Copper-catalyzed N-alkylation of sulfonamides with benzylic alcohols: Catalysis and mechanistic studies

Article abstract of DOI:10.1002/adsc.200900490

The N-alkylation of sulfonamides with alcohols is efficiently performed in the presence of easily available copper catalysts via hydrogen borrowing methodology. Applying a copper acetate/potassium carbonate system the reaction of sulfonamides and alcohols gave the corresponding secondary amines in excellent yield. In situ HR-MS analysis indicated that bissulfonylated amines are formed under air atmosphere, which act as self-stabilizing Iigands for the catalytic system. UV-visible measurements suggest the interaction between the copper centre and the bissulfonylated amine. Reactions of benzyl alcohol-d ₇ with p-toluenesulfonamide, Nbenzyl-p-toluenesulfonamide or N-benzylidenetoluenesulfonamide revealed that the reaction proceeds via a transfer hydrogenation mechanism and the whole process is micro-reversible. Competitive reactions of benzyl alcohol and benzyl alconol-d₇ with ptoluenesulfonamide revealed a kinetic isotope effect (kH/kD) of 3.287 (0.192) for the dehydrogenation of benzyl alcohol and 0.611 (0.033) for the hydrogenation of the N-benzylidene-p-toluenesulfonamide intermediate, which suggests that dehydrogenation of the alcohol is the rate-determining step.

Full text of DOI:10.1002/adsc.200900490

FULL PAPERS
DOI: 10.1002/adsc.200900490
Copper-Catalyzed N-Alkylation of Sulfonamides with Benzylic
Alcohols: Catalysis and Mechanistic Studies
Xinjiang Cui,a,b Feng Shi,a,* Man Kin Tse,c Dirk Gçrdes,d Kerstin Thurow,d
Matthias Beller,c and Youquan Denga,*
a
Centre for Green Chemistry and Catalysis, Lanzhou Institute of Chemical Physics, Chinese Academy and Science,
Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-496-8116; phone: (+86)-931-496-8116; e-mail: fshi@lzb.ac.cn or lydeng@lzb.ac.cn
Graduate School of Chinese Academy and Science, Beijing 100049, Peopleꢀs Republic of China
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock, 18059 Rostock, Germany
Center for Life Science Automation (CELISCA), Universitꢂt Rostock, 18119 Rostock, Germany
b
c
d
Received: July 12, 2009; Revised: September 8, 2009; Published online: November 18, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900490.
Abstract: The N-alkylation of sulfonamides with al-
ACHTUNGTRENeNGNU nesulfonamide revealed that the reaction proceeds
cohols is efficiently performed in the presence of via a transfer hydrogenation mechanism and the
easily available copper catalysts via hydrogen bor- whole process is micro-reversible. Competitive reac-
rowing methodology. Applying a copper acetate/po- tions of benzyl alcohol and benzyl alcohol-d7 with p-
tassium carbonate system the reaction of sulfon- toluenesulfonamide revealed a kinetic isotope effect
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
under air atmosphere, which act as self-stabilizing li- termediate, which suggests that dehydrogenation of
gands for the catalytic system. UV-visible measure- the alcohol is the rate-determining step.
ments suggest the interaction between the copper
centre and the bissulfonylated amine. Reactions of
benzyl alcohol-d7 with p-toluenesulfonamide, N- Keywords: alcohols; alkylation; C N bond forma-
benzyl-p-toluenesulfonamide or N-benzylidenetolu- tion; copper catalysts; sulfonamides
À
Introduction
kylated sulfonamides is carried out mainly via con-
densation of amines with sulfonyl chlorides.[7] Al-
Nitrogen-containing compounds are of significant im- though this protocol is efficient and various N-alkylat-
portance as building blocks for pharmaceuticals and ed products can be obtained, the usage of sulfonyl
novel bio-active compounds.[1] In the past decades, chlorides results in storage and handling problems.[8]
À
versatile catalytic procedures for carbon-nitrogen (C
Other known methods, such as reductive amination of
N) bond formation, for instance, amination of aryl sulfonamides and nucleophilic substitutions with alkyl
halides,[2] hydroaminations[3] and hydroaminomethyla- halides have also been employed.[9] But all these
tions[4] have been developed. Nevertheless, further methods suffer from the generation of unwanted inor-
improvements are still possible.
ganic salts.
With respect to alkylated amides, N-alkylated sulfo-
Recently, significant attention has been focused on
namides constitute an important class of compounds the N-alkylation of amines with alcohols as the alkyla-
because the sulfonamide moiety is found in a large tion reagents. Clearly, alcohols are readily available,
number of agrochemicals and pharmaceuticals.[5] In non-expensive, and non-toxic. However, the direct
addition, sulfonamides have also been used as pro- use of alcohols as alkylation reagents is limited due to
tecting groups, which can be readily removed.[6] Thus, the poor electrophilicity of most alcohols. Based on
N-alkylated sulfonamides are easily converted to give the hydrogen borrowing methodology,[10] this draw-
primary amines. Unfortunately, the preparation of al- back can be overcome due to the in situ generation of
Adv. Synth. Catal. 2009, 351, 2949 – 2958
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2949

Xinjiang Cui et al.
FULL PAPERS
Table 1. N-Alkylation of p-toluenesulfonamide with benzyl
alcohol using different copper catalysts.[a]
Entry Catalyst
Conv.
[%][b]
Sel.
3:4:5:6:7[d]
[%][c]
1
2
3
4
5
6
7
8
CuCl
CuCl2
CuBr
CuCO3·Cu(OH)2 21
CuBr2
27
27
21
56
85
24
33
63
93
94
68
3:45:38:6:8
5:33:45:6:11
1:68:22:5:4
2:66:25:5:2
4:37:47:4 :12
3:20:49:7 :21
11:12:55:7:15
8:63:21:6:2
Scheme 1. Transfer-hydrogenative alkylation of amines with
alcohols.
30
46
54
44
CuSO4
Cu
Cu
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
a much more reactive aldehyde (Scheme 1, a). Until
today, many transition metal catalysts, based on ruthe-
nium,[11] rhodium,[12] platinum[13], and iridium[14] com-
plexes have been employed for alkylations of amines
with alcohols since the first homogeneous catalysts
for such transformations were introduced by Grigg[15]
and Watanabe.[16] Interestingly, N-alkylations of sul-
[a]
Reaction conditions: 2.5 mmol (428 mg) p-toluenesulfon-
amide, 10 mmol (1080 mg) benzyl alcohol, 1 mol%
copper, 1508C, 12 h, air, 40-mL sealed pressure tube.
The conversion was directly measured from the peak
area of GC-MS.
The selectivity was measured from the peak area of GC-
MS. Beside N-benzyl-p-toluenesulfonamide 1, the only
by-product from p-toluenesulfonamide was N-benzyli-
dene-p-toluenesulfonamide 2.
The distribution of products from benzyl alcohol. The
ratio was obtained from the peak area of GC-MS. 3=
benzaldehyde; 4=benzyl alcohol; 5=dibenzyl ether; 6=
benzyl benzoate; 7=unknown.
AHCTUNGTRENNUNG
[b]
[c]
ACHTUNGTRENNUNGfonamides and carboxamides have also been realized
successfully via a carbocation mechanism using ben-
zylic and allylic alcohols as N-alkylating reagents.[17]
In addition, only two reports on the catalytic N-alky-
lation of sulfonamides with alcohols in the presence
of ruthenium catalysts are known till now.[18] Obvious-
ly, the use of such noble metal catalysts is limited due
to their high price and the indispensable need of sta-
bilizing ligands.[19] Thus, it is of significant importance
[d]
to find more economic catalyst systems for transfer higher conversion, that is, ~50%, was observed if
hydrogenative alkylations. In this respect copper is an CuSO4, Cu(NO3)2 or Cu(OAc)2 were applied (Table 1,
A
ACHTUNGTRENNUNG
interesting option, which has been employed as a het- entries 6–8). Unfortunately, large amounts of side-
erogeneous catalyst using alcohols as alkylating re- products such as dibenzyl ether and benzyl benzoate
agent.[20]
derived from benzyl alcohol were observed (Table 1,
Recently, we demonstrated for the first time that entries 6 and 7). Clearly, these side-products cause
the alkylation of sulfonamides with alcohol proceeds severe problems in product purification and benzyl al-
in the presence of copper acetate via hydrogen bor- cohol recycling. Notably, the side-reactions from
rowing methodology.[11a] Herein, we report a full ac- benzyl alcohol were less pronounced when Cu
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
are also presented.
Recently, it has been shown that the presence of
base promotes the transfer hydrogenative coupling of
sulfonamides with alcohols.[18] Thus, different bases
were used as additive to improve the conversion of
the copper-catalyzed alkylation reaction (Table 2). As
Results and Discussion
Initially, the reaction of p-toluenesulfonamide with a typical base in hydrogen borrowing reactions,[21]
benzyl alcohol was studied as model reaction to inves- KO-t-Bu was tested first (Table 2, entry 1). Similar ac-
tigate the activity of different copper catalysts. In gen- tivity was obtained in comparison with the base-free
eral, the amination reaction was carried out under system with increased selectivity to N-benzyl-p-tolu-
base-free condition at 1508C for 12 h in the presence ene sulfonamide. Clearly, this result suggests that the
of 1 mol% copper salt. In order to promote the for- addition of base promotes the hydrogenation of the
mation of the desired product, an excess amount of imine intermediate.
benzyl alcohol with respect to amine was used (4:1).
If common strong bases such as KOH and NaOH
As shown in Table 1 all copper salts tested showed were used as co-catalyst, the reaction is facilitated.
some activity for the conversion of p-toluenesulfon- The conversions were 54% and 67% with 88% and
ACHTUNGTRENNUNGamide. For example, 20–30% conversion was obtained 95% selectivity, respectively (Table 2, entries 2 and 3).
when CuCl, CuCl2, CuBr, CuCO3·Cu(OH)2 or CuBr2 To our delight, almost 100% conversion and >90%
were used as catalysts (Table 1, entries 1–5). Much selectivity are achieved in the presence of K2CO3 or
2950
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2949 – 2958

Copper-Catalyzed N-Alkylation of Sulfonamides with Benzylic Alcohols
FULL PAPERS
Table 2. Cu
ACHTUNGTRENNUNG(OAc)2/base-catalyzed alkylation of p-toluenesul-
as CuACHTUNGTRNEUNG(OAc)2 was exhibited by using CuCl2 and CuBr2
fonamide with benzyl alcohol.[a]
as catalysts (Table 3, entries 4 and 5). With these cata-
lysts conversion of p-toluenesulfonamide and selectiv-
ity towards N-benzyl-p-toluenesulfonamide were
around 90% and >90% selectivity was also achieved
based on consumed benzyl alcohol. However, still
~5% of the imine intermediate remained. Thus, the
optimal choice for the alkylation of sulfonamides is
Entry
Cu catalyst
Conv. [%]
Sel. [%]
3:4:5
1
2
KO-t-Bu
NaOH
39
84
9:86:4
54
67
>99
>93
46
88
95
90
99
11:83:6
10:84:6
11:85:5
12:84:4
5:89:6
3
KOH
4
5
Na2CO3
K2CO3
the CuACHTUNGTRNEUG(N OAc)2/K2CO3 system.
6
K3PO4·3H2O
K2CO3
58
Typically, hydrogen borrowing reactions are per-
formed under an inert atmosphere. Hence, the best
reaction was performed under argon to check its
effect on the catalytic activity, too. However, only
moderate conversion was detected (Table 4, entry 1).
Apparently, the presence of a catalytic amount of air/
oxygen promotes the reaction. In the presence of
7[b]
>99
>99
11:89:0
[a]
Reaction conditions: see Table 1. 10 mol% base were
added in each case.
20 mol% K2CO3 were used.
[b]
Na2CO3 (Table 2, entries 4 and 5). Furthermore, only 7 mol% oxygen, the conversion of p-toluenesulfon-
a moderate result was obtained when K3PO4 was ap- amide was increased from 48% to 84% (Table 4,
AHCTUNGTRENNUNG
plied (Table 2, entry 6). Finally, it was found that p- entry 2). More than 90% conversion and >99% selec-
toluenesulfonamide was quantitatively converted into tivity was obtained with 14 mol% oxygen. However,
the alkylated product with the addition of 20 mol% if the amount of oxygen was further increased to
K2CO3 (Table 2, entry 7). It is worth mentioning that 70 mol%, the conversion of p-toluenesulfonamide and
the side-products originated from benzyl alcohol are the selectivity to N-benzyl-p-toluenesulfonamide
effectively inhibited when a catalytic amount of base dropped to 82% and 36%, respectively (Table 4, en-
was added in all cases. Normally, the by-products are tries 4 and 5). It is likely that the presence of too
benzaldehyde and dibenzyl ether. In the presence of much oxygen inhibits the transfer hydrogenation step.
20 mol% K2CO3, the only detectable by-product on
GC-MS analysis was benzaldehyde. Quantitative anal- catalyst systems, in situ HR-MS analysis of the model
ysis revealed selectivities to N-benzyl p-toluenesulfon- reaction in the presence of Cu(OAc)2/K2CO3/air and
amide and benzaldehyde of 94% and 6%, respective- Cu(OAc)2/K2CO3/Ar was performed. To our delight,
ly, based on the consumed benzyl alcohol. HR-MS analysis revealed that compound 8 was
Next, the catalyst activities of different copper salts formed in the Cu(OAc)2/K2CO3/air system compared
in the presence of K2CO3 were tested as shown in with the Cu(OAc)2/K2CO3/Ar (Scheme 2).
Table 3. Apparently, this compound is formed via oxidation
In order to elucidate the effect of oxygen on the
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Under these conditions copper salts, that is, CuCl of benzyl alcohol and condensation with p-toluenesul-
and CuBr, exhibited low activity. The conversion of p- fonamide. It is likely that the formation of this com-
toluenesulfonamide was ~30% and large amounts of pound is the reason for the remarkably higher catalyt-
the corresponding imine intermediate remained at the ic activity under air.
end (Table 3, entries 1 and 2). When using CuSO4 as
Therefore, 8 was separately synthesized and added
catalyst, the conversion of p-toluenesulfonamide was to the reaction of p-toluenesulfonamide and benzyl
quite low but large amounts of undesirable ether and
ester derived from benzyl alcohol were produced
(Table 3, entry 3). Here, the selectivity based on
benzyl alcohol was lower than 50%. Similar activity
Table 4. Alkylation of p-toluenesulfonamide in the presence
of air/oxygen.[a]
Entry Atmosphere/O2:p-toluenesulfona- Conv.
Sel.
[%]
mide[b]
[%]
Table 3. Alkylation of p-toluenesulfonamide in the presence
1
2
3
4
5
Ar/0%
48
84
93
81
82
>99
95
>99
82
of copper-K2CO3 catalysts.[a]
Air/7%
Air/14%
O2/35%
O2/70%
Entry
Catalyst
Conv. [%]
Sel. [%]
1
2
3
4
5
6
CuCl
31
36
21
89
90
93
87
25
86
93
95
>99
36
CuBr
CuSO4
CuCl2
CuBr2
[a]
[b]
Reaction conditions: see Table 1.
By tuning the volume of the reaction tube and reaction
environment (air or pure oxygen), reaction systems with
different oxygen:p-toluenesulfonamide mol ratio were
obtained. The mol ratio was estimated according to PV=
nRT.
Cu
N
[a]
Reaction conditions: see Table 1. 10 mol% K2CO3.
Adv. Synth. Catal. 2009, 351, 2949 – 2958
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2951

Xinjiang Cui et al.
FULL PAPERS
Scheme 2. Compound 8 observed in CuACHTNUTGRNEG(UN OAc)2/K2CO3/air
system by HR-MS.
Scheme 3. Reaction of N-benzylidenetoluenesulfonamide
with benzyl alcohol.
Table 5. Reaction of p-toluenesulfonamide and benzyl alco-
hol in the presence of 8.[a]
Time [h]
0
3
6
12
without (1)[b]
(1)[b]
0
0
26
49
48
76
93
99
[a]
Reaction conditions: see Table 1.
Conversion of p-toluenesulfonamide. The data were ob-
[b]
tained by GC-MS.
alcohol in the presence of 10 mol% K2CO3. Indeed,
nearly full conversion and excellent selectivity were
obtained with the addition of 2 mol% of compound 8,
while 93% conversion was attained in the absence of
8 (Table 5). These results give strong evidence that
the bissulfonylated amine 8 acts as a stabilizing ligand
to the copper catalyst in the N-alkylation reaction of
p-toluenesulfonamide. A low amount of oxygen disfa-
vours the formation of such ligands, at the same time,
the transfer hydrogenation step is restrained with an
excess of oxygen resulting in large amounts of imine.
Thus, 14 mol% of oxygen give the best results for the
overall reaction.
Scheme 4. Reaction of N-benzylidene-p-toluenesulfonamide
with benzyl alcohol-d7.
Further GC-MS investigations of the model reac-
tion revealed that N-benzylidene-p-toluenesulfon-
ACHTUNGTRENNUNG
to >99% N-benzyl-p-toluenesulfonamide in the end. this experiment showed the formation of the expected
Simultaneously, benzaldehyde is also detected at the N-benzyl-p-toluenesulfonamide-d1 and also benzalde-
early stage of the reaction. These results indicate that hyde-d6, which supports the proposed hydrogen bor-
N-benzylidene-p-toluenesulfonamide is the main in- rowing mechanism. Meanwhile, compounds 3 and 11
termediate, which is formed via condensation of ben- were also produced, which suggests that the reaction
1
zaldehyde and sulfonamide. The following hydrogena- is reversible. Noteworthy, based on H NMR meas-
tion is the rate-determining step in this process.
To confirm that Cu(OAc)2/K2CO3 is active in trans- which is consistent with the result found in the GC-
fer hydrogenations a competition experiment between MS analysis, that is, 1.38:1.
urements, the ratio of products 10 and 11 is 1.38:1,
AHCTUNGTRENNUNG
N-benzylidene-p-toluenesulfonamide and benzyl alco-
Then, the reaction of p-toluenesulfonamide and
hol was performed (Scheme 3). As expected, N-ben- benzyl alcohol-d7 was conducted to clarify the posi-
zylidenetoluenesulfonamide was fully converted into tion of deuterium in compounds 10/11 and 12/13
N-benzyl-p-toluenesulfonamide in the end with con- (Scheme 5). This reaction provided evidence of the
1
comitant formation of benzaldehyde.
hydride transfer. According to H NMR and GC-MS
Isotopic tracing is an ideal method for mechanistic analyses, the major product (>95%) was N-benzyl-p-
investigations. Therefore, the reaction of N-benzyli- toluenesulfonamide-d7. There were no deuterated NH
dene-p-toluenesulfonamide with benzyl alcohol-d7 or OH groups observed in the final product. More-
was further studied (Scheme 4). GC-MS analysis of over, deuterium was not incorporated into the ring of
2952
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2949 – 2958

Copper-Catalyzed N-Alkylation of Sulfonamides with Benzylic Alcohols
FULL PAPERS
Scheme 7. The reversible pathway of the reaction between
benzyl alcohol and N-benzyl-p-toluenesulfonamide.
Scheme 5. Alkylation of p-toluenesulfonamide with benzyl
alcohol-d7.
p-toluenesulfonamide. Clearly, the deuterium atoms cohol is important in order to achieve high yield of
eliminated from benzyl alcohol were added to the in the alkylated sulfonamide due to the reversibility of
situ generated methylene group rather than other po- the reaction.
sitions. The results outlined above provide experimen-
Isotope competitive reactions are a convenient
tal evidence that the reaction is micro-reversible. This method to determine whether the hydride elimination
is also in good accordance with the reported result- is the rate-determining step.[12] In the current work,
s.[18a,23]
the competitive reaction was carried out with p-tolu-
ACHTUNGTRENNeUNG nesulfonamide and deuterated benzyl alcohol-d7/
However, the reversibility of the whole reaction
route is unclear in spite of the hydrogen borrowing benzyl alcohol. According to GC-MS analysis, the re-
mechanism. Hence, we reacted benzyl alcohol-d7, N- action took place with high conversion (>99%) and
benzyl-p-toluenesulfonamide and CuACHTNUTRGNE(UNG OAc)2/K2CO3 selectivity (>99%). Due to the micro-reversibility of
together. Based on the GC-MS analysis, N-benzyl-p- the process four different products were obtained. As
toluenesulfonamide-d7 and N-benzylidene-p-toluene- it was shown in Scheme 8, 1 and 10 were derived
sulfonamide-d6 were detected (Scheme 6). At the from benzyl alcohol and 12 and 14 were products
same time, a small amount of non-deuterated benzal- from deuterated benzyl alcohol. After ion selective
dehyde was formed. However, no benzyl alcohol mass spectra calibration, their characteristic m/z+
(C6H5CH2OH) was observed. This means that the numbers are 106, 107, 112 and 113, respectively.
imine formed from the condensation of the aldehyde Based on the corresponding peak area, the mol ratio
and amine is more easily hydrogenated to the corre- of compounds 1, 10, 12 and 14 was as follows: Peak
sponding secondary amine than the aldehyde, which area106:107:112:113 =7.409
G
ACHTUGTNREN(UNG 0.236):2.377ACHTUNGTRENN(UGN 0.027):1.
has been proven by a DFT study.[22] These results in-
dicate also the reversibility of the whole reaction.
On the basis of the studies above, the alkylation of were calibrated from the ratio of compounds 1, 10, 12
p-toluenesulfonamide and benzyl alcohol proceeds via and 14.
a domino dehydrogenation-condensation-hydrogena-
tion sequence. First, the hydride is removed tempora-
rily from alcohol and a more reactive carbonyl com-
pound is produced. Then, nucleophilic condensation
takes place between the corresponding aldehyde and
Proton-CH /Proton-CH - =(1)+(10)+(14)+(12)]ꢄ3/[(1)ꢄ2+
(10)ꢄ1+(14)ꢄ1]=2.080 (0.016):1
3
2
Protonaromatic/Proton-CH - =[(1)ꢄ9+(10)ꢄ9+(14)ꢄ4+(12)ꢄ
2
4]/[(1)ꢄ2+(10)ꢄ1+(14)ꢄ1]=5.956 (0.449):1
the sulfonamide, generating the imine intermediate. To our delight, these ratios confirm exactly the data
1
Finally, this imine is reduced to form the desired from H NMR measurements:
product (Scheme 7). The presence of excess benzyl al-
Proton-CH /Proton-CH - =2.094ACHTNUGTRENNUNG
3
2
AHCTUNGTRENNUNG
2
Thus, the ratio of 1, 10, 12, and 14 is reliable for a ki-
netic study. The numbers of KIE1 and KIE2 were cali-
brated as follows:
KIE1 =k[H]/k[D]dehydrogenation =product(1)+product(10)]/
[product(14)+product(12)]=3.287 (0.192):1
KIE2 =k[H]/k[D]hydrogenation =[product(1)/product(10)]/(k[H]/
k[D]dehydrogenation)=0.611 (0.033):1
The observation of a primary kinetic isotope effect
(KIE1) of 3.287 (0.192) in the N-alkylating reaction of
p-toluene sulfonamide provided strong evidence for
Scheme 6. Reaction of benzyl alcohol-d7 with N-benzyl-p-
toluenesulfonamide.
Adv. Synth. Catal. 2009, 351, 2949 – 2958
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2953

Xinjiang Cui et al.
FULL PAPERS
Scheme 8. An illustration of the kinetic studies by isotope competitive reactions.
À
C H cleavage as rate-determining step. A similar As shown in Table 6, benzyl alcohols with different
result has been reported by DFT studies and transfer functional groups are well tolerated. More specifical-
hydrogenation of imines with the Ru-based Shvo cat- ly, benzyl alcohols substituted with electron-donating
alyst,[23] but far smaller compared to hydrogen atom
abstraction by other metal-oxo-complexes.[23] This
result is also in consistent with the GC-MS analysis.
Benzaldehyde is formed at the early stage of the reac-
tion but its concentration remains constant during the
reaction. The secondary kinetic isotope effect of 0.611
(0.033) is obtained for the hydrogenation step.
To study the interaction of reactants and catalyst
UV-visible measurements were performed. The spec-
tra of different mixtures were given in Figure 1. Clear-
ly, there was no absorbance in the UV-visible area for
benzyl alcohol, p-toluenesulfonamide, ligand 8 or
their mixtures (Figure 1, I–III; 400–1000 nm). Howev-
er, strong absorbing peaks were observed at 698 nm
after CuACHTUNGTRENNUNG(OAc)2 was added (Figure 1, IV–VI). The ab-
sorbing strength decreased in the presence of p-tolue-
nesulfonamide or ligand in comparison with benzyl al-
cohol. This indicates that the interaction between
Cu2+ and p-toluenesulfonamide or ligand 8 occurred
although no new adsorbing peak is observed. After
the addition of potassium carbonate, all the adsorbing
peaks disappeared. Precipitation of copper ions might
be the reason for this but it is still not clear at this
stage.
Figure 1. UV-visible spectra of (I) PhCH2OH, (II)
PhCH2OH+TsNH2, (III) PhCH2OH+TsNH2 +ligand 8,
(IV) PhCH2OH+Cu
(OAc)2, (VI) PhCH2OH+TsNH2 +ligand 8+Cu
(VII) PhCH2OH+TsNH2 +Cu(OAc)2 +K2CO3 and (VIII)
alkylation of sulfonamides with alcohols was tested. PhCH2OH+TsNH2 +ligand 8+Cu(OAc)2 +K2CO3.
ACHTUNGTRENNUNG
Finally, based on the optimized reaction conditions,
the generality of the CuACHTUNGTRENUNG(OAc)2/K2CO3 catalyst for the
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
2954
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2949 – 2958

Copper-Catalyzed N-Alkylation of Sulfonamides with Benzylic Alcohols
FULL PAPERS
Table 6. Catalytic N-alkylation of p-toluenesulfonamide with
Table 6. (Continued)
different benzylic alcohols.[a]
Entry
Product
Yield [%][b]
87[d]
Entry
1
Product
Yield [%][b]
94[c]
17[c]
18
0
2
3
93
19[e]
71
92[c]
4
5
6
7
8
9
91[c]
89[c]
94
20
0
21[f]
99
99
22[f]
90
[a]
Reaction conditions: see Table 1. 20 mol% K2CO3.
Isolated yield.
[b]
[c]
[d]
91
30 mo% K2CO3.
Selectivity based on GC-MS. The by-product is imine.
Conversion is 100%.
93
[e]
[f]
1 mol% Cu
ACHTUNGTRENNUNG
1 mol% CuAHCUTNGTRENNUNG
10
11
12
92
89
92
as well as electron-withdrawing groups in ortho-,
meta-and para-position of the aryl ring afforded the
expected products in excellent yields. All additional
functional groups, that is, F, Cl, Br, CH3, CF3, OCH3,
SCH3, (CH3)2CH and OCF3, were stable (Table 6, en-
tries 1–14). In comparison with the ortho-, meta- sub-
stituted groups, the para-position of the aromatic ring
is less active. However, with an increasing amount of
base, excellent yields are also achieved.
13
95
Interestingly, not only simple benzyl alcohols gave
the desired products in excellent yield, but also thio-
phen-2-ol led to the corresponding sulfonamide in
93% yield (Table 6, entry 15). In case of pyridine de-
rivatives it was difficult to isolate the imine from the
sulfonamide although high conversion and selectivity
are observed (Table 6, entries 16 and 17). Unfortu-
nately, primary (non-benzylic) aliphatic or secondary
alcohols did not react under these conditions (Table 6,
entries 18 and 20). On the other hand, the coupling of
aliphatic alcohols and secondary benzylic alcohols
with p-toluenesulfonamide proceeded directly using
14
89
15
93
16[c]
93[d]
Adv. Synth. Catal. 2009, 351, 2949 – 2958
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2955

Xinjiang Cui et al.
FULL PAPERS
Cu
21 and 22). In this way, it should pass through a car- and >98% selectivity (Table 7, entry 7). The isolated
bocation mechanism.[17]
yield of N-benzylmethanesulfonamide was 95%.
A
E
ACHTUNGTRENaNGNU mide with benzyl alcohol provided full conversion
Furthermore, reactions of benzyl alcohol with vari- There was no decomposition of starting material ob-
ous sulfonamides bearing different functional groups served with cyclopropanesulfonamide or 2-(trimethyl-
were tested. As shown in Table 7, substituted groups silyl)ethanesulfonamide as starting material. Here, the
on the aromatic ring had no negative influence on the isolated yields were 97% and 94%, respectively
alkylation reactions and the corresponding secondary (Table 7, entries 8 and 9).
sulfonamides were produced in 91–97% isolated
yields (Table 7, entries 1–4). By comparing the N-al-
kylation reactions of p-toluenesulfonamide, 3-meth- Conclusions
ACHTUNGTRENNUNGoxybenzenesulfonamide and 4-bromobenzenesulfon-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
phene-2-sulfonamide and naphthalene-2-sulfonamide, K2CO3 system allows for a benign alkylation of sulfo-
89% and 91% isolated yields were also obtained namides with alcohols in good to excellent yields.
(Table 7, entries 5 and 6).
Mechanistic studies proved the transfer hydrogena-
À
The developed catalyst system works also with ali- tion mechanism and C H cleavage as the rate-deter-
phatic sulfonamides. The reaction of methanesulfon- mining step.
Table 7. Alkylation of different sulfonamides with benzyl al-
cohol.[a]
Experimental Section
Entry
1
Product
Yield [%][b]
95
General Procedure for Alkylation Reactions
All reactions were carried out in pressure tubes (~38 mL,
Aldrich).
Typically,
2.5 mmol
p-toluenesulfonamide
(428 mg), 10.0 mmol benzyl alcohol (1080 mg), 1 mol% Cu-
AHCTUNGTERN(GNUN OAc)2 (4.6 mg) catalyst and 0.5 mmolK2CO3 (69.0 mg)
were added, respectively. Then, the pressure tube was sealed
and the reaction mixture was stirred at 1508C (oil bath tem-
perature) for 12 h. Then it was cooled to room temperature.
~20 mL acetone were added to dissolve the reaction mixture
which was filtered through celite. The acetone and benzyl al-
cohol were removed under vacuum and a yellow solid was
obtained. It was further washed with diethyl ether/hexane to
remove benzyl alcohol residue and soluble impurities. After
it was further dried under reduced pressure, a white solid
were obtained; yield: 625 mg (96%). All the products were
analyzed by 1H NMR, 13C NMR and MS.
2
3
97
91
4
96
5
6
7
8
89[c]
91
General Procedure for the Reaction of Benzyl
Alcohol-d7 and p-Toluenesulfonamide
0.5 mmol
(85.6 mg)
p-toluenesulfonamide,
2.0 mmol
95
(230.0 mg) benzyl alcohol-d7, 0.91 mg CuAHCTUNGRT(ENNUNG OAc)2 (1 mol%
Cu) catalyst and 0.1 mmol (13.9 mg) K2CO3 were added into
a 5-mL reaction tube, respectively. Then, it was sealed and
reacted at 1508C (oil bath temperature) for 12 h. After it
had been cooled to room temperature, the reaction mixture
was dissolved in acetone and analyzed by GC-MS. Then, it
was filtrated through celite. The acetone and benzyl alcohol-
d7 were removed under vacuum and a yellow solid was ob-
tained. It was further washed with diethyl ether/hexane to
remove benzyl alcohol-d7 residues and soluble impurities.
After it was further dried under reduced pressure tio afford
a white solid; yield: ~85 mg.
97
9
94
[a]
Reaction conditions: see Table 1. 20 mol% K2CO3.
Isolated yield.
[b]
[c]
40 mol% K2CO3.
2956
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2949 – 2958

Copper-Catalyzed N-Alkylation of Sulfonamides with Benzylic Alcohols
FULL PAPERS
ration under reduced pressure and the mixture was washed
with hexane to remove the impurities. All samples were ana-
lyzed by GC-MS and H NMR.
General Procedure for the Reaction of Benzyl
Alcohol or Benzyl Alcohol-d7 and (E)-N-
Benzylidene-4-methylbenzenesulfonamide
1
0.5 mmol (129.5 mg) (E)-N-benzylidene-4-methylbenzene-
sulfonamide, 2.0 mmol (230.0 mg) benzyl alcohol, 0.91 mg
General Procedure for the Synthesis of Compound 8
a): TsNH2 (3.42 g, 0.02 mol) and K2CO3 (6.9 g, 0.05 mol)
were dissolved in 200 mL THF and stirred for 20 min at
room temperature, then cooled to 08C with an ice-bath.
Benzoyl chloride (36 g, 0.026 mol) in 100 mL THF was drop-
ped into the reaction mixture. After stirring for 48 h, a
white precipitate formed, and the reaction mixture was then
refluxed for 12 h. The reaction was quenched by 50%
H2SO4 and was extracted with 100 mL ethyl acetate twice.
After recrystallization from diethyl ether and drying under
vacuum, white crystals of N-tosylbenzamide were obtained;
yield: 90%.
CuACHTUNGTRENNUNG(OAc)2 (1 mol% Cu) catalyst and 0.1 mmol
(13.9 mg) K2CO3 were added into a 5-mL reaction tube, re-
spectively. Then, it was sealed and reacted at 1508C (oil
bath temperature) for 3 h. After it had been cooled to room
temperature, the reaction mixture was dissolved in acetone
and analyzed by GC-MS. Then, it was filtered through
celite. The acetone and benzyl alcohol-d7 were removed by
evaporation. The mixture was further washed with diethyl
ether/hexane and a white solid were obtained after drying
under reduced pressure; yield: 130 mg.
b): A mixture of N-tosylbenzamide (2.40 g, 8.7 mmol) and
PCl5 (1.90 g, 8.8 mmol) was dissolved in benzene (30 mL) at
room temperature, and stirred at this temperature for 0.5 h.
Then the reaction mixture was refluxed overnight and
traced by TLC. The solvent was removed under vacuum,
and the crude product was recrystallized from diethyl ether
to afford the N-sulfonylketimine as a white solid; yield:
65%.
c): To the suspension of dried sodium salt of 4-methylben-
zenesulfonamide (0.97 g, 5 mmol) in benzene (30 mL), an
equimolar amount of the N-sulfonylketimine (1.46 g, 5 mL)
was added. Then the mixture was refluxed for 14 h and
traced by TLC analysis. The product was purified by chro-
matography (Et2O); yield: 70%.
General Procedure for High-Resolution Mass
Spectrometry (HR-MS) Measurement
2 reactions were done in parallel (one under argon flow and
the other one under air). 5.0 mmol p-toluenesulfonamide
(855 mg), 20.0 mmol benzyl alcohol (2160 mg), and 1 mol%
Cu [CuACHTUNGTRENNUNG(OAc)2 (9.1 mg)] were added into a 50-mL reaction
tube, respectively. Then, the reaction mixture was stirred at
1508C. After it was reacted for 3 h, a ~100 mg sample was
dropped into ~1 mL methanol for HR-MS analysis. Then,
1 mmol (138.0 mg) K2CO3 was added to the reaction mixture
and analyzed again after 15 min. HR-MS experiments were
performed with an Agilent Series 1200 HPLC system and an
Agilent 1969 A time-of-flight mass spectrometer (Wald-
bronn, Germany) The TOF-MS conditions in negative ioni-
zation mode with a dual sprayer API-ES source were as fol-
lows: nebulizer and drying gas, nitrogen; nebulizer pressure,
35 psig; drying gas flow, 10 LminÀ1; drying gas temperature,
3008C; capillary voltage, 4 kV; fragmentor voltage, 215 V;
skimmer voltage, 60 V; octopole voltage, 250 V; mass refer-
ence (m/z), 112.98558 and 1033.98810. The sample was in-
jected into a mobile phase of 10% H2O (0.1% HCOOH):
90% MeOH.
General Procedure for UV-Visible Measurements
Eight samples including (I) benzyl alcohol, (II) benzyl alco-
hol/p-toluenesulfonamide, (III) benzyl alcohol/p-toluenesul-
fonamide/ligand 8, (IV) benzyl alcohol/Cu
benzyl alcohol/p-toluenesulfonamide/Cu(OAc)2, (VI) benzyl
alcohol/p-toluenesulfonamide/ligand 8/Cu(OAc)2, (VII)
benzyl alcohol/p-toluenesulfonamide/Cu(OAc)2/K2CO3 and
(VIII) benzyl alcohol/p-toluenesulfonamide/ligand 8/Cu-
(OAc)2/K2CO3 with the same composition as the real reac-
ACHTUNGRTENN(UNG OAc)2, (V)
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
General Procedure for the Reaction of Benzyl
Alcohol-d7 and N-Benzyl-p-toluenesulfonamide
tion system were prepared and measured with UV-visible
spectroscopy (Agilent 8453). All the samples were prepared
under ultrasonic conditions and allowed to settle overnight
to get a limpid solution. Then the solution was measured di-
rectly at 25.08C.
0.2 mmol
2.0 mmol (230.0 mg) benzyl alcohol-d7, 0.025 mmol (4.6 mg)
Cu(OAc)2 and 0.5 mmol (69.0 mg) K2CO3 were added into a
(52.4 mg)
N-benzyl-p-toluenesulfonamide,
ACHTUNGTRENNUNG
5-mL reaction tube respectively. Then, it was sealed and re-
acted at 1508C (oil bath temperature) for 12 h. After it was
cooled to room temperature, the reaction mixture was dis-
solved in acetone and analyzed by GC-MS.
Acknowledgements
General Procedure for Isotope Effect Studies (3
Reactions were run in Parallel)
This work has been supported by the Chinese Academy of
Sciences, the DFG (SPP 1118 and Leibniz prize) and the
BMBF. F. Shi thanks the Alexander-von-Humboldt-Stiftung
for a Fellowship.
0.5 mmol (85.6 mg) p-toluenesulfonamide, 2.0 mmol benzyl
alcohol (230.0 mg), 20 mol% K2CO3 (13.6 mg), 1 mol%
CuACHTUNGTRENNUNG(OAc)2 (0.9 mg) were successively added into a 5-mL re-
action tube. Then the tube was sealed and stirred at 1508C
(oil bath temperature) for 12 h. After it had been cooled to References
room temperature, ~5 mL acetone were added to dissolve
the mixture. The reaction mixture was filtrated through
celite. Acetone and benzyl alcohol were removed by evapo-
[1] a) R. N. Salvatore, C. H. Yoon, K. W. Jung, Tetrahedron
2001, 57, 7785–7811; b) J. F. Hartwig, in: Handbook of
Adv. Synth. Catal. 2009, 351, 2949 – 2958
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2957

Xinjiang Cui et al.
FULL PAPERS
Organo-palladium Chemistry for Organic Synthesis,
Vol. 1, (Ed.: E.-I. Negishi), Wiley-Interscience, New
York, 2002, p 1051.
[12] N. Tanaka, M. Hatanka, Y. Watanabe, Chem. Lett.
1992, 575–579.
[13] Y. Tsuji, R. Takeuchi, H. Ogawa, Y. Watanabe, Chem.
[2] a) S. L. Buchwald, C. Mauger, G. Mignani, U. Scholz,
Adv. Synth. Catal. 2006, 348, 23–29; b) O. Navarro, N.
Marion, J. Mei, S. P. Nolan, Chem. Eur. J. 2006, 12,
5142–5148; c) R. Severin, S. Doye, Chem. Soc. Rev.
2007, 36, 1407–1420.
[3] a) K. C. Hultzsch, D. V. Gribkov, F. Hampel, J. Organo-
met. Chem. 2005, 690, 4441–4452; b) J. F. Hartwig,
Pure Appl. Chem. 2004, 76,507–516; c) J. Seayad, A.
Tillack, C. G. Hartung, M. Beller, Adv. Synth. Catal.
2002, 344, 795–813; d) M. Beller, C. Breindl, M. Eich-
berger, C. G. Hartung, J. Seayad, O. Thiel, A. Tillack,
H. Trauthwein, Synlett 2002, 1579–1594.
Lett. 1986, 293–294.
[14] a) G. Cami-Kobeci, P. A. Slatford, M. K. Whittlesey,
J. M. J. Williams, Bioorg. Med. Chem. Lett. 2005, 15,
535–537; b) G. Cami-Kobeci, J. M. J Williams, Chem.
Commun. 2004, 1072–1073; c) R. Yamaguchi, S. Kawa-
goe, C. Asai, K. I. Fujita, Org. Lett. 2008, 10, 181–184.
[15] R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit, N. Tong-
penyai, J. Chem. Soc. Chem. Commun. 1981, 611–612.
[16] Y. Watanabe, Y. Tsuji, Y. Ohsugi, Tetrahedron Lett.
1981, 22, 2667–2670.
[17] a) H. Qin, N. Yamagiwa, S. Matsunga, M. Shibasaki,
Angew. Chem. 2007, 119, 413–417; Angew. Chem. Int.
Ed. 2007, 46, 409–413; b) B. Sreedhar, P. S. Reddy,
M. A. Reddy, B. Neelima, R. Arundhathi, Tetrahedron
Lett. 2007, 48, 8174–8177; c) U. Jana, S. Maiti, S.
Biswas, Tetrahedron Lett. 2008, 49, 858–862.
[4] a) K. S. Mꢁller, F. Koc, S. Ricken, P. Eilbracht, Org.
Biomol. Chem. 2006, 4, 826–835; b) L. Routaboul, C.
Buch, H. Klein, R. Jackstell, M. Beller, Tetrahedron
Lett. 2005, 46, 7401–7405.
[5] a) A. Natarajan, Y. Guo, F. Harbinski, Y. H. Fan, H.
Chen, L. Luus, J. Diercks, H. Aktas, M. Chorev, J. A.
Halperin, J. Med. Chem. 2004, 47, 4979–4982; b) N. K.
Koehler, C. Y. Yang, J. Varad, Y. Lu, X. W. Wu, M. Liu,
D. Yin, M. Bartels, B. Y. Xu, P. P. Roller, Y. Q. Long, P.
Li, M. Kattah, M. L. Cohn, K. Moran, E. Tilley, J. R.
Richert, S. N. Wang, J. Med. Chem. 2004, 47, 4989–
4997; c) D. C. Cole, W. J. Lennox, S. Lombardi, J. W.
Ellingboe, R. C. Bernotas, G. J. Tawa, H. Mazandarani,
D. L. Smith, G. Zhang, J. Coupet, L. E. Schechter, J.
Med. Chem. 2005, 48, 353–356; d) M. Banerjee, A.
Poddar, G. Mitra, A. Surolia, T. Owa, B. Bhattachar-
yya, J. Med. Chem. 2005, 48, 547–555.
[18] a) M. H. S. A. Hamid, C. L. Allen, G. W. Lamb , A. C.
Maxwell, H. C. Maytum, A. J. A. Watson, J. M. J. Wil-
liams, J. Am. Chem. Soc. 2009, 131, 1766–1774; b) F.
Shi, M. K. Tse, S. L Zhou, M. M. Pohl, J. Radnik, S.
Huebner, K. Jaehnisch, A. Bruecker, M. Beller, J. Am.
Chem. Soc. 2009, 131, 1775–1779, and references cited
therein.
[19] a) D. Hollmann, A. Tillack, R. Jackstell, M. Beller,
Chem. Asian J. 2007, 2, 403–412; b) K. I. Fujita, Y.
Enoki, R. Yamaguchi, Tetrahedron 2008, 64, 1943–
1954; c) B. Blank, M. Madalska, R. Kempe, Adv. Synth.
Catal. 2008, 350, 749–758; d) A. Tillack, D. Hollmann,
D. Michalik. M. Beller, Tetrahedron Lett. 2006, 47,
8881–8885.
[6] K. S. Quaal, S. Ji, Y. M. Kim, W. D. Closson, J. A. Zu-
bieta, J. Org. Chem. 1978, 43, 1311–1316.
[20] a) W. Hammerschmidt, A. Baiker, A. Wokaun, W.
[7] a) L. F. Fieser, M. Fieser, Reagents for Organic Synthe-
sis, Wiley, New York, 1967, Vol. 1, p 1179; b) S. Cad-
dick, J. D Wilden, S. J. Wadman, H. D. Bush, D. B.
Judd, Org. Lett. 2002, 4, 2549–2551.
[8] a) S. Caddick, D. Hamza, S. J. Wadman, J. D. Wilden,
Org. Lett. 2002, 4, 1775–1777; b) M. H. S. A. Hamid,
J. M. J. Williams, Chem. Commun. 2007, 725–727.
[9] S. Caddick, J. D. Wilden, D. B. Judd, J. Am. Chem. Soc.
2004, 126, 1024–1025.
[10] a) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams,
Adv. Synth. Catal. 2007, 349, 1555–1575; b) G. W.
Lamb, J. M. J. Williams, Chim. Oggi 2008, 26, 17–19;
c) G. Guillena, D. J. Ramꢅn, M. Yus, Angew. Chem.
2007, 119, 2410–2416; Angew. Chem. Int. Ed. 2007, 46,
2358–2364.
[11] a) F. Shi, M. K. Tse, X. J. Cui, D. Gçrdes, D. Michalik,
K. Thurow, Y. Q Deng, M. Beller, Angew. Chem. Int.
Ed. 2009, doi: 10.1002/anie.200901510; b) Y. Watanabe,
Y. Morisaki, T. Kondo, T. Mitsudo, J. Org. Chem. 1996,
61, 4214–4218.
´
Fluhr, Appl. Catal. 1986, 20, 305–312; b) J. Kijenski,
P. J. Niedzielski, A. Baiker, Appl. Catal. 1989, 53, 107–
115; c) R. Vultier, A. Baiker, A. Wokaunb, Appl. Catal.
1987, 30, 167–176.
[21] N. A. Balcells, E. Clot, D. Gnanamgari, R. H. Crabtree,
O. Eisenstein, Organometallics 2008, 27, 2529–2535.
[22] a) J. S. M. Samec, J-E. Bꢂckvall, Chem. Eur. J. 2002, 8,
2955–2961; b) N. Backstroma, N. A. Burtona, S. Ture-
gaa, C. I. F. Watta, J. Phys. Org. Chem. 2008, 21, 603–
613.
[23] a) K. K. Banerji, J. Chem. Soc. Perkin Trans. 2 1973,
435–437; b) C. M. Che, W. T. Tang, W. O. Lee, K. Y.
Wong, T. C. Lau, Dalton Trans. Zeitschrift wurde erst
2003 gerꢀndet! 1992, 1551–1556; c) N. Y. Oh, Y. Suh,
M. J. Park, M. S. Seo, J. Kim, W. Nam, Angew. Chem.
2005, 117, 4307–4311; Angew. Chem. Int. Ed. 2005, 44,
4235–4239; d) H. E. Gottlieb, V. Kotlyar, A. Nudel-
man, J. Org. Chem. 1997, 62, 7512–7515.
2958
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2949 – 2958