Copper-catalyzed alkylation of sulfonamides with alcohols

Article abstract of DOI:10.1002/anie.200901510

Water is the only by-product in an efficient and atom-economical Cu(OAc)₂-catalyzed coupling of alcohols with sulfonamides (see proposed mechanism; Ts= p-toluenesulfonyl). It was discovered that bissulfonylated amidines formed as intermediates when the transhydrogenative C-N bond-forming reaction is carried out in air act as novel ligands to stabilize the catalyst.

Full text of DOI:10.1002/anie.200901510

Communications
DOI: 10.1002/anie.200901510
À
C N Bond Formation
Copper-Catalyzed Alkylation of Sulfonamides with Alcohols**
Feng Shi,* Man Kin Tse, Xinjiang Cui, Dirk Gꢀrdes, Dirk Michalik, Kerstin Thurow,
Youquan Deng, and Matthias Beller*
The environmentally benign synthesis of carbon–nitrogen
bonds is a central, but still challenging, area of organic
synthesis.[1] In this context, salt-free alkylation reactions of
amines through transhydrogenation processes have attracted
significant attention in recent years.[2] The application of
Scheme 1. Catalytic N-alkylation of sulfonamides with alcohols.
alcohols as alkylating agents has the advantages of high atom
efficiency and the formation of water as the only side product.
Unfortunately, to date only catalysts based on expensive
precious metals—typically Ru or Ir—are known for these
valuable transformations. On the other hand, the catalytic
activity of readily available copper complexes in amination
reactions, for example, coupling reactions of aryl halides, is
well known.[3] A few copper complexes also display trans-
hydrogenative activity in hydrostannation[4] and hydrosilyla-
tion reactions.[5] However, to the best of our knowledge, this
potential has never been exploited in the alkylation of amines
or amides.
On the basis of previous studies by others and us on the
ruthenium-catalyzed alkylation of amines,[3,6] we became
interested in environmentally benign alkylation reactions of
amides and sulfonamides.[7,8] The resulting products are useful
intermediates for the synthesis of pharmaceuticals and agro-
chemicals.[9] Herein, we describe the successful alkylation of
sulfonamides with alcohols in the presence of copper catalysts
(Scheme 1).
significant conversion (ca. 50%) and high selectivity (99%)
for the alkylated sulfonamide were observed. Notably, both
high conversion (93%) and excellent selectivity (> 99%)
were observed when the reaction was performed in air
(Table 1). Careful HRMS analysis revealed the formation of
Table 1: Coupling of p-toluenesulfonamide and benzyl alcohol.[a]
Entry
Atmosphere
Conversion [%]
Selectivity [%]
1
2
3
Ar
CO2
air
48
51
93
>99
>99
>99
[a] Reaction conditions: p-toluenesulfonamide (428 mg, 2.5 mmol),
benzyl alcohol (1.08 g, 10 mmol), Cu(OAc)2 (4.6 mg, 1 mol%), K2CO3
(69 mg, 10 mol%), 1508C, 12 h. Reactions were carried out in a 40 mL
sealed pressure tube. Conversion and selectivity were determined
directly from the GC-MS peak areas.
This novel reaction was observed during an investigation
of the coupling of p-toluenesulfonamide and benzyl alcohol in
the presence of various potential catalysts. When readily
available Cu(OAc)2 was used in the presence of K2CO3,
the bissulfonylated amidine 1 as a new reaction intermediate
with the Cu(OAc)2/K2CO3/air system; this intermediate was
not formed when the reaction was carried out in the absence
of K2CO3 under argon or in air, or with Cu(OAc)2 and K2CO3
under argon (Figure 1; see also Figure S1 in the Supporting
Information).
[*] Prof. Dr. F. Shi, X. Cui, Prof. Dr. Y. Deng
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
No.18, Tianshui Middle Road, 730000 Lanzhou (China)
Fax: (+86)931-496-8116
E-mail: fshi@lzb.ac.cn
Homepage: http://www.licp.ac.cn
Dr. D. Michalik, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
Dr. M. K. Tse, Dr. D. Gꢂrdes, Prof. Dr. K. Thurow
Center for Life Science Automation (CELISCA)
Universitꢁt Rostock
Friedrich-Barnewitz-Strasse 8, 18119 Rostock (Germany)
[**] This research was 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 an AvH Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901510.
Figure 1. HRMS spectra of 1 formed during the coupling reaction (I)
and synthesized 1 (II).
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Apparently, 1 was formed by the oxidation of benzyl
alcohol and condensation with p-toluenesulfonamide. We
assumed that 1 acts as a stabilizing ligand to provide an active
copper catalyst for dehydrogenation/hydrogenation reac-
tions.[10] Thus, we synthesized 1 separately and added it to
the original system to test its activity. Indeed, high catalyst
activity and full conversion were observed in the presence of
preformed compound 1 (Figure 2).
Scheme 3. Reaction of [D7]benzyl alcohol and (E)-N-benzylidene-4-
methylbenzenesulfonamide.
reaction mixture confirmed the formation of products 2–5
(see Figures S3–S11 in the Supporting Information). (E)-N-
Benzylidene-4-methylbenzenesulfonamide was fully con-
sumed within 3 h. This result strongly supports our hypothesis.
The observation of compounds 2, 3, and 5 suggests the
reversibility of the whole process. According to ion-selective
mass spectra, the ratio of 4 to 5 is 1.38:1 (area of peak at
m/z 107/area of peak at m/z 113). This ratio is in perfect
Figure 2. Coupling of p-toluenesulfonamide and benzyl alcohol with or
without the addition of 1.
The activation of the hydroxy group by the active Cu
species is an unexpected feature of the present reaction. In
analogy to the ruthenium-catalyzed amination of alcohols, we
propose that the reaction occurs through a hydrogen-borrow-
ing mechanism (Scheme 2).
1
agreement with the results of H NMR spectroscopic studies
(see Figure S12 in the Supporting Information). Kinetic
investigations of the coupling of benzyl alcohol and p-
toluenesulfonamide demonstrated that benzaldehyde is
formed at an early stage of the process, and that its
concentration is then kept almost constant during the
reaction. After a longer time (> 18 h), approximately 4%
(E)-N-benzylidene-4-methylbenzenesulfonamide is formed.
All these results are in good agreement with the proposed
reaction mechanism in Scheme 2.
Finally, the Cu(OAc)2/K2CO3/air system was applied to
the coupling of other alcohols and sulfonamides. To avoid
contamination from minor degradation products of 1, this
ligand was only added in coupling reactions of benzyl alcohol
and p-toluenesulfonamide. In all other cases, the respective
ligand is formed in situ: an example of catalyst self-stabiliza-
tion. The corresponding alkylated sulfonamides were
obtained in good to excellent yields (71–99%; Table 2).
Aromatic, heteroaromatic, and aliphatic substrates reacted
well. Moreover, a range of functional groups, such as halo (Br,
Cl), thiomethyl, and trialkylsilyl groups, were tolerated well.
On the other hand, primary (nonbenzylic) aliphatic alcohols
did not react under these conditions. Depending on the
starting material, the concentration of K2CO3 had a signifi-
cant influence on the yield. Notably, the coupling of
secondary aliphatic and benzylic alcohols with p-toluenesul-
fonamide proceeded directly with Cu(OTf)2 or Cu(OAc)2 as
the catalyst in the absence of a base (Table 2, entries 8 and 9).
In conclusion, we have demonstrated that the alkylation
of sulfonamides with alcohols is possible with copper
catalysts. The practical Cu(OAc)2/K2CO3/air system enables
the atom-efficient alkylation of sulfonamides in excellent
Scheme 2. Proposed mechanism. Ts=p-toluenesulfonyl.
In the overall process, the primary alcohol acts as the
hydrogen donor. Hence, no additional hydrogen or hydrogen-
transfer reagent is required. To understand the proposed
mechanism, we investigated the coupling of [D7]benzyl
1
alcohol and p-toluenesulfonamide in more detail. H NMR
spectroscopic analysis of the resulting product (see Figure S2
in the Supporting Information) revealed that the dehydrogen-
ation–imide formation–hydrogenation sequence is reversible.
The reaction of [D7]benzyl alcohol with (E)-N-benzyli-
dene-4-methylbenzenesulfonamide was also used to test
whether this domino process proceeds through a transhydro-
genation mechanism (Scheme 3). If this hypothesis is right, 4
should be formed as a product. GC-MS analysis of the
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Table 2: Scope of the sulfonamide–alcohol coupling.[a]
Entry Sulfonamide Alcohol Product
Experimental Section
General procedure for coupling reactions: All reactions were carried
out in a pressure tube (ca. 38 mL, Aldrich). p-Toluenesulfonamide
(0.428 g, 2.5 mmol), benzyl alcohol (1.08 g, 10.0 mmol), Cu(OAc)2
(4.6 mg, 1 mol% Cu), and K2CO3 (69.0 mg, 0.5 mmol) were placed in
the pressure tube, the tube was sealed well, and the reaction mixture
was stirred (250 rpm) at 1508C (oil-bath temperature) under air for
12 h. The reaction mixture was then cooled to room temperature,
acetone (ca. 20 mL) was added, and the mixture was filtered through
Celite to remove the precipitated salts. The acetone and benzyl
alcohol were removed under vacuum. The resulting yellow solid was
washed with diethyl ether/hexane to remove residual benzyl alcohol
and soluble impurities and then dried again under reduced pressure to
give a white solid (625 mg, 96%). For quantitative analysis of the
benzyl alcohol consumed in the reaction, dioxane (ca. 1.75 g,
20 mmol) was added, and the resulting solution was analyzed by
GC/FID (FID = flame ionization detector; HP 6890) with an external
standard. The amount of benzyl alcohol consumed in three reactions
performed in parallel was 2.78, 2.52, and 2.65 mmol (2.65 Æ
0.130 mmol).
Yield
[%][b]
1
96
2
3
4
5
6
91
97
89
94
95
Coupling reactions of [D7]benzyl alcohol: p-Toluenesulfonamide
(85.6 mg, 0.5 mmol) or (E)-N-benzylidene-4-methylbenzenesulfona-
mide (129.5 mg, 0.5 mmol), [D7]benzyl alcohol (230.0 mg, 2.0 mmol),
Cu(OAc)2 (0.91 mg, 1 mol% Cu), and K2CO3 (13.9 mg, 0.1 mmol)
were placed in a 5 mL pressure tube, which was then sealed and
heated at 1508C (oil-bath temperature) for 12 h (or 3 h). The reaction
mixture was then cooled to room temperature, dissolved in acetone,
and analyzed by GC-MS. The mixture was filtered through Celite, and
the acetone and [D7]benzyl alcohol were removed under vacuum. The
resulting solid was washed with diethyl ether/hexane and then dried
again under reduced pressure to give a white solid (ca. 85 mg from p-
toluenesulfonamide; 130 mg, 99% from (E)-N-benzylidene-4-meth-
ylbenzenesulfonamide).
7
93
71
8[c]
9[d]
99
HRMS measurements: Two reactions were carried out in parallel
(one under argon flow and the other in air). p-Toluenesulfonamide
(0.855 g, 5.0 mmol), benzyl alcohol (2.16 g, 20.0 mmol), and
Cu(OAc)2 (9.1 mg, 1 mol% Cu) were placed in a glass vessel (ca.
50 mL), and the reaction mixture was stirred vigorously (500–
750 rpm) at 1508C for 3 h. A sample of the reaction mixture (ca.
100 mg) was shaken in methanol (ca. 1 mL) and then analyzed by
HRMS. K2CO3 (138.0 mg, 1 mmol) was then added to the reaction
mixture, which was analyzed again after 15 min.
10
11
12
89
94
92
HRMS experiments were performed with an Agilent series 1200
HPLC system and an Agilent 1969 A time-of-flight mass spectrom-
eter. The TOF-MS conditions in negative ionization mode with a
dual-sprayer API-ES source (API = atmospheric pressure ionization)
were as follows: 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 reference, m/z 112.98558
and 1033.98810. The sample was injected into a mobile phase of H2O
(0.1% HCOOH)/MeOH (1:9).
13
14
15
16
96
95
95
91
Received: March 19, 2009
Revised: June 3, 2009
Published online: July 6, 2009
[a] Reaction conditions: see Table 1; K2CO3 (0.2 equiv) for entries 1–3, 5,
10, 11, 13, 14, and 16; K2CO3 (0.3 equiv) for entries 6, 12, and 15; K2CO3
(0.4 equiv) for entries 4 and 7. [b] Yield of the isolated product. [c] No base
was used; Cu(OTf)2 (1 mol%) was used in place of Cu(OAc)2. [d] No base
was used. Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
À
Keywords: amidines · C N bond formation · copper ·
.
hydrogen borrowing · sulfonamides · sustainable chemistry
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