Decarboxylative cyclizations and cycloadditions of palladium-polarized aza-ortho-xylylenes

Article abstract of DOI:10.1016/j.tet.2009.04.071

Vinyl benzoxazinones undergo decarboxylation in the presence of palladium catalysts to form palladium-polarized aza-ortho-xylylenes, which are versatile reaction intermediates. These palladium-polarized aza-ortho-xylylenes are generated under exceptionall

Full text of DOI:10.1016/j.tet.2009.04.071

Tetrahedron 65 (2009) 5102–5109
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Decarboxylative cyclizations and cycloadditions of palladium-polarized
aza-ortho-xylylenes
*
Chao Wang, Nirmal Pahadi, Jon A. Tunge
Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Vinyl benzoxazinones undergo decarboxylation in the presence of palladium catalysts to form palladium-
polarized aza-ortho-xylylenes, which are versatile reaction intermediates. These palladium-polarized
aza-ortho-xylylenes are generated under exceptionally mild conditions and undergo a plethora of dif-
ferent reactions depending on the reaction conditions. Specifically, they undergo dimerization reactions
to produce macrocycles, cyclizations to form dihydroquinolines, cycloadditions with electrophilic
p-bonds, and nucleophilic attack by amines. Thus, a wide array of structurally unique aniline derivatives
can be accessed from these unique intermediates.
Received 2 February 2009
Received in revised form 8 April 2009
Accepted 20 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
diastereoselective cycloadditions to generate highly substituted pi-
peridine derivatives.3
Previously, we have shown that palladium catalysts effect the
decarboxylation of vinyl oxazinones to form zwitterionic -allyl pal-
The related vinyl benzoxazinones (3) undergo similar palladium-
induced decarboxylation (Scheme 2).4 However, these substrates give
rise to aza-ortho-xylylene synthons (C).5 The decarboxylation of vinyl
benzoxazinones under conditions of palladium catalysis occurs at
25 ꢀC and is thus significantly milder than thermal decarboxylation of
benzoxazinones, which typically requires temperatures near 200 ꢀC.6
In addition, the aza-ortho-xylylene equivalents generated in the
presence of palladium are more polarized than standard aza-ortho-
xylylenes. Thus, while standard aza-ortho-xylylenes preferentially
react with electron rich olefins, palladium-polarized aza-ortho-xyly-
lenes (D) prefer to react with electron deficient olefins. Herein, we
further describe the cyclization and cycloaddition chemistry of these
unique intermediates.
p
ladium intermediates (A, Scheme 1).1 Thus, vinyl oxazinones can be
equated with zwitterionic synthons (B). In the absence of other
electrophiles, the zwitterionic intermediate cyclizes to form vinyl
azetidines withhighdiastereoselectivity. Moreover, inthepresence of
suitably electrophilic Michael acceptors,2 the intermediates undergo
Ts
N
Ts
N
Ts
N
cat.
Pd(PPh3)4
O
O
25 °C, CH2Cl2
R
PdL2
Ts
A
B
Ts
Ts
N
Ts
cat.
Pd(PPh3)4
N
O
O
O
N
N
O
O
O
25 °C, CH2Cl2
R
R
R
3
C
1
Ts
N
cat.
Pd(PPh3)4
Ts
N
25 ºC
Ar
cat.
Pd(PPh3)4
NC
CN
Ar
CN
Ts
N
Ts
N
+
R
CN
25 °C, CH2Cl2
2
PdL2
Scheme 1.
D
palladium-polarized
Aza-o-xylylene
* Corresponding author. Tel.: þ1 785 864 4136; fax: þ1 785 864 5396.
E-mail address: tunge@ku.edu (J.A. Tunge).
Scheme 2.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.071

C. Wang et al. / Tetrahedron 65 (2009) 5102–5109
5103
Table 1
Formation of macrocycles
NHCO2Me
OH
R
1) PCC
NHCO2Me
OH
Ts
2) 2 equiv (vinyl)MgBr
N
+
K2CO3
H
N
O
N
Ts
Ts
O
R
R
5 mol % Pd(PPh3)4
rt, Tol
O
+
Ts
N
Ts
O
N
-CO2
Scheme 3.
R
2. Decarboxylative macrocycloadditions
R
N
To begin, vinyl benzoxazinone was synthesized from ortho-
hydroxymethyl phenylcarbamate (Scheme 3).4 Specifically, the al-
cohol was oxidized to the aldehyde with PCC on alumina,7 followed
by addition of a vinyl Grignard reagent. This procedure often pro-
duced the desired benzoxazinone, however, the ratio of cyclized
and uncyclized carbamate was not always reproducible. Thus, the
product of Grignard addition was treated with potassium carbonate
to ensure high-yielding cyclization.8 Finally, N-tosylation under
standard conditions gave the desired starting material.6 Impor-
tantly, this process could be carried out without chromatographic
purification of any intermediates.
Entry
R
Conditions
Vinyl JHH (Hz)
Product
Yields (%)
1
2
3
4
H
Toluene, 25 ꢀ
C
16.2
16.2
16.2
9.8
trans-4a
trans-4b
trans-4c
cis-4d
36
87
94
92
Me
OMe
F
Toluene, 25 ꢀC
Toluene, 25 ꢀ
CICH2CH2CI, 60 ꢀ
C
C
macrocycles obtained from toluene (4a–c) were clearly the trans–
trans geometry (J¼16.2 Hz). These results suggested that the con-
formation of the zwitterionic p-allyl intermediate may be different
in different solvents, with the syn-allyl complex being favored in
toluene and the anti-allyl complex being more accessible in di-
chloroethane (Scheme 5).
Next, vinyl carbamate 3a was treated with Pd(PPh3)4 in toluene
at room temperature. After 10 min, 1H NMR spectroscopic analysis
indicated the clean formation of the 12-membered macrocycle 4a,
however, the product was isolated in only 36% yield (Scheme 4).9
The low isolated yield led us to believe that the zwitterionic in-
termediate may also form oligomers or polymers under the re-
action conditions. It is also important to note that, in contrast to
saturated vinyl oxazinones, which rapidly form vinyl azetidines
under these conditions (Scheme 1),1 the formation of vinyl azeti-
dines is never observed in the reactions of vinyl benzoxazinones.
PdL2
PdL2
N
N
Ts
Ts
D
D
syn-
anti-
Ts
N
Ts
Ts
N
N
5 mol%
Pd(PPh3)4
O
toluene
N
N
Ts
N
Ts
O
Ts
N
Ts
3a
4a
Scheme 5.
Next, in an attempt to test for the presence of free aza-ortho-
xylylenes in this reaction media, the same reaction was conducted
in the presence of butyl vinyl ether. It was reasoned that if a free
aza-ortho-xylylene was being formed, then the electron rich olefin
should trap the intermediate via [4þ2] cycloaddition (Scheme 6).
Since, no cycloaddition product was observed, we conclude that
free aza-ortho-xylylene intermediates are not formed to any ap-
preciable extent under our reaction conditions.
Ts
N
Ts
N
L2Pd
+
N
Ts
PdL2
N
Ts
L2Pd
Scheme 4.
Given the discovery of a rapid, formal [6þ6] cycloaddition, we
briefly examined the generality of this macrocycloaddition. As can
be seen in Table 1, addition of groups to the position para to the
tosylamide significantly improved the isolated yields of products. To
explain this observation, we speculate that the group is blocking
electrophilic aromatic substitution that can take place with the
protio derivative. Surprisingly, the fluorine-containing derivative
did not form any isolable products when allowed to react under
analogous conditions in toluene at room temperature. However,
switching the solvent to dichloroethane and performing the re-
action at 60 ꢀC did allow for the isolation of a high yield of the
fluorinated macrocycle. Interestingly, the coupling constant for the
olefinic protons (J¼9.8 Hz) of the macrocyclic product (4d) indicated
that the product had an exclusively cis–cis geometry whereas the
5 mol %
PdL2
Pd(PPh3)4
O
rt, Tol
-CO2
N
Ts
O
N
Ts
-Pdo
OBu
N
N
Ts
OBu
Ts
Scheme 6.

5104
C. Wang et al. / Tetrahedron 65 (2009) 5102–5109
Table 2
OBu
Ts
R2
N
5 mol %
Pd(PPh3)4
R1
R2
R1
5 mol % Pd(PPh3)4
rt, CH2Cl2
O
O
CO2
toluene
-CO2
O
N
Ts
N
Ts
N
Ts
N
Ts
O
4a
3
5
110 ºC
overnight
Entry
R1
H
p-Me
p-MeO
p-F
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
Me
Me
Me
Me
5a
5b
5c
5d
5e
5f
65
50
80
51
77
94
92
82
PdL2
PdL2
N
N
Ts
N
Ts
H
5a Ts
p-Me
p-MeO
p-F
anti-D
syn-D
5g
5h
Scheme 7.
Conducting the same trapping experiment at 100 ꢀC led to an
interesting result. While the macrocycle (4a) was formed cleanly as
the kinetic product, it quantitatively converted to the hydro-
quinoline (5a) upon heating overnight (Scheme 7).10 With the
knowledge that hydroquinolines are the thermodynamic product,
we set forth to develop a decarboxylative cyclization that would
give rise to hydroquinolines. Here, it proved important to consider
Other vinyl benzoxazinones reacted similarly to 3a. Thus, sub-
jecting a variety of vinyl benzoxazinones to catalytic Pd(PPh3)4 in
dichloromethane at room temperature produced the desired
dihydroquinolines in good to excellent yields (Table 2). While most
yields were satisfactory, the yield of the fluorinated product 5d was
somewhat low at 51%. Careful investigation of this crude reaction
mixture showed that the mass balance was made up by macrocycle
4d. Notably, the 2-methallyl derivative of the fluorinated carbamate
produced cyclized product 5h in substantially higher yield (82%)
and the macrocycle was not observed in the crude reaction mixture.
Thus, the methallyl group (R2¼CH3) appears to sterically preclude
formation of macrocycles, which leads to high product yields in
each case where the 2-substituted allyl groups were utilized (5e–
h). In fact, performing the reaction of methallyl reactant 3f in tol-
uene, a solvent that typically favors macrocycloaddition, lead to
exclusive formation of the dihydroquinoline product with no evi-
dence of macrocycle formation (Scheme 9). While the methyl group
may sterically slow intermolecular macrocycloaddition, it may also
the conformations of the
p-allyl complex that give rise to the
macrocycle vs hydroquinoline. While the trans-macrocycle is as-
suredly formed from the thermodynamically more stable syn
conformation of the
p-allyl complex (syn-D), the hydroquinoline
must be formed from the less stable anti-conformation (anti-D,
Scheme 7). Thus, in most cases, the trans macrocycles are probably
the kinetic product because they are derived from the more stable
conformation.
3. Decarboxylative cyclizations
With the goal of biasing the conformation such that the anti-
conformation of the p-allyl complex would be viable, our attention
bias the conformation of the
p-allyl complex by disfavoring the syn-
p-allyl complex. Although steric bulk is tolerated in the 2-position
turned to chlorinated solvents. Our previous results suggested that
the trans macrocycle was favored in toluene, but in ClCH2CH2Cl we
were able to access a cis macrocycle. These results indicated that
the anti-conformation of zwitterionic intermediate may be more
accessible in dichloroethane. Investigation of several solvents
quickly led to the conclusion that dichloromethane was the ideal
solvent for decarboxylative cyclization. Ultimately, treatment of the
vinyl benzoxazinone 3a with 5 mol % Pd(PPh3)4 in CH2Cl2 at room
temperature for 4 h effected complete conversion of the starting
material and product 5a was isolated in 65% yield (Scheme 8).
Importantly, monitoring the reaction by 1H NMR spectroscopy
showed that macrocycle 4a was not an intermediate in the reaction.
Furthermore, the same analysis showed that vinyl azetidines are
not intermediates in this transformation.1,11 Therefore, it appears
that the dihydroquinoline is the kinetic product in dichloro-
methane solvent.
of the allyl group, there is a limit on sterics that are tolerated in the
cyclization; a substrate (3i) with a terminally disubstituted vinyl
Me
Me
Me
5 mol % Pd(PPh3)4
tol, 110 ºC
Me
N
Ts
O
5f
N
Ts
O
Me
Me
3f
Ts
N
N
Ts
Me
4f not observed
Me
Ts
N
Me
X
PdL2
X
N
Ts
anti
PdL2
5 mol % Pd(PPh3)4
O
Me
syn
rt, CH2Cl2
N
Ts
O
N
Ts
65%
Me
3a
5a
Me
5 mol % Pd(PPh3)4
PdL2
O
Me
Me
rt, CH2Cl2
N
Ts
N
Ts
N
Ts
O
or d-Tol, 110 °C
3i
5i
Scheme 8.
Scheme 9.

C. Wang et al. / Tetrahedron 65 (2009) 5102–5109
5105
group does not undergo any reaction, even under forcing condi-
tions (110 ꢀC) and only starting material is present after 12 h. Since
decarboxylation after formation of a -allyl palladium complex is
facile and generally leads to irreversible transformation of the re-
actant, this experiment suggests that substrate (3i) is unreactive
5 mol %
O
O
O
p
N
N
H
CN
CN
H
N
Ts
O
X
PPh2 Ph2P
X
Y
toward formation of the requisite p-allyl palladium complex.
+
N
2.5 mol % Pd2dba3
4-6 hrs
Y
33
Another current limitation of the decarboxylative cyclization to
form dihydroquinolines is the inability to use protecting groups
other than tosyl. For example, unprotected and benzyl protected
vinyl oxazinones do not react under any conditions (Scheme 10).
Ts
CN
CN
60-99% yield, 84-99% ee
>20:1 dr
Presumably, these substrates can form
p-allyl palladium com-
Scheme 12.
plexes, but decarboxylation to form the relatively unstable aniline
anion is unfavorable. Use of the more tractable nosyl protecting
group did lead to substantial decarboxylative cyclization,12 but the
formation of a large amount of oligomeric/polymeric material
limits the utility of that protecting group in our chemistry. Lastly,
the benzoyl protecting group does facilitate decarboxylative cycli-
zation, however, the benzoyl group is non-innocent and takes part
in the cyclization to form benzoxazine 6a in high yield. This
transformation is expected on the basis of Cook’s precedent that
oxazoles can be formed in a similar manner.13
development of a highly asymmetric cycloaddition, which utilizes
a variant of the well-known Trost ligand (Scheme 12).4,14
In our communication of the asymmetric decarboxylative
cycloaddition of electron deficient olefins, we provided a stereo-
chemical rationale based on Lloyd-Jones’ mnemonic for the C1-
symmetric complex of the Trost ligand with Pd(0).15 Since that
time, Lloyd-Jones has refined his model to incorporate a critical H-
bonding interaction between the incoming nucleophile and the
amide NH in the ligand backbone.16 In doing so, he has developed
a new mnemonic device that nicely predicts our observed stereo-
chemistry. Specifically, they found that the Trost ligand binds to
palladium to produce 8, which exists in a conformation represented
as E. Simplifying this further, leads to a predictive model that has
sterically hindering groups represented as A, B, and C, while there is
an attractive interaction with the NH (Fig. 1). Thus, the nucleophile
prefers to align on the left side of the palladium complex to max-
imize H-bonding with the NH group, while the aryl (Ar) group di-
rects itself up and away from a steric interaction with ligand
backbone (C). Such an H-bond-directed attack of the nucleophile on
5 mol % Pd(PPh3)4
O
N
R
CD2Cl2, rt
< 5 % conversion
N
R
O
R = H, Bn
R = H, Bn
5 mol % Pd(PPh3)4
CD2Cl2, rt
O
Polymer
byproducts
N
O
O
N
Ns
the
p-allyl complex accounts for our observed stereochemistry.
Ns
In addition to benzylidene malononitriles, a variety of other
electrophiles were investigated for their ability to intercept the
polarized aza-o-xylylene intermediates. Simple enones, like methyl
vinyl ketone, are not electrophilic enough to out-compete intra-
molecular cyclization, thus dihydroquinoline is the only product.
Other acrylonitrile derivatives are, however, electrophilic enough to
promote cycloaddition rather than cyclization. For instance, phe-
nylsulfonyl acrylonitrile provides the products in good yield using
just 1 equiv of electrophile (Scheme 13). Moreover, the products are
formed as single diastereomers; presumably the stereochemistry is
governed by a cyclization where all of the large groups occupy
pseudo-equatorial positions about the six-membered ring. Cyano-
coumarins are also adequate partners in the cycloaddition chem-
istry, however, higher concentrations of cyanocoumarin are
required to achieve similar yields to the sulfonyl acrylonitrile.
O
N
5 mol % Pd(PPh3)4
CH2Cl2
O
N
Ph
O
Ph
6a, 96%
Scheme 10.
4. Decarboxylative cycloaddition of olefins
While attempts to intercept aza-ortho-xylylene intermediates
with electron rich olefins such as butyl(vinyl) ether were un-
successful, coordination of palladium is expected to polarize the aza-
ortho-xylylene toward reaction with electron deficient olefins. Thus,
allowing the vinyl benzoxazinone (3a, X¼Ts) to react with 1 equiv of
benzylidene malononitrile produced the cycloaddition product 7a in
excellent yield with good diastereoselectivity (Scheme 11). Here, the
nosyl protecting group also produced a high yield of product, how-
ever, 5 equivofMichael acceptor were required to achieve highyields.
Thus, we proceeded to use the tosyl-protected benzoxazinones in the
R
R
C
O
C
NH
OC
N
O
O
H
A
Ph
N
H
N
H
Pd
P
P
B
P
P
Pd
8
Ph2
Ph2
E
O
Ar C
NH
C
CN
CN
N
X
O
Z
Ts
NH
5 mol % Pd(PPh3)4
N
A
Z
A
CH2Cl2, rt
99%
N
X
Ph
B
Ph
CN
CN
7a
B
X = Ts. 99%, (+/-) dr=8.9:1
X = Ns, 92%, (+/-) dr>19:1
Lloyd-Jones' mnemonic
favored transition state
Scheme 11.
Figure 1.

5106
C. Wang et al. / Tetrahedron 65 (2009) 5102–5109
Table 3
Decarboxylative aminations
R
O
N
Ts
O
NR2
NH
S(O)2Ph
CN
R
5 mol % Pd(PPh3)4
CH2Cl2, rt
b
Ts
6 mol % Pd(PPh3)4
N
Ts
Ph
O
Ph
CN
+
rt, tol
-CO2
NR2
N
Ts
O
S(O)2Ph
R = H, 80%
R = CH3, 75%
NH
Ts
O
O
l
O
CN
N
Ts
Pd(PPh3)4
CH2Cl2
O
Entry
1
Amine
Product
b:I
Yield (%)
97
CN
O
N
Ts
H
H
N
10a
>19:1
>19:1
>19:1
O
3 eq
83%
H
N
Scheme 13.
2
3
10b
10c
96
98
H2N
Investigation of the reaction by 1H NMR spectroscopy shows that
product is formed as a 7:1 mixture along with dihydroquinoline
produced via intramolecular cyclization.
Ph
H2N
4
5
10d
10e
10f
>19:1
d
82a
<5
65
Ph
5. Decarboxylative cycloaddition of tosyl isocyanate
H2N
Ph
Electrophiles other than Michael acceptors are also viable
partners for decarboxylative cycloaddition. For example, treatment
of the vinyl benzoxazinone 3a with tosyl isocyanate produced the
dihydroquinazolinone (9a, Scheme 14).17 Unfortunately, the same
reaction performed with a chiral Trost ligand that was successful in
cycloaddition of Michael acceptors led to only low enantiose-
lectivity in the formation of 9a (24% ee).
Ts
6
>1:19
HN
Ph
a
Obtained as a 1.2:1 mixture of diastereomers.
nucleophilic attack at the more hindered allyl terminus. While it is
relatively unusual to observe attack at the more hindered allyl
terminus of palladium p
-allyl complexes,18 our current hypothesis
is that the basic tosylamide acts to direct the addition via a six-
membered transition state (Scheme 15). Such a hypothesis is con-
sistent with Cooks’ detailed studies on similar systems.19
O
Ts
O
5 mol % Pd(PPh3)4
N
N
Ts
O
H
CH2Cl2, rt
55%
N
N
Ts
L2Pd
(+/-) 9a
Ts-N=C=O
PdL2
N
N
H
NH
Ts
N
Ts
O
Ts
N
N
Ts
O
N
O
Ts
Scheme 15.
Scheme 14.
Analogous treatment of the benzoxazinone 3a with aniline failed
to give any product, presumably due to the lower nucleophilicity of
aniline relative to aliphatic amines. However, an activated aniline
derivative does participate in the reaction (entry 6, Table 3). Here,
a near thermoneutral proton transfer can produce the anionic sul-
fonamide nucleophile, which is substantially more reactive than
aniline (Scheme 16). Another interesting feature of the reactionwith
6. Decarboxylative aminations
The reaction of tosyl isocyanate with the vinyl oxazinone
amounts to the amination of the more hindered -allyl terminus,
p
where the amination is clearly directed, so a six-membered ring is
formed. Next, we became curious whether free amine nucleophiles
would react with the aza-ortho-xylylene intermediates with the
standard regiochemical preference for reaction at the less hindered
allyl terminus.18 Toward this end, vinyl benzoxazinone 3a was
treated with pyrrolidine in the presence of catalytic Pd(PPh3)4. In-
terestingly, the pyrrolidine reacted exclusively at the more hin-
dered allyl terminus to provide the aminated product 10a in
excellent yield (97%) and piperidine reacts similarly (Table 3, en-
tries 1 and 2). In addition, primary benzylamines react to give clean
monoallylation with the same regiochemical preference for
L2Pd
L2Pd
H
N
Ts
Ph
Ts
N(Ts)Ph
10f
N
N
Ts
NH
Ts
Ph
NH
Ts
Scheme 16.

C. Wang et al. / Tetrahedron 65 (2009) 5102–5109
5107
R'
N
R'
N
Ts
NH
Ts
HNR'2
Ts
N
Ts
Ts
O
N
O
C
N
O
N
Ts
N
R
O
N
EWG
EWG
R'
Ts
R = COPh
EWG
EWG
O
N
Ts
R'
N
Ph
Scheme 17.
N-tosyl aniline is the regiochemistry of the isolated product. While
the more basic amines produced the branched product with high
selectivity, N-tosyl aniline produced the linear product exclu-
sively.20 Once again, we attribute this divergent behavior to the
generation of the sulfonamide anion prior to C–N bond formation.
8.2.1. (7E,15E)-5,13-Ditosyl-5,6,13,14-tetrahydrodibenzo[b,h]-
[1,7]diazacyclododecine (4a)
1H NMR (400 MHz, CDCl3):
d 2.47 (6H, s, CH3Ts), 3.62 (2H, dd,
J¼13.2, 5.9 Hz, CH2), 3.73 (6H, s, CH3), 4.66 (2H, ddd, J¼13.2, 5.9,
1.3 Hz, CH2), 5.46 (2H, dt, J¼16.1, 5.9 Hz, ]CHCH2), 6.94 (2H, d,
J¼7.8 Hz, Ar CH), 7.15–7.25 (4H, m, Ar CH), 7.28 (2H, d, J¼8.6 Hz, Ar
CH), 7.41 (4H, d, J¼8.6 Hz, Ar CH), 7.50 (2H, d, J¼16.1 Hz, ]CH), 7.83
7. Conclusions
(4H, d, J¼8.1 Hz, Ar CH). 13C NMR (100 MHz, CDCl3):
d 21.7 (CH3Ts),
50.9 (CH2), 124.6 (]CHCH2), 127.0 (Ar CH), 128.2 (Ar CH), 128.4 (Ar
CH), 128.5 (Ar CH), 129.0 (Ar CH), 129.6 (quat. Ar C), 130.0 (Ar CH),
136.0 (quat. Ar C), 137.3 (]CH), 139.0 (quat. Ar C), 143.9 (quat. Ar C).
FTIR (CH2Cl2): nmax 3053, 2926, 1346, 1271, 1161, 760. HRMS calcd
for C32H34N3O4S2 [MþNH4] 588.1991, found 588.1990.
In conclusion, palladium-polarized aza-ortho-xylylenes are ver-
satile intermediates that can be generated under mild conditions via
decarboxylation of vinyl benzoxazinones. These intermediates un-
dergo dimerization reactions to produce macrocycles, cyclizations
to form dihydroquinolines, cycloadditions with electrophilic
p-
bonds, and nucleophilic attack by amines. Thus, a wide array of
structurally unique aniline derivatives can be accessed (Scheme 17).
8.2.2. (7Z,15Z)-2,10-Difluoro-5,13-ditosyl-5,6,13,14-
tetrahydrodibenzo[1,7]diazacyclododecine (4d)
1H NMR (400 MHz, CDCl3):
d 2.36 (6H, s, CH3Ts), 4.46 (4H, dd,
8. Experimental
8.1. General
J¼3.73,1.39 Hz, CH2), 5.67 (2H, dt, J¼9.8, 4.26 Hz, ]CHCH2), 6.29 (2H,
d, J¼9.8 Hz, ]CH), 6.91 (2H, t, J¼8.75 Hz, Ar CH), 7.11 (4H, d,
J¼7.89 Hz, Ar CH), 7.19–7.26 (2H, m, Ar CH), 7.33 (4H, d, J¼8.2 Hz, Ar
CH), 7.53 (2H, d, J¼8.2 Hz, Ar CH). 13C NMR (100 MHz, CDCl3):
d 21.6
Toluene and methylene chloride were dried over activated alu-
mina. Commercially available reagents were used without additional
purification unless otherwise stated. Products were purified on silica
gel from Sorbent Technologies (230ꢁ400 mesh, 60 Å porosity, pH
6.5–7.5). 1H and 13C NMR spectra were obtained on a Bruker Avance
400 or Bruker Avance 500 DRX spectrometer and referenced to re-
sidual protio solvent signals. Structural assignments are based on 1H,
13C, DEPT-135, COSY, and HMQC spectroscopies, and by comparison
with literature data.10 High resolution mass spectrometry was per-
formed on an AUTOSPEC-Q tandem hybrid mass spectrometer (VG
Analytical Ltd, Manchester, UK). FTIR spectra were acquired on
a Shimadzu FTIR-8400S spectrometer. HPLC analysis was performed
on a Shimadzu SCL-10A VP instrument.
(CH3Ts), 45.1 (CH2), 113.0 (Ar CH), 117.8 (quat. Ar C), 118.6 (]CHCH2),
122.3 (Ar CH),124.3 (]CH),127.2 (Ar CH),128.2 (Ar CH),129.2 (Ar CH),
136.1 (quat. Ar C), 143.8 (quat. Ar C), 156.8 (quat. Ar C),158.8 (quat. Ar
C). FTIR (CH2Cl2): nmax 3065, 2926, 1612, 1472, 1263, 1167, 750. HRMS
calcd for C32H28F2N2O4S2Na [MþNa] 629.1356, found 629.1359.
8.3. General procedure for catalytic decarboxylative
dihydroquinoline synthesis from vinyl benzoxazinanones
In a Schlenk tube under argon, Pd(PPh3)4 (0.05 mmol) and vinyl
benzoxazinanone 1a (1 mmol) were dissolved in methylene chlo-
ride (5 mL). The resulting yellow solution was stirred at ambient
temperature under Ar until the completion of the reaction was
indicated by TLC (generally 1–4 h). Following solvent evaporation
under reduced pressure, the crude product was purified via flash
chromatography (SiO2, 7:1 hexane/ethyl acetate).
8.2. General procedure for catalytic decarboxylative
macrocycloaddition to form 4
In a Schlenk tube under argon, Pd(PPh3)4 (0.05 mmol) and vinyl
benzoxazinanone 1 (1 mmol) were dissolved in 5 mL of toluene.
The resulting yellow solution was stirred at ambient temperature
under Ar until reaction completion was indicated by TLC (ca.
10 min). Following solvent evaporation under reduced pressure,
the crude product was purified via flash chromatography (SiO2, 2:1
hexane/ethyl acetate).
8.3.1. 6-Methyl-1-tosyl-1,2-dihydroquinoline (5b)
1H NMR (400 MHz, CDCl3):
d 2.32 (3H, s, overlapping CH3Ts,
CH3), 2.35 (3H, s, overlapping CH3Ts, CH3), 4.41 (2H, dd, J¼4.1,
1.6 Hz, CH2), 5.56 (1H, dt, J¼9.6, 4.1 Hz, ]CHCH2), 5.98 (1H, d,
J¼9.6 Hz, ]CH), 6.75 (1H, s, Ar CH), 7.08 (3H, d, J¼8.1 Hz, Ar CH),
7.31 (2H, d, J¼8.3 Hz, Ar CH), 7.59 (1H, d, J¼8.1 Hz, Ar CH). 13C NMR

5108
C. Wang et al. / Tetrahedron 65 (2009) 5102–5109
(100 MHz, CDCl3):
d
21.0 (overlapping CH3, CH3Ts), 21.6 (over-
8.5.1. 4-Methyl-N-(2-(1-(pyrrolidin-1-yl)allyl)phenyl)-
lapping CH3, CH3Ts), 45.5 (CH2), 123.8 (]CHCH2), 126.0 (]CH),
126.7 (Ar CH), 127.0 (Ar CH), 127.3 (Ar CH), 128.7 (Ar CH), 129.0 (Ar
CH), 129.3 (quat. Ar C), 132.4 (quat. Ar C), 136.4 (quat. Ar C), 136.5
(quat. Ar C), 143.3 (quat. Ar C). FTIR (CH2Cl2): nmax 3053, 2986, 1489,
1421, 1271, 1258, 895. HRMS calcd for C17H18NO2S [Mþ] 300.1058,
found 300.1059.
benzenesulfonamide (10a)
1H NMR (400 MHz, CDCl3):
d 1.85 (4H, s), 2.39 (3H, s, CH3Ts and
CH2, overlapping), 2.55 (2H, br s), 3.69 (1H, d, J¼8.84 Hz), 4.96 (1H,
d, J¼9.92 Hz), 5.09 (1H, d, J¼16.84 Hz), 5.87–5.78 (1H, m), 6.93 (1H,
d, J¼7.16 Hz), 6.99 (1H, d, J¼7.16 Hz), 7.19–7.15 (1H, m), 7.28–7.25
(1H, m), 7.53 (1H, d, J¼8.04 Hz), 7.80 (1H, d, J¼8.04 Hz),11.87 (1H, br
s). 13C NMR (100 MHz, CDCl3):
d 21.5, 23.6, 51.8, 74.3, 117.2, 118.0,
8.3.2. 6-Methoxy-3-methyl-1-tosyl-1,2-dihydroquinoline (5g)
123.0, 127.0, 128.2, 128.7, 128.8, 129.5, 136.4, 137.1, 137.8, 143.4. FTIR
(CH2Cl2): nmax 2935, 1494, 1338, 1151, 756, 655. HRMS calcd for
C20H24N2O2SNa [MþNa] 379.1456, found 379.1451.
1H NMR (400 MHz, CDCl3):
d 1.65 (3H, s, CH3), 2.36 (3H, s,
CH3Ts), 3.81 (3H, s, OCH3), 4.23 (2H, s, CH2), 5.66 (1H, s, ]CH), 6.41
(1H, d, J¼2.8 Hz, Ar CH), 6.79 (1H, dd, J¼8.8, 2.8 Hz, Ar CH), 7.09 (2H,
d, J¼8.1 Hz, Ar CH), 7.25 (2H, d, J¼8.1 Hz, Ar CH), 7.61 (1H, d,
8.5.2. 4-Methyl-N-(2-(1-(piperidin-1-yl)allyl)phenyl)-
J¼8.8 Hz, Ar CH). 13C NMR (100 MHz, CDCl3):
d
20.8 (CH3), 21.6
benzenesulfonamide (10b)
(CH3Ts), 49.6 (CH2), 55.5 (OCH3), 110.8 (Ar CH), 112.0 (Ar CH), 121.0
(]CH), 126.5 (quat. Ar C), 126.9 (Ar CH), 128.2 (Ar CH), 128.9 (Ar
CH), 131.8 (quat. Ar C), 134.4 (]C), 135.8 (quat. Ar C), 143.3 (quat. Ar
C), 158.3 (quat. Ar C). FTIR (CH2Cl2): nmax 3052, 2929, 1346, 1259,
1165. HRMS calcd for C18H19NO3SNa [MþNa] 352.0984, found
352.0982.
1H NMR (400 MHz, CDCl3):
d 1.49 (2H, br s), 1.68 (4H, m), 2.40
(3H, s, CH3Ts), 2.49 (4H, br s), 3.62 (1H, d, J¼9.60 Hz), 5.08 (2H, dd,
J¼18.50, 13.50 Hz), 5.76 (1H, dt, J¼16.9, 9.9 Hz), 6.99–6.95 (2H, m),
7.20–7.16 (1H, m), 7.28–7.25 (2H, m), 7.47 (1H, d, J¼8.00 Hz), 7.77
(2H, d, J¼7.77 Hz), 12.18 (1H, br s). 13C NMR (100 MHz, CDCl3):
d
21.5, 24.3, 26.0, 51.1, 74.1, 118.9, 119.4, 123.4, 126.9, 128.1, 128.6,
129.0, 129.6, 134.4, 137.5, 138.2, 143.3. FTIR (CH2Cl2): nmax 2935,
1492, 1340, 1150, 754. HRMS calcd for C21H26N2NaO2S [MþNa]
393.1613, found 393.1611.
8.4. General procedure for decarboxylative cycloadditions
In a Schlenk tube under argon, Pd(PPh3)4 (0.05 mmol), vinyl
benzoxazinanone 1 (1 mmol), and the electrophile (1–1.1 mmol)
were dissolved in 5 mL of methylene chloride. The resulting yel-
low solution was stirred at ambient temperature under Ar until
reaction completion was indicated by TLC (generally 4–6 h). Fol-
lowing solvent evaporation under reduced pressure, the crude
product was purified via flash chromatography (SiO2, 5:1 hexane/
ethyl acetate).
8.5.3. N-(2-(1-(Benzylamino)allyl)phenyl)-4-
methylbenzenesulfonamide (10c)
1H NMR (400 MHz, CDCl3):
d 2.37 (3H, s, CH3Ts), 3.65 (1H, d,
J¼13.04 Hz), 3.74 (1H, d, J¼13.04 Hz), 4.14 (1H, d, J¼6.76 Hz), 5.05
(2H, t, J¼10.40 Hz), 5.84–5.76 (1H, m), 7.02–6.97 (2H, m), 7.21–716
(3H, m), 7.35 (3H, m), 7.40 (2H, d, J¼7.60 Hz), 7.60 (1H, d, J¼7.60 Hz),
7.66 (2H, d, J¼7.60 Hz), 11.31 (1H, br s). 13C NMR (100 MHz, CDCl3):
d
21.4, 50.9, 65.1, 117.1, 119.3, 123.4, 127.1, 127.5, 127.8, 128.3, 128.5,
128.7, 129.4, 136.9, 137.5, 138.4, 143.2. FTIR (CH2Cl2): nmax 3028,
1494, 1150, 933, 756. HRMS calcd for C23H25N2O2SNa [MþH]
393.1637, found 393.1630.
8.4.1. 2-Phenyl-1-tosyl-4-vinyl-1,2-dihydroquinoline-3,3(4H)-
dicarbonitrile (7a)
1H NMR (400 MHz, CDCl3):
d 2.47 (3H, s, CH3Ts), 2.56 (1H, d,
J¼9.6 Hz, CHCH]), 5.09 (1H, d, J¼16.8 Hz, CH]CH(H)trans), 5.61
(1H, dd, J¼10.1, 1.0 Hz, CH]CH(H)cis), 5.77 (1H, s, CHPh), 5.91 (1H,
dt, J¼16.8, 10.1 Hz, CH]CH2), 7.17 (1H, d, J¼7.7 Hz, Ar CH), 7.29 (2H,
d, J¼7.7 Hz, Ar CH), 7.39–7.51 (5H, m, Ar CH), 7.51–7.67 (4H, m, Ar
CH), 7.89 (1H, dd, J¼7.99, 1.04 Hz, Ar CH). 13C NMR (100 MHz,
8.5.4. (E)-4-Methyl-N-(3-(2-(4-methylphenylsulfonamido)-
phenyl)allyl)-N-phenylbenzenesulfonamide
1H NMR (500 MHz, CDCl3):
d 2.41 (3H, s, CH3Ts), 2.47 (3H, s,
CH3Ts), 4.23 (2H, d, J¼6.5 Hz), 5.83 (1H, dt, J¼15.7, 6.4 Hz), 6.10 (1H,
br s), 6.21 (1H, d, J¼15.70 Hz), 7.10–7.06 (3H, m), 7.18–7.13 (2H, m),
7.29–7.22 (3H, m), 7.30 (1H, br s), 7.37–7.32 (2H, m), 7.52 (2H, d,
J¼8.25 Hz), 7.56 (2H, d, J¼8.25 Hz). 13C NMR (100 MHz, CDCl3):
CDCl3):
d 21.6 (CH3Ts), 49.1 (CHCH]), 50.0 (CCN2), 65.8 (CHPh),
111.2 (CN), 113.9 (CN), 125.0 (]CH2), 126.8 (Ar CH), 127.0 (Ar CH),
127.3 (Ar CH), 128.2 (Ar CH), 128.6 (Ar CH), 129.2 (Ar CH), 129.3
(CH]CH2), 129.6 (Ar CH), 130.0 (Ar CH), 130.2 (Ar CH), 131.6 (quat.
Ar C), 134.5 (quat. Ar C), 135.1 (quat. Ar C), 136.7 (quat. Ar C), 145.1
(quat. Ar C). FTIR (CDCl3): nmax 3053, 2986, 2305, 1597, 1483, 1421,
1262, 895. HRMS calcd for C26H21N3O2SNa [MþNa] 462.1252, found
462.1251. HPLC, Diacel Chiralpak AD-H column (96% hexane/IPA,
1.0 mL/min), tR (S,S)¼22.8 min, tR (R,R)¼32.1 min. N-nosyl derivative:
1-(4-nitrophenylsulfonyl)-2-phenyl-4-vinyl-1,2-dihydroquinoline-
d
21.6 (CH3Ts), 21.6 (CH3Ts), 52.9, 124.5, 126.3, 127.2, 127.3, 127.8,
128.1, 128.6, 128.6, 128.7, 128.8, 129.1, 129.5, 129.7, 131.4, 133.2,
135.19, 136.4, 139.2, 143.7, 143.9. HRMS calcd for C29H28N2O4S2Na
[MþNa] 555.1388, found 555.1351.
References and notes
3,3(4H)-dicarbonitrile. 1H NMR (400 MHz, CDCl3):
d 3.02 (1H, d,
1. Wang, C.; Tunge, J. A. Org. Lett. 2006, 8, 3211–3214.
2. (a) Kuhn, O.; Mayr, H. Angew. Chem., Int. Ed. 1999, 38, 343–346; (b) Lemek, T.;
Mayr, H. J. Org. Chem. 2003, 68, 6880–6886.
3. For related cycloadditions see: (a) Aoyagi, K.; Nakamura, H.; Yamamoto, Y.
J. Org. Chem. 2002, 67, 5977–5980; (b) Sekido, M.; Aoyagi, K.; Nakamura, H.;
Kabuto, C.; Yamamoto, Y. J. Org. Chem. 2001, 66, 7142–7147.
4. Wang, C.; Tunge, J. A. J. Am. Chem. Soc. 2008, 130, 8118–8119.
5. Wojciechowski, K. Eur. J. Org. Chem. 2001, 3587–3605.
J¼9.5 Hz, CHCH]), 5.33 (1H, d, J¼16.8 Hz, CH]CH(H)trans), 5.69
(1H, d, J¼10.2 Hz, CH]CH(H)cis), 5.86 (1H, s, CHPh), 5.95 (1H, ddd,
J¼16.6, 10.2, 9.5 Hz, CH]CH2), 6.97–8.26 (overlapping Ar CH).
8.5. General procedure for decarboxylative amination
6. Consonni, R.; Dalla Croce, P.; Ferraccioli, R.; La Rosa, C. J. Chem. Soc., PerkinTrans.1
1996, 1809–1814.
Pd(PPh3)4 (0.012 mmol), vinyl benzoxazinanone 3a (0.2 mmol),
and the amine (0.3 mmol) were dissolved in methylene chloride
(1.0 mL) in a well-sealed reaction vial under argon. The resulting
solution was stirred at ambient temperature under Ar until reaction
completion was indicated by TLC (generally 30 min to 1 h). Fol-
lowing solvent evaporation under reduced pressure, the crude
product was purified via flash chromatography (SiO2, 4:1 hexane/
ethyl acetate).
7. Chong, P. Y.; Janicki, S. Z.; Petillo, P. A. J. Org. Chem. 1998, 63, 8515–8521.
8. Rauno, G.; Luis, J.; Concepcion, P.; Jesus, H. R. Tetrahedron 1989, 45, 203–214.
9. For a related macrocyclic triflamide see: Satake, A.; Ishii, H.; Shimizu, I.; Inoue,
Y.; Hasegawa, H.; Yamamoto, A. Tetrahedron 1995, 51, 5331–5340.
10. (a) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.; Nishida, A. J. Org. Chem.
2006, 71, 4255–4261; (b) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson,
K. P. J. Org. Chem. 1996, 61, 3584–3585; (c) Weissman, A.; Muren, J. F. J. Med.
Chem. 1971, 14, 49–53.
11. Fugami, K.; Miura, K.; Morizawa, Y.; Oshima, K.; Utimoto, K.; Nozaki, H. Tetra-
hedron 1989, 45, 3089–3098.

C. Wang et al. / Tetrahedron 65 (2009) 5102–5109
5109
12. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373–
6374; (b) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett.
1997, 38, 5253–5256.
16. Personal communication of a manuscript that is submitted for publication Butts,
C. P.; Filali, E.; Lloyd-Jones, G. C.; Norrby, P. O.; Sale, D. A.; Schramm, Y. J. Am.
Chem. Soc., in press.
13. (a) Cook, G. R.; Shanker, P. S.; Pararajasingham, K. Angew. Chem., Int. Ed. 1999,
38, 110–113; (b) Cook, G. R.; Sun, L. Org. Lett. 2004, 6, 2481–2484.
14. Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114,
9327–9343.
15. Lloyd-Jones, G. C.; Stephen, S. C.; Fairlamb, I. J. S.; Martorell, A.; Dominguez, B.;
Tomlin, P. M.; Murray, M.; Fernandez, J. M.; Jeffery, J. C.; Riis-Johannessen, T.;
Guerziz, T. Pure Appl. Chem. 2004, 76, 589–601.
17. Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836–11837.
18. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422.
19. Cook, G. R.; Yu, H.; Sankaranarayanan, S.; Shanker, P. S. J. Am. Chem. Soc. 2003,
125, 5115–5120.
20. Investigation of the early stages of the reaction by 1H NMR spectroscopy does
not show any branched product, thus the linear product is suspected to be the
kinetic product.