Intramolecular Palladium(II)-Catalyzed 6-endo C-H Alkenylation Directed by the Remote N-Protecting Group: Mechanistic Insight and Application to the Synthesis of Dihydroquinolines

Article abstract of DOI:10.1021/acs.joc.9b03174

A protocol for the Pd(II)-catalyzed C-H alkenylation reaction of substituted N-allylanilines via an unusual 6-endo process has been developed. A density functional theory (DFT) study of the mechanistic pathway has shown that the coordination of the remote

Full text of DOI:10.1021/acs.joc.9b03174

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Article
Intramolecular Palladium(II)-catalyzed 6-endo C-H alkenylation
directed by the remote N-protecting group. Mechanistic
insight and application to the synthesis of dihydroquinolines
Asier Carral-Menoyo, Lia Sotorríos, Veronica Ortiz-de-Elguea, Aitor Diaz-
Andres, Nuria Sotomayor, Enrique Gomez-Bengoa, and Esther Lete
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03174 • Publication Date (Web): 30 Dec 2019
Downloaded from pubs.acs.org on January 2, 2020
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The Journal of Organic Chemistry
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Intramolecular Palladium(II)-catalyzed 6-endo C-H
alkenylation directed by the remote N-protecting group.
Mechanistic insight and application to the synthesis of
dihydroquinolines
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a
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Asier Carral-Menoyo, Lia Sotorríos, Verónica Ortiz-de-Elguea, Aitor Diaz-Andrés, Nuria
a
b
a
Sotomayor,* Enrique Gómez-Bengoa* and Esther Lete*
aDepartamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco /
Euskal Herriko Unibertsitatea UPV/EHU. Apdo. 644. 48080 Bilbao (Spain)
bDepartamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco / Euskal
Herriko Unibertsitatea UPV/EHU, Apdo. 1072. 20080 San Sebastián, Spain
nuria.sotomayor@ehu.es; enrique.gomez@ehu.es; esther.lete@ehu.es
R2
CH O
3
R2
OCH3
Pd(II)
[O]
H
H CO
3
N
H CO
3
N
Z
Z
O
O
6-endo-trig
5
7-92%
Abstract. A protocol for the Pd(II)-catalyzed C-H alkenylation reaction of substituted N-allylanilines
via an unusual 6-endo process has been developed. A DFT study of the mechanistic pathway has shown
that the coordination of the remote protecting group to the palladium center is determinant for the
control of the regioselectivity in favor of the 6-endo process. The reaction would proceed via prior
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activation of the alkene. This procedure constitutes a mild and efficient method for the synthesis of 1,4-
dihydroquinoline derivatives from simple and readily accessible substrates.
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Introduction
Transition-metal catalyzed C-H functionalization reactions of (hetero)arenes have emerged as very
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powerful tools for the formation of carbon-carbon bonds, and as a good alternative to traditional cross-
coupling chemistry. No prefunctionalized coupling precursors, as halides or pseudohalides are required,
though a stoichiometric oxidant is needed to regenerate the active catalytic species. These reactions can
typically be carried out under mild conditions, even in aqueous media, avoiding the need for rigorous
exclusion of oxygen. In the last years, there has been great progress in the intermolecular
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dehydrogenative Heck reaction (DHR) or Fujiwara –Moritani reaction. This reaction consists of the
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Pd(II)–catalyzed direct coupling between a Csp -hybridized reaction partner and an alkene followed by
2
2

-hydride elimination towards the site of initial migratory insertion, which formally provides a sp –sp
carbon–carbon bond. The main issue of these type of reactions has been the control of site selectivity,
that has been addressed by using either electronically activated substrates or directing groups/ligands are
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able to coordinate the metal center and facilitate the catalyst approach to the selected C-H. The
potential of its intramolecular variant for the synthesis of carbocyclic and heterocyclic frameworks,
however, remains relatively underexplored, and has been mainly applied to electron-rich heteroarenes
such as indole and pyrrole. As in related Heck cyclizations, the regioselectivity is determined by the ring
size and the preferential exo processes, which has been attributed to the strain involved in the approach
of the arylpalladium intermediate. Thus, annulated indoles and pyrroles have been prepared via 5-, 6-
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and/or 7-exo-trig cyclizations of C-3 and/or C-2 substituted derivatives with unactivated alkenes. The
procedure has also been applied to the construction of benzofurans and chromenes using electron-rich
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arenes. Specifically, our group has reported intramolecular dehydrogenative Heck reactions of aryl
homoallyl ethers and N-homoallylanilines, which provide direct access to highly and diversely
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substituted chromenes and (dihydro)quinolines, respectively. On the other hand, endo-trig cyclizations
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are rare and have been reported when the exo processes are blocked, and the palladium hydride
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elimination is not possible, as described by Lu in the synthesis of carbazoles (Scheme 1a).
The palladium-catalyzed cyclization / carboalkoxylation of C-2 and C-3 alkenyl indoles to give
carbazoles and cyclohepta[b]indoles via either 6 or 7-exo-trig, as well as 6-endo-trig processes is still an
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exception in dehydrogenative Heck-type cyclizations. Similarly, exo cyclizations are generally favored
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using activated alkenes (bearing an EWG). Thus, Pd(II)-catalyzed intramolecular reactions of N-
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phenylacrylamides afford oxindoles via formal 5-exo-trig processes, (Scheme 1b), and in some cases,
even when β-hydride elimination is not possible, the Ar-Pd(II)-intermediate prefers to undergo a
nucleophile capture or a subsequent C-H alkylation.10 However, we have demonstrated that the
intramolecular 6-endo-trig C–H alkenylation of related N-alkyl substituted N-phenylacrylamides gives
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-substituted quinolin-2[1H]-ones, showing that the reaction can be switched to the -position of the
acrylamide by selecting the catalyst, oxidant, and experimental conditions. On the other hand, Glorius12
has achieved the synthesis of indoles by a formal Pd(II)-catalyzed oxidative 5-endo cyclization of
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substituted N-arylenamine carboxylates, although, as in the work of Oestreich, a free NH is required for
the success of the reaction (Scheme 1c). The size of the formed ring can also be decisive for the
regioselectivity, as in the cyclization of 1-(1H-indol-1-yl)prop-2-enone derivatives to give 3H-
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pyrrolo[1,2-a]indol-3-ones that takes place via a 5-endo-trig cyclization (Scheme 1d).
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Previous Work:
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a)
b)
Pd(II)
O]
[
H
N
6
-endo-trig
N
Ref. 7
CH3
CH3
Pd(II)
[O]
H
O
O
5
-exo-trig
N
N
CH3
H
R
H
Ref. 9
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CO2CH3
Pd(II)
H
[
O]
5
-endo-trig
N
N
H
H
R
Ref. 12
CO2CH3
d)
R1
R1
Pd(II)
[O]
R3
H
5-endo-trig
N
N
R3
Ref. 13
R2
O
R2
O
This Work:
R2
R2
e)
R
Pd(II)
H
[
O]
6
-endo-trig
N
N
R
Z
Z
O
O
Scheme 1. Intramolecular Pd(II)-catalyzed alkenylation reactions through endo and exo processes.
Two alternative mechanistic pathways have been generally proposed for the initial palladation that
would be determinant for the endo/exo selectivity (Scheme 2). The reaction could proceed through an
arene metalation-alkene insertion (Scheme 2a) or alkene activation-arene insertion (Scheme 2b). Both
reaction pathways have been proposed to explain endo and exo insertions, in some cases without
providing experimental or theoretical evidences in favor of any of them. However, both pathways differ
in the stereochemical outcome and may lead to the formation of different diastereomers using the
appropriate substrate: in pathway a), the (hetero)aryl palladium(II) intermediate would undergo a syn
olefin insertion, followed by syn -hydride elimination. On the other hand, anti nucleophilic attack of
the arene to the Pd(II) complex would take place on an Pd(II)-coordinated alkene (pathway b) In both
cases, reductive elimination generates the reaction product and a Pd(0) complex that can be reoxidized
to Pd(II). Thus, there is stereochemical support for a mechanism involving initial palladation of the
(hetero)arene4a,5a,c or attack of the heteroarene to the palladium-complexed olefin.8,14 This Friedel-Crafts
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9
type mechanism has also been proposed for the obtention of oxyndoles (Scheme 1b), but also,
depending on the substrate used, different mechanismsm have been propsed, such as the electrophilic
palladation of an electron rich enamine, followed by deprotonation of the aromatic ring (Scheme 1c).12
Hence, a mechanistic understanding of the reaction is required in order to obtain selectively the desired
reaction products. In the context of our interest in this type of cyclization reactions6,11 we decided to
study the Pd(II)-catalyzed intramolecular alkenylation of N-protected allyl anilines to obtain
dihydroquinolines (DHQ) through a 6-endo process (Scheme 1d).
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(
Het)
Ar
(Het)
Ar
II
Pd X
2
a)
b)
arene palladation
alkene activation
II
Pd X
[O]
II
Pd X
2
(Het)
(Het)
Ar
Ar
Pd(0)
anti attack
XPdII
II
Pd X
(
Het)
Ar
(Het)
Ar
and/or
exo
syn -elimination
endo
syn -elimination
(
Het)
Ar
(Het)
Ar
or
n-exo
(n+1)-endo
Scheme 2. Schematic mechanistic pathways for the intramolecular Pd(II)-catalyzed alkenylation
reactions.
Partially hydrogenated quinolines are important structural frameworks present in a myriad of
bioactive natural products and pharmaceuticals, as well as building blocks in organic synthesis.15
Among them 1,4-dihydroquinolines (1,4-DHQ) have attracted special attention, due to their important
biological activities. For example, 4-aryl-1,4-dihydroquinoline derivatives have been characterized as a
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novel class of ABCB1 inhibitors to reverse the multidrug resistance of anticancer drugs. Besides, 1,4-
dihydroquinoline is the core of the azapodophyllotoxins, known antiproliferative microtubule
1
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destabilizing agents that have expressed very pronounced antitumor activity. 1,4-DHQ can also be
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used as drug carriers for specific delivery to the CNS in the treatment of Alzheimer’s disease or
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cerebral ischemia/reperfusion injury,19 as well as in the targeting of PET radioligands for brain
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imaging. On the other hand, they are used as building blocks in the synthesis of pyridoacridones, a
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family of marine alkaloids that exhibits an array of biological activities (Figure 1). Therefore, the
synthesis of substituted 1,4-dihydroquinolines is interesting in both synthetic and medicinal chemistry.
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R
R
O
CH O
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O
OEt
O
CH O
N
R1
3
N
R1
R
R1 = Me, Bn
-aryl-1,4DHQ
ABCB1 inhibitor
R1 = H, Me
4
Azapodophyllotoxins
antitumor
Figure 1. Selected biologically active 1,4-dihydroquinolines
Although many examples of the catalytic synthesis of quinolines and tetrahydroquinolines have been
reported,23 there have been relatively few examples of the preparation of 1,4-dihydroquinoline
derivatives. Herein we report a joint experimental and DFT study on the 6-endo cyclization on N-
protected allyl anilines that has led to an efficient method for the synthesis of 1,4-dihydroquinoline
derivatives from simple and readily accessible substrates. The protecting group on nitrogen atom has been
shown to be crucial to favor the endo cyclization process.
Results and Discussion
We selected carbamate 1aa as a model substrate (Scheme 3), using as starting point the reaction
conditions that had been previously optimized for the 6-endo cyclization of N-aryl acrylamides to
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quinolones. Under these conditions, quinoline 2 was obtained, although in a low yield (31%), together
with decomposition products. Quinoline 2 would be obtained from a 6-endo cyclization followed by
deprotection under the strongly acidic conditions, and further oxidation.
PdCl (CH CN) (5 mol%)
2
3
2
OCH3
OCH3
PhCO tBu (1.2 equiv)
3
Cu(OAc)2 (5 mol%)
p-TsOH (1 equiv.)
AcOH, rt, 24 h
H CO
3
N
H3CO
N
O
OCH3
1aa
2 (31%)
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Scheme 3. Cyclization of 1aa
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Consequently, to avoid the deprotection and additional oxidation, we switched to milder reaction
conditions, using dioxane as solvent and p-benzoquinone as the only oxidant (Table 1). The use of p-
toluensulfonic acid is also important to enhance the reactivity probably through the formation of a more
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electrophilic Pd(II) species. Under these conditions, the 6-endo cyclization took place with complete
regioselectivity, obtaining 1,2-dihydroquinoline 3aa in high isolated yield (85%) after 16 h at room
temperature (Table 1, entry 1). Formation of indole 4aa, through a 5-exo process was not detected.
Interestingly, when the protecting group is changed to a t-butyl carbamate (1ba, Table 1, entry 2), under
the same reaction conditions the reaction was sluggish, obtaining 3ba in much lower yield (38%), along
with trace amounts of the 5-exo cyclization product 4ba (not isolated) and decomposition products. An
increase in the catalyst loading to a 10 mol% (Table 1, entry 3) resulted in a faster reaction (1.5 h at
room temperature). However, although the dihydroquinoline 3ba was obtained in higher yield (58%),
the reaction was not selective, isolating a significant amount of indole 4ba, through a 5-exo process. The
change of the palladium precatalyst (Table 1, entry 4) gave a similar result. The use of a monoprotected
aminoacid24 (Boc-Val-OH) in this case did not accelerate the reaction rate, and led also to a non
selective reaction (entry 5), also when the palladium source was changed trying to obtain more
electrophilic palladium intermediates (Table 1, entries 6 and 7). The use of benzyl carbamate 1ca led
also to the regioselective formation of 3ca (Table 1, entry 8). A significant difference in reactivity was
observed when the nitrogen is protected as an amide: acetyl protected 1da (Table 1, entry 9), did not
react at all under the conditions used for 1aa (Table 1, entry 1). It was necessary to increase the catalyst
loading and to heat the reaction to 70 ºC to obtain full conversion (Table 1, entry 10). Although the 6-
endo cyclization was the major reaction pathway obtaining a good yield of 3da, indole 4da was also
isolated from the reaction mixture. Thus, the protecting group used has a strong influence in both the
reactivity and the regioselectivity of the reaction, obtaining the best results with the methyl carbamate.
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Table 1. Optimization of reaction conditions: protecting group
OCH3
OCH3
OCH3
Pd (II) (5-10 mol%)
p-BQ (1 equiv.)
pTsOH (1 equiv.)
H3CO
N
H3CO
N
H CO
N
3
dioxane
R1
R1
R1
O
O
O
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1
3aa-3da
4ba,da
entry
1
R1
[Pd(II)] (mol%)
t (h)
3
Yield
4
Yield
(%)
a
a
(%)
1
2
3
4
5
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7
8
9
1aa
1ba
1ba
1ba
1ba
1ba
1ba
1ca
1da
1da
OCH3
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
OBn
Pd(CH CN) Cl (5)
16b
16b
1.5b
1.5b
3aa
3ba,
3ba
3ba
3ba
3ba
3ba
3ca
-d
85
38
58
56
-
-
3
2
2
Pd(CH CN) Cl (5)
3
2
2
Pd(CH CN) Cl (10)
4ba
4ba
4ba
4ba
4ba
-
16
13
3
2
2
Pd(PhCN) Cl (10)
2
2
c
2b
Pd(PhCN) Cl (10)
59
15
2
2
c
3b
16e
3e
Pd(PhCN) (BF ) (10)
2
4 2
c
6b
21f
14f
Pd(OAc) (10)
2
Pd(CH CN) Cl (10)
3b
67
3
2
2
CH3
Pd(CH CN) Cl (5)
20b
1g
-
3
2
2
1
0
CH3
Pd(CH CN) Cl (10)
3da
85
4da
10
3
2
2
a
b
c
Yield (%) of isolated pure compound. room temperature. Boc-Val-OH (20 mol%) was used as
d
e
1
ligand. no reaction. Yield determined by H NMR using DMAP as internal standard (55%
conversion). Yield determined by H NMR using DMAP as internal standard (51% conversion). 70
ºC.
f
1
g
Next, we extended the reaction to substrates bearing substituents on the alkene (1ab-al, Table 2). In
all cases an electron rich aromatic ring was used, as we have previously shown in related reactions that
6
it is required to obtain good reactivity. It is noteworthy that in the all cases, the corresponding 1,4-
dihydroquinolines 5 were obtained with complete regioselectivity. No formation of the indoles, or the
1
2
corresponding 1,2-dihydroquinolines, was detected by NMR. Thus, 2-butenylaniline 1ab (R = R =
CH ) gave only a moderate yield of 5ab (Table 2, 57%), also in the presence of Boc-Val-OH. However,
3
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the reaction is best suited for the synthesis of 4-aryl substituted dihydroquinolines obtaining 5ac-5al
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with high yields and complete regioselectivity under the standard conditions (Table 2).
Table 2. Synthesis of 4-substituted dihydroquinolines 5.a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R2
R2
OCH3
CH O
3
Pd(CH CN) Cl (5 mol%)
3
2
2
p-BQ (1 equiv.)
pTsOH (1 equiv.)
dioxane, rt, 16 h
H CO
3
N
H CO
3
N
OR1
OR1
O
O
1
5
CH3O
CH3
CH3O
Ph
N
CH O
Ph
N
3
H3CO
N
H3CO
3
H CO
O
OCH3
O
OCH3
O
OtBu
5bc 73%
86%b,c
5
ab 57%
56%b,c
5ac 77%
79%c
9%b,c
85%b,c,d
8
CH3
CH3
CH3O
CH3
CH3O
3
CH O
H3CO
N
H3CO
N
3
H CO
N
O
OCH3
O
OCH3
O
OCH3
5ad 82%
5ae 92%
5af 82%
Ph
OCH3
OCH3
CH3O
CH3O
3
CH O
H3CO
N
H3CO
N
3
H CO
N
O
OCH3
O
OCH3
O
OCH3
5ag 82%
tBu
5ah 81%
5ai 73%
F
CH3O
CH3O
3
CH O
H3CO
N
H3CO
N
3
H CO
N
O
OCH3
O
OCH3
O
OCH3
5aj 87%
5ak 72%
5%b,c
5al 82%
8
a
b
Yield (%) of isolated pure product by column chromatography. Boc-Val-OH (10 mol%) was used
c
d
as ligand. Pd(PhCN) Cl (5 mol%) was used as catalyst. 1 mmol scale.
2
2
The use of Pd(PhCN) Cl in the reaction of 1ac gave 5ac in a similar yield (79%). However, the use
2
2
of Boc-Val-OH as ligand improved significantly the yield (5ac, 5bc, 5ak). The yield of 5ac was
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comparable when the reaction was carried out in a 1 mmol scale (85 vs 89% yield). In this case, the use
of the t-butyl carbamate as protecting group (1bc) did not imply a loss of selectivity, as 5bc was
obtained in similar yield, not detecting the formation of the indole in any case.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The regioselectivity of the reaction completely changed when electron withdrawing groups were
introduced in the terminal position of the alkene (Table 3). Under the standard conditions, no reaction
was observed for 1am, and in this case, an increase of the catalyst loading to 10 mol% and heating to 70
ºC was required. Under these conditions indole 4am was selectively obtained in a moderate yield (Table
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
, entry 1). The same result was obtained with the Boc-protected substrate 1bm, although indole 4bm
was isolated with lower yield (Table 3, entry 2), observing decomposition of the substrate. The reaction
could be extended to different esters 1an-1aq, obtaining selectively the indoles 4 with moderate to good
yields (Table 3, entries 3-6). .
Table 3. Use electron deficient alkenes. Synthesis of indoles 4
O
O
OR2
PdCl (CH CN) (10 mol%)
OCH3
OCH3
OR2
2
3
2
p-BQ (1 equiv.)
N
COR1
H CO
3
N
COR1
H3CO
pTsOH (1 equiv.)
dioxane, 70 ºC, 4.5 h
1
4
entry
1
R1
R2
4
Yield
(%)
a
1
2
3
4
5
6
1am OCH3 CH3
1bm OtBu CH3
1an OCH3 Et
1ao OCH3 nBu
1ap OCH3 tBu
1aq OCH3 Bn
4am
4bm
4an
4ao
4ap
4aq
68
41
68
63
54
78
aYield (%) of isolated pure product.
The results obtained show that the regioselectivity of the reaction is strongly influenced on one side
by the protecting group on the nitrogen, and on the other side, by the nature of the alkene, leading to 6-
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endo or 5-exo pathways. At this point, additional experiments were carried out in order to establish the
scope and limitations of the reaction, and provide additional information on the possible reaction
pathway. First, control experiments were carried out with 1ac (Scheme 4a). In the absence of palladium,
the reaction does not take place and unreacted 1ac is recovered after 24 h at rt. When the reaction was
carried out in the absence of p-TsOH, decomposition products were obtained. Finally, just a minor
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
amount of 5ac (<5%) was observed by H NMR when the reaction was performed with no oxidant. The
reaction is not compatible with substitution on the internal position of the alkene. Under standard
conditions, 1ar was unreactive, whereas only decomposition products were obtained when the reaction
was heated at 70 ºC (Scheme 4b). The influence of the protecting group on nitrogen is clear, as only
decomposition products were obtained when N-methyl aniline 1ea is treated under the standard reaction
conditions at rt or at 70 ºC. (Scheme 4c).
OCH3
Ph
CH O
Ph
a)
3
PdCl (CH CN)
2
3
2
p-BQ
H CO
3
N
H CO
3
N
pTsOH
CO Me dioxane, rt, 24 h
2
CO Me
2
1ac
5ac
a1) no PdCl2(CH3CN)2; BQ (1 equiv), p-TsOH(1 equiv.): no reaction
a2) PdCl2(CH3CN)2 (5 mol%); BQ (1 equiv), no p-TsOH: decomposition
a3) PdCl2(CH3CN)2 (5 mol%); no BQ, p-TsOH (1 equiv): < 5% 5ac
PdCl (CH CN)
2
b)
OCH3
2
3
(
5-10 mol%)
CH3
no reaction
(rt, 16 h)
p-BQ (1 equiv.)
decomposition
H CO
3
N
pTsOH (1 equiv.)
(70 ºC, 1.5 h)
CO Me
dioxane
2
1ar
OCH3
c)
PdCl (CH CN) (5 mol%)
2
3
2
p-BQ (1 equiv.)
decomposition
H CO
3
N
pTsOH (1 equiv.)
dioxane, rt, 2.5 h
or 70 ºC, 1 h
CH3
1ea
Scheme 4. Additional experiments
In view of these results, we next studied the effect of a p-toluensulfonyl group under the reaction
conditions. Recently, N-allyl-arylsulfonamides have been used as precursors of tetrahydroquinolines in
1
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a palladium catalyzed cascade reaction with benzenesulfonyl chlorides.25 The proposed mechanism
involves the initial coordination of the alkene to an arylpalladium(II) intermediate formed by oxidative
addition of the sulfonyl chloride to Pd(0). Although the reaction results in a formal 6-endo cyclization,
the proposed mechanistic pathway does not involve the cyclization of a substituted alkene. Under our
reaction conditions, sulfonamide 1fa gave 1,2-dihydroquinoline 3fa with complete regioselectivity in an
excellent yield (Table 4, entry 1), comparable to that obtained with carbamate 1aa (Table 1, entry 1).
However, 1fb afforded a regioisomeric mixture of 1,2- and 1,4-dihydroisoquinolines 3fb and 5fb (Table
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
, entry 2). In addition, 5fc and 5fd were selectively obtained, although with moderate yields (Table 4,
entries 3 and 4).
Table 4. Use of N-tosyl-protected anilines 1f
CH O
R1
3
R1 PdCl (CH CN)
2
OCH3
2
3
H CO
3
N
(
5 mol%)
SO Tol
2
p-BQ (1 equiv.)
3
H CO
3
N
pTsOH (1 equiv.)
dioxane, rt, 16 h
R1
CH O
3
SO Tol
2
1fa-1fd
H CO
3
N
SO Tol
2
5
entry
1
R1
3
Yield
(
5
Yield
(%)
a
a
%)
3fa 87
1fb CH3 3fb 64
1
2
3
4
1fa H
5fa
5fb
5fc
5fd
-
26
42
60
1fc Ph
1fd Bn
3fc -
3fd -
aYield (%) of isolated pure product.
At this point, we decided to examine this reactivity pattern computationally, to get a more precise
insight on the mechanistic course of the reaction. Substrate 1aa was considered a useful starting point
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2
6
for DFT calculations, to explore the main role of the palladium catalyst in the mechanism (alkene
activation or arene palladation, Scheme 2), and the subsequent 5-exo/6-endo selectivity of the
cyclization process. Three key features of the reaction ought to be explained during the study, namely,
the unusual 6-endo selectivity, the large influence of the N-protecting group on the reaction outcome,
and the preference for 1,2- or 1,4-dihydroquinoline final product depending on the nature of the
substituent at the alkene terminus. According to Scheme 2a, a hypothetical arene palladation would be
followed by a syn insertion of the alkene into the Ar-Pd bond, which could occur through 5-exo or 6-
endo pathways. Interestingly, the DFT computed activation barriers for palladium complexes of very
diverse electronic properties show a general high preference for 5-exo insertion (Figure 2) in
disagreement with the experimental results.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
L1 L2
L1
Pd
CH O
CH O
3
3
Pd
L2
N
H CO
3
H CO
3
N
OCH3
O
O
OCH3
5
-exo
6-endo
favored
favored
computationally
experimentally
‡

G (6-endo)
-
L1
L2 G (5-exo)
‡
TS1 OAc
TS2 OAc
TS3 MeCN MeCN
TS4 MeCN
TS5 none
OAc
none
10.7
6.7
6.1
5.9
3.4
none
none
Figure 2. Computed activation energies for the alkene insertion into the Ar-Pd bond with complexes of
different electronic properties
While this phenomenon presents no exception, more electron rich complexes like the anionic Pd(II)
ǂ
species in TS1 show the largest exo/endo energy difference (G = 10.7 kcal/mol). Decreasing the
electronic charge in the metal center reduces consistently the exo preference (note the trend from TS1 to
TS5 in Figure 2), but even the dicationic Pd complex in TS5, which lacks L1 and L2, is still not able to
ǂ
explain the formation of the quinoline moiety (G = 3.4 kcal/mol). Thus, these data served to clearly
1
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discard a mechanism involving cyclization after a previous arene palladation step, as hypothesized in
Scheme 2a.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Meanwhile, low activation barriers were measured when the palladium complexes are activating the
alkene towards a S Ar cyclization step (Scheme 2b). However, once again, the major product of the
E
reaction was predicted to be the 5-exo derivative, by a difference of 0.8 kcal/mol when an acetate is
coordinated to the metal centre (TS6, Figure 3) and 2.2 kcal/mol for the chloride derivative.
Noteworthy, if the coordination of the oxygen of the carbamate to the palladium centre is considered
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
7
(
Figure 4), the interesting effect of a complete inversion of the endo/exo selectivity is observed. In all
cases, the quinoline adduct becomes the preferred adduct (TS8-TS11), as experimentally noted. If a
chloride is still coordinated to palladium, as in TS8, the activation energies are high, over 28 kcal/mol.
The replacement of the chloride by a second molecule of MeCN reduces the values below 20 kcal/mol,
predicting a feasible reaction in the experimental conditions. The endo regioselectivity is general for
terminal (TS9) and substituted alkenes (TS10 and TS11), and the energy difference with respect to the
5
-exo counterparts is always high (3.0-10.0 kcal/mol), ensuring a complete regioselectivity. Even more,
the tosylamide group can play a similar role, and the activation energies for the 6-endo approach are in
the three cases (TS12-TS14) largely lower than those of the 5-exo transition states. The sense of
regioselectivity seems logical, since the coordination of the carbamate to palladium induces a larger ring
strain in the exo structures. On the other hand, the participation of the carbamate in the reaction through
intramolecular coordination to the metal can help explaining the effect of the different substituents of
nitrogen (Table 1). For example, increasing the steric bulkiness of the carbamate (OtBu, Table 1, entries
2
-8) or replacing the carbamate by an amide (Table 1, entries 9-10) can reduce their coordination ability,
affecting negatively the reactivity and/or selectivity of the process.
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L3
+
+
1
2
3
4
5
6
7
8
9
L3
L2
L1
CH O
Pd L2
L1
CH O
3
3
H
H
O
Pd


N
CH O
CH O
N
3
3
OMe
O
OMe
5-exo
6-endo
G‡ (6-endo - 5-exo) = 0.8 kcal/mol
1
2
3
TS6, L , L = OAc, L = MeCN
TS7, L = Cl, L = MeCN, L = MeCN G‡ (6-endo - 5-exo) = 2.2 kcal/mol
1
2
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Predicted endo/exo selectivity of the S Ar to the Pd(II) activated alkene
E
R
CH O
CH O
R
3
NCMe
L
3
H
H
NCMe
Pd
Pd
O

+
+
N
L
CH O
CH O
N
3
3
O
Z
Z
5-exo
6-endo
‡
‡
L
R
G (5-exo) G (6-endo)
TS8
TS9
Cl
MeCN
H
33.5
22.6
26.2
25.7
28.8
19.7
16.4
11.8
H
Z
Z
= NCO2Me
= NSO2Tol
TS10 MeCN Me
TS11 MeCN Ph
TS12 MeCN
TS13 MeCN Me
TS14 MeCN Ph
H
18.9
21.4
23.3
14.3
14.2
11.9
TS9 (5-exo)
L = MeCN
TS9 (6-endo)
L = MeCN
Figure 4. Computed activation energies for the cyclization after alkene activation by the Pd complexes.
The formation of different amounts of 1,2- or 1,4-dihydroquinoline products depending on the
substitution at the alkene terminus is difficult to rationalize at the first sight. Thus, we calculated the -
elimination of the H atoms at the 2 or 4 positions of the cyclized palladium complexes, to ascertain
whether the adduct formation is under kinetic or thermodynamic control. Interestingly, the calculations
show that the 1,2-dihydro adduct 3 is slightly (ca. 1 kcal/mol) more stable than 5 regardless the R
substituent (hydrogen, methyl, phenyl) present in the benzylic position, in complete disagreement with
the results in Table 4. Thus, the regioselectivity is not dictated by the relative stability of adducts 3 and
5
. Gratifyingly, during the study of the kinetic conditions, the substrate bearing a terminal alkene (R=H,
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ǂ
TS15, Figure 5) was predicted to be deprotonated preferentially (G = 2.4 kcal/mol) at the benzylic
position to afford the 1,2-dihydro adduct, as in the experimental result (entry 1, Table 4). The
conjugation of the forming double bond is probably responsible for this behavior. On the other hand,
with phenyl as substituent (TS17), the computed and experimental selectivities also match, favoring the
major 1,4-dihydro product. The steric hindrance between MeO/Ph and Ph/Pd moieties probably induces
a severe increase in the activation barrier of the 1,2-dihydro transition state. The methyl group shows a
mixed behavior; while TS16 is energetically in between the two other cases, the reaction is
experimentally non-selective (entry 2, Table 4). Nonetheless, the calculations are not able to predict
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
correctly the right sense of selectivity for the methyl case, probably due to its borderline character.
NCMe
CH O R H
NCMe
NCMe
CH O
R
3
3
Pd
Pd NCMe
H
CH O
N
CH O
N
3
3
SO Tol
SO Tol
2
2
1,2-dihydro
1,4-dihydro
‡
‡

G (1,4) - G (1,2)
TS15, R = H
+ 2.4
- 2.1
- 4.5
TS16, R = CH3
TS17, R = Ph
Figure 5. Computed activation energies for the -elimination step, and comparison of the 1,2- and
,4-dihydro pathways
1
Along these lines, we also found that the reaction is not stereospecific, and the 1,4-dihydroquinoline is
formed, regardless of the geometry of the double bond in the starting material. Thus, (Z)-1ac required
heating at 70º C and 10 mol% of catalyst to react, but yielded 1,4-dihydroquinoline 5ac with good yield,
not detecting the formation of the 1,2-dihydroquinoline (Scheme 5a). A mechanism involving a
palladium catalyzed Claisen rearrangement followed by a 5-exo oxidative cyclization has been proposed
5
b
for the obtainment of benzofurans from allyl aryl ethers. To rule out a related mechanism for the
formation of the dihydroquinolines, the Claisen transposition product of 1aa (o-allylaniline 6) was
prepared. Under the standard reaction conditions, the aza-Wacker reaction took place efficiently in only
3
h at rt, but exclusively through a 5-exo pathway, leading to 2-methylindole 7 in high yield (Scheme
1
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5
b). Finally, we studied the cyclization reaction using a chiral non-racemic carbamate as protecting
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
group on the nitrogen. For this purpose, we selected the carbamate derived from (–)-menthol as
protecting group. We reasoned that the coordination of the carbonyl with palladium in transition states
such as those depicted in Figure 4 could favor a closer disposition of the auxiliary to the stereocenter
being formed, and thus some extent of diastereoselectivity could be obtained that would not be expected
without the coordination effect. As shown on Scheme 6, the reaction took place in good yield, and with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
8
modest, but appreciable, diastereoselectivity in the case of 5gc. Thus, the possibility of a modest 1,7-
induction supports the coordination of the remote protecting group with palladium in the transition state
leading to the C-C bond formation.
a)
OCH3
CH O
Ph
3
PdCl (CH CN)
2
p-BQ (1 equiv.)
2
3
Ph
H CO
3
N
pTsOH (1 equiv.)
3
H CO
N
CO Me
dioxane
CO Me
2
2
(
Z)-1ac
5ac
a) PdCl (CH CN) (5 mol%), rt, 16 h: no reaction.
2
3
2
b) PdCl (CH CN) (10 mol%), 70ºC, 1h: 5ac (76%)
2
3
2
b)
OCH3
OCH3
PdCl (CH CN) (5 mol%)
2
3
2
p-BQ (1 equiv.)
CH3
CO Me
H CO
3
NH
CO Me
pTsOH (1 equiv.) H CO
dioxane, rt, 3 h
N
3
2
2
6
7 (78%)
Scheme 5. Additional experiments
PdCl (CH CN)
2
(5 mol%)
p-BQ (1 equiv.)
2
3
OCH3
R
CH O
R
N
3
pTsOH (1 equiv.)
H CO
3
N
dioxane, H CO
3
rt, 16 h
O
O
O
O
iPr
iPr
1
1
gb R = CH3
gc R = Ph
5gb (67%, dr 58:42)
5gc (78%, dr 63:37)
5gl (79%, dr 58:42)
1gl R = 1-Naphthyl
Scheme 6. Cylization of carbamates 1g.
To sum up, a reaction pathway proposal in accordance with the computational and experimental data
is shown in Scheme 7. Thus, the cyclization reaction would involve attack of the electron-rich aromatic
ring onto the palladium-complexed olefin of A. As discussed earlier (see Figures 3 and 4), the formation
1
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of intermediate B through a 6-endo process would be energetically favored by the effect of the
coordination of palladium to the oxygen atom of protecting group on nitrogen. Finally, syn -hydride
elimination of H-2 or H-4 would account for the formation of 1,2-dihydro- or 1,4-dihydroquinolines 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
or 5 respectively. The formation of the more stable 1,2-dihydroquinoline is favored when R = H,
2
whereas H-4 elimination is preferential when R = Ar (Figure 5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OCH3
H3CO
II
N
R2
Z
Ox
O
Pd Ln
alkene activation
Pd0
OCH3
R2
L
R2
3
CH O
N
CH3O
H-4 syn-elimination
or
Pd
L
Z
O
H-2 syn-elimination
A
CH3O
N
+
2
5
Z
O
R2
L
anti attack
CH3O
or
Pd
L
R2
CH3O
O
H3CO
N
B
Z
CH3O
N
R2
CH3O
+2
3
Z
O
L
H3CO
N Pd
L
Z
O
Scheme 7. Mechanistic proposal.
In conclusion, an efficient procedure for the synthesis of 4-substituted 1,4-dihydroquinolines via
Pd(II)-catalyzed 6-endo intramolecular C-H alkenylation reaction of readily accessible N-allylanilines
has been developed. The regioselectivity is controlled by the nature of the protecting group on the
nitrogen atom. DFT studies have provided understanding of the factors that govern this unusual 6-endo
process, in agreement with the observed outcome of these cyclizations. The reaction proceeds via prior
activation of the alkene, being the coordination of the remote protecting group to the palladium center
crucial to favor the formation of the six-membered ring
Experimental Section
1
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General experimental methods. Melting points were determined in unsealed capillary tubes and are
1
2
uncorrected. IR spectra were obtained using an ATR. NMR spectra were recorded at 20-25 ˚C, at 300
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
13
1
MHz for H and 75.5 MHz for C in CDCl solutions. Assignments of individual C and H resonances
3
are supported by DEPT experiments and 2D correlation experiments (COSY, HSQCed or HMBC).
Mass spectra were recorded under electron impact (EI) at 70 eV, chemical ionization (CI) at 230 eV, or
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
with an ESI source. Exact mass was obtained using a TOF detector. TLC was carried out with 0.2 mm
thick silica gel plates. Visualization was accomplished by UV light. Flash column chromatography was
performed on silica gel (230-400 mesh). All solvents used in reactions were anhydrous and purified
according to standard procedures. All air- or moisture-sensitive reactions were performed under argon;
the glassware was dried (130 ˚C) and purged with argon. Heating blocks with temperature control were
used, when necessary, for the reactions that required heating. Palladium catalysts were commercially
available, and were used without further purification: PdCl (CH CN) (99% purity), Pd(OAc) (98%)
2
3
2
2
and Pd(CHCN) (BF ) (99.9%).
4
4 2
Computational methods. All structures were optimized using density functional theory (DFT) as
implemented in Gaussian with B3LYP as functional, 6-31G** as basis set for non-metallic atoms, and
LANL2DZ as basis set for palladium. Final energies were obtained performing single-point calculations
on the previously optimized structures using the M06 functional, 6-311+G** as basis set for non-
metallic atoms and SDD for palladium. Solvation factors were introduced with the IEF-PCM method,
using 1,4-dioxane as solvent. The stationary points were characterized by frequency calculations in
order to verify that they have the right number of imaginary frequencies.
Synthesis of substituted N-allylanilines 1. Substrates 1 were prepared following the synthetic
schemes described in the Supporting Information (Schemes S1, S2 and S3).
Alkylation reactions. Synthesis of substituted N-allylanilines 1a,b,c,g. General procedure
(
Scheme S1 a and c). Over a solution of the corresponding N-protected 3,5-dimethoxyaniline (1 mmol)
in dry DMF (15 mL) at 0 ºC under argon atmosphere, NaH (60 % in mineral oil) (1.1 mmol) was added.
The reaction was stirred at 0 ºC for 1 h, and afterwards, the corresponding allyl chloride (1.2 mmol) was
1
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added. Then, the reaction was allowed to warm up to room temperature and stirred for 3-7.5 h.
Afterwards, water (20 mL) was added and the aqueous layer was extracted with AcOEt (3 × 15 mL).
The organic extracts were dried (Na SO ) and concentrated in vacuo. Flash column chromatography
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
4
(
silica gel, hexane/AcOEt) afforded the corresponding N-substituted N-allyl-3,5-dimethoxyanilines 1aa-
gc.
Methyl
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
allyl(3,5-dimethoxyphenyl)carbamate
(1aa).
Prepared
from
methyl
(3,5-
dimethoxyphenyl)carbamate (0.64 g, 3.03 mmol), NaH (60% in mineral oil) (0.13 g, 3.33 mmol) and
allyl chloride (0.30 mL, 3.64 mmol). The reaction mixture was stirred at room temperature for 3 h. After
work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 7/3) 1aa was
1
obtained as an oil (0.69 g, 91 %): H NMR (300 MHz, CDCl ): δ 3.64 (s, 3H), 3.69 (s, 6H), 4.15-4.21
3
(m, 2H), 5.05- 5.17 (m, 2H), 5.86 (ddt, J = 17.0, 10.2, 5.8 Hz, 1H), 6.30 (t, J = 2.2 Hz, 1H), 6.36 (d, J =
1
3
1
2
.2 Hz, 2H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 52.7, 53.2, 55.2, 98.5, 106.1, 116.9, 133.9,
3
-1
+
143.7, 155.6, 160.7 ppm; IR (ATR): 1702 cm ; MS (EI) m/z (rel intensity): 251.1 (M , 93), 236.1 (100);
+
HRMS (CI-TOF): calcd. for C H NO : 252.1236 [MH ]; found, 252.1234.
1
3
18
4
(
E)-Methyl-but-2-en-1-yl(3,5-dimethoxyphenyl)carbamate (1ab). Prepared from methyl (3,5-
dimethoxyphenyl)carbamate (0.46 g, 2.20 mmol), NaH (60% in mineral oil) (96.7 mg, 2.42 mmol) and
E)-1-chlorobut-2-ene (0.26 mL, 2.64 mmol). The reaction mixture was stirred at room temperature for
(
7
h. After work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 8/2) 1ab
1
was obtained as an oil and as a mixture of rotamers in a 75:25 ratio (0.51 g, 88 %): H NMR (300 MHz,
CDCl ): δ 1.57 (d, J = 6.0 Hz, 3H, minor rotamer), 1.64-1.68 (m, 3H, major rotamer), 3.69 (s, 3H, both
3
rotamers), 3.76 (s, 6H, both rotamers), 4.07-4.22 (m, 2H, major rotamer), 4.27 (d, J = 6.3 Hz, minor
1
3
1
rotamer), 5.53-5.62 (m, 2H, both rotamers), 6.33-6.40 (m, 3H, both rotamers) ppm; C{ H} NMR (75.5
MHz, CDCl ): δ 12.8 (minor rotamer), 17.7 (major rotamer), 47.2 (minor rotamer), 52.6 (major
3
rotamer), 52.8 (both rotamers), 55.3 (both rotamers), 98.6 (major rotamer), 98.7 (minor rotamer), 106.4
(both rotamers), 126.1 (minor rotamer), 126.5 (major rotamer), 127.1 (minor rotamer), 128.6 (major
rotamer), 143.8 (both rotamers), 155.7 (major rotamer), 155.8 (minor rotamer), 160.7 (minor rotamer),
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+
1
60.8 (major rotamer) ppm; IR (ATR): 1702 cm ; MS (EI) m/z (rel intensity): 265.2 (M , 49), 236.1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(
100); HRMS (ESI-TOF): calcd. for C H NO : 266.1392 [MH ]; found, 266.1403
1
4
20
4
Methyl cinnamyl(3,5-dimethoxyphenyl)carbamate (1ac). Prepared from methyl (3,5-
dimethoxyphenyl)carbamate (0.30 g, 1.43 mmol), NaH (60% in mineral oil) (62.9 mg, 1.57 mmol) and
cinnamyl chloride (0.24 mL, 1.71 mmol). The reaction mixture was stirred at room temperature for 3 h.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
After work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 7/3) 1ac was
1
obtained as an oil (0.45 g, 70 %): H NMR (300 MHz, CDCl ): δ 3.74 (s, 9H,), 4.40 (d, J = 6.2 Hz, 2H),
3
1
3
1
6
1
.07-6.60 (m, 5H,), 7.12-7.41 (m, 5H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 52.9, 53.0, 55.4, 98.8,
3
-
1
06.5, 125.1, 126.5, 127.7, 128.6, 132.6, 136.7, 143.7, 155.9, 160.9 ppm; IR (ATR): 1702 cm ; MS (EI)
+
m/z (rel intensity): 327.2 (M , 16), 236.1 (56), 117.1 (100); HRMS (ESI-TOF): calcd. for C H NO :
1
9
22
4
+
3
28.1549 [MH ]; found, 328.1565.
Methyl (Z)-(3,5-dimethoxyphenyl)(3-phenylallyl) carbamate ((Z)-1ac). Prepared from methyl (3,5-
dimethoxyphenyl)carbamate (0.45 g, 2.1 mmol), NaH (60% in mineral oil) (93.5 mg, 2.3 mmol) and
29
(
Z)-(3-chloroprop-1-en-1-yl)benzene (0.39 g, 2.5 mmol). The reaction mixture was stirred at room
temperature for 5.5 h. After work-up and purification by flash column chromatography (silica gel,
1
hexane/AcOEt 8/2) afforded (Z)-1ac as a solid (0.54 g, 78 %): mp (CH Cl ) 65-67 ºC; H NMR (300
2
2
MHz, CDCl ): δ 3.72 (s, 6H), 3.74 (s, 3H), 4.60 (dd, J = 6.3, 1.8 Hz, 2H), 5.84 (dt, J = 12.0, 6.3 Hz,
3
1
H), 5.35-5.38 (m, 1H), 6.39 (d, J = 2.0 Hz, 2H), 6.58 (d, J = 12.0 Hz, 1H), 7.11-7.35 (m, 5H) ppm;
1
3
1
C{ H} NMR (75.5 MHz, CDCl ): δ 48.7, 53.0, 55.3, 98.8, 105.1, 127.1, 128.3, 128.7, 128.8, 131.1,
3
-1
+
136.5, 143.5, 155.8, 160.8 ppm; IR (ATR): 1690 cm ; MS (ESI) m/z (rel intensity): 328.2 (MH , 60),
+
2
24.1 (100); HRMS (ESI-TOF): calcd. for C H NO : 328.1549 [MH ]; found, 328.1548.
1
9
22
4
Methyl (3,5-dimethoxyphenyl)(2-methylallyl)carbamate (1ar). Prepared from methyl (3,5-
dimethoxyphenyl)carbamate (0.22 g, 1.05 mmol), NaH (60% in mineral oil) (46.3 mg, 1.16 mmol) and
-chloro-2-methylprop-1-ene (0.12 mL, 1.26 mmol). The reaction mixture was stirred at room
3
temperature for 3 h. After work-up and purification by flash column chromatography (silica gel,
1
hexane/AcOEt 6/4) 1ar was obtained as an oil (0.25 g, 89 %): H NMR (300 MHz, CDCl ): δ 1.75 (s,
3
2
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3
2
H), 3.71 (s, 3H), 3.76 (s, 6H), 4.18 (s, 2H), 4.80-4.88 (m, 2H), 6.30-6.36 (m, 1H), 6.41 (d, J = 1.5 Hz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 20.1, 53.0, 55.4, 56.2, 98.2, 104.9, 112.0, 141.2, 143.9
3
-1
+
(C ), 156.0, 160.6 ppm; IR (ATR): 1706 cm ; MS (EI) m/z (rel intensity): 265.2 (M , 80), 250.2 (100);
1
+
HRMS (ESI-TOF): calcd. for C H NO : 266.1392 [MH ]; found, 266.1401.
1
4
20
4
tert-Butyl allyl(3,5-dimethoxyphenyl)carbamate (1ba). Prepared from tert-butyl (3,5-
dimethoxyphenyl)carbamate (0.47 g, 1.86 mmol), NaH (60% in mineral oil) (82.0 mg, 2.05 mmol) and
allyl chloride (0.18 mL, 2.24 mmol). The reaction mixture was stirred at room temperature for 4 h. After
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 9/1) 1ba was
1
obtained as an oil (0.39 g, 72 %): H NMR (300 MHz, CDCl ): δ 1.46 (s, 9H), 3.76 (s, 6H), 4.20 (d, J =
3
5.5 Hz, 2H), 5.07-5.23 (m, 2H), 5.92 (qd, 1H, J = 10.6, 5.5 Hz), 6.31 (t, J = 2.0 Hz, 1H), 6.42 (d, J = 2.0
13
1
Hz, 2H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 28.3, 53.0, 55.3, 80.4, 97.9, 104.8, 116.3, 134.4,
3
-1
+
1
44.4, 154.2, 160.5 ppm; IR (ATR): 1699 cm ; MS (ESI) m/z (rel intensity): 294.2 (MH , 6), 238.1
+
(100); HRMS (ESI-TOF): calcd. for C H NO : 294.1705 [MH ]; found, 294.1715.
1
6
24
4
tert-Butyl cinnamyl(3,5-dimethoxyphenyl)carbamate (1bc). Prepared from tert-butyl (3,5-
dimethoxyphenyl)carbamate (0.63 g, 2.50 mmol), NaH (60% in mineral oil) (0.11 g, 2.75 mmol) and
cinnamyl chloride (0.42 mL, 3.00 mmol). The reaction mixture was stirred at room temperature for 7.5
h. After work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 9/1) 1bc
1
was obtained as a solid (0.91 g, 98 %): mp (CH Cl ) 63-64 ºC; H NMR (300 MHz, CDCl ): δ 1.48 (s,
2
2
3
9
H), 3.76 (s, 6H), 4.40 (d, J = 6.2 Hz, 2H), 6.22-6.38 (m, 2H), 6.39-6.57 (m, 3H,), 7.18-7.42 (m, 5H)
1
3
1
ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 28.3, 52.6, 55.4, 80.5, 98.1, 105.0, 125.8, 126.4, 127.5,
3
-1
1
28.5, 131.9, 136.9, 144.6, 154.3, 160.6 ppm; IR (ATR): 1685 cm ; MS (ESI) m/z (rel intensity): 370.2
+
+
(MH , 6), 314.1 (100); HRMS (ESI-TOF): calcd. for C H NO : 370.2018 [MH ]; found, 370.2024.
2
2
28
4
Benzyl
allyl(3,5-dimethoxyphenyl)carbamate
(1ca).
Prepared
from
benzyl
(3,5-
dimethoxyphenyl)carbamate (0.40 g, 1.41 mmol), NaH (60% in mineral oil) (61.9 mg, 1.55 mmol) and
allyl chloride (0.14 mL, 1.69 mmol). The reaction mixture was stirred at room temperature for 5 h. After
work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 9/1) 1ca was
2
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1
obtained as an oil (0.40 g, 86 %): H NMR (300 MHz, CDCl ): δ 3.76 (s, 6H), 4.28 (dt, J = 5.8, 1.4 Hz,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
2
H), 5.12- 5.24 (m, 4H), 5.85-6.03 (m, 1H), 6.37 (t, J = 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 2H), 7.25-7.41
1
3
1
(m, 5H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 53.3, 55.3, 67.3, 98.8, 106.1, 117.1, 127.8, 127.9,
3
-1
1
28.4, 133.9, 136.6, 143.8, 155.1, 160.7 ppm; IR (ATR): 1702 cm ; MS (ESI) m/z (rel intensity): 328.2
+
+
(MH , 93); HRMS (ESI-TOF): calcd. for C H NO : 328.1541 [MH ]; found, 328.1558.
19 22 4
0
1
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6
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2
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9
0
N-Allyl-N-(3,5-dimethoxyphenyl)acetamide
(1da).
Prepared
from
N-(3,5-
dimethoxyphenyl)acetamide (0.28 g, 1.43 mmol), NaH (60% in mineral oil) (62.9 mg, 1.57 mmol) and
allyl chloride (0.14 mL, 1.72 mmol). The reaction mixture was stirred at room temperature for 3 h. After
work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 5/5) 1da was
1
obtained as an oil (0.32 g, 97 %): H NMR (300 MHz, CDCl ): δ 1.80 (s, 3H), 3.67 (s, 6H), 4.26 (d, J =
3
6
.2 Hz, 2H), 5.02- 5.20 (m, 2H), 5.87 (ddt, J = 16.8, 10.7, 6.2 Hz, 1H), 6.31 (d, J = 2.1 Hz, 2H), 6.42 (t,
1
3
1
J = 2.1 Hz, 1H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 22.5, 51.8, 55.4, 99.5, 106.4, 117.7, 133.3,
3
-1
+
144.7, 161.2, 169.9 ppm; IR (ATR): 1652 cm ; MS (EI) m/z (rel intensity): 235.1 (M , 84), 192.1 (100);
+
HRMS (CI-TOF): m/z calcd. for C H NO : 236.1287 [MH ]; found, 236.1294.
1
3
18
3
(
1R,2S,5R)-2-Isoprpyl-5-methylcyclohexyl allyl(3,5-dimethoxyphenyl)carbamate (1ga). Prepared
from (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (3,5-dimethoxyphenyl)carbamate (A, see below)
0.45 g, 1.36 mmol), NaH (60% in mineral oil) (59.6 mg, 1.49 mmol) and allyl chloride (0.13 mL, 1.63
(
mmol). The reaction mixture was stirred at room temperature for 4 h. After work-up and purification by
flash column chromatography (silica gel, hexane/AcOEt 9/1) 1ga was obtained as an oil (0.37 g, 72 %):
[α]D20 –36.9 (c 2.75, CH Cl ); H NMR (300 MHz, CDCl ): δ 0.73-0.93 (m, 10H), 0.93-1.14 (m, 2H),
1
2
2
3
1
6
.22-1.38 (m, 1H), 1.39-1.57 (m, 1H), 1.58-1.71 (m, 2H), 1.86-1.99 (m, 1H), 2.05-2.16 (m, 1H), 3.76 (s,
H), 4.23 (d, J = 5.6 Hz, 2H), 4.62 (td, J = 10.8, 4.3 Hz, 1H), 5.11-5.22 (m, 2H), 5.84-6.00 (m, 1H),
1
3
1
6.32 (t, J = 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz, 2H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 16.3, 20.8,
3
2
2.0, 23.4, 26.2, 31.4, 34.3, 41.2, 47.1, 53.1, 55.3, 75.8, 98.4, 104.9, 116.7, 134.2 , 144.2, 155.0, 160.6
-1
+
ppm; IR (ATR): 1700 cm ; MS (ESI) m/z (rel intensity): 376.2 (MH , 23), 238.1 (87); HRMS (ESI-
+
TOF): calcd. for C H NO : 376.2488 [MH ]; found, 376.2491.
22 34
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(
1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (3,5-dimethoxyphenyl)carbamate (A): Over a solution of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
commercially available 3,5-dimethoxyaniline (0.67 g, 4.4 mmol) and pyridine (0.69 g, 8.8 mmol) in dry
THF (20 mL) under argon atmosphere, (1R)-(-)-menthyl chloroformate (1.1 mL, 4.8 mmol) was added
dropwise. The reaction was stirred for 16 h at room temperature and afterwards the solvent was
removed under reduced pressure. The crude reaction was dissolved in CH
a 10% aqueous solution of HCl (2 × 15 mL) and with water (15 mL). The combined organic extracts
were dried (Na SO ) and concentrated in vacuo. The resulting residue was purified by flash column
chromatography (silica gel, petroleum ether/AcOEt 9/1) affording the title compound as a solid (1.1 g,
2
Cl (30 mL) and washed with
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
2
0
1
7
5 %): mp (CH Cl ) 89-91 ºC; [α] –118.4 (c 1.15 , CH Cl ); H NMR (300 MHz, CDCl ): δ 0.75-
2 2 D 2 2 3
0.91 (m, 10H), 0.93-1.13 (m, 2H), 1.24-1.38 (m, 1H), 1.38-1.57 (m, 1H), 1.60-1.70 (m, 2H), 1.88-2.02
(
m, 1H), 2.01-2.11 (m, 1H), 3.74 (s, 6H), 4.62 (td, J = 10.8, 4.3 Hz, 1H), 6.16 (t, J = 2.2 Hz, 1H), 6.66
1
3
1
(
d, J = 2.2 Hz, 2H), 6.91 (br s, 1H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 16.4, 20.8, 22.0, 23.5,
3
26.2, 31.4, 34.2, 41.3, 47.2, 55.3, 75.1, 95.7, 96.7, 140.2, 153.4, 161.1 ppm; IR (ATR): 3357, 1739 cm-;
+
MS (ESI) m/z (rel intensity): 358.2 (MNa , 100), 198.1 (18); HRMS (ESI-TOF): calcd. for
+
C H NO Na: 358.1994 [MNa ]; found, 358.1993.
1
9
29
4
(1R,2S,5R)-2-Isoprpyl-5-methylcyclohexyl [(E)-but-2-en-1-yl](3,5-dimethoxyphenyl)carbamate
(
1gb). Prepared from A (0.42 g, 1.3 mmol), NaH (60% in mineral oil) (55.4 mg, 1.4 mmol) and crotyl
chloride (0.15 mL, 1.5 mmol). The reaction mixture was stirred at room temperature for 7 h. After
work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 9/1) 1gb was
obtained as an oil (0.40 g, 82 %): [α]D20 –42.9 (c 0.74, CH Cl ); H NMR (300 MHz, CDCl ): δ 0.77-
1
2
2
3
0
.92 (m, 10H), 0.92-1.09 (m, 2H), 1.24-1.36 (m, 1H), 1.42-1.54 (m, 1H), 1.57-1.66 (m, 2H), 1.67 (d, J =
.0 Hz, 3H), 1.86-1.96 (m, 1H), 2.07-2.15 (m, 1H), 3.77 (s, 6H), 4.09-4.34 (m, 2H), 4.61-4.72 (dt, J =
4
1
3
1
10.8, 4.3 Hz, 1H), 5.49-5.65 (m, 2H), 6.32 (t, J = 2.0 Hz, 1H), 6.40 (br s, 2H) ppm; C{ H} NMR (75.5
MHz, CDCl ): δ 16.3, 17.7, 20.9, 22.1, 23.4, 26.2, 31.4, 34.3, 41.3, 47.2, 52.5, 55.4, 75.7, 98.4, 105.1,
3
-1
1
26.8, 128.2, 144.3, 155.0, 160.5 ppm; IR (ATR): 1695 cm ; MS (ESI) m/z (rel intensity): 412.2
+
+
(
MNa , 100); HRMS (ESI-TOF): calcd. for C H NO Na: 412.2464 [MNa ]; found, 412.2455.
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The Journal of Organic Chemistry
(1R,2S,5R)-2-Isoprpyl-5-methylcyclohexyl cinnamyl(3,5-dimethoxyphenyl)carbamate (1gc).
1
2
Prepared from A (0.21 g, 0.64 mmol), NaH (60% in mineral oil) (28.1 mg, 0.70 mmol) and cinnamyl
chloride (0.11 mL, 0.77 mmol). The reaction mixture was stirred at room temperature for 7 h. After
work-up and purification by flash column chromatography (silica gel, hexane/AcOEt 9/1) 1gc was
obtained as an oil (0.21 g, 71 %): [α]D20 –95.2 (c 1.05, CH Cl ); H NMR (300 MHz, CDCl ): δ 0.77-
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
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5
6
1
2
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.94 (m, 10H), 0.94-1.15 (m, 2H), 1.26-1.39 (m, 1H), 1.41-1.58 (m, 1H), 1.60-1.75 (m, 2H), 1.88-2.06
(m, 1H), 2.10-2.20 (m, 1H), 3.75 (s, 6H), 4.31-4.49 (m, 2H), 4.61-4.72 (m, 1H), 6.25-6.37 (m, 2H),
1
3
1
6
2
.43-6.54 (m, 3H), 7.19-7.38 (m, 5H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 16.3, 20.8, 22.1, 23.4,
3
6.3, 31.4, 34.3, 41.3, 47.2, 52.7, 55.4, 75.9, 98.6, 105.0, 125.5, 126.4, 127.6, 128.5, 132.1, 136.8,
-1
+
144.2, 155.1, 160.7 ppm; IR (ATR): 1695 cm ; MS (ESI) m/z (rel intensity): 474.3 (MNa , 77), 314.1
+
(
10) ; HRMS (ESI-TOF): calcd. for C H NO Na: 474.2620 [MNa ]; found, 474.2623.
2
8
37
4
N-allyl-3,5-dimethoxy-N-methylaniline (1ea). (Scheme S1c) Over a solution of 3,5-dimethoxy-N-
methylaniline (0.20 g, 1.22 mmol) in DMSO (5 mL), powder KOH (0.14 g, 2.47 mmol) was added.
After 15 min, allyl bromide (0.13 mL, 1.46 mmol) was added dropwise at room temperature and the
reaction was heated at 50 ºC (heating block with temperature control) for 1 h. Then, water (10 mL) was
added and the mixture was extracted with AcOEt (3 × 10 mL). The combined organic extracts were
dried (Na SO ) and concentrated in vacuo. Flash column chromatography (silica gel, petroleum
2
4
1
ether/AcOEt 9/1) afforded 1ea as an oil (0.15 g, 60 %): H NMR (300 MHz, CDCl ): δ 2.94 (s, 3H),
3
3
.79 (s, 6H), 3.91 (dt, J = 5.1, 1.6 Hz, 2H), 5.15-5.21 (m, 2H), 5.85 (ddt, J = 17.0, 10.2, 5.1 Hz), 5.93 (s,
1
3
1
3H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 38.2, 55.2, 55.3, 88.6, 91.8, 116.2, 133.8, 151.4, 161.6
3
-1
+
ppm; IR (ATR): 1612 cm ; MS (CI) m/z (rel intensity): 208.1 (MH , 97), 207.1 (100), 176.1 (32);
+
HRMS (CI-TOF): calcd. for C H NO : 208.1338 [MH ]; found, 208.1320.
1
2
18
2
Alkylation reactions. Synthesis of tosylamides 1fa-1fd. General procedure (Scheme S1d). Over a
solution of N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide (1 mmol) in dry acetone (20 mL),
K CO (2.5 mmol) and the corresponding allyl bromide (1.5 mmol) were added under argon
2
3
atmosphere. The reaction mixture was heated at reflux (heating block) for 16 h and then, it was allowed
2
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to cool down to room temperature. Afterwards, CH Cl (20 mL) was added and the mixture was washed
2
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
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5
5
5
5
5
5
5
5
5
6
with water (15 mL). The aqueous phase was extracted with CH Cl (2 × 10 mL) and the combined
2
2
organic extracts were dried (Na SO ) and concentrated in vacuo. Flash column chromatography (silica
2
4
gel, hexane/AcOEt 8/2) afforded the corresponding N-allyl-N-(3,5-dimethoxyphenyl)-4-
methylbenzenesulfonamides 1fa-1fd.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
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8
9
0
N-allyl-N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide (1fa). Prepared from N-(3,5-
dimethoxyphenyl)-4-methylbenzenesulfonamide (0.40 g, 1.32 mmol), K CO (0.45 g, 3.29 mmol) and
2
3
allyl bromide (0.17 mL, 1.97 mmol). After work-up and purification by flash column chromatography
1
1
fa was obtained as a solid (0.41 g, 89 %): mp (CH Cl ) 82-84 ºC; H NMR (300 MHz, CDCl ): δ 2.42
2
2
3
(s, 3H), 3.70 (s, 6H), 4.13 (d, J = 6.1 Hz, 2H), 5.00-5.18 (m, 2H), 5.64-5.86 (m, 1H), 6.21 (d, J = 1.8 Hz,
13
1
1
H), 6.37 (t, J = 1.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H) ppm; C{ H} NMR
(
75.5 MHz, CDCl ): δ 21.5, 53.6, 55.4, 100.0, 107.0, 118.7, 127.8, 129.4, 132.8, 135.5, 140.9, 143.5,
3
-1
-1
+
160.6 ppm; IR (ATR): 1345 cm , 1155 cm ; MS (ESI) m/z (rel intensity): 370.1 (MNa , 100), 348.1
+
+
(
MH , 52), 193.1 (57); HRMS (ESI-TOF): calcd. for C H NO SNa: 370.1089 [MNa ]; found,
18 21 4
3
70.1091.
E)-N-(but-2-en-1-yl)-N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide (1fb). Prepared
from N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide (0.30 g, 0.98 mmol), K CO (0.34 g, 2.45
(
2
3
mmol) and crotyl bromide (0.18 mL, 1.47 mmol). After work-up and purification by flash column
chromatography 1fb was obtained as a solid and as a mixture of rotamers in a 83:17 ratio (0.30 g, 83
1
%): mp (CH Cl ) 101-102 ºC; H NMR (300 MHz, CDCl ): δ 1.59-1.54 (m, 3H, minor rotamer), 1.55-
2
2
3
1
.59 (m, 3H, major rotamer), 2.41 (s, 3H, both rotamers), 3.70 (s, 6H, both rotamers), 4.02-4.09 (m, 2H,
major rotamer), 4.14-4.20 (m, 2H, minor rotamer), 5.30-5.58 (m, 2H, both rotamers), 6.19 (d, J = 2.3
Hz, 2H, major rotamer), 6.21 (d, J = 2.3 Hz, 2H, minor rotamer), 6.36 (t, J = 2.3 Hz, 1H, both rotamers),
13
1
7
.25 (d, J = 8.3 Hz, 2H, both rotamers), 7.54 (d, J = 8.3 Hz, 2H both rotamers); C{ H} NMR (75.5
,
MHz, CDCl ): δ 12.9 (minor rotamer), 17.7 (major rotamer), 21.5 (both rotamers), 47.4 (minor
3
rotamer), 53.1 (major rotamer), 55.4 (both rotamers), 100.0 (both rotamers), 106.9 (minor rotamer),
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1
07.1 (major rotamer), 124.7 (minor rotamer), 125.5 (major rotamer), 127.8 (major rotamer), 128.4
minor rotamer), 129.3 (major rotamer), 129.4 (minor rotamer), 130.2 (both rotamers), 135.8 (both
rotamers), 141.1 (both rotamers), 143.3 (both rotamers), 160.5 (both rotamers) ppm; IR (ATR): 1285,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
-1
+
+
1
160 cm ; MS (ESI) m/z (rel intensity): 384.1 (MNa , 100), 362.1 (MH , 78), 308.1 (24), 207.1 (59);
+
HRMS (ESI-TOF): calcd. for C H NO SNa: 384.1246 [MNa ]; found, 384.1241.
1
9
23
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-Cinnamyl- N -(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide (1fc). Prepared from N-
(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide (0.27 g, 0.87 mmol), K CO (0.30 g, 2.16 mmol)
2
3
and cinnamyl bromide (0.26 g, 1.30 mmol). After work-up and purification by flash column
1
chromatography 1fc was obtained as a solid (0.21 g, 58 %): mp (CH Cl ) 123-126 ºC; H NMR (300
2
2
MHz, CDCl ): δ 2.41 (s, 3H), 3.68 (s, 6H), 4.32 (dd, J = 6.5, 1.0 Hz, 2H), 6.14 (dt, J = 15.8, 6.5 Hz,
3
1
7
H), 6.28 (d, J = 2.2 Hz, 2H), 6.38 (t, J = 2.2 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 7.17-7.30 (m, 7H),
1
3
1
.61 (d, J = 8.3 Hz, 2H); C{ H} NMR (75.5 MHz, CDCl ): δ 21.6, 53.4, 55.4, 100.1, 107.1, 124.2,
3
-1
126.5, 127.8, 128.6, 129.5, 133.7, 135.7, 136.4, 141.1, 143.6, 160.7 ppm; IR (ATR): 1345, 1155 cm ;
+
+
MS (ESI) m/z (rel intensity): 446.1 (MNa , 53), 424.2 (MH ,100), 117.1 (89); HRMS (ESI-TOF): calcd.
+
for C H NNaO S: 446.1402 [MNa ]; found, 446.1397.
2
4
25
4
(E)-N-(3,5-dimethoxyphenyl)-4-methyl-N-(4-phenylbut-2-en-1-yl) benzene sulfonamide (1fd).
Prepared from N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide (0.30 g, 0.99 mmol), K CO3
2
3
0
(0.34 g, 2.47 mmol) and (E)-(4-bromobut-2-en-1-yl)benzene (0.31 g, 1.48 mmol). After work-up and
1
purification by flash column chromatography 1fd was obtained as an oil (0.40 g, 92 %): H NMR (300
MHz, CDCl ): δ 2.41 (s, 3H), 3.26 (d, J = 6.6 Hz, 2H), 3.67 (s, 6H), 4.16 (d, J = 6.4 Hz, 2H), 5.38-5.71
3
(m, 2H), 6.24 (d, J = 2.3 Hz, 2H), 6.42 (t, J = 2.3 Hz, 1H), 6.84-6.99 (m, 2H), 7.10-7.30 (m, 5H), 7.58
1
3
1
(d, J = 8.3 Hz, 2H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 21.6, 38.4, 53.0, 55.4, 100.2, 107.3,
3
126.0, 126.1, 127.8, 128.4, 128.5, 129.5, 134.1, 135.7, 139.7, 140.9, 143.5, 160.7 ppm; IR (ATR): 1360,
-1
+
1
170 cm ; MS (ESI) m/z (rel intensity): 438.2 (MH , 100), 308.1 (25), 131.1 (22); HRMS (ESI-TOF):
+
calcd. for C H NO S: 438.1739 [MH ]; found, 438.1746.
2
5
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Metathesis reactions. Synthesis of carbamates 1ad-1gl. General procedure (Scheme S2a). Two
different procedures were employed depending on the styrene used: In case of a liquid styrene, a
solution of allyl(3,5-dimethoxyphenyl)carbamate 1aa or 1ga (1 mmol) and the corresponding styrene (5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
nd
mmol) in dry CH Cl (2.3 mL) was added via cannula over a solution of 2 Generation Grubbs Catalyst
2
2
(
0.05 mmol) in dry CH Cl (1.1 mL) under argon atmosphere. In case of a solid styrene, a solution of
2 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2nd Generation Grubbs Catalyst (0.05 mmol) in dry CH Cl (1.1 mL) was added via cannula over a
2
2
solution of allyl(3,5-dimethoxyphenyl)carbamate 1aa or 1ga (1mmol) and the corresponding styrene (5
mmol) in dry CH Cl (2.3 mL) under argon atmosphere. In both cases, the reaction mixture was stirred
2
2
at reflux (heating block) for 24 h and the volatile compounds were evaporated in vacuo. The obtained
residue was purified by flash column chromatography (silica gel, petroleum ether/AcOEt) to obtain the
corresponding carbamates 1ad-1gl.
Methyl (E)-(3,5-dimethoxyphenyl)[3-(p-tolyl)allyl]carbamate (1ad). Prepared from 1aa (0.28 g,
nd
1.13 mmol) and 4-methylstyrene (0.74 mL, 5.65 mmol) in dry CH Cl (2.6 mL) and 2 Generation
2
2
Grubbs Catalyst (48.0 mg, 0.056 mmol) in dry CH Cl (1.3 mL). Purification by flash column
2
2
chromatography (silica gel, petroleum ether/AcOEt 8/2) afforded 1ad as a solid (0.27 g, 70 %): mp
1
(
CH Cl ) 93-95 ºC; H NMR (300 MHz, CDCl ): δ 2.34 (s, 3H), 3.74 (s, 3H), 3.76 (s, 6H), 4.38 (d, J =
2
2
3
6
.3 Hz, 2H), 6.26 (dt, J = 15.9, 6.3 Hz, 1H), 6.37 (t, J = 2.2 Hz, 1H), 6.40-6.50 (m, 3H), 7.11 (d, J = 8.0
1
3
1
Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 21.2, 53.0, 55.4, 98.8,
3
-1
1
06.5, 124.0, 126.4, 129.2, 132.5, 133.9, 137.5, 143.7, 155.8, 160.8 ppm; IR (ATR): 1690 cm ; MS
+
(ESI) m/z (rel intensity): 343.2 342.2 (MH , 100), 224.1 (7); HRMS (ESI-TOF): calcd. for C H NO :
2
0
24
4
+
3
42.1705 [MH ]; found, 342.1711.
Methyl (E)-(3,5-dimethoxyphenyl)[3-(m-tolyl)allyl]carbamate (1ae). Prepared from 1aa (0.37 g,
nd
1.49 mmol) and 3-methylstyrene (0.99 mL, 7.44 mmol) in dry CH Cl (3.4 mL) and 2 Generation
2
2
Grubbs Catalyst (63.2 mg, 0.074 mmol) in dry CH Cl (1.7 mL). Purification by flash column
2
2
1
chromatography (silica gel, petroleum ether/AcOEt 8/2) afforded 1ae as an oil (0.31 g, 61 %): H NMR
300 MHz, CDCl ): δ 2.36 (s, 3H), 3.75 (s, 3H), 3.76 (s, 6H), 4.39 (d, J = 6.1 Hz, 2H), 6.22-6.50 (m,
(
3
2
8
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Page 29 of 58
The Journal of Organic Chemistry
1
3
1
5
1
H), 6.99-7.29 (m, 4H) ppm; C{ H} NMR (75.5 MHz, CDCl ): δ 21.4, 53.0, 55.4, 98.8, 106.4, 123.6,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
24.8, 127.1, 128.4, 132.7, 136.6, 138.1, 143.7, 155.8, 160.8 ppm; IR (ATR): 1702 cm ; MS (ESI) m/z
+
(rel intensity): 342.2 (MH , 100), 224.1 (12); HRMS (ESI-TOF): calcd. for C H NO : 342.1705
2
0
24
4
+
[
MH ]; found, 342.1714.
Methyl (E)-(3,5-dimethoxyphenyl)[3-(o-tolyl)allyl]carbamate (1af). Prepared from 1aa (0.34 g,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
nd
1
.36 mmol) and 2-methylstyrene (0.91 mL, 6.78 mmol) in dry CH Cl (3.1 mL) and 2 Generation
2
2
Grubbs Catalyst (57.5 mg, 0.068 mmol) in dry CH Cl (1.5 mL). Purification by flash column
2
2
1
chromatography (silica gel, petroleum ether/AcOEt 8/2) afforded 1af as an oil (0.35 g, 75 %): H NMR
(
300 MHz, CDCl ): δ 2.28 (s, 3H), 3.74 (s, 3H), 3.77 (s, 6H), 4.41 (dd, J = 6.4, 1.4 Hz, 2H), 6.15 (dt, J
3
= 15.7, 6.4 Hz, 2H), 6.38 (t, J = 2.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 2H), 6.68 (d, J = 15.7 Hz, 1H), 7.10-
13
1
7
.19 (m, 3H), 7.37-7.43 (m, 1H); C{ H} NMR (75.5 MHz, CDCl ): δ 19.7, 53.0, 55.4, 98.8, 106.5,
3
-1
1
25.9, 126.1, 126.4, 127.5, 130.2, 130.8, 135.4, 136.0, 143.6, 155.8, 160.8 ppm; IR (ATR): 1702 cm ;
+
MS (ESI) m/z (rel intensity): 342.2 (MH , 100), 224.1 (13); HRMS (ESI-TOF): calcd. for C H NO :
2
0
24
4
+
3
42.1705 [MH ]; found, 342.1712.
Methyl (E)-(3,5-dimethoxyphenyl)[3-(3-methoxyphenyl)allyl]carbamate (1ah). Prepared from 1aa
nd
(
0.13 g, 0.50 mmol) and 3-vinylanisole (0.35 mL, 2.52 mmol) in dry CH Cl (1.1 mL) and 2
2 2
Generation Grubbs Catalyst (21.4 mg, 0.025 mmol) in dry CH Cl (0.6 mL). Purification by flash
2
2
column chromatography (silica gel, petroleum ether/AcOEt 8/2) afforded 1ah as an oil (0.11 g, 61 %):
1
H NMR (300 MHz, CDCl ): δ 3.73 (s, 3H), 3.75 (s, 6H), 3.80 (s, 3H), 4.38 (d, J = 5.9 Hz, 2H), 6.21-
3
6.53 (m, 5H), 6.76-6.82 (m, 1H), 6.87-6.91 (m, 1H), 6.92-6.98 (m, 1H), 7.17-7.27 (m, 1H) ppm;
13
1
C{ H} NMR (75.5 MHz, CDCl ): δ 52.9, 53.0, 55.2, 55.4, 98.8, 106.4, 111.8, 113.3, 119.1, 125.4,
3
-1
1
29.5, 132.5, 138.2, 143.7, 155.8, 159.8, 160.8 ppm; IR (ATR): 1706 cm ; MS (ESI) m/z (rel intensity):
+
+
358.2 (MH , 100), 224.1 (15); HRMS (ESI-TOF): calcd. for C H NO : 358.1654 [MH ]; found,
2
0
24
5
3
58.1664.
Methyl (E)-[3-([1,1`-biphenyl]-4-yl)allyl](3,5-dimethoxyphenyl)carbamate (1ai). Prepared from
nd
1
aa (0.35 g, 1.41 mmol) and 4-vinylbiphenyl (1.27 mL, 7.05 mmol) in dry CH Cl (3.2 mL) and 2
2 2
2
9
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