1,2,3,4-tetrahydropyridine (23)
Yield: 70%; yellow solid; mp 78–80 °C; [a]D20 –33 (c 0.15, CHCl3);
88% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
17.6 (minor), tR = 20.5 (major).
469.1581.
1H NMR (300 MHz, CDCl3): d = 9.10 (dd, J = 4.2, 1.8 Hz, 1 H),
8.22 (dd, J = 8.3, 1.7 Hz, 1 H), 7.95 (m, 2 H), 7.52 (dd, J = 8.3, 4.1
Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.20–7.03 (m, 8 H), 6.89 (m, 2
H), 6.46 (dd, J = 5.4, 3.6 Hz, 1 H), 5.75 (d, J = 3.4 Hz, 1 H), 4.11
(m, 1 H), 2.75 (m, 1 H), 2.46 (m, 1 H), 2.00 (m, 1 H), 1.85–1.55 (m,
4 H), 1.25–1.15 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.9, 144.0, 139.1, 137.5,
137.0, 136.6, 133.8, 133.7, 128.8, 128.1, 128.0, 127.6, 127.5, 126.8,
126.3, 126.0, 125.3, 122.0, 81.6, 73.1, 40.7, 37.6, 33.2, 31.6, 29.1,
25.9, 22.6.
(2S,4S)-4,6-Diphenyl-2-(4-methoxyphenyl)-1-[(8-quinolyl)sul-
fonyl]-1,2,3,4-tetrahydropyridine (27)
Yield: 58%; yellow solid; mp 78–80 °C; 5% ee; HPLC (OD) (1.0
mL/min; n-hexane–i-PrOH, 95:5): tR = 54.7 (minor), tR = 67.2 (ma-
jor).
1H NMR (300 MHz, CDCl3): d = 8.91 (dd, J = 4.1, 1.7 Hz, 1 H),
8.19 (dd, J = 8.4, 1.8 Hz, 1 H), 7.91 (ddd, J = 15.7, 8.2, 1.4 Hz, 2
H), 7.46 (dd, J = 8.4, 4.2 Hz, 1 H), 7.40–7.29 (m, 3 H), 7.15–6.95
(m, 7 H), 6.74–6.68 (m, 4 H), 6.44 (t, J = 7.4, Hz, 1 H), 5.69 (d,
J = 3.5 Hz, 1 H), 3.71 (s, 3 H), 3.02 (m, 1 H), 2.65 (m, 1 H), 2.25
(m, 1 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.9, 144.0, 139.1, 137.5,
137.0, 136.6, 133.8, 133.7, 128.8, 128.1, 128.0, 127.6, 127.5, 126.8,
126.3, 126.0, 125.3, 122.0, 81.6, 73.1, 40.7, 37.6, 33.2, 31.6, 29.1,
25.9, 22.6.
(2R,4S)-2-tert-Butoxy-4,6-diphenyl-1-[(8-quinolyl)sulfonyl]-
1,2,3,4-tetrahydropyridine (24)
20
Yield: 35%; white solid; mp 66–68 °C; [a]D –13 (c 0.4, CHCl3);
68% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 98:2): tR =
54.7 (minor), tR = 78.1 (major).
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

PAPER
Inverse-Electron-Demand Diels–Alder Reactions
123
(2R,4S)-4-(4-Fluorophenyl)-6-phenyl-2-propoxy-1-[(8-
(2R,4S)-4-(2-Furyl)-6-phenyl-2-propoxy-1-[(8-quinolyl)sulfo-
quinolyl)sulfonyl]-1,2,3,4-tetrahydropyridine (36)
nyl]-1,2,3,4-tetrahydropyridine (39)
Yield: 52%; white solid; mp 56–58 °C; [a]D –17 (c 0.4, CHCl3);
20
20
Yield: 75%; white solid; mp 62–64 °C; [a]D –81 (c 0.4, CHCl3);
92% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
31.9 (minor), tR = 42.7 (major).
77% ee; HPLC (AS) (1.0 mL/min; n-hexane–i-PrOH, 94:6): tR
71.12. (minor), tR = 74.5 (major).
=
1H NMR (300 MHz, CDCl3): d = 9.10 (dd, J = 4.2, 1.8 Hz, 1 H),
8.20 (dd, J = 8.3, 1.7 Hz, 1 H), 7.93 (m, 2 H), 7.52 (dd, J = 8.3, 4.1
Hz, 1 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.16–7.01 (m, 5 H), 6.89 (m, 2
H), 6.78 (m, 2 H), 6.30 (dd, J = 5.1, 3.3 Hz, 1 H), 5.65 (d, J = 3.3
Hz, 1 H), 3.94 (dq, J = 9.4, 6.6 Hz, 1 H), 3.67 (dq, J = 9.4, 6.6 Hz,
1 H), 2.85 (td, J = 7.3, 3.4 Hz, 1 H), 2.46 (ddd, J = 13.6, 7.2, 5.6 Hz,
1 H), 2.02 (ddd, J = 13.9, 5.5, 3.4 Hz, 1 H), 1.52 (m, 2 H), 0.82 (t,
J = 7.4 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 9.06 (dd, J = 4.2, 1.8 Hz, 1 H),
8.17 (dd, J = 8.4, 1.8 Hz, 1 H), 7.90 (m, 2 H), 7.50 (dd, J = 8.3, 4.1
Hz, 1 H), 7.31 (t, J = 7.9 Hz, 1 H), 7.14–7.01 (m, 6 H), 6.30 (dd,
J = 4.7, 3.5 Hz, 1 H), 6.11 (dd, J = 3.1, 1.9 Hz, 1 H), 5.81 (d, J = 2.5,
1 H), 5.67 (d, J = 3.4 Hz, 1 H), 3.89 (dq, J = 9.4, 6.6 Hz, 1 H), 3.65
(dq, J = 9.4, 6.6 Hz, 1 H), 3.04 (td, J = 8.0, 5.2 Hz, 1 H), 2.42 (ddd,
J = 13.9, 7.8, 5.6 Hz, 1 H), 1.95 (ddd, J = 13.9, 5.3, 3.4 Hz, 1 H),
1.50 (m, 2 H), 0.79 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 151.0, 144.0, 140.7, 138.9, 137.5,
137.2, 136.6, 133.8, 133.7, 133.5, 129.6, 129.5, 128.8, 127.7, 127.6,
127.0, 125.4, 124.8, 122.2, 114.9, 114.7, 84.7, 70.2, 39.7, 36.7,
22.9, 10.8.
MS–FAB: m/z (%) = 443.0 (78) [M+ – OPr].
HRMS–FAB: m/z [M+] calcd for C29H28O3N2FS: 503.18043; found:
13C NMR (75 MHz, CDCl3): d = 157.2, 151.0, 143.8, 140.6, 138.9,
137.4, 137.1, 136.5, 133.7, 128.8, 127.7, 127.5, 127.3, 127.2, 125.3,
122.1, 121.1, 110.1, 104.8, 84.4, 69.9, 35.8, 30.9, 22.9, 10.8.
MS–FAB: m/z (%) = 416.1 (100) [M+ – OPr].
HRMS–FAB: m/z [M+] calcd for C27H27N2O4S: 475.1613; found:
475.1610.
503.18046.
(2R,4S)-4-tert-Butyl-6-phenyl-2-propoxy-1-[(8-quinolyl)sulfo-
(2R,4S)-4-(2-Naphthyl)-6-phenyl-2-propoxy-1-[(8-quinolyl)sul-
nyl]-1,2,3,4-tetrahydropyridine (40)
Yield: 61%; white solid; mp 65–67 °C; [a]D 82 (c 0.5, CHCl3);
20
fonyl]-1,2,3,4-tetrahydropyridine (37)
20
Yield: 69%; white solid; mp 68–70 °C; [a]D –97 (c 0.4, CHCl3);
90% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
33.7 (minor), tR = 42.1 (major).
84% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
11.6 (major), tR = 15.9 (minor).
1H NMR (300 MHz, CDCl3): d = 9.09 (dd, J = 4.2, 1.8 Hz, 1 H),
8.16 (m, 2 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.49 (m, 2 H), 7.38–7.15
(m, 5 H), 7.00 (m, 1 H), 6.57 (dd, J = 7.7, 5.8 Hz, 1 H), 5.78 (d,
J = 4.0 Hz, 1 H), 4.12 (dq, J = 9.4, 6.6 Hz, 1 H), 3.79 (dq, J = 9.4,
6.6 Hz, 1 H), 2.25 (m, 1 H), 1.67 (m, 1 H), 1.22 (m, 1 H), 0.98 (t,
J = 7.3 Hz, 3 H), 0.82 (m, 2 H), 0.26 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.2, 139.3, 138.3, 137.0,
136.6, 134.2, 133.5, 129.2, 128.9, 127.8, 127.7, 127.3, 126.1, 125.2,
121.9, 87.5, 69.9, 42.1, 36.9, 30.3, 26.8, 22.9, 10.9.
1H NMR (300 MHz, CDCl3): d = 9.20 (dd, J = 4.2, 1.8 Hz, 1 H),
8.32 (dd, J = 8.4, 1.7 Hz, 1 H), 8.06 (m, 2 H), 7.83 7.61 (m, 4 H),
7.51–7.33 (m, 4 H), 7.26–7.10 (m, 6 H), 6.46 (dd, J = 5.5, 3.8 Hz, 1
H), 5.92 (d, J = 3.3 Hz, 1 H), 4.10 (dq, J = 9.5, 6.6 Hz, 1 H), 3.79
(dq, J = 9.5, 6.6 Hz, 1 H), 3.04 (td, J = 7.3, 3.4 Hz, 1 H), 2.65 (ddd,
J = 13.6, 7.5, 5.7 Hz, 1 H), 2.22 (ddd, J = 13.7, 7.1, 3.7 Hz, 1 H),
1.65 (m, 2 H), 0.94 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.0, 142.2, 139.1, 137.5,
137.3, 136.6, 133.8, 133.7, 133.3, 132.1, 128.8, 127.8, 127.7, 127.6,
127.5, 127.0, 126.6, 126.3, 125.9, 125.5, 125.4, 122.2, 85.0, 70.2,
40.1, 37.7, 22.9, 10.9.
(2R,4S)-6-(4-Chlorophenyl)-4-phenyl-2-propoxy-[(8-
quinolyl)sulfonyl]-1,2,3,4-tetrahydropyridine (41)
20
Yield: 73%; white solid; mp 58–60 °C; [a]D –35 (c 0.4, CHCl3);
MS–FAB: m/z (%) = 475.1 (78) [M+ – OPr].
HRMS–FAB: m/z [M+] calcd for C33H31O3N2S: 535.20554; found:
90% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
30.8 (major), tR = 37.0 (minor).
535.20674.
1H NMR (300 MHz, CDCl3): d = 9.10 (dd, J = 4.2, 1.8 Hz, 1 H),
8.24 (dd, J = 8.3, 1.7 Hz, 1 H), 8.02 (m, 2 H), 7.53 (dd, J = 8.4, 4.2
Hz, 1 H), 7.42 (m, 1 H), 7.28–7.0 (m, 7 H), 6.83 (m, 2 H), 6.34 (dd,
J = 5.6, 3.8 Hz, 1 H), 5.74 (d, J = 3.4 Hz, 1 H), 3.96 (dq, J = 9.5, 6.7
Hz, 1 H), 3.67 (dq, J = 9.5, 6.7 Hz, 1 H), 2.63 (td, J = 7.3, 3.4 Hz, 1
H), 2.44 (ddd, J = 13.6, 7.2, 5.6 Hz, 1 H), 1.99 (ddd, J = 13.5, 7.2,
3.8 Hz, 1 H), 1.56 (m, 2 H), 0.86 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.2, 143.9, 137.6, 137.3,
136.7, 136.3, 133.9, 133.8, 133.5, 128.8, 128.2, 128.1, 127.9, 127.8,
126.9, 126.4, 125.4, 122.2, 85.2, 70.1, 40.7, 37.6, 22.9, 10.9.
Anal. Calcd for C33H31O3N2S: C, 74.13; H, 5.66; N, 5.24; S, 6.00.
Found: C, 73.89; H, 5.94; N, 4.87; S, 5.69.
(2R,4S)-4-(4-Methoxyphenyl)-6-phenyl-2-propoxy-1-[(8-
quinolyl)sulfonyl]-1,2,3,4-tetrahydropyridine (38)
20
Yield: 65%; white solid; mp 72–74 °C; [a]D –27 (c 0.4, CHCl3);
80% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
50.12. (minor), tR = 55.5 (major).
1H NMR (300 MHz, CDCl3): d = 9.09 (dd, J = 4.2, 1.8 Hz, 1 H),
8.21 (dd, J = 8.3, 1.7 Hz, 1 H), 7.96 (m, 2 H), 7.52 (dd, J = 8.3, 4.1
Hz, 1 H), 7.36 (t, J = 7.9 Hz, 1 H), 7.20–7.03 (m, 5 H), 6.75 (d,
J = 8.7 Hz, 2 H), 6.62 (d, J = 8.7 Hz, 2 H), 6.36 (dd, J = 5.6, 3.8 Hz,
1 H), 5.65 (d, J = 3.3 Hz, 1 H), 3.99 (dq, J = 9.5, 6.7 Hz, 1 H), 3.69
(dq, J = 9.5, 6.7 Hz, 1 H), 3.64 (s, 3 H), 2.61 (td, J = 7.3, 3.4 Hz, 1
H), 2.46 (ddd, J = 13.5, 7.1, 5.6 Hz, 1 H), 1.95 (ddd, J = 13.7, 5.5,
3.4 Hz, 1 H), 1.54 (m, 2 H), 0.86 (t, J = 7.4 Hz, 3 H).
MS–FAB: m/z (%) = 459.1 (100) [M+ – OPr].
HRMS–FAB: m/z [M+] calcd for C29H28O3N2ClS: 519.1503; found:
519.1547.
Anal. Calcd for C29H27O3N2ClS: C, 67.10; H, 5.29; N, 5.40; S, 6.18.
Found: C, 67.48; H, 5.53; N, 5.03; S, 5.84.
13C NMR (75 MHz, CDCl3): d = 155.7, 148.7, 141.7, 136.7, 135.1,
134.7, 134.4, 131.6, 131.3, 126.5, 125.3, 124.6, 124.4, 123.0, 119.8,
111.2, 82.8, 67.8, 52.9, 38.5, 34.5, 20.6, 8.5.
(2R,4S)-4-Phenyl-2-propoxy-1-[(8-quinolyl)sulfonyl]-6-[4-(tri-
fluoromethyl)phenyl]-1,2,3,4-tetrahydropyridine (42)
20
Yield: 69%; white solid; mp 68–70 °C; [a]D –43 (c 0.4, CHCl3);
91% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
37.8 (major), tR = 40.4 (minor).
Anal. Calcd for C30H30N2O4S: C, 70.01; H, 5.88; N, 5.44; S, 6.23.
Found: C, 69.86; H, 6.01; N, 5.22; S, 5.89.
1H NMR (300 MHz, CDCl3): d = 9.09 (dd, J = 4.2, 1.7 Hz, 1 H),
8.23 (dd, J = 8.3, 1.6 Hz, 1 H), 7.99 (m, 2 H), 7.55 (dd, J = 8.3, 4.1
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124
J. Esquivias et al.
PAPER
Hz, 1 H), 7.44–7.28 (m, 6 H), 7.14–7.02 (m, 3 H), 6.83 (m, 2 H),
6.32 (dd, J = 5.5, 3.6 Hz, 1 H), 5.83 (d, J = 3.4 Hz, 1 H), 3.98 (dq,
J = 9.5, 6.7 Hz, 1 H), 3.69 (dq, J = 9.5, 6.7 Hz, 1 H), 2.69 (td,
J = 7.2, 3.4 Hz, 1 H), 2.41 (ddd, J = 13.6, 7.6, 5.6 Hz, 1 H), 1.99
(ddd, J = 13.8, 6.9, 3.7 Hz, 1 H), 1.55 (m, 2 H), 0.86 (t, J = 7.4 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.1, 144.0, 142.7, 137.2,
136.7, 136.3, 133.9, 133.8, 129.3, 128.9, 128.3, 128.1, 127.9, 127.0,
126.4, 125.4, 124.7, 124.6, 122.3, 85.1, 70.3, 40.3, 37.7, 22.9, 10.8.
126.0, 125.4, 124.7, 122.4, 119.0, 110.9, 84.3, 70.2, 35.7, 34.7,
23.0, 10.9.
(2R,4S)-4-Phenyl-2-propoxy-4-styryl-1-[(8-quinolyl)sulfonyl]-
1,2,3,4-tetrahydropyridine (49)
Yield: 68%; yellow solid; mp 80–81 °C; [a]D20 –13 (c 0.4, CHCl3);
20% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
24.2 (major), tR = 43.4 (minor).
1H NMR (300 MHz, CDCl3): d = 9.05 (dd, J = 4.2, 1.8 Hz, 1 H),
8.35 (dd, J = 8.3, 1.7 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.93 (d,
J = 8.4 Hz, 1 H), 7.52 (dd, J = 8.3, 4.1 Hz, 1 H), 7.40 (t, J = 7.8 Hz,
1 H), 7.21–7.00 (m, 7 H), 6.90 (m, 3 H), 6.36 (d, J = 16.0 Hz, 1 H),
6.25 (dd, J = 5.0, 4.3 Hz, 1 H), 5.70 (d, J = 3.5 Hz, 1 H), 3.78 (dq,
J = 9.4, 6.6 Hz, 1 H), 3.50 (dq, J = 9.4, 6.6 Hz, 1 H), 2.70 (m, 1 H),
2.52 (m, 1 H), 2.03 (ddd, J = 13.7, 6.0, 3.3 Hz, 1 H), 1.49 (m, 3 H),
0.82 (t, J = 7.3 Hz, 3 H).
MS–FAB: m/z (%) = 494.1 (100) [M+ – OPr].
HRMS–FAB: m/z [M+] calcd for C30H28F3N2O3S: 553.1694; found:
553.1691.
(2R,4S)-6-(2-Naphthyl)-4-phenyl-2-propoxy-1-[(8-quinolyl)sul-
fonyl]-1,2,3,4-tetrahydropyridine (43)
Yield: 67%, white solid; mp 78–80 °C; 6% ee; HPLC (AD) (0.7
mL/min; n-hexane–i-PrOH, 90:10): tR = 45.8 (major), tR = 60.2
(minor).
13C NMR (75 MHz, CDCl3): d = 151.2, 144.7, 143.9, 137.4, 136.9,
136.7, 135.3, 134.3, 133.9, 129.4, 128.9, 128.5, 128.2, 127.9, 127.6,
127.4, 126.6, 125.5, 123.2, 122.2, 85.0, 69.7, 39.4, 42.1, 26.0, 10.8.
1H NMR (300 MHz, CDCl3): d = 9.13 (dd, J = 4.2, 1.8 Hz, 1 H),
8.21 (dd, J = 8.4, 1.7 Hz, 1 H), 7.89 (m, 2 H), 7.69 (m, 1 H), 7.60–
7.41 (m, 4 H), 7.40–7.28 (m, 3 H), 7.26–7.03 (m, 4 H), 6.88 (m, 2
H), 6.45 (dd, J = 5.5, 3.8 Hz, 1 H), 5.90 (d, J = 3.3 Hz, 1 H), 4.09
(dq, J = 9.5, 6.6 Hz, 1 H), 3.75 (dq, J = 9.5, 6.6 Hz, 1 H), 2.77 (td,
J = 7.3, 3.4 Hz, 1 H), 2.57 (ddd, J = 13.6, 7.5, 5.7 Hz, 1 H), 2.06
(ddd, J = 13.7, 7.1, 3.7 Hz, 1 H), 1.59 (m, 2 H), 0.88 (t, J = 7.4 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.5, 137.4, 137.2, 136.6,
136.4, 133.9, 133.6, 133.0, 132.8, 128.8, 128.2, 128.0, 127.9, 127.5,
127.1, 127.0, 126.3, 125.8, 125.6, 125.3, 125.2, 124.6, 122.1, 85.2,
70.2, 40.8, 37.8, 23.0, 10.9.
(2R,4S)-2-Hydroxy-4,6-diphenyl-1-[(8-quinolyl)sulfonyl]-
1,2,3,4-tetrahydropyridine (51)
To a soln of 21 (91% ee, 99 mg, 0.21 mmol) in CH2Cl2 (2 mL) at 0
°C was added BF3·OEt2 (0.026 mL, 0.21 mmol). The mixture was
stirred at 0 °C for 2 h before it was quenched with sat. aq NH4Cl (10
mL). The mixture was extracted with CH2Cl2 (2 × 15 mL) and the
combined organic phase was dried (Na2SO4) and concentrated. The
residue was purified by flash chromatography (deactivated silica
gel, n-hexane–EtOAc, 3:1); this afforded 51.
Yield: 82 mg (88%); white solid; mp 67–69 °C; [a]D20 +17 (c 0.4,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 9.00 (dd, J = 4.2, 1.7 Hz, 1 H),
8.22 (dd, J = 8.3, 1.7 Hz, 1 H), 7.84 (dd, J = 7.4, 1.3 Hz, 1 H), 7.54
(dd, J = 8.2, 1.3 Hz, 1 H), 7.44 (dd, J = 8.3, 4.2 Hz, 1 H), 7.21–7.02
(m, 6 H), 6.91–6.62 (m, 5 H), 5.65 (s, 1 H), 5.05 (dd, J = 2.7, 1.3 Hz,
1 H), 3.83 (ddd, J = 9.5, 6.7, 2.8 Hz, 1 H), 2.51 (dddd, J = 14.0, 6.7,
3.0, 1.4 Hz, 1 H), 2.08 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 151.1, 144.7, 144.3, 139.0, 137.5,
137.3, 135.9, 133.9, 133.2, 128.9, 128.2, 128.0, 127.7, 127.6, 126.9,
126.4, 126.2, 125.4, 122.2, 85.2, 71.4, 45.2, 33.4.
(2R,4S)-6-(4-Chlorophenyl)-2-propoxy-4-styryl-1-[(8-
quinolyl)sulfonyl]-1,2,3,4-tetrahydropyridine (46)
Yield: 63%; white solid; mp 65–67 °C; [a]D20 –140 (c 0.2, CHCl3);
92% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
28.7 (major), tR = 38.1 (minor).
1H NMR (300 MHz, CDCl3): d = 9.06 (dd, J = 4.2, 1.8 Hz, 1 H),
8.19 (dd, J = 8.3, 1.7 Hz, 1 H), 7.95 (dd, J = 8.1, 1.3 Hz, 1 H), 7.86
(dd, J = 7.5, 1.4 Hz, 1 H), 7.51 (dd, J = 8.3, 4.1 Hz, 1 H), 7.35 (t,
J = 7.9 Hz, 1 H), 7.20–7.15 (m, 4 H), 7.00–6.95 (m, 4 H), 6.16 (m,
3 H), 5.36 (d, J = 3.6 Hz, 1 H), 3.87 (dq, J = 9.4, 6.6 Hz, 1 H), 3.70
(dq, J = 9.4, 6.6 Hz, 1 H), 2.66 (m, 1 H), 2.13 (ddd, J = 14.0, 7.7,
3.8 Hz, 1 H), 1.96 (dt, = 14.0 and 2.7 Hz, 1 H), 1.55 (m, 3 H), 0.87
(t, J = 7.3 Hz, 3 H).
Tetracyclic Compounds 52–54; General Procedure
To a soln of 21 (91% ee, 99 mg, 0.21 mmol) in CH2Cl2 (2 mL) at 0
°C was added BF3·OEt2 (0.026 mL, 0.21 mmol). The mixture was
stirred at 0 °C for 2 h before it was cooled to –78 °C and treated with
the nucleophile (1.2 equiv). The mixture was stirred for 30 min at
–78 °C, and then quenched with sat. aq. NH4Cl (10 mL) and extract-
ed with CH2Cl2 (2 × 15 mL). The combined organic phase was
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography (deactivated silica gel, n-hexane–EtOAc, 3:1).
13C NMR (75 MHz, CDCl3): d = 151.1, 143.9, 137.9, 137.4, 136.5,
135.0, 133.8, 133.6, 133.4, 133.3, 129.2, 128.8, 128.6, 128.5, 128.4,
128.0, 127.4, 126.0, 125.3, 122.4, 122.2, 84.3, 70.1, 35.6, 35.1,
23.1, 10.9.
(2R,4S)-6-(4-Cyanophenyl)-2-propoxy-4-styryl-1-[(8-
quinolyl)sulfonyl]-1,2,3,4-tetrahydropyridine (47)
Yield: 70%; yellow solid; mp 85–86 °C; [a]D20 –102 (c 0.4, CHCl3);
92% ee; HPLC (AD) (0.7 mL/min; n-hexane–i-PrOH, 90:10): tR =
45.9 (minor), tR = 53.5 (major).
1H NMR (300 MHz, CDCl3): d = 9.06 (dd, J = 4.2, 1.8 Hz, 1 H),
8.21 (dd, J = 8.3, 1.7 Hz, 1 H), 7.96 (m, 2 H), 7.52 (dd, J = 8.3, 4.1
Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.26 (d,
J = 8.4 Hz, 2 H), 7.15 (m, 5 H), 6.16 (m, 2 H), 6.05 (m, 1 H), 5.51
(d, J = 3.6 Hz, 1 H), 3.86 (dq, J = 9.4, 6.6 Hz, 1 H), 3.68 (dq,
J = 9.4, 6.6 Hz, 1 H), 2.62 (m, 1 H), 1.92 (m, 1 H), 1.55 (m, 3 H),
0.87 (t, J = 7.3 Hz, 3 H).
Compound 52
Yield: 82%; white solid; mp 76–78 °C; [a]D20 –203 (c 0.4, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.15–6.94 (m, 12 H), 6.78 (dd,
J = 7.4, 1.4 Hz, 1 H), 6.44 (t, J = 7.5 Hz, 1 H), 6.18 (m, 1 H), 5.59
(ddd, J = 7.9, 4.9, 2.9 Hz, 1 H), 5.21 (dd, J = 2.7, 0.8 Hz, 1 H), 5.16
(dd, J = 6.8, 2.5 Hz, 1 H), 4.01 (ddd, J = 15.4, 4.9, 1.2 Hz, 1 H), 3.82
(ddd, J = 15.3, 2.6, 0.8 Hz, 1 H), 3.60 (m, 1 H), 2.73 (dtd, J = 13.9,
6.1, 1.0 Hz, 1 H), 1.91 (ddd, J = 14.2, 8.4. and 2.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 144.0, 140.8, 138.0, 136.9, 130.8,
128.8, 127.9, 127.7, 127.6, 127.5, 127.4, 127.0, 125.8, 123.7, 123.4,
122.6, 121.0, 119.5, 117.4, 72.9, 45.6, 36.4, 31.6.
13C NMR (75 MHz, CDCl3): d = 151.2, 144.4, 143.9, 137.2, 136.6,
134.9, 134.2, 133.3, 133.0, 131.5, 129.6, 128.9, 128.5, 127.7, 127.2,
MS–FAB: m/z (%) = 427.1 (100) [M+ + H].
Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York

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Inverse-Electron-Demand Diels–Alder Reactions
125
HRMS–FAB: m/z [M+] calcd for C26H23N2O2S: 427.1403; found:
427.1435.
(2) This reaction was first achieved by Yamamoto using a
stoichiometric amount of a chiral boron complex. See:
Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
(3) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem.
Int. Ed. 1998, 37, 979. (b) Kobayashi, S.; Kusakabe, K.-i.;
Komiyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220.
(c) Kobayashi, S.; Kusakabe, K.-i.; Ishitani, H. Org. Lett.
2000, 2, 1225. (d) For the use of hydrazones as dienophiles,
see: Kobayashi, S.; Ueno, M.; Saito, S.; Mizuki, Y.; Ishitani,
H.; Yamashita, Y. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5476. (e) Yamashita, Y.; Mizuki, Y.; Kobayashi, S.
Tetrahedron Lett. 2005, 46, 1803.
Compound 53a
Yield: 71%, white solid; mp 83–85 °C; [a]D20 –323 (c 0.34, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.44–7.18 (m, 16 H), 6.94 (dd,
J = 7.4, 1.5 Hz, 1 H), 6.63 (t, J = 7.6 Hz, 1 H), 6.22 (dd, J = 10.0,
1.5 Hz, 1 H), 5.77 (d, J = 3.8 Hz, 1 H), 5.65 (dd, J = 9.8, 4.9 Hz, 1
H), 5.25 (dd, J = 5.1, 1.1 Hz, 1 H), 4.20 (m, 1 H), 3.66 (ddd,
J = 10.5, 5.0, 2.2 Hz, 1 H), 2.80 (dtd, J = 14.2, 5.2, 1.2 Hz, 1 H),
2.04 (ddd, J = 14.2, 10.6. and 2.2 Hz, 1 H), 1.15 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 143.8, 139.8, 138.1, 137.4, 130.8,
128.8, 128.3, 128.0, 127.8, 127.5, 127.0, 124.1, 123.8, 122.0, 118.5,
117.2, 70.8, 49.2, 36.1, 32.4, 17.7.
(4) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 4018.
(5) (a) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 1998, 37, 3121. (b) Yao, S.; Saaby,
S.; Hazell, R. G.; Jørgensen, K. A. Chem. Eur. J. 2000, 6,
2435. (c) García Mancheño, O.; Gómez Arrayás, R.;
Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456.
(d) García Mancheño, O.; Gómez Arrayás, R.; Adrio, J.;
Carretero, J. C. J. Org. Chem. 2007, 72, 10294.
(6) (a) Guillarme, S.; Whiting, A. Synlett 2004, 711.
(b) Di Bari, L.; Guillarme, S.; Hanan, J.; Henderson, A. P.;
Howard, J. A. K.; Pescitelli, G.; Probert, M. R.; Salvadori,
P.; Whiting, A. Eur. J. Org. Chem. 2007, 5771.
(7) Shang, D.; Xin, J.; Liu, Y.; Zhou, X.; Liu, X.; Feng, X.
J. Org. Chem. 2008, 73, 630.
Compound 54a
Yield: 60%; white solid; mp 79–81 °C; [a]D20 –354 (c 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.31–7.12 (m, 11 H), 7.01 (dd,
J = 7.4, 1.4 Hz, 1 H), 6.61 (t, J = 7.6 Hz, 1 H), 6.36 (d, J = 9.6 Hz,
1 H), 5.82 (dd, J = 9.6, 5.9 Hz, 1 H), 5.75 (dd, J = 5.1, 2.2 Hz, 1 H),
5.12 (dd, J = 1.9, 1.5 Hz, 1 H), 4.20 (m, 1 H), 3.66 (ddd, J = 10.5,
5.0, 2.2 Hz, 1 H), 2.80 (dtd, J = 14.2, 5.2, 1.2 Hz, 1 H), 2.04 (ddd,
J = 14.2, 10.6. and 2.2 Hz, 1 H), 1.15 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 143.8, 139.8, 138.1, 137.4, 130.8,
128.8, 128.3, 128.0, 127.8, 127.5, 127.0, 124.1, 123.8, 122.0, 118.5,
117.2, 70.8, 49.2, 36.1, 32.4, 17.7.
(8) Jurčík, V.; Arai, K.; Salter, M. M.; Yamashita, Y.;
Kobayashi, S. Adv. Synth. Catal. 2008, 350, 647.
(9) (a) Sundén, H.; Ibrahem, I.; Eriksson, L.; Córdova, A.
Angew. Chem. Int. Ed. 2005, 44, 4877. (b) Akiyama, T.;
Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128,
13070. (c) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem.
Int. Ed. 2006, 45, 4796. (d) Akiyama, T.; Tamura, Y.; Itoh,
J.; Morita, H.; Fuchibe, K. Synlett 2006, 141. (e) Newman,
C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.;
Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216.
(10) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617.
(11) Sundararajan, G.; Prabagaran, N.; Varghese, B. Org. Lett.
2001, 3, 1973.
Anal. Calcd for C27H24N2O2S: C, 73.61; H, 5.49; N, 6.36; S, 7.28.
Found: C, 73.28; H, 5.68; N, 6.04; S, 7.89.
Compound 54b
Yield: 15%; white solid; mp 83–85 °C; [a]D20 –134 (c 0.4, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.45–7.15 (m, 11 H), 6.94 (dd,
J = 7.2, 1.4 Hz, 1 H), 6.64 (dd, J = 7.8, 7.3 Hz, 1 H), 6.23 (d, J = 9.8
Hz, 1 H), 5.81 (d, J = 3.6 Hz, 1 H), 5.62 (dd, J = 9.7, 5.4 Hz, 1 H),
5.18 (dd, J = 11.2, 3.1 Hz, 1 H), 4.09 (m, 1 H), 3.76 (ddd, J = 10.4,
7.0, 3.6 Hz, 1 H), 2.74 (m, 1 H), 2.30 (ddd, J = 13.4, 7.1, 3.3 Hz, 1
H), 1.30 (d, J = 6.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.0, 140.2, 138.3, 136.9, 131.8,
128.8, 127.8, 127.7, 127.6, 127.2, 127.4, 127.0, 125.8, 123.7, 123.4,
122.6, 121.0, 119.5, 117.4, 72.9, 36.4, 31.4, 18.3.
(12) Magesh, C. J.; Makesh, S. V.; Perumal, P. T. Bioorg. Chem.
Lett. 2004, 14, 2035.
(13) For a review on the ADAR of 1-azadienes, see: Behforouz,
M.; Ahmadian, M. Tetrahedron 2000, 56, 5259.
(14) (a) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A.
M. J. Am. Chem. Soc. 1991, 113, 1713. (b) Boger, D. L.;
Corbett, W. L. J. Org. Chem. 1993, 58, 2068; and references
cited therein.
Acknowledgment
The ‘Ministerio de Ciencia e Innovación’ (MICINN, BQU2003-
0508), and ‘Consejería de Educación de la Comunidad Autónoma
de Madrid’ (CAM) and the UAM (Project CCG07-UAM/PPQ-
1799) are gratefully acknowledged for financial support. J.E. thanks
the MICINN for a Predoctoral Fellowship. A generous allocation of
computer time at the ‘Centro de Computación Científico-UAM’ is
also acknowledged.
(15) Clark, R. C.; Pfeiffer, S. S.; Boger, D. L. J. Am. Chem. Soc.
2006, 128, 2587.
(16) For recent examples on diastereoselective ADAR of 1-aza-
dienes, see: (a) Aversa, M. C.; Barattucci, A.; Bilardo, M.
C.; Bonaccorsi, P.; Giannetto, P. Synthesis 2003, 2241.
(b) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629.
(c) See also: Tarver, J. E. Jr.; Terranova, K. M.; Joullié, M.
M. Tetrahedron 2004, 60, 10277. (d) Palacios, F.; Vicario,
J.; Aparicio, D. Tetrahedron Lett. 2007, 48, 6747.
(17) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418.
(18) Han, B.; Li, J.-L.; Ma, C.; Zhang, S. J.; Chen, Y.-C. Angew.
Chem. Int. Ed. 2008, 47, 9971.
(19) For the Cu(OTf)2-catalyzed intramolecular ADAR of a 2-
cyano-1-azadiene containing an enol ether component, see:
Motorina, I. A.; Grierson, D. S. Tetrahedron Lett. 1999, 40,
7215.
References
(1) For a recent review on stereoselective aza-Diels–Alder
reactions, see: (a) For a review on catalytic asymmetric aza-
Diels–Alder reactions, see: Rowland, G. B.; Rowland, E. B.;
Zhang, Q.; Antilla, J. C. Curr. Org. Chem. 2006, 10, 981.
(b) Kobayashi, S. In Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S.; Jørgensen, K. A., Eds.; Wiley-
VCH: Weinheim, 2002, Chap. 5, 187–209.
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PAPER
(32) Unit cell parameters: a = 9.4345 (2), b = 11.1796 (3), c =
(20) (a) Sugimoto, H.; Nakamura, S.; Hattori, M.; Ozeki, S.;
Shibata, N.; Toru, T. Tetrahedron Lett. 2005, 46, 8941.
(b) Nakamura, S.; Nakashima, H.; Sugimoto, H.; Shibata,
N.; Toru, T. Tetrahedron Lett. 2006, 47, 7599.
21.8461 (6); space group P212121. CCDC 641861 contains
the supplementary crystallographic data for this compound.
These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(c) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 9588.
(d) Nakamura, S.; Nakashima, H.; Sugimoto, H.; Sano, H.;
Hattori, M.; Shibata, N.; Toru, T. Chem. Eur. J. 2008, 14,
2145. (e) Nakamura, S.; Nakashima, H.; Yamamura, A.;
Shibata, N.; Toru, T. Adv. Synth. Catal. 2008, 350, 1209.
(f) Lu, G.; Morimoto, H.; Matsunaga, S.; Shibasaki, M.
Angew. Chem. Int. Ed. 2008, 47, 6847.
(33) Critical NOE contacts for 54a and 54b are shown in Figure 3
below.
O
O
O
S
N
O
S
N
Ph
N
H
(21) (a) Esquivias, J.; Gómez Arrayás, R.; Carretero, J. C. J. Org.
Chem. 2005, 70, 7451. (b) Esquivias, J.; Gómez Arrayás,
R.; Carretero, J. C. Angew. Chem. Int. Ed. 2006, 45, 629.
(c) Salvador González, A.; Gómez Arrayás, R.; Carretero, J.
C. Org. Lett. 2006, 8, 2977. (d) Esquivias, J.;
Ph
N
H
H
H
Me
Me
H
H
H
H
Ph
H
Ph
H
54a
54b
Goméz Arrayás, R.; Carretero, J. C. Angew. Chem. Int. Ed.
2007, 46, 9257. (e) Salvador González, A.; Gómez Arrayás,
R.; Rodríguez Rivero, M.; Carretero, J. C. Org. Lett. 2008,
10, 4335.
Figure 3
(34) The supplementary crystallographic data for 54b can be
found in the Supporting Information of ref. 22.
(22) For a recent communication of this work, see: Esquivias, J.;
Gómez Arrayás, R.; Carretero, J. C. J. Am. Chem. Soc. 2007,
129, 1480.
(23) For the synthesis of 2-pyridylsulfonyl imines 1–4 and 7–10,
see ref. 21a. For the synthesis of 8-quinolylsulfonyl imines
20, 28–35, 44, 45, and 48, see ref. 22.
(24) In agreement with literature data, only decomposition
products were obtained in the reactions of N-tosyl-, N-(2-
thienylsulfonyl)-, and N-(2-pyridylsulfonyl)imines of
benzaldehyde with 5 in the presence of 10 mol% of
Cu(OTf)2 after 48 hours at room temperature.
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(25) Amounts of dienophile lower than 20 equivalents led to
incomplete conversions.
(26) Similar enantioselectivities were obtained in other solvents,
such as toluene (61% ee), 1,2-dichloroethane (62% ee),
tetrahydrofuran (58% ee), or 1,4-dioxane (60% ee).
(27) (a) For the optimized preparation of the DBFOX-Ph ligand,
see: Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka,
J.; Wada, E.; Curran, D. P. J. Org. Chem. 1997, 62, 6454.
(b) Ulrich, I.; Oderaotoshi, Y.; Kanemasa, S.; Curran, D. P.
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(28) Dichloromethane proved to be the optimal solvent (DCE led
to poorer endo selectivity while no reaction was observed in
toluene, Et2O, or THF).
(29) The Ni(ClO4)2·6H2O and DBFOX-Ph led to a complex that
contains three molecules of water. Kanemasa’s group
previously observed a decrease of asymmetric induction
when the reaction is performed in the presence of molecular
sieves. See, for instance: Itoh, S.; Kanemasa, S. J. Am.
Chem. Soc. 2002, 124, 13394.
(30) For an example of the preparation of a chiral [1,2,4]benzo-
thiadiazine-5,5-dioxide with activity as an AMPA receptor
modulator, see: Cobley, C. J.; Foucher, E.; Lecouve, J.-P.;
Lennon, I. C.; Ramsdem, J. A.; Thominot, G. Tetrahedron:
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Synthesis 2009, No. 1, 113–126 © Thieme Stuttgart · New York