Palladium-Catalyzed cascade sp2 c?H bond functionalizations allowing one-Pot access to 4?Aryl-1,2,3,4-tetrahydroquinolines from n?Allyl?N?arylsulfonamides

Article abstract of DOI:10.1021/acscatal.6b02586

We have developed a palladium-catalyzed cascade reaction allowing an efficient synthesis of 4-aryl-1,2,3,4-tetrahydroquinolines from N-allyl-N-arylsulfonamides and benzenesulfonyl chlorides. In this transformation, two C(sp²)?C(sp³) bonds were formed via activation of C(sp²)?H bonds. The reaction proceeds using the easily accessible catalyst PdCl₂, with Li₂CO₃ as inexpensive base and CuBr as additive, and tolerates a wide variety of substituents on both reaction partners.

Full text of DOI:10.1021/acscatal.6b02586

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Article
Palladium-Catalyzed Cascade sp2 C-H Bond Functionalizations
Allowing the One Pot Access to 4-Aryl-1,2,3,4-
tetrahydroquinolines from N-Allyl-N-arylsulfonamides
Kedong Yuan, Jean-François Soulé, Vincent Dorcet, and Henri Doucet
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02586 • Publication Date (Web): 24 Oct 2016
Downloaded from http://pubs.acs.org on October 27, 2016
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Palladium-Catalyzed Cascade sp2 C-H Bond
Functionalizations Allowing the One Pot Access to
4-Aryl-1,2,3,4-tetrahydroquinolines from N-Allyl-N-
arylsulfonamides
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Kedong Yuan,[a,b] Jean-François Soulé,*[b] Vincent Dorcet,[b] Henri Doucet*[b]
[a] Tianjin Key Laboratory of Advanced Functional Porous Material, Institute for New Energy
Materials & Low-Carbon Technologies, School of Materials Science and Engineering, Tianjin
University of Technology, Tianjin 300384, China.
[b] UMR 6226 CNRS-Université de Rennes 1, 35042 Rennes, France.
KEYWORDS Palladium • C-H activation • catalysis • desulfitative coupling • cascade
ABSTRACT We have developed a palladium-catalyzed cascade reaction allowing an efficient
synthesis of 4-aryl-1,2,3,4-tetrahydroquinolines from N-allyl-N-arylsulfonamides and
benzenesulfonyl chlorides. In this transformation, two C(sp2)-C(sp3) bonds were formed via
activation of C(sp2)-H bonds. The reaction proceeds using easily accessible PdCl2 catalyst, with
Li2CO3 as inexpensive base and CuBr as additive and tolerates a wide variety of substituents on
both reaction partners.
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Introduction
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One current important area of modern synthetic chemistry is the development of methods
minimizing both the requisite number of steps and formation of wastes. Among these methods,
the metal-catalyzed functionalization of C-H bonds has emerged as a simpler and “greener” way
for the access to useful molecules for biological or material applications, as such processes are
capable of forming similar products while avoiding the use of stoichiometric organometallic
reagents. Most of the examples of such C-H bond functionalizations concern the formation of C-
C bonds via arylations, alkylations or alkenylations;1 whereas, the formation of two C-C bonds
via consecutive Heck type reaction followed by an sp2 C-H bond activation has attracted less
attention.2,3 Among rare examples, Fagnou et al. described the formation of indolines from 2-
bromoaniline derivatives and heteroarenes via a domino palladium-catalyzed Heck-
intermolecular direct arylation.3d In 2012, Wu et al. described the synthesis of 4-polyfluoroaryl
pyrrolo[1,2-a]quinolines via intermolecular followed by intramolecular palladium-catalyzed sp2
C-H bond activations.3e Recently, Zhu and co-workers reported the synthesis of [3,4]-fused
oxindoles via a double palladium-catalyzed sp2 C-H bond activation.3g On the other hand, the
Heck reaction4,5 using N-allylbenzenesulfonamides and aryl halides as coupling partners has
been described by Y. Dong (Scheme 1 top).6
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In this article, we report on the unexpected one pot synthesis of 4-aryl-1,2,3,4-
tetrahydroquinolines, from N-allyl-N-benzenesulfonamides and ArSO2Cl through a palladium-
catalyzed cascade desulfitative addition–cyclization reaction (Scheme 1, bottom).7-9 It should be
mentioned that 1,2,3,4-tetrahydroquinoline is an important motif found in numerous compounds
with important antitumoral, antibacterial or antioxidant activities.10 Several methods are leading
to the synthesis of 1,2,3,4-tetrahydroquinolines, including partial reduction of quinolines,
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condensation of anilines with two molecules of an aldehyde, or from a Schiff base and an
alkene.10,11 However, most of these methods involve a multi-steps synthesis and in several cases
does not allow the introduction of specific functional groups at the desired positions.
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Scheme 1.
Results and discussion
The N-allyl-N-arylsulfonamides 1-22 were first prepared in high yields from anilines, methyl- or
benzene-sulfonyl chlorides and allyl bromides (Scheme 2).
Scheme 2. Structures of 1-22
We then examined the influence of the conditions on the products formation using N-allyl-N-p-
tolylbenzenesulfonamide 1 and 4-methylbenzenesulfonyl chloride as the coupling partners
(Table 1). Using PdCl2 catalyst and Li2CO3 as base in dioxane as reaction conditions, which had
been previously found operative for direct arylations of heterocycles,12 no reaction occurred. On
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the other hand, under the same conditions, but in the presence of 1.1 equiv. of CuBr as additive,
the unexpected 4-tolyl-1,2,3,4-tetrahydroquinoline 24 –resulting from a formal 6-endo-trig
cyclization after desulfitative addition– was obtained in 75% yield with 89% conversions of 1
(Table 1, entry 2). It should be noted that no formation of the expected Heck type product 23
was observed under these conditions. The use of Pd(OAc)2, PdCl2(MeCN)2, PdCl(C3H5)(dppb),
Pd(TFA)2 or Pd2(dba)3 catalysts did not increase the yield in the desired product 24 (Table 1,
entries 3-7). With Pd2(dba)3 catalyst in the absence of CuBr, deallylated 1 was the major
product. With PdCl2 catalyst, a decrease of the CuBr loading to 0.1 equiv. had almost no
influence on the yield in 24; whereas using 1 mol% CuBr gave 24 in low yield (Table 1, entries
9-11). Then, the influence of several bases was examined using 5 mol% of PdCl2 associated to
0.5 equiv. of CuBr. Lower yields in 24 were obtained with K2CO3 and Na2CO3; whereas,
Cs2CO3 or a reaction without base were completely ineffective (Table 1, entries 12-15). The
decrease of the reaction temperature to 100 °C also affords 24 in good yield (Table 1, entry 16).
The influence of a few solvents was also investigated. No reaction occurred in xylene or DMF;
whereas 1 was obtained in 65% yield in diethyl carbonate (Table 1, entries 17-19). The addition
of 1.2 equiv. of TEMPO was found to quench almost completely the reaction without its
incorporation in 1 or 2. This result suggests that no radical species is involved in this 6-endo-trig
cyclization (Table 1, entry 20). From 1 using 5 mol% PdCl2 catalyst in the presence of CuBr and
Li2CO3 at 140 °C, but without benzenesulfonyl chloride, no cyclization to afford a 1,2,3,4-
tetrahydroquinoline occurred and 1 was recovered (Table 1, entry 21). When CuBr2 was used as
additive instead of CuBr, a low conversion of 1 was observed, and 24 was formed in very low
yield together with unidentified side-products (Table 1, entry 22). Finally, the replacement of 1
by tert-butyl allyl(phenyl)carbamate led to several unidentified side-products; whereas, the
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desired cyclized product was not detected by GC/MS analysis of the crude mixture (Table 1,
entry 23).
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Table 1. Influence of the Reaction Conditions for the Po-Catalyzed Functionalization of 1.
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Entry
Catalyst (mol%)
Base
CuBr (equiv.)Temp (°C)
Conv.
of 1 (%)
Yield in 24
(%)
1
PdCl2
PdCl2
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
K2CO3
Na2CO3
Cs2CO3
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-
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140
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140
140
140
140
<10
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76
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74
100
88
80
23
73
85
0
0
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75
74
68
67
53
trace
83
73
20
31
42
0
2
1.1
1.1
1.1
1.1
1.1
1.1
-
3
Pd(OAc)2
PdCl2(CH3CN)2
PdCl(C3H5)(dppb)
Pd(TFA)2
Pd2(dba)3
Pd2(dba)3
PdCl2
4
5
6
7
8
9
0.5
0.1
0.01
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5f
0.5
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23
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
40
83
0
0
PdCl2
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
74
0a
PdCl2
PdCl2
0
0b
PdCl2
72
<10
0
65c
<5d
0e
PdCl2
PdCl2
PdCl2
30
<20g
<10
-
PdCl2
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a
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Conditions: 1 (1 equiv.), p-TolSO2Cl (2 equiv.), base (3 equiv), 1,4-dioxane. in xylene, in DMF, in diethyl
d
e
f
carbonate, p-TolSO2Cl (1 equiv.) and TEMPO as additive (1.2 equiv.), without p-TolSO2Cl. CuBr2 instead of
CuBr, g Using tert-butyl allyl(phenyl)carbamate instead of 1.
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The use of benzenesulfonyl chlorides as coupling partner is crucial for this reaction, as 4-
bromotoluene under conditions i led to starting material 1; whereas the use of PdCl(C3H5)(dppb)
catalyst and K2CO3 as base in DMF (conditions ii) selectively afforded the Heck type product 23
in 77% yield (Scheme 3).
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Scheme 3. Control Reaction with an Aryl Bromide
Then, the scope of the ArSO2Cl substituent for the synthesis of 4-aryl-1,2,3,4-
tetrahydroquinoline derivatives from 1 was examined using 5 mol% PdCl2 catalyst in the
presence of 0.5 equiv. of CuBr and Li2CO3 at 140 °C as reaction conditions (Scheme 4). Both 4-
cyano- and 4-methoxybenzenesulfonyl chlorides afforded the target products 25 and 26 in 72%
and 95% yields, respectively. The reaction also proceeded nicely in the presence of PhSO2Cl or
1-naphthyl-SO2Cl to give 27 and 28 in 75% and 71% yields, respectively. A thiophene-2-
carboxylate bearing a SO2Cl substituent at C3 was also employed. Again the expected product
29 was obtained in good yield. The influence of the SO2R moiety on the N-allyl-N-
arylsulfonamide was also investigated. A 4-bromobenzenesulfonamide was tolerated to afford
30 in 67% yield, without cleavage of the C-Br bond. The reaction also proceeds nicely with N-
allyl-N-phenylmethanesulfonamide 3, as the coupling with 4-methyl-, 4-chloro-, and 4-bromo-
benzenesulfonyl chlorides affords the target products 31-33 in 74-75% yields. A lower yield in
34 was obtained from 2,3,4-trifluorobenzenesulfonyl chloride and 3. It is worth mentioning that
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even 5-bromothiophene-2-sulfonyl chloride afforded the desired product 35 in 78% yield,
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without cleavage of the thienyl C-Br bond.
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Scheme 4. Scope of the ArSO2Cl and SO2R1 Substituents.
The influence of the substituents on the aniline moiety was also examined (Scheme 5). From N-
allyl-N-(4-bromophenyl)methanesulfonamide 4 and p-TolSO2Cl as reaction partner, 36 was
obtained in 42% yield. A 4-iodo substituent on the aniline was also tolerated to afford 37 and 40
in 68% and 67% yields. In both cases, the reaction was highly chemoselective, as the C–X
bonds were not involved in the cascade process. Electron-donating substituents on the aniline
part were tolerated as both N-allyl-N-(4-methylphenyl)methanesulfonamide 6 and N-allyl-N-(4-
methoxyphenyl)methanesulfonamide 7 led to 38 and 39 in good yields.
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The influence of substituent on the N-allyl moiety was also investigated. From (E)-N-(but-2-
enyl)-N-phenylmethanesulfonamide 8 and p-TolSO2Cl, 41 was obtained in 81% as a single
diastereomer. Similar results were obtained for the coupling of 8 and 9 with 4-fluoro- and 4-
methoxybenzenesulfonyl chlorides affording 42 and 43 in 78% and 88% yields, respectively.
The trans-stereochemistry was unambiguously assigned by X-ray analysis of 43 (see SI). The
regioselectivity of the reaction with aniline derivatives bearing meta-bromo or meta-methoxy
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substituents was then studied.
In both cases, the formation of mixture of 1,2,3,4-
tetrahydroquinolines was obtained. The major products 44a and 45a arises from coupling at less
hindered position. Similar regioselectivity was observed using 3,4-dimethylaniline, as 46a and
46b were obtained in 12:5 ratio. The reactivity of several fluoro-containing N-allyl-N-
(aryl)methanesulfonamides was also examined.
4-Fluoroaniline and 3,5-difluoroaniline
derivatives 13 and 14 gave the 1,2,3,4-tetrahydroquinolines 47 and 48 in 72% and 77% yields,
respectively with formation of only trace amount of Heck type products. On the other hand, a
very significant effect of aniline ortho-fluoro or methyl substituents was observed. From both N-
(2,4-difluorophenyl)methanesulfonamide 15 and N-(2-methylphenyl)methanesulfonamide 16
using p-TolSO2Cl as the reaction partner, only the Heck type products 49 and 50 were obtained.
This result might be explained by lower degree of freedom of C–N bond, which prevents the
suitable conformation for the formal 6-endo-trig cyclization. An aniline substituted at C4 by an
electron-withdrawing group such as ethyl ester led to a mixture of Heck type product 51a and
tetrahydroquinoline 51b in 5:1 ratio; whereas, an aniline bearing a para-thienyl at C4 only gave
tetrahydroquinoline 52 in 83% yield.
Finally the reactivity of N-allyl-N-
cyclohexylmethanesulfonamide 19 was examined. No sp3 C-H bond functionalization of the
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cyclohexyl moiety was observed and the Heck type product 53 was selectively obtained in 78%
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Scheme 5. Scope of the Substituents on the Aniline and Allyl moieties.
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Interestingly, the reaction is not limited to the use of aniline derivatives. From 5-aminopyrazole
derivative 54 and 4-methyl- or 4-chloro-benzenesulfonyl chlorides, the expected products 55 and
56 were obtained in 83% and 81% yields, respectively (Scheme 6). Even 5-bromothiophene-2-
sulfonyl chloride reacts with 54 to afford 57 in 85% yield, without cleavage of the thienyl C-Br
bond.
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Scheme 6. Reactivity of 5-Aminopyrazole Derivative 54.
Then, a set of reactions was performed in order to get a better insight into the reaction
mechanism. N-cinnamyl-N-phenylsulfonamide derivative 20 in the presence of CuBr and
Li2CO3 at 140 °C, with or without Pd-catalyst was recovered unreacted (Scheme 7, a). On the
other hand, from 20 and PhSO2Cl, the Heck type product 58 was selectively obtained in 57%
yield (Scheme 7, b). This is probably due to the higher acidity of the C-H bond of the CHPh2
motif obtained after insertion of the C=C bond into the Ar-Pd bond, which favors the β-H
elimination. From N-allyl-N-(2,4,6-trimethylphenyl)methanesulfonamide 21, again only the
Heck type product 59 was obtained in 38% yield (Scheme 7, c). No sp3 C-H bond activation of
the aniline methyl substituents was observed. The presence of a SO2R substituent on the aniline
derivative is also crucial as N-allyl-N-ethylaniline 60 led to 61 in 68% yield (Scheme 7, d).
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Scheme 7. Mechanistic Investigations
Finally, labelling experiments were carried out. From deuterated aniline derivative 22, 62 was
obtained in 63% yield, without any incorporation of deuterium (Scheme 8, top). An equimolar
mixture of 4 and 22 led to the formation of 31 and 62 in 56:44 ratio showing no significant effect
of the use of a deuterated aniline derivative on the reaction rate (Scheme 8, middle). This result
suggests that the C-H bond activation step is probably not rate limiting for the catalytic cycle.
From the N-allyl-N-phenylmethanesulfonamide 63 containing two deuterium atoms on the allyl
moiety (Scheme 8, bottom), the formation of 64 as a mixture of two diastereomers was observed.
The deuterium migration seems to confirm a mechanism involving a
by a reinsertion in the Pd-D species (See scheme 9).
β-D elimination followed
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p-Tol
PdCl2 5 mol%
d5
p-Tol-SO2Cl
2 equiv.
+
N
d4
CuBr (0.5 equiv.),
dioxane, Li2CO3,
140 °C, 20h
SO2Me
N
22 1 equiv.
62 63%
SO2Me
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N
p-Tol
p-Tol
SO2Me
PdCl2 5 mol%
4 1 equiv.
p-Tol-SO2Cl
d4
62
+
+
CuBr (0.5 equiv.),
dioxane, Li2CO3,
140 °C, 20h
1 equiv.
N
N
d5
31 SO2Me
SO2Me
N
Ratio 31:62 56:44
SO2Me
22 1 equiv.
D
p-Tol
D
Ph
N
D
D
PdCl2 5 mol%
p-Tol-SO2Cl
2 equiv.
+
SO2Me
CuBr (0.5 equiv.),
dioxane, Li2CO3,
140 °C, 20h
N
63 1 equiv.
SO2Me
64 57%
Ratio of diastereomers 53:47
Scheme 8. Experiments using Deuterated Derivatives
Although the mechanism is not yet elucidated, on the basis of the preliminary mechanistic study
and on the previous reports, a catalytic cycle can be proposed (Scheme 9). The first step of is
probably the oxidative addition of ArSO2Cl to a Pd(0) species and release of SO2 to afford the
Pd(II) intermediate A, although a Pd(II)/Pd(IV) mechanism is also possible.13 Then, A affords B
by coordination of the N-allyl-N-phenylmethanesulfonamide. Insertion of the allyl C=C bond
into the Ar-Pd bond affords C. Then, C-H bond activation affords the 6-membered palladacycle
D and releases LiCl/LiHCO3. As benzylic C-H are quite acidic, D might give E via β-H
elimination. Finally, reinsertion in the Pd-D bond affords the 7-membered palladacycle F which
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releases, via reductive elimination, the 1,2,3,4-tetrahydroquinoline derivative and regenerates
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Pd(0).
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D
D
Ar
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D
N
Ar
SO2Cl
D
SO2
PdCl
N
Pd(0)
MeO2S
Reductive
Elimination
Oxidative
Addition
Ar
A
MeO2S
Ar
D
D
Pd
D
D
Ar
Cl
Pd
Ar
N
MeO2S
F
N
N
MeO2S
B
MeO2S
Ar
-Elimination
D
Insertion
Ar
Pd
Cl
Pd
H
D
D
D
N
Ar
D
D
MeO2S
N
O
E
Me
Pd
N
S
O
Li2CO3
LiCl, LiHCO3
C
S
O2Me
D
Scheme 9. Proposed Catalytic Cycle
Formation of 1,2,3,4-tetrahydroquinoline does not result from a Pd-catalyzed cyclisation of the
β-elimination product (See, scheme 7, a). Currently available data do not allow to explain the
remarkable effect of copper in this reaction. It might work in synergy with palladium for the
desulfitative process,14 or activate palladium.
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Conclusions
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In summary, we report here the first palladium-catalyzed synthesis of 4-aryl-1,2,3,4-
tetrahydroquinoline derivatives via successive insertion of an alkene into a Pd-Ar bond followed
by an intramolecular sp2 C-H functionalization. The reaction is chemo- and diastereo-selective
and proceeds with an easily accessible phosphine-free air stable palladium catalyst, and Li2CO3
as inexpensive base associated to CuBr. The reaction can be successful for a variety of
substituents both on aniline, allyl and on the benzenesulfonyl moieties. Due to the described
usefulness of 1,2,3,4-tetrahydroquinoline derivatives, such simple reaction conditions offer a
new attractive method for access to such structures.
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Experimental Section
General procedure for the synthesis of N-allyl-N-phenylmethanesulfonamides 1-22, 54, 63:
A mixture of the aniline derivative (5 mmol) and triethylamine (0.505 g, 5 mmol) was stirred in
CH2Cl2 (15 mL) at 22 °C, then, R2SO2Cl (5 mmol) was slowly added to the mixture and the
reaction was monitored by TLC. When a complete conversion of the starting material was
observed, the mixture was concentrated then filtrated through a short silica column and
evaporated to afford the desired aryl sulfamide. A mixture of this aryl sulfamide, allyl bromide
derivative (7.5 mmol) and K2CO3 (1.725 g, 12.5 mmol) in acetone (30 mL) was refluxed
overnight. After reaction cooling down, the mixture was concentrated and purified by silica gel
chromatography (ethyl acetate/pentane) to afford the desired products 1-22, 54 and 63.
General procedure for the synthesis of 24-53, 55-62 and 64:
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To an oven dried 25 mL Schlenk tube under argon, N-allyl-N-phenylsulfonamides (0.5 mmol),
arenesulfonyl chlorides (1.0 mmol), PdCl2 (4.4 mg, 0.0025 mmol), CuBr (0.035 g, 0.25 mmol),
Li2CO3 (0.110 g, 1.5 mmol) and 1,4-dioxane (1.5 mL) were successively added. Then, the
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o
reaction mixture was settled in a preheated (140 C) oil bath for 20 h under stirring. Upon the
reaction finished, the crude mixture was purified on silica chromatography (ethyl ether/ pentane,
ethyl acetate/ pentane).
4-p-Tolyl-1-tosyl-1,2,3,4-tetrahydroquinoline
(24):
From
N-allyl-N-p-
tolylbenzenesulfonamide 1 (0.144 g, 0.5 mmol) and 4-methylbenzenesulfonyl chloride (0.191 g,
1
1 mmol), 24 was obtained in 83% (0.156 g) yield as a white solid: mp 107-109 °C. H NMR
(400 MHz, CDCl3): δ 7.97 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.29-7.20 (m, 3H), 7.02
(t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.9 Hz, 2H), 6.78 (d, J = 7.7 Hz, 1H), 6.55 (d, J = 8.3 Hz, 2H),
4.15-4.07 (m, 1H), 3.83 (dd, J = 8.5, 7.0 Hz, 1H), 3.80-3.70 (m, 1H), 2.45 (s, 3H), 2.31 (s, 3H),
2.00-1.88 (m, 1H), 1.77-1.65 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 143.6, 142.0, 137.0,
136.8, 136.0, 132.9, 130.3, 129.7, 129.1, 128.1, 127.4, 126.8, 125.0, 124.6, 45.5, 43.0, 30.3, 21.6,
21.0. Elemental analysis: calcd (%) for C23H23NO2S (377.50): C 73.18, H 6.14; found: C 73.30,
H 6.00.
ASSOCIATED CONTENT
Supporting Information.
Reaction procedures and 1H and 13C NMR of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
E-mail: jean-francois-soule@univ-rennes1.fr; henri.doucet@univ-rennes1.fr
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
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ACKNOWLEDGMENT
We thank the ministère de la recherche for a fellowship to K. Y. and the Centre National de la
Recherche Scientifique and “Rennes Metropole” for providing financial support.
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