N-benzylation/benzylic C-H amidation cascade by the (ζ3- Benzyl)palladium system in aqueous media: An effective pathway for the direct construction of 3-phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadiazine 1,1-dioxides

Article abstract of DOI:10.1002/adsc.201300317

We demonstrate a unique strategy for a benzylation/benzylic C-H amidation cascade reaction by the (ζ³-benzyl)palladium system derived from a palladium catalyst and benzyl alcohol. This tandem process is devised as a new synthetic route for 3-phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadiazine-1,1- dioxide. Water plays an important role for the smooth generation of the (ζ³-benzyl)palladium species, and a bis-benzylated Pd(II) intermediate would be formed in our catalytic system. Atom economical processes such as benzylic C-H activation, cascade reactions and chemoselective reactions in aqueous media have been developed.

Full text of DOI:10.1002/adsc.201300317

FULL PAPERS
DOI: 10.1002/adsc.201300317
À
N-Benzylation/Benzylic C H Amidation Cascade by the
(h3-Benzyl)palladium System in Aqueous Media: An Effective
Pathway for the Direct Construction of 3-Phenyl-3,4-dihydro-
(2H)-1,2,4-benzothiadiazine 1,1-Dioxides
Hidemasa Hikawa,a,* Naoya Matsuda,a Hideharu Suzuki,a Yuusaku Yokoyama,a,*
and Isao Azumayaa
a
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Fax : (+81)-47-472-1595; phone: (+81)-47-472-1591; e-mail: hidemasa.hikawa@phar.toho-u.ac.jp or
yokoyama@phar.toho-u.ac.jp
Received: April 17, 2013; Revised: June 21, 2013; Published online: August 13, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300317.
Abstract: We demonstrate a unique strategy for would be formed in our catalytic system. Atom eco-
À
À
a benzylation/benzylic C H amidation cascade reac- nomical processes such as benzylic C H activation,
tion by the (h3-benzyl)palladium system derived cascade reactions and chemoselective reactions in
from a palladium catalyst and benzyl alcohol. This aqueous media have been developed.
tandem process is devised as a new synthetic route
for
3-phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadia-
À
zine-1,1-dioxide. Water plays an important role for Keywords: benzyl alcohol; benzylation; C H activa-
the smooth generation of the (h3-benzyl)palladium tion; palladium; 3-phenyl-3,4-dihydro-(2H)-1,2,4-
species, and a bis-benzylated Pd(II) intermediate benzothiadiazine 1,1-dioxides; water
Introduction
lyzed hydrogen–deuterium (H-D) exchange reaction
proceeded in D2O in the presence of H2 gas.[5]
The palladium-catalyzed activation of carbon-hydro-
We have been developing a unique strategy for
3
À
gen bonds for coupling reactions is a promising strat- benzylation and C H activation by the (h -benzyl)pal-
3
egy in organic synthesis.[1] Amidation of C
(sp ) H ladium system derived from a palladium catalyst and
À
bonds has been particularly attractive since N-con- benzyl alcohol in water.[6] Notably, water may activate
taining compounds, especially N-heterocycles, are the sp C O bond, then stabilize the OHÀ by hydra-
ubiquitous in natural products and pharmaceuticals.[2] tion for the smooth generation of the activated Pd(II)
The (h3-benzyl)palladium moiety is one of the most cation species,[8] which can then undergo innovative
powerful and useful catalysts for the formation of direct transformation reactions. In our previous work,
carbon-carbon and carbon-nitrogen bonds.[3] Palladi- the reaction of anthranilic acid gave the dibenzylated
um-catalyzed benzylation with benzyl alcohols is es- product A (Scheme 1, A).[6c] The carboxyl group
pecially interesting, because it is known that the reac- played an important role as a directing group in the
3
[7]
À
À
tivity of benzyl alcohols towards Pd(0) is poor com- benzylic C H activation. In contrast, by replacing the
pared with of benzyl halides, esters, carbonates or carboxylic acid with a carboxamide group, benzylic
phosphates. Only a few papers describe the palladi- C H amidation of the N-benzylated intermediate oc-
À
um-catalyzed benzylation with benzylic alcohols in curred, followed by dehydrogenation, to give quinazo-
aqueous media.[4] Water activates the benzyl alcohol linone B (Scheme 1, B).[6b]
via hydration of the hydroxy group for generation of
In light of our ongoing efforts to develop versatile
3
the (h3-benzyl)palladium species. Although water is benzylation/C H activation cascades by the (h -ben-
À
becoming increasingly popular as a medium for chem- zyl)palladium system in water, we here demonstrate
À
ical reactions, palladium-catalyzed C H functionaliza- the direct construction of 3-phenyl-3,4-dihydro-(2H)-
tion in water is extremely rare. As one example, 1,2,4-benzothiadiazine 1,1-dioxides 3 from o-amino-
Sajiki and co-workers reported that the Pd/C-cata- benzenesulfonamides 1 and various benzyl alcohols 2.
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N-Benzylation/Benzylic C H Amidation Cascade by the (h -Benzyl)palladium System in Aqueous Media
Scheme 1. Our previous work.
Results and Discussion
zero-valent palladium, Pd
tion proceeded slowly (entry 4, 32%). Since the reac-
First, we heated a mixture of o-aminobenzenesulfon- tion resulted in low yield when using Pd(PPh3)4 in-
amide 1a and benzyl alcohol 2a (5 equiv.) in the pres- stead of the water-soluble ligand (entry 5, 16%) or
ence of Pd(OAc)2 (5 mol%) and sodium diphenyl- when using EtOH, AcOH, 1,4-dioxane or DMF as
2ACHTNUGTREN(NNUG dba)3, was used, the reac-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
phosphinobenzene-3-sulfonate (TPPMS, 10 mol%) in a solvent (entries 6–9, 0–44%), water must play an
water at 1208C for 16 h in a sealed tube. The cyclized important role in our catalytic system. Indeed, in bi-
product 3a was obtained in 61% isolated yield along phasic systems such as toluene/H2O (1:1) or 1,4-diox-
with the dibenzylated 4a in 27% isolated yield ane/H2O (1:1), the reaction proceeded smoothly and
(Scheme 2), while the cyclized product B was only ob- the cyclized 3a was obtained selectively (entry 10,
tained selectively from o-aminobenzamide (Scheme 1, 79%, entry 11, 62%, entry 12, 81% and 80% isolated
B). The nitrogen nucleophilicity of sulfonamides yield). In contrast, use of 1,4-dioxane/H2O (10:1) re-
might be poor compared to carboxamides.
sulted in no reaction (entry 13). To our surprise, use
Thus, we investigated the effects of catalysts and of DMSO/H2O (1:1), DMF/H2O (1:1) or EtOH/H2O
À
solvents to improve the selectivity of the benzylic C
H amidation (Table 1). When 1a was almost com- The formation of a water cluster might be essential in
(1:1) resulted in low yields (entries 14–16, 17–39%).
pletely consumed at 1008C in 16 h, the reaction af- our catalytic system.[9] When using PdCl
forded cyclized 3a in 58% yield along with 4a in 15% ganic solvents such as toluene, EtOH, 1,4-dioxane or
yield (entry 1). After 1 h, the reaction afforded 3a in DMF, or when using PdCl2A(PPh3)2, PdCl2A(dppf) or
33% yield along with 5a in 9% yield (entry 2). The re- PdCl2A(PCy3)2 in toluene, the reaction did not afford
2ACHTUNGERTN(NUNG PPh3)2 in or-
C
CHTUNGTRENNUNG
CTHUNGTRENNUNG
action did not proceed in the absence of the palladi- cyclized 3a (entries 17 and 18). Interestingly, use of
um catalyst and phosphine ligand or in the presence toluene/H2O (1:1) also resulted in no reaction
of only TPPMS, and recovery of SM 1a was detected (entry 19). Therefore, in our catalytic system, water
by TLC analysis. With regard to the palladium cata- plays an important role in activation of benzyl alcohol
lyst, the use of PdCl2 gave the cyclized 3a in 75% 2a and stabilization of hydroxide ion by hydration,
yield along with 4a in 18% yield (entry 3). When the followed by formation of water-soluble activated
Scheme 2. Pd-catalyzed reaction of o-aminobenzenesulfoneamide 1a.
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Table 1. Effects of catalysts and solvents.[a]
Entry
Catalyst
Solvent
Conversion [%][c]
3a
58
33
75
32
16
24
4a
15
0
18
0
0
0
3
0
0
5
0
5
0
0
0
0
5a
0
9
0
0
0
0
0
0
0
0
0
0
0
0
0
13
0
1
Pd
Pd
N
H2O7
H2O
H2O
H2O
H2O
EtOH
AcOH
1,4-dioxane
2[b]
3
PdCl2/TPPMS
4
5
6
7
8
9
10
11[f]
12
13
14
15
16
17
18
19
20
21
22
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
PdCl
PdCl
PdCl
Pd
Pd
Pd
(dba)3[d]/TPPMS
44
0[e]
DMF
0[e]
toluene/H2O (1:1)
1,4-dioxane/H2O (1:1)
1,4-dioxane/H2O (1:1)
1,4-dioxane/H2O (10:1)
DMSO/H2O (1:1)
DMF/H2O (1:1)
EtOH/H2O (1:1)
toluene, EtOH, 1,4-dioxane or DMF
toluene
toluene/H2O (1:1)
phthalate buffer (pH 4)
aq. NaHCO3 (3 equiv.)
aq. K2CO3 (3 equiv.)
79
62
81 (80% yield)
0[e]
17
36
39
2A
2A(PPh3)2, PdCl
2A(PPh3)2
trace[e]
trace[e]
trace[e]
38
0
0
0
13
0
2A
E
0
0
28
24
0
12
14
0
[a]
Reaction conditions: 1 (1 mmol), Pd catalyst (5 mol%), ligand (10 mol%), benzyl alcohol 2a (2 equiv.), solvent (4 mL),
1008C, 16 h in sealed tube.
[b]
[c]
[d]
[e]
[f]
After 1 h.
The yield was determined by 1H NMR analysis of the crude product using p-nitroanisole as an internal standard.
2.5 mol%.
By TLC analysis.
Using 3 equiv. of 2a.
Pd(II)/TPPMS cation species in water. With regard to o-aminobenzenesulfonamides 1 with benzyl alcohol
the acidic and basic aqueous conditions, when using 2a using Pd
phthalate buffer (pH 4), C H amidation was sup- Table 2. The benzyl alcohols with electron-donating
(OAc)2 and TPPMS are summarized in
À
pressed slightly to give cyclized 3a in 38% yield, while methyl, ethyl and methoxy groups resulted in good
À
C H benzylation also occurred to give 4a in 13% yields (3b, 75%; 3c, 71%; 3d, 79%; 3e, 70%; 3f, 71%).
yield (entry 1 vs. 20). In the presence of a base such The sterically demanding ortho-substituted methyl
as NaHCO3 or K2CO3, the reaction proceeded very group was also tolerated in the reaction (3g, 60%).
slowly (entries 21 and 22). Basset and co-workers re- The o-aminobenzenesulfonamide 1 with methyl or
ported that the p-allyl palladium intermediate was un- phenyl groups resulted in good yields (3h, 86%; 3i,
stable under basic conditions.[10] Since our results 89%). The sulfonamide 1 with a bromo group pro-
were consistent with these reports on the palladium- duced desired 3j in moderate yield with the carbon-
catalyzed allylation with allylic alcohols, (h3-benzyl)- halogen moiety left intact, which could be employed
palladium was proposed to be an intermediate here in for further manipulation (3j, 50%). N-Methyl-2-ami-
analogy to the allylic substitution reaction.
nobenzenesulfonamide also afforded the cyclized 3k
Results for the reaction of o-aminobenzenesulfona- in good yield (76%). The sterically demanding N-
mide 1a with a number of benzyl alcohols 2 or several methyl substituent did not influence the intramolecu-
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N-Benzylation/Benzylic C H Amidation Cascade by the (h -Benzyl)palladium System in Aqueous Media
Table 2. Scope of o-aminobenzenesulfonamides 1 and alcohols 2.[a]
[a]
Reaction conditions: 1 (1 mmol), PdACHTUNRGTNEUNG(OAc)2 (5 mol), TPPMS (10 mol%), benzyl alcohols 2 (2 equiv.), H2O (4 mL), 1008C,
16 h in sealed tube. Yield of isolated product.
1208C, 16 h, benzyl alcohols 2 (5 equiv.).
[b]
lar cyclization. The reaction of 2-thiophenemethanol
2b afforded only N-substituted 5b in 70% yield.
When we tested the reaction of 3a with palladium
catalyst and benzyl alcohol 2a, the reaction did not
Next, the reactions using substrates with electron- occur (Scheme 4). This observation suggested that cy-
withdrawing groups were examined (Table 3). The re- clized 3a was not the intermediate for formation of di-
action of 2-amino-5-fluorobenzenesulfonamide 1b benzylated 4a via benzylation to the imine. Addition-
proceeded slowly to give cyclized 3l along with diben- ally, while dehydrogenation of aminal 9 proceeded
zylated 4b (entries 1 and 2). The reaction of o-amino- smoothly to afford quinazolinone 10 in our previous
benzenesulfonamide 1a with 4-fluorobenzyl alcohol work (Scheme 5, A), dehydrogenation of 3a did not
2b gave cyclized 3m in 38% yield along with mono-N- occur in the present work. Since the nitrogen basicity
benzylated 5c in 7% yield (entry 3). Furthermore, the was decreased by the sulfonamide group, the palladat-
presence of the strong electron-withdrawing trifluoro- ed intermediate could not form to give dehydrogenat-
methyl group in the aromatic ring of benzyl alcohol ed B (Scheme 5, B).
resulted in no reaction (entry 4). In contrast, as ex-
These results and our previous report[6] suggest the
pected from the result of entry 11 in Table 1, use of following mechanism of the formation of cyclized 3
1,4-dioxane/H2O (1:1) gave only cyclized 3l in good and dibenzylated 4 from o-aminobenzenesulfona-
yield (entry 5, 88%).
mides 1 and benzyl alcohols 2 in water. As shown in
Several control experiments were performed to ex- Scheme 6, N-benzylated 5 reacts with the (h3-benzyl)-
clude the possibility of some reaction pathways. First, palladium(II) complex 11 to form bis-benzylated
palladium-catalyzed reaction of N-benzylated 5a with Pd(II) intermediate, which is in flux between at least
benzyl alcohol 2a gave the cyclized 3a in 95% yield three species; there are two possible combinations of
(Scheme 3, A). In contrast, electron-withdrawing h3-p-benzyl/h1-s-benzyl palladium (I and II) and one
fluoro or trifluoromethyl groups resulted in no reac- bis-p-benzyl species III. To form the cyclized 3 or di-
tion. Since the reaction of 2-[4-(trifluoromethyl)ben- benzylated 4, there are two possible mechanisms in-
zylamino]benzenesulfonamide 5d did not give deuter- volving the h3-p-benzyl/h1-s-benzyl intermediate I
ated 5d’ in D2O in our catalytic system, benzylic C H (paths A and B). The (h3-p-benzyl)palladium(II) oxi-
activation did not occur (Scheme 3, B). Furthermore, dizes the N-benzylated 5 via C H activation to the
À
À
benzyl alcohol 2a played an important role in the ben- corresponding imine 7, which immediately cyclizes to
zylic C H amidation step, since the reaction did not product 3 (path A). The nucleophilic s-benzyl anion
À
proceed in its absence (Scheme 3, C).
ligand attacked the electrophilic h3-p-benzyl ligand of
intermediate I or ion pairs I’ to afford dibenzylated 4
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Table 3. Effect of electron-withdrawing groups.[a]
Entry 1
2
Solvent
Temperature [oC] Yield [%][b]
1
2
1b
1b
2a (2 equiv.)
2a (5 equiv.)
H2O
H2O
100
120
3l: 29%, 4b: 17%
3l: 49%, 4b: 17%
3
1a
2b (5 equiv.)
H2O
H2O
120
120
3m: 38%, 5c: 7%
4
5
1a
1b
2c (5 equiv.)
2a (2 equiv.)
no reaction
3l: 88%
dioxane/H2O (1:1) 120
[a]
Reaction conditions: 1 (1 mmol), PdACTHNURTGNENG(U OAc)2 (5 mol%), TPPMS (10 mol%), benzyl alcohol 2a (2 or 5 equiv.), solvent
(4 mL), 100–1208C, 16 h in sealed tube.
Yield of isolated product.
[b]
(path B). Yamamoto and co-workers reported that fonamide nitrogen (path C). Therefore, the o-amino-
bis-p-allylpalladium complexes exhibit nucleophilic benzenesulfonamides 1 or benzyl alcohols 2 with elec-
reactivity although it is widely accepted that mono- tron-donating methyl, ethyl and methoxy groups af-
(p-allyl)PdX-type complexes, where X is an electron- forded only cyclized 3 selectively (see Table 2). In ad-
withdrawing group such as Cl, OAc, exhibit electro- dition, cyclization of intermediate II affords desired 3,
philic reactivity.[11] Chruma reported palladium-cata- toluene 14 and regenerated Pd(0) through reductive
lyzed benzylation of benzyl diphenylglycinate imines elimination. We were delighted to observe that
to the corresponding homobenzylic imines.[12] There- indeed toluene 14 was obtained in the reaction mix-
fore, intermediate I with more reactive nucleophilic ture (see the Supporting Information).
h1-s-benzyl ligand and less reactive electrophilic h3-p-
Importantly, use of a biphasic system afforded only
benzyl ligand might be formed in our catalytic system. desired products 3 in spite of the possibility of form-
These processes should be favored by electron-with- ing dibenzylated product 4 (see entries 11 and 12 in
drawing R1 and R2 groups on intermediate I or ion Table 1, and entry 2 in Table 3). As shown in
pairs I’, since these will stabilize the negative charge Scheme 7, after water soluble intermediate I afforded
on appropriate nucleophilic carbon. Indeed, 2-amino- imine 7, which moved to the organic phase, nucleo-
5-fluorobenzenesulfonamide 1b afforded cyclized 3l philic attack of the sulfonamide group proceeded
and dibenzylated 4b (see entries 1 and 2 in Table 3). smoothly to afford desired cyclized 3a (path A). In
In contrast, the electron-donating R1 and R2 groups contrast, in the aqueous phase, the amidation of inter-
can stabilize the d+ charge in the p-benzyl intermedi- mediate I proceeded slowly since nitrogen nucleophi-
ate II (this charge is already stabilized by the nitrogen licity of the sulfonamide group was weak due to hy-
lone pair) making the position more electrophilic for dration in water. Indeed, under acidic conditions such
direct intramolecular nucleophilic attack from the sul-
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N-Benzylation/Benzylic C H Amidation Cascade by the (h -Benzyl)palladium System in Aqueous Media
Scheme 3. Pd-catalyzed reaction of N-benzylated 5.
a number of reports have emerged on the borrowing
hydrogen methodology using benzyl alcohols 2 as
starting materials.[15] Owing to their low toxicity and
cost, direct transformations of benzyl alcohols 2 to
valuable chemicals have attracted much attention in
organic synthesis. Notably, our (h3-benzyl)palladium
system 11 works on a quite different mechanism from
the hydrogen transfer methodology with benzyl alco-
hols 2. To the best of our knowledge, there are no ex-
amples of the synthesis of 3 from benzyl alcohols 2.
In our previous work,[6b] the reaction of o-amino-
benzamide 20 with benzyl-a,a-d2 alcohol 2a’ gave qui-
nazolinone B and deuterated toluene 14 (14a:14b=
1:9) (Table 4, entry 1). Surprisingly, the reaction of 1a
afforded deuterated toluene 14 (14a:14b=1.6:1)
Scheme 4. Pd-catalyzed reaction of 3a.
as AcOH or buffer solution (pH 4), amidation was (entry 2). These results suggested that N- and C-palla-
suppressed (see entries 6 and 16 in Table 1).
dation might occur (Scheme 9).
3,4-Dihydro-(2H)-1,2,4-benzothiadiazine 1,1-diox-
In our catalytic system, benzyl alcohol 2a afforded
ides are key units in a wide range of relevant pharma- benzaldehyde 17 and toluene 14 in 56% and 26%, re-
cophores with a broad spectrum of activities.[13] Inter- spectively (Scheme 10, A). The reaction of benzyl-
molecular cyclization of o-aminobenzenesulfonamide a,a-d2 alcohol 2a’ gave deuterated benzaldehyde 17’
1a with benzaldehyde 17 is the most practical method and deuterated toluene
14 (14a:14b=2.1:1)
of synthesizing desired 3a (Scheme 8).[14] However, (Scheme 10, B). The deuterated toluene 14a would
benzaldehydes 17 are chemically unstable and their form through b-hydride elimination of intermediate
syntheses from benzyl alcohols 2 are achieved by oxi- 18.
dative methods such as PCC, Swern oxidation, TPAP
The sulfonamide analogues display a slightly differ-
and TEMPO, which are undesirable from an environ- ent reactivity to the benzamides (Scheme 11). Since
mental point of view. Alternatively, in recent years the nitrogen nucleophilicity of 1a was decreased by
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Scheme 5. Pd-catalyzed dehydrogenation of 3a.
the sulfonamide group, benzaldehyde 17 might be would like to consider the possibility of palladium
formed smoothly by the (h3-benzyl)palladium. nanoparticles in further investigation.
Indeed, dehydrogenation of electron deficient 3a did
not occur in the present work, while dehydrogenation
of electron sufficient aminal 9 proceeded smoothly to Conclusions
afford quinazolinone 10 in our previous work.
Thus, cyclized 3 might be formed from not only N- In summary, we have demonstrated a N-benzylation/
3
À
benzylated 5a (C- and N-palladation) but also benzal- benzylic C H amidation strategy by the (h -benzyl)-
dehyde 17. However, palladium-catalyzed reaction of palladium system for the direct construction of 3-
N-benzylated 5a with benzyl alcohol 2a gave the cy- phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadiazine 1,1-di-
clized 3a in 95% yield (see Scheme 3, A), and the re- oxides 3. In a biphasic system such as 1,4-dioxane/
action of 1a afforded 3a in 33% yield along with 5a in H2O, benzylic C H amidation proceeds with high se-
9% yield, after 1 h (see Table 1, entry 2). Therefore, lectivity. The domino reactions achieved N-benzyla-
À
À
N-benzylated 5a should be one of the intermediate tion and benzylic C H amidation in water, which
for cyclized 3a and dibenzylated 4a.
played an important role in the activation of the ben-
In general, almost all known organic transforma- zylic alcohols to form the corresponding palladium
tions tend to be inefficient in organic solvents. We complexes. Water is still not commonly used as a sol-
have been developing atom economical and environ- vent in organic synthesis despite its distinctive proper-
mentally benign reactions with green processes, such ties. Furthermore, the (h3-benzyl)palladium system
À
À
as unprotected syntheses, benzylic C H activations, could be used for not only benzylation, but also C H
cascade reactions and chemoselective reactions in activation, and bis-benzylated Pd(II) intermediate
aqueous media. We demonstrated the only unprotect- would be formed in our catalytic system. We are cur-
ed synthesis and pH-controlled chemoselectivity in rently investigating the scope of various nucleophiles
the presence of water,[16] as well as the activation of on the benzylation/C-H activation cascade reaction
unreactive molecules such as allylic or benzylic alco- using (h3-benzyl)palladium from benzyl alcohols in
hols followed by formation of activated Pd(II) cation aqueous media.
species. Notably, since water molecules have unusual
chemical and physical properties such as strongly
polar hydrogen bonds, water should play an important
role in development of new and efficient reactions in
Experimental Section
organic chemistry.
General Procedure (A)
Additionally, palladium nanoparticles might play an
important role in our catalytic system. Palladium
nanoparticles are known to exhibit higher catalytic ac-
tivity, as compared with other related molecular cata-
lyst.[17] Bao reported that coupling reaction by utiliz-
ing palladium nanoparticles in the p-benzyl p-allylpal-
ladium system.[18] However, this observation has not
A
mixture of o-aminobenzenesulfoneamide
1
(0.17–
1 mmol), palladium(II) acetate (5 mol%), sodium diphenyl-
phosphinobenzene-3-sulfonate (TPPMS, 10 mol%) and
benzyl alcohol 2 (2–5 equiv.) in H2O (0.5–4 mL) or 1,4-diox-
ane (2 mL)/H2O (2 mL) was heated at 1008C for 16 h in
a sealed tube. After cooling, the reaction mixture was
poured into water and extracted with EtOAc. The organic
been investigated in detail at this stage. Therefore, we layer was washed with brine, dried over MgSO4 and concen-
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N-Benzylation/Benzylic C H Amidation Cascade by the (h -Benzyl)palladium System in Aqueous Media
trated under vacuum. The residue
was purified by flash column chroma-
tography (silica gel, hexanes/EtOAc)
to give desired products 3, dibenzy-
lated 4 and mono-N-benzylated 5.
General Procedure (B)
A mixture of o-aminobenzenesulfo-
neamide 1a (1.7 g, 10 mmol), K2CO3
(1.4 g,
10 mmol),
NaI
(2.2 g,
15 mmol), and benzyl chloride
6
(15 mmol) in DMF (20 mL) was
stirred at room temperature for 1 d
under argon. The reaction mixture
was poured into water and extracted
with EtOAc. The organic layer was
washed with brine, dried over MgSO4
and concentrated under vacuum. The
residue was purified by flash column
chromatography (silica gel, hexanes/
EtOAc) to give desired products 5.
3-Phenyl-3,4-dihydro-(2H)-1,2,4-
benzothiadiazine 1,1-dioxide (3a):[15c]
Following the general procedure (A),
3a was obtained as a white solid;
yield: 208 mg (80%); mp 128–1308C;
IR (KBr): n=3388, 3215, 1316,
1162 cmÀ1
;
1H NMR
(400 MHz,
DMSO-d6): d=5.78 (d, J=11.6 Hz,
1H), 6.77 (ddd, J=8.0, 8.0, 1.2 Hz,
1H), 6.91 (dd, J=8.0, 0.8 Hz, 1H),
7.31 (ddd, J=7.2, 7.2, 1.6 Hz, 1H),
7.39 (s, 1H), 7.40–7.50 (m, 3H), 7.53
(dd, J=8.0, 1.6 Hz, 1H), 7.67 (dd, J=
8.0, 2.4 Hz, 2H), 7.89 (d, J=11.6 Hz,
1H); 13C NMR (100 MHz, DMSO-
d6): d=68.4, 116.4, 116.7, 121.6,
123.7, 127.5, 128.5, 129.1, 132.8, 137.3,
143.9; MS (EI): m/z (%)=260 (M+,
89), 92 (100).
3-(4-Methylphenyl)-3,4-dihydro-
(2H)-1,2,4-benzothiadiazine 1,1-diox-
ide (3b):[15c] Following the general
procedure (A), 3b was obtained as
a red solid; yield: 205 mg (75%); mp
147–1498C; IR (KBr): n=3388, 3245,
1
1316, 1164 cmÀ1; H NMR (400 MHz,
DMSO-d6): d=2.34 (s, 1H), 5.73 (d,
J=12.0 Hz, 1H), 6.75 (dd, J=7.6,
7.6 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H),
7.20–7.35 (m, 4H), 7.50–7.55 (m,
3H), 7.83 (d, J=12.0 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=
20.8, 68.2, 116.3, 116.6, 121.5, 123.7,
127.4, 129.0, 132.8, 134.4, 138.5,
143.9; MS (EI): m/z (%)=274 (M+,
89), 92 (100).
3-(3-Methylphenyl)-3,4-dihydro-
(2H)-1,2,4-benzothiadiazine 1,1-diox-
ide (3c): Following the general proce-
dure (A), 3c was obtained as a white
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(A), 3e was obtained as a red solid; yield: 204 mg (70%);
mp 157–1598C; IR (KBr): n=3359, 3210, 1317, 1164 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=3.79 (s, 3H), 5.72 (d,
J=12.0 Hz, 1H), 6.75 (dd, J=8.0, 8.0 Hz, 1H), 6.90 (d, J=
8.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 7.25–7.35 (m, 2H),
7.51 (dd, J=8.0, 1.2 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.80
(d, J=12.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=
55.3, 68.0, 113.8, 116.3, 116.6, 121.5, 123.7, 128.9, 129.5,
132.8, 143.9, 159.8; MS (EI): m/z (%)=290 (M+, 66), 92
(100).
3-(3-Methoxyphenyl)-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine 1,1-dioxide (3f): Following the general procedure (A),
3f was obtained as a white solid; yield: 207 mg (71%); mp
Scheme 7. Reaction in a biphasic system.
180–1828C; IR (KBr): n=3358, 3223, 1315, 1163 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=3.79 (s, 3H), 5.74 (d,
J=12.0 Hz, 1H), 6.76 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 6.91
(dd, J=8.8, 0.8 Hz, 1H), 7.00 (ddd, J=8.4, 2.4, 1.2 Hz, 1H),
7.21 (d, J=7.6 Hz, 1H), 7.27–7.40 (m, 4H), 7.52 (dd, J=7.6,
0.8 Hz, 1H), 7.86 (d, J=12.0 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): d=55.2, 68.3, 112.8, 115.0, 116.3, 116.7, 119.8,
121.6, 123.7, 129.6, 132.8, 138.7, 143.8, 159.4; MS (EI): m/z
(%)=290 (M+, 100).
solid; yield: 194 mg (71%); mp 171–1738C; IR (KBr): n=
3396, 3210, 1310, 1159 cmÀ1 1H NMR (400 MHz, DMSO-
;
d6): d=2.35 (s, 3H), 5.73 (d, J=12.0 Hz, 1H), 6.76 (ddd, J=
7.6, 7.6, 1.2 Hz, 1H), 6.91 (dd, J=8.4, 0.8 Hz, 1H), 7.25 (d,
J=7.6 Hz, 1H), 7.28–7.34 (m, 2H), 7.36 (s, 1H), 7.45 (d, J=
7.6 Hz, 1H), 7.49 (s, 1H), 7.52 (dd, J=7.6, 1.6 Hz, 1H), 7.84
(d, J=12.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=
21.0, 68.4, 116.3, 116.7, 121.6, 123.7, 124.6, 128.1, 128.4,
129.7, 132.8, 137.2, 137.7, 143.9; MS (EI): m/z (%)=274
(M+, 100); anal. calcd. for C14H14N2O2S: C 61.29, H 5.14, N
10.21; found: C 61.27, H 5.18, N 10.12.
3-(2-Methylphenyl)-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine-1,1-dioxide (3g): Following the general procedure (A),
3g was obtained as a white solid; yield: 165 mg (60%); mp
182–1848C; IR (KBr): n=3356, 3287, 1325, 1154 cmÀ1
;
3-(4-Ethylphenyl)-3,4-dihydro-(2H)-1,2,4-benzothiadiazine
1,1-dioxide (3d): Following the general procedure (A), 3d
was obtained as a white solid; yield: 228 mg (79%); mp
1H NMR (400 MHz, DMSO-d6): d=2.40 (s, 3H), 5.97 (d,
J=12.0 Hz, 1H), 6.77 (dd, J=6.8, 6.8 Hz, 1H), 6.94 (t, J=
8.0 Hz, 1H), 7.20–7.40 (m, 5H), 7.53 (d, J=6.8 Hz, 1H),
7.70–7.75 (m, 1H), 7.80 (d, J=12.0 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=18.4, 64.8, 116.5, 116.7, 121.7,
123.8, 126.0, 126.6, 128.8, 130.3, 132.8, 135.1, 135.9, 144.2;
MS (EI): m/z (%)=274 (M+, 91), 118 (100).
142–1448C; IR (KBr): n=3375, 3222, 1312, 1164 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=1.19 (t, J=7.6 Hz, 3H),
2.64 (q, J=7.6 Hz, 2H), 5.73 (d, J=12.4 Hz, 1H), 6.75 (dd,
J=7.6, 7.6 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 7.28–7.36 (m,
4H), 7.51 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.84
(d, J=12.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=
15.8, 28.0, 68.2, 116.3, 116.6, 121.5, 123.7, 127.5, 127.9, 132.8,
134.7, 143.9, 144.9; MS (EI): m/z (%)=288 (M+, 100).
7-Methyl-3-phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine 1,1-dioxide (3h): Following the general procedure (A),
3h was obtained as a white solid; yield: 40 mg (86%); mp
182–1848C; IR (KBr): n=3357, 3283, 1323, 1153 cmÀ1
;
3-(4-Methoxyphenyl)-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine 1,1-dioxide (3e):[15c] Following the general procedure
1H NMR (400 MHz, DMSO-d6): d=2.23 (s, 3H), 5.73 (d,
Scheme 8. Development of a new activated catalyst in aqueous media.
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N-Benzylation/Benzylic C H Amidation Cascade by the (h -Benzyl)palladium System in Aqueous Media
Table 4. Pd-catalyzed reaction with benzyl-a,a-d2 alcohol 2a’.[a]
Entry
20 or 1a (R=)
Time [h]
Ratio of 14a/14b
1
2
CONH2 (20)
SO2NH2 (1a)
16
8
1:9
1.6:1
Scheme 9. Formation of deuterated toluene 14.
Scheme 10. Pd-catalyzed reaction of benzyl-a,a-d2 alcohol 2a’.
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Hidemasa Hikawa et al.
FULL PAPERS
Scheme 11. Pd-catalyzed reaction of amide 20 or sulfonamide 1a.
J=12.0 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.8,
1.6 Hz, 1H), 7.18 (s, 1H), 7.34 (s, 1H), 7.40–7.50 (m, 3H),
7.60–7.70 (m, 2H), 7.85 (d, J=12.0 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=19.8, 68.5, 116.5, 121.5, 123.2,
125.8, 127.5, 128.5, 129.0, 133.8, 137.4, 141.7; MS (EI): m/z
(%)=274 (M+, 100); anal. calcd. for C14H14N2O2S: C 61.29,
H 5.14, N 10.21; found: C 60.97, H 4.98, N 10.13.
mp 166–1688C; IR (KBr): n=3381, 1319, 1148 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=2.30 (s, 3H), 6.30 (s,
1H), 6.86 (dt, J=8.4, 1.2 Hz, 1H), 7.10 (dd, J=8.4, 0.4 Hz,
1H), 7.41 (ddd, J=7.2, 7.2, 1.6 Hz, 1H), 7.45–7.62 (m, 7H);
13C NMR (100 MHz, DMSO-d6): d=28.6, 70.9, 116.7, 117.8,
118.3, 125.0, 127.7, 128.7, 129.3, 133.3, 134.7, 143.2; MS (EI):
m/z (%)=274 (M+, 20), 180 (100); HR-MS-EI: m/z= cmÀ1
(M+), calcd. for C14H14N2O2S: 274.0776.
3,7-Diphenyl-3,4-dihydro-(2H)-1,2,4-benzothiadiazine 1,1-
dioxide (3i): Following the general procedure (A), 3i was ob-
tained as a white solid; yield: 149 mg (89%); mp 186–
7-Fluoro-3-phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine 1,1-dioxide (3l): Following the general procedure (A),
3l was obtained as a white solid; yield: 246 mg (88%); mp
1
1888C; IR (KBr): n=3370, 3227, 1307, 1158 cmÀ1; H NMR
161–1638C; IR (KBr): n=3384, 3211, 1317, 1163 cmÀ1
;
(400 MHz, DMSO-d6): d=5.84 (d, J=11.0 Hz, 1H), 7.03 (d,
J=8.4 Hz, 1H), 7.32 (dd, J=7.2, 7.2 Hz, 1H), 7.40–7.55 (m,
5H), 7.58 (s, 1H), 7.63 (d, J=7.2 Hz, 2H), 7.65–7.75 (m,
3H), 7.77 (d, J=2.0 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=68.4, 117.1, 121.1,
121.9, 125.7, 126.9, 127.6, 128.5, 129.0, 129.2, 131.2, 137.2,
138.8, 143.3; MS (EI): m/z (%)=336 (M+, 100); anal. calcd.
for C19H16N2O2S: C 67.84, H 4.79, N 8.33; found: C 67.77, H
4.72, N 8.31.
1H NMR (400 MHz, DMSO-d6): d=5.75 (d, J=12.0 Hz,
1H), 6.96 (dd, J=9.2, 4.4 Hz, 1H), 7.27 (ddd, J=8.8, 8.8,
2.8 Hz, 1H), 7.35–7.50 (m, 5H), 7.66 (dd, J=8.0, 2.0 Hz,
2H), 8.00 (d, J=12.0 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6): d=68.4, 109.5 (J=24 Hz), 118.3 (J=7 Hz), 121.0 (J=
23 Hz), 121.2 (J=7 Hz), 127.5, 128.5, 129.2, 137.1, 140.7,
153.5 (J=237 Hz); MS (EI): m/z (%)=278 (M+, 100); anal.
calcd. for C13H11N2O2SF: C 56.10, H 3.98, N 10.07; found: C
56.31, H 3.98, N 10.11.
7-Bromo-3-phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine 1,1-dioxide (3j): Following the general procedure (A),
3j was obtained as a white solid; yield: 70 mg (50%); mp
3-(4-Fluorophenyl)-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine 1,1-dioxide (3m):[15d] Following the general procedure
(A), 3m was obtained as a white solid; yield: 105 mg (38%);
mp 193–1958C; IR (KBr): =3384, 3206, 1604, 1506, 1304,
172–1748C; IR (KBr): n=3397, 3220, 1315, 1161 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=5.78 (d, J=12.0 Hz,
1H), 6.89 (d, J=9.2 Hz, 2H), 7.42–7.50 (m, 4H), 7.62–7.68
(m, 4H), 8.04 (d, J=12.0 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): d=68.3, 107.0, 118.7, 122.7, 125.7, 127.6, 128.6,
129.3, 135.5, 136.8, 143.1; MS (EI): m/z (%)=340 (M+ +2,
100), 338 (M+, 97); anal. calcd. for C13H11N2O2SBr: C 46.03,
H 3.27, N 8.26; found: C 46.46, H 3.29, N 8.33.
1164 cmÀ1 1H NMR (400 MHz, CDCl3): d=4.60–4.70 (m,
;
2H), 6.01 (d, J=12.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.93
(dd, J=7.2, 7.2 Hz, 1H), 7.15 (dd, J=8.8, 8.8 Hz, 2H), 7.35
(ddd, J=8.4, 7.6, 1.6 Hz, 1H), 7.56 (dd, J=8.4, 4.8 Hz, 2H),
7.70 (dd, J=8.4, 1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6): d=67.7, 115.2, 115.4, 116.6 (d, J=46 Hz), 121.6, 123.7,
129.8 (d, J=8.6 Hz), 132.9, 133.7 (d, J=2.9 Hz), 143.8, 162.4
(d, J=244 Hz); MS (EI): m/z (%)=278 (M+, 84), 92 (100).
4-Methyl-3-phenyl-3,4-dihydro-(2H)-1,2,4-benzothiadia-
zine 1,1-dioxide (3k):[14c] Following the general procedure
(A), 3k was obtained as a white solid; yield: 104 mg (76%);
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N-Benzylation/Benzylic C H Amidation Cascade by the (h -Benzyl)palladium System in Aqueous Media
2-(1,2-Diphenylethylamino)benzenesulfonamide (4a): Fol-
lowing the general procedure (A), 4a was obtained as
a white solid; yield: 96 mg (27%); mp 130–1328C; IR
J=7.6 Hz), 133.2, 135.3 (d, J=2.9 Hz), 144.4, 161.2 (d, J=
241 Hz); MS (EI): m/z (%)=280 (M+, 45), 109 (100).
2-(4-Trifluoromethylbenzylamino)benzenesulfonamide
(5d): Following the general procedure (B), 5d was obtained
as a white solid; yield: 2.38 g (72%); mp 163–1658C; IR
1
(KBr): n=3376, 3284, 1345, 1158 cmÀ1; H NMR (400 MHz,
DMSO-d6): d=3.05 (dd, J=14.0, 6.0 Hz, 1H), 3.12 (dd, J=
13.6, 8.4 Hz, 1H), 4.78 (dd, J=13.6, 6.0 Hz, 1H), 6.47 (d, J=
6.0 Hz, 1H), 6.51 (d, J=8.0 Hz, 1H), 6.58 (ddd, J=8.0, 8.0,
1.2 Hz, 1H), 7.10–7.35 (m, 9H), 7.35–7.50 (m, 4H), 7.57 (dd,
J=8.0, 1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=
44.2, 58.2, 112.9, 115.0, 125.3, 126.4, 126.6, 127.0, 128.1,
128.3, 129.3, 133.0, 138.0, 143.0, 143.8; MS (EI): m/z (%)=
(KBr): n=3415, 3300, 1599, 1325, 1115 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d=4.52 (d, J=5.2 Hz, 2H), 4.82 (brs,
2H), 6.34 (brs, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.81 (ddd, J=
8.0, 7.2, 0.8 Hz, 1H), 7.36 (ddd, J=8.8, 7.2, 1.6 Hz, 1H), 7.46
(d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.84 (dd, J=8.0,
1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=45.6,
112.1, 115.1, 124.3 (d, J=270 Hz), 125.2 (q, J=3.9 Hz),
125.4, 127.5 (q, J=32 Hz), 127.6, 128.3, 133.2, 144.4 (d, J=
23 Hz); MS (EI): m/z (%)=330 (M+, 62), 248 (100); HR-
MS-EI: m/z=330.0648 (M+), calcd. for C13H13FN2O2S:
330.0650.
352
(M+,
1.0),
261
(100);
anal.
calcd.
for
C20H20N2O2S·0.2H2O: C 67.47, H 5.77, N 7.87; found: C
67.36, H 5.73, N 7.87.
2-(1,2-Diphenylethylamino)-5-fluorobenzenesulfonamide
(4b): Following the general procedure (A), 4b was obtained
as a white solid; yield: 64 mg (17%); mp 148–1508C; IR
1
(KBr): n=3369, 3284, 1349, 1153 cmÀ1; H NMR (400 MHz,
DMSO-d6): d=3.04 (dd, J=14.0, 5.2 Hz, 1H), 3.11 (dd, J=
14.0, 8.0 Hz, 1H), 4.77 (dd, J=14.0, 6.0 Hz, 1H), 6.31 (d, J=
5.6 Hz, 1H), 6.51 (dd, J=9.6, 4.4 Hz, 1H), 7.08 (ddd, J=9.2,
9.2, 3.2 Hz, 1H), 7.15–7.30 (m, 8H), 7.35 (dd, J=8.8, 3.2 Hz,
1H), 7.41 (d, J=7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6): d=44.2, 58.4, 114.2 (d, J=25 Hz), 114.4 (d, J=7 Hz),
120.0 (d, J=23 Hz), 125.6 (d, J=6 Hz), 126.4, 126.6, 127.0,
128.1, 128.3, 129.3, 137.9, 140.6, 142.8, 152.3 (J=233 Hz);
MS (EI): m/z (%)=370 (M+, 2.0), 279 (100); anal. calcd. for
C20H19N2O2SF: C 64.85, H 5.17, N 7.56; found: C 64.53, H
5.23, N 7.49.
Acknowledgements
This work was supported by JSPS KAKENHI Grant
Number 25460026.
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1H), 7.27 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (dd, J=7.6, 7.6 Hz,
2H), 7.35–7.45 (m, 4H), 7.64 (dd, J=8.0, 1.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=46.1, 112.1, 114.9,
125.1, 126.9, 127.0, 128.2, 128.4, 133.2, 139.1, 144.6; MS (EI):
m/z (%)=262 (M+, 36), 180 (100).
2-[(2-Thienylmethyl)amino]benzenesulfonamide
(5b):
Following the general procedure (A), 5b was obtained as
a white solid; yield: 189 mg (70%); mp 113–1158C; IR
(KBr): n=3425, 3375, 3281, 1332, 1165 cmÀ1
;
1H NMR
(400 MHz, DMSO-d6): d=4.64 (d, J=6.0 Hz, 2H), 6.47 (dd,
J=6.0, 6.0 Hz, 1H), 6.68 (ddd, J=6.8, 6.8, 1.2 Hz, 1H), 6.83
(d, J=7.6 Hz, 1H), 6.98 (dd, J=5.2, 3.6 Hz, 2H), 7.05–7.15
(m, 1H), 7.31 (ddd, J=7.2, 7.2, 1.2 Hz, 1H), 7.37 (s, 2H),
7.39 (dd, J=5.2, 1.2 Hz, 1H), 7.64 (dd, J=8.0, 1.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=41.6, 112.2, 115.3,
124.8, 125.2, 125.4, 126.8, 128.2, 133.2, 142.8, 144.2; MS (EI):
m/z (%)=268 (M+, 42), 97 (100); HR-MS-EI: m/z=
268.0340 (M+), calcd. for C11H12N2O2S2: 268.0340.
2-(4-Fluorobenzylamino)benzenesulfonamide (5c): Fol-
lowing the general procedure (B), 5c was obtained as
a white solid; yield: 1.99 g (71%); mp 134–1368C; IR (KBr):
n=3388, 3269, 1566, 1512 cmÀ1
;
1H NMR (400 MHz,
DMSO-d6): d=4.46 (d, J=6.0 Hz, 2H), 6.49 (dd, J=6.0,
6.0 Hz, 1H), 6.60–6.70 (m, 2H), 7.16 (tt, J=8.8, 2.0 Hz, 1H),
7.27 (dt, J=8.0, 1.2 Hz, 1H), 7.35–7.50 (m, 4H), 7.65 (dd,
J=8.0, 1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=
45.3, 112.1, 115.1, 115.1 (d, J=30 Hz), 125.3, 128.3, 128.9 (d,
Adv. Synth. Catal. 2013, 355, 2308 – 2320
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Hidemasa Hikawa et al.
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Adv. Synth. Catal. 2013, 355, 2308 – 2320