Room-temperature ortho-alkoxylation and -halogenation of N-tosylbenzamides by using palladium(II)-catalyzed C-H activation

Article abstract of DOI:10.1002/chem.201303923

The N-tosylcarboxamide group can direct the room-temperature palladium-catalyzed C-H alkoxylation and halogenation of substituted arenes in a simple and mild procedure. The room-temperature stoichiometric cyclopalladation of N-tosylbenzamide was first studied, and the ability of the palladacycle to react with oxidants to form C-X and C-O bonds under mild conditions was demonstrated. The reaction conditions were then adapted to promote room-temperature ortho-alkoxylations and ortho-halogenations of N-tosylbenzamides using palladium as catalyst. The scope and limitation of both alkoxylations and halogenations was studied and the subsequent functional transformation of the N-tosylcarboxamide group through nucleophilic additions was evaluated. This methodology offers a simple and mild route to diversely functionalized arenes.

Full text of DOI:10.1002/chem.201303923

DOI: 10.1002/chem.201303923
Full Paper
&
CÀH Activation
Room-Temperature ortho-Alkoxylation and -Halogenation of N-
Tosylbenzamides by Using Palladium(II)-Catalyzed CÀH Activation
Florent Pꢀron,[a, b] Christine Fossey,[a, b] Jana Sopkova-de Oliveira Santos,[a, b] Thomas Cailly,[a, b]
and Frꢀdꢀric Fabis*[a, b]
Abstract: The N-tosylcarboxamide group can direct the
room-temperature palladium-catalyzed CÀH alkoxylation and
halogenation of substituted arenes in a simple and mild pro-
cedure. The room-temperature stoichiometric cyclopallada-
tion of N-tosylbenzamide was first studied, and the ability of
perature ortho-alkoxylations and ortho-halogenations of N-
tosylbenzamides using palladium as catalyst. The scope and
limitation of both alkoxylations and halogenations was stud-
ied and the subsequent functional transformation of the N-
tosylcarboxamide group through nucleophilic additions was
the palladacycle to react with oxidants to form CÀX and CÀ evaluated. This methodology offers a simple and mild route
O bonds under mild conditions was demonstrated. The reac-
tion conditions were then adapted to promote room-tem-
to diversely functionalized arenes.
sition of azo compounds,[7] anilides,[8] ureas,[9] and carba-
mates.[10] Ketones[11] and imines[12] have been used to perform
the mild formation of CÀC and CÀO bonds, whereas N-me-
thoxy-[13] and N-pivaloyloxybenzamide[14] groups have been
used to create both CÀC and CÀN bonds leading to heterocy-
cles such as phenanthridin-6(5H)-ones and isoquinolinones at
room temperature. Most of these transformations are direct-
ing-group dependent and groups able to direct multiple CÀH
transformations at room temperature are still needed. The N-
tosylcarboxamide group has recently been described in the
synthesis of isoindolinone derivatives through CÀH activation
reactions,[15] and by our group as a transformable group able
to direct ortho CÀH arylation.[16] In these examples, the reac-
tions were all performed between 120 and 1308C. During the
investigations of this directing group in other CÀH transforma-
tions, we found that ortho-alkoxylation could occur at room
temperature. Herein, we wish to report our investigations on
the use of N-tosylbenzamides in room-temperature CÀH alkox-
ylation and halogenation.
Introduction
Over the past four decades, the development of transition-
metal-catalyzed transformations has profoundly revolutionized
organic chemistry. Among them, Pd-catalyzed cross-coupling
reactions are probably the most prominent examples of such
a progress, finding applications in all the areas in which organ-
ic chemistry is involved.[1] More recently, transition-metal-cata-
lyzed CÀH bond functionalization has emerged as a new and
promising method for more atom-economical transformations
extending the scope of this chemistry.[2] In this field, the aro-
matic C(sp2)-H functionalization has been successfully applied
to the formation of CÀC, CÀN, CÀO, and CÀX bonds using, in
most cases, a directing group to enhance regioselectivity in
the ortho position.[3] However, these reactions generally require
the use of harsh reaction conditions: high temperature and/or
acidic conditions.[4] More recently, the development of milder
reaction conditions has become the subject of deep investiga-
tions.[5,6] To date, the most prominent examples of groups able
to direct mild CÀH activation reactions can be divided in two
main categories: amino and carbonyl-based derivatives. Thus,
CÀC, CÀX, and CÀO bonds have been formed at the ortho po-
Results and Discussion
In aromatic CÀH activation reactions using PdII as a catalyst,
the insertion of the metal in the CÀH bond leading to a palla-
dacycle is commonly accepted as the determining step.[17] We
started by screening various solvents to evaluate the cyclopal-
ladation reaction at room temperature starting from the N-to-
sylbenzamide 1a and using stoichiometric amounts of
[Pd(OAc)2] (Table 1). In all cases the reactions were stopped
[a] Dr. F. Pꢀron, Dr. C. Fossey, Prof. Dr. J. Sopkova-de Oliveira Santos,
Dr. T. Cailly, Prof. Dr. F. Fabis
Normandie Universitꢀ (France)
[b] Dr. F. Pꢀron, Dr. C. Fossey, Prof. Dr. J. Sopkova-de Oliveira Santos,
Dr. T. Cailly, Prof. Dr. F. Fabis
Universitꢀ de Caen Basse-Normandie
CERMN (EA 4258 - FR CNRS 3038 INC3M
- SF 4206 ICORE) UFR des Sciences Pharmaceutiques
Bd Becquerel, CS 14032 Caen cedex 5 (France)
Fax: (+33)231566803
1
after 18 h, and the ratio of 1a/2a was determined by H NMR
spectroscopy (Table 1). In solvents commonly used in CÀH acti-
vation reactions (Table 1, entries 1–6), a partial conversion of
1a in a nearly 1:1 ratio was observed. But using MeOH as the
solvent, we were pleased to see that the reaction was almost
E-mail: frederic.fabis@unicaen.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303923.
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Table 1. Solvent screening for room-temperature formation of palladacy-
cle 2a.
Scheme 1. Synthesis of palladacycle 2b (yield of isolated 2b).
Entry
Solvent
1a/2a[a]
1
2
3
4
5
6
7
AcOH
MeCN
1,2-DCE[c]
PhMe
AcOH/CHCl3 (2:1)
1,4-dioxane
MeOH
46:54
44:56
47:53
49:51
40:60
39:61
3:97
8
9
10
11
EtOH
iPrOH
CF3CH2OH
CD3OD[b]
14:86
59:41
50:50
15:85
[a] Ratio determined by using 1H NMR spectroscopy. [b] Temperature was
set to 228C (see the Supporting Information for details). [c] 1,2-Dichloro-
ethane.
complete.[13b,14a,b,18] The use of other alcohols as solvents did
not improve the conversion, whereas performing the reaction
in CD3OD allowed us to monitor the formation of palladacycle
2a by recording NMR spectra at different times (Figure 1).[19]
Scheme 2. X-ray structure of palladacycle 2b.
The reactivity of 2b in MeOH at room temperature toward
various additives commonly used in CÀH activation reactions
was then investigated. Thus, palladacycle 2b was treated at
258C for 0.25 h with PhI(OAc)2, N-iodosuccinimide (NIS), or
IOAc[20] and 1H NMR spectra of the crudes were recorded
(Table 2). By using PhI(OAc)2, a full conversion to the corre-
sponding methoxylated derivative 3a was observed, and the
use of NIS and IOAc led quantitatively to the iodinated com-
pound 4a. Taken together, these results with stoichiometric
amounts of [Pd(OAc)2] indicates that both the formation of the
Table 2. Methoxylation and iodination of palladacycle 2b.
1
Figure 1. Formation of 2a in CD3OD monitored by using H NMR spectrosco-
py.
To confirm the structure of palladacycle 2a, the reaction was
repeated using a slight excess of [Pd(OAc)2] (1.1 equiv) in
MeOH (Scheme 1). Unfortunately, attempts to characterize 2a
in a pure form failed and the exact nature of the ligands L was
not established. Nevertheless, the crude palladacycle 2a, was
stirred in MeCN at room temperature for 0.25 h to afford
a characterizable palladacycle. Thus, palladacycle 2b was iso-
lated in 94% yield and suitable single-crystals for X-ray analysis
were obtained from slow evaporation in MeCN. The obtained
ORTEP plot for 2b is depicted in Scheme 2.
Additive
Observed
products (X)
1H NMR ratio[a]
PhI(OAc)2
NIS
IOAc[b]
3a (OMe)
4a (I)
4a (I)
100
100
100
1
[a] Ratio determined by using H NMR spectroscopy and a pure sample of
material as a reference. [b] Reaction conditions: IOAc (1.05 equiv; gener-
ated from PhI(OAc)2 (0.52 equiv) and I2 (0.52 equiv)).[20]
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palladacycle and the subsequent functionalization can be per-
formed at room temperature in MeOH with PhI(OAc)2, NIS, and
IOAc.
were isolated starting from 1j,k,n. The unsubstituted N-tosyl-
benzamide 1o showed a similar reactivity affording a mixture
of di- and monomethoxylated derivatives, thus 3o was isolated
in 76% yield.
The catalytic methoxylation at room temperature was then
investigated by using [Pd(OAc)2] (10 mol%) and PhI(OAc)2
(1 equiv) in MeOH (Table 3). Starting from 1a, we observed the
Compound 1b was then evaluated toward alkoxylation
using EtOH and iPrOH as solvents (Scheme 3). Thus, using the
same protocol, the corresponding ethoxy and isopropoxy de-
Table 3. Catalytic room-temperature methoxylation of N-tosylbenz-
amides.[a]
Scheme 3. Catalytic room-temperature alkoxylation of N-tosylbenzamide 1b
(yield of isolated 1b).
rivatives 3p,q were isolated in 69 and 60% yields, respectively.
In both cases, the total completion was not observed even if
the reaction times or the amount of PhI(OAc)2 were increased.
The use of tBuOH as solvent under the same conditions did
not afford the corresponding alkoxylated derivative. As previ-
ously reported,[8c,21] only starting material was recovered un-
changed even if the temperature of the reaction was increased
(result not shown).
We then turned our attention to the room-temperature cata-
lyzed ortho-halogenation. Unlike the methoxylation, the condi-
tions of halogenation had to be optimized for the catalytic
process to work in MeOH. Therefore, starting from 2-methyl-N-
tosylbenzamide 1b and using NIS as the halogenating agent,
the reaction had to be performed in the presence of trifluoro-
acetic acid (TFA)[7,8b,22] to afford the corresponding ortho-iodi-
nated product 4b with a good conversion (Table 4). Regarding
the acidic conditions used for iodination with NIS, we found
that iodination can be performed using IOAc.[20] Thus, under
these neutral conditions, 2-chloro and 2-fluoro-N-tosylbenza-
mides 1a,e were iodinated in high yields. These conditions
were successfully applied to 3-bromo- and 3-methyl-N-tosyl-
benzamides 1 f,g affording the ortho-iodinated derivatives
4d,e in good yields. As for the methoxylation, starting from
the deactivated 3-trifluoromethyl-N-tosylbenzamide (1i) the re-
action did not go to completion and a lower yield was isolat-
ed. We then studied the catalytic ortho-iodination from para-
substituted substrates. Thus, using 1k, 1l, 1n, or 1m, the reac-
tion led to inseparable mixtures of starting material, ortho-iodi-
nated and ortho-diiodinated products (results not shown). For
example, the 4-NO2 derivative 4g was isolated in only 11%
yield.
[a] Yields of the isolated products. [b] A scale of 2 g was used. [c] Yields
of the isolated dimethoxylated compounds.
clean formation of the expected methoxylated compound 3a
isolated in 95% yield. The scope of the reaction was further
studied with various substituted N-tosylbenzamides 1b–o. The
methoxylated compounds were easily obtained by using
ortho- and meta-substituted starting materials and the reac-
tions were generally completed within 24–48 h. In the case of
deactivated starting material 1d and 1i, total conversion was
never observed resulting in lower yields even if an extended
reaction time was used for 3d. Starting from para-substituted
substrates 1j–n, the decreased yields of the isolated products
were due in all cases to the formation of dimethoxylated com-
pounds. Substantial amounts of dimethoxylated derivatives
The room-temperature catalytic bromination was then evalu-
ated by using ortho- and meta-substituted starting materials
(Table 5). Thus, by treating 1a, 1b, 1 f, and 1g with N-bromo-
succinimide (NBS) and TFA we were pleased to isolate after
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Table 4. Catalytic room-temperature iodination of N-tosylbenzamides.[a]
Table 6. Catalytic room-temperature chlorination of N-tosylbenzamides.[a]
[a] Yields of the isolated products. [b] Reaction conditions: NCS
(1.2 equiv), TFA (10 equiv). [c] Ratio in parentheses are of chlorinated/me-
1
thoxylated products in the crude material as determined by H NMR spec-
troscopy.
gether with the clean halogenation reactions observed with
NBS, NIS, and IOAc indicates that NCS behaves differently.
Therefore, we can hypothesize that either NCS is playing the
role of PhI(OAc)2 to form a pro-methoxylation active species
and/or that a competition between CÀO and CÀCl bond for-
mation takes place at the reductive-elimination step.
[a] Yields of the isolated products. [b] Reaction conditions: IOAc 1.5 equiv
(generated from PhI(OAc)2 0.75 equiv and I2 0.75 equiv).[20] [c] Reaction
conditions: NIS 1.2 equiv, TFA 10 equiv
Finally, the ability of the N-tosylcarboxamide group to give
valuable synthetic intermediates through functional transfor-
mations was evaluated (Scheme 4). Starting from 3 f, the N-to-
sylcarboxamide group was first methylated[15,23] to give 7,
which was submitted to various nucleophilic additions. Thus,
using MeMgBr (2 equiv), the addition of two methyl groups
was observed and compound 8 was isolated in 90% yield. The
use of NaOH and MeONa as nucleophiles gave the correspond-
ing carboxylic acid 9 and ester 10 in 71 and 82% yields, re-
spectively. Reduction with LiAlH4 afforded the expected benzyl-
ic alcohol 11 in 90% yield. Interestingly, phosphorus ylide 12
was obtained in 86% yield by treating 7 with methyltriphenyl-
phosphonium bromide. Ylide 12 was then further treated with
benzaldehyde to afford a mixture of Z and E alkenes 13 in
81% yield.
Table 5. Catalytic room-temperature bromination of N-tosylbenzamides.[a]
Conclusion
We have found that the palladium-catalyzed ortho-alkoxylation
and ortho-halogenations of N-tosylbenzamides can be per-
formed in good yields at room temperature using methanol as
the solvent. Both alkoxylation using PhI(OAc)2 and iodination
with IOAc, generated from the mixture I2/PhI(OAc)2, occurred in
very mild conditions using a simple procedure. However, the
alkoxylation reaction scope seems to be limited to the use of
non-hindered alcohols. With regard to the halogenation reac-
tions, the use of para-substituted starting materials led to com-
plex mixtures, whereas the use of NCS afforded both chlorinat-
ed and methoxylated derivatives. Furthermore, the ability of
the N-tosylcarboxamide group to be transformed in a variety
of relevant functional groups has been highlighted. These re-
sults could serve in the development of other CÀH activation
[a] Yields of the isolated products. [b] Reaction conditions: NBS
(1.2 equiv), TFA (10 equiv).
complete conversion the expected ortho-brominated deriva-
tives 5a–d in good yields. The same reaction conditions were
then applied to perform chlorination (Table 6). Therefore, by re-
placing NBS by N-chlorosuccinimide (NCS), compound 1b was
ortho-chlorinated to give 6a along with the ortho-methoxylat-
ed derivative 3b in a ratio of 87:13. Similar results were ob-
served by using meta-substituted starting materials 1 f and 1g.
It appears that using NCS in MeOH leads to a competition be-
tween chlorination and methoxylation. These results taken to-
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1H), 6.42 (t, J=7.8 Hz, 1H), 6.23 (d,
J=7.8 Hz, 1H), 2.47 (s, 3H), 2.39 (s,
3H), 2.02 ppm (s, 3H); 13C NMR
(500 MHz, CDCl3): d=175.7, 143.5,
143.2, 138.8, 132.7, 131.5, 131.3,
129.9, 129.3 (2C), 127.7 (2C), 127.5,
21.7, 4.1, 2.1 ppm; IR (KBr): n˜ =
3420, 3067, 2928, 2321, 2294,
1659, 1552, 1432, 1281, 1251, 933,
841, 746, 661, 579, 550 cmÀ1
HRMS/ESI: m/z calcd for
454.9448
;
C16H14ClN2O3PdS:
[MÀCH3CN+H]+; found: 454.9463.
General procedure B for ortho-al-
koxylation of N-tosylbenzamide
1a–o: In a round bottom flask, N-
tosylbenzamide 1a–o (1 equiv)
was added to a solution of PhI-
(OAc)2 (1 equiv) and [Pd(OAc)2]
Scheme 4. N-methylation and subsequent functional transformations of 3 f.
(0.1 equiv) in MeOH, EtOH, or
iPrOH (8.3 mLmmolÀ1 of 1a–o).
This mixture was stirred at 258C (see Table 2 and Scheme 4 for re-
action times) and monitored by TLC. Upon completion, the result-
ing mixture was diluted with EtOAc, filtered through a pad of
Celite and the solvent was evaporated. The crude residue was puri-
fied by silica gel chromatography using cyclohexane/EtOAc (4:1 to
3:2 gradient) as the eluent to obtain the desired products 3a–q.
reactions and find applications in the synthesis of functional-
ized arenes under mild conditions.
Experimental Section
2-Chloro-6-methoxy-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(3a): Starting from N-tosylbenzamide 1a (0.200 g, 0.65 mmol),
using general procedure B, compound 3a was obtained as a white
solid (0.208 g, 95%). M.p. 140–1428C. 1H NMR (400 MHz, CDCl3):
d=7.97 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.27 (t, J=
8.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.76 (s,
3H), 2.45 ppm (s, 3H); the NH signal is missing; 13C NMR (100 MHz,
CDCl3): d=162.4, 157.6, 145.4, 135.5, 132.6, 132.3, 129.7 (2C), 128.8
(2C), 123.1, 122.3, 109.7, 56.3, 21.7 ppm; IR (KBr): n˜ =3198, 3045,
2946, 1691, 1595, 1466, 1272, 1151, 783 cmÀ1; HRMS/ESI: m/z calcd
for C15H14ClNO4SNa: 362.0230 [M+Na]+; found: 362.0212.
Syntheses
General procedure A for the preparation of substituted N-tosyl-
benzamides 1a–o: A round-bottom flask under N2 was filled with
p-toluene sulfonamide (1 equiv), EtOAc (2 mLmmolÀ1), NEt3
(2.5 equiv), and 4-dimethylaminopyridine (DMAP; 0.005 equiv). A
solution of acyl chloride (1.1 equiv) in PhMe (0.8 mLmmolÀ1) was
added through a syringe over 15 min. The mixture was stirred for
1 hour at 558C under N2, cooled to room temperature and
quenched with an aqueous solution of hydrochloric acid (0.5m,
3 mLmmolÀ1). The resulting mixture was then extracted with
EtOAc (3 times). The combined organic layers were dried on
MgSO4, filtered and evaporated. The crude was purified by passing
through a pad of silica gel eluting with CH2Cl2.
General procedure C for ortho-halogenation of N-tosylbenza-
mide 1a,b,f,g using NXS: In a round-bottom flask, N-tosylbenza-
mide 1a,b,f,g (1 equiv) and trifluoroacetic acid (10 equiv) was
added to a solution of NXS (1.2 equiv) and [Pd(OAc)2] (10 mol%) in
MeOH (12.8 mLmmolÀ1 of 1a,b,f,g). The reaction was stirred at
258C (see Tables 3–5 for reaction times). The resulting mixture was
diluted with EtOAc, filtered through a pad of Celite and the solvent
was evaporated. The crude was purified by silica gel chromatogra-
phy using cyclohexane/EtOAc (4:1 to 3:2 gradient) as the eluent to
obtain the desired product 4b or 5a–d or 6a–c.
2-Fluoro-N-(4-methylbenzenesulfonyl)benzenecarboxamide
Starting from 2-fluorobenzoyl chloride (2.43 g, 15.3 mmol), using
(1e):
general procedure A, N-tosylbenzamide 1e was obtained as
a
white solid (3.93 g, 92% yield). M.p. 137–1388C. 1H NMR
(400 MHz, CDCl3): d=9.01 (brs, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.99
(td, J=12.3, 4.0 Hz, 1H), 7.56 (m, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.26
(td, J=7.6, 0.9 Hz, 1H), 7.16 (ddd, J=12.3, 8.4, 0.9 Hz, 1H),
2.44 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=161.0 (d, J=
249 Hz), 160.5 (d, J=3 Hz), 145.5, 135.8 (d, J=10 Hz), 135.5, 132.6,
129.8 (2C), 129.0 (2C), 125.5 (d, J=3 Hz), 118.6 (d, J=10 Hz), 116.6
(d, J=25 Hz), 21.8 ppm; IR (KBr): n˜ =3325, 3088, 2923, 1705, 1595,
1428, 1350, 1167, 753 cmÀ1; HRMS/ESI: m/z calcd for C14H13FNO3S:
294.0594 [M+H]+; found: 294.0597.
2-Bromo-6-chloro-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(5a): Starting from N-tosylbenzamide 1a (0.100 g, 0.32 mmol),
using general procedure C with NBS, compound 5a was obtained
1
as a white solid (0.097 g, 77%). M.p. 72–748C; H NMR (400 MHz,
CDCl3): d=7.99 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.36 (d,
J=8.2 Hz, 2H), 7.30 (d, J=8.1 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H),
2.46 ppm (s, 3H); the NH signal is missing; 13C NMR (100 MHz,
CDCl3): d=162.6, 145.8, 135.4, 134.9, 132.3, 132.2, 131.4, 129.8 (2C),
128.9 (2C), 128.8, 120.1, 21.9 ppm; IR (KBr): n˜ =3216, 3045, 2923,
1712, 1448, 1349, 1170, 1090, 776 cmÀ1; HRMS/ESI: m/z calcd for
C14H12BrClNO3S: 387.9404 [M+H]+; found: 387.9404.
Synthesis of palladacycle 2b: [Pd(OAc)2] (0.229 g, 1.02 mmol) was
added to a solution of 1a (0.300 g, 0.97 mmol) in MeOH (6 mL).
The reaction mixture was stirred at 258C for 18 h. The crude mix-
ture was filtered through a pad of Celite. The Celite pad was
washed with MeOH (25 mL) and the solution was evaporated to
dryness. MeCN (25 mL) was added, the solution was stirred at 258C
for 0.5 h and evaporated to afford palladacycle 2b as a yellow
solid (0.452 g, 94%). M.p.>2508C; 1H NMR (400 MHz, CDCl3): d=
7.95 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 6.87 (d, J=7.8 Hz,
General procedure D for ortho-iodination of N-tosylbenzamide
1a,e,f,g,i,m using IOAc: PhI(OAc)2 (0.75 equiv), I2 (0.75 equiv) and
MeOH (12.8 mLmmolÀ1 of 1a,e,f,g,i,m) were added in a round-
bottom flask. The reaction was stirred for 0.25 h at room tempera-
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ture. N-Tosylbenzamide 1a,e,f,g,i,m (1 equiv) and [Pd(OAc)2]
(10 mol%) were added to the solution and the reaction was stirred
at 258C (see Table 3 for reaction times). The resulting mixture was
diluted with EtOAc, filtered through a pad of Celite, and the sol-
vent was evaporated. The crude residue was purified by silica gel
chromatography using cyclohexane/EtOAc (4:1 to 3:2 gradient) as
the eluent to obtain the desired product 4a,c–g.
Keywords: alkoxylation · CÀH activation · halogenation ·
palladium · synthetic methods
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ich), Wiley-VCH Verlag GmbH, Weinheim, Germany, 2004.
[2] a) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. 2012, 124,
9092–9142; Angew. Chem. Int. Ed. 2012, 51, 8960–9009; b) J. Wencel-
Delord, F. Glorius, Nat. Chem. 2013, 5, 369–375.
2-Chloro-6-iodo-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(4a): Starting from N-tosylbenzamide 1a (0.100 g, 0.32 mmol),
using the general procedure D, compound 4a was obtained as
a white solid (0.134 g, 95%). M.p. 85–868C; 1H NMR (400 MHz,
CDCl3): d=8.41 (brs, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.67 (dd, J=8.0,
0.8 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.34 (dd, J=8.0, 0.9 Hz, 1H),
7.03 (t, J=8.0 Hz, 1H), 2.46 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=164.1, 145.8, 139.1, 137.9, 134.8, 132.5, 131.3, 129.8 (2C), 129.6,
129.1 (2C), 92.1, 21.9 ppm; IR (KBr): n˜ =3214, 3058, 2959, 1702,
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1445, 1349, 1170, 1089, 777 cmÀ1
; HRMS/ESI: m/z calcd for
C14H12ClINO3S: 435.9265 [M+H]+; found: 435.9266.
5-Bromo-2-methoxy-N-methyl-N-(4-methylbenzenesulfonyl)benzene-
carboxamide (7): K2CO3 (1.21 g, 8.74 mmol) and iodomethane
(544 mL, 8.74 mmol) were added to a stirred solution of 3 f (1.68 g,
0.74 mmol) in DMF (30 mL). After stirring at room temperature
during 3 h, the solution was evaporated, water (50 mL) was added
and the resulting mixture was extracted with ethyl acetate (3ꢂ
80 mL). The combined organic layers were dried on MgSO4, filtrat-
ed and evaporated. The crude product was purified by silica gel
chromatography using cyclohexane/EtOAc (7:3) as the eluent. 7
was obtained as a white solid (1.57 g, 91% yield). M.p. 139–1418C.
1H NMR (400 MHz, CDCl3): d=7.71 (d, J=8.4 Hz, 2H), 7.46 (dd, J=
8.8, 2.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.16 (d, J=2.5 Hz, 1H), 6.75
(d, J=8.8 Hz, 1H), 3.75 (s, 3H), 3.31 (s, 3H), 2.45 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=167.4, 155.1, 145.0, 135.7, 134.3,
130.8, 129.6 (2C), 128.2 (2C), 126.9, 112.7, 112.5, 55.9, 33.6,
21.6 ppm; IR (KBr): n˜ =3006, 2954, 2850, 1682, 1595, 1488, 1350,
1164, 1026, 829, 691 cmÀ1; HRMS/ESI: calcd for C16H16BrNO4SNa:
419.9876 [M+Na]+; found: 419.9877.
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2-(5-Bromo-2-methoxyphenyl)propan-2-ol (8): Methylmagnesium
bromide (3.0m in diethyl ether, 0.335 mL, 1.0 mmol) was added
dropwise to a solution of 7 (0.200 g, 0.50 mmol) in THF (4 mL)
under N2 at 08C. The reaction mixture was allowed to warm to
room temperature and stirred for 6 h under N2. The resulting mix-
ture was quenched with water (10 mL) and extracted with ethyl
acetate (3ꢂ15 mL). The combined organic layers were washed
with a saturated solution of NaCl then dried on MgSO4, filtrated
and evaporated. The crude product was purified by silica gel chro-
matography using cyclohexane/ethyl acetate (9:1) as the eluent. 8
was obtained as a white solid (0.110 g, 90% yield). M.p. 76–788C;
1H NMR (400 MHz, CDCl3): d=7.44 (d, J=2.5 Hz, 1H), 7.34 (dd, J=
8.7, 2.5 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 3.89 (s, 3H), 1.58 ppm (s,
6H); OH signal is missing; 13C NMR (100 MHz, CDCl3): d=156.0,
138.1, 130.7, 129.0, 113.6, 113.0, 72.3, 55.5, 29.4 (2C); IR (KBr): n˜ =
3292, 3073, 2962, 2934, 2838, 1486, 1390, 1240, 1070, 809,
627 cmÀ1
; HRMS/ESI: m/z calcd for C10H13BrO2Na: 266.9991
[M+Na]+; found: 266.9993.
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Acknowledgements
This work was supported by funding from CNRS and ERDF. The
IS:CE-Chem project and the Interreg IVA France-(Channel)-Eng-
land program are gratefully thanked for their financial support.
[19] See the Supporting Information for details.
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Received: October 7, 2013
Revised: December 13, 2013
Published online on && &&, 2014
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Chem. Eur. J. 2014, 20, 1 – 8
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FULL PAPER
&
CÀH Activation
F. Pꢀron, C. Fossey,
J. Sopkova-de Oliveira Santos, T. Cailly,
F. Fabis*
&& – &&
Mild method for diverse arenes:
tosylcarboxamide group to be trans-
formed in useful functional groups, this
methodology offers a simple and mild
route to diversely functionalized arenes
(see scheme).
Room-Temperature ortho-Alkoxylation
and -Halogenation of N-
Tosylbenzamides by Using
Palladium(II)-Catalyzed CÀH Activation
Room-temperature palladium-catalyzed
ortho-alkoxylations and ortho-halogena-
tions of N-tosylbenzamides are de-
scribed. Along with the ability of the N-
&
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Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
8
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!