Manganese dioxide catalyzed N-alkylation of sulfonamides and amines with alcohols under air

Article abstract of DOI:10.1021/ol202582c

By simply running the reactions under air and solvent-free conditions using catalytic amounts of manganese dioxide, a practical and efficient N-alkylation method for a variety of sulfonamides and amines using alcohols as green alkylating reagents was developed.

Full text of DOI:10.1021/ol202582c

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6184–6187
Manganese Dioxide Catalyzed
N-Alkylation of Sulfonamides and Amines
with Alcohols under Air
Xiaochun Yu, Chuanzhi Liu, Lan Jiang, and Qing Xu*
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou 325035, China
qing-xu@wzu.edu.cn
Received September 23, 2011
ABSTRACT
By simply running the reactions under air and solvent-free conditions using catalytic amounts of manganese dioxide, a practical and efficient
N-alkylation method for a variety of sulfonamides and amines using alcohols as green alkylating reagents was developed.
Organonitrogen compounds such as amine and amide
derivatives are not only important nitrogen sources in
synthesis but also important chemicals abounding in nat-
ural products as well as biochemically and pharmaceuti-
cally active molecules.1 In addition to other methodologies
such as transition-metal-catalyzed amination of organo-
halides, reductive amination of carbonylcompounds, etc.,2
in recent years, N-alkylation of amines and amides with
alcohols catalyzed by transition metal complexes, namely,
the borrowing hydrogen or hydrogen autotransfer
methodology, has been considered as a greener and more
environmentally benign alternative for amine derivatives
using alcohols as the alkylating reagents in a one-pot
manner and high atom efficiency achievable by producing
water as the only byproduct.3 However, there still remains
much room for improvement of the method, because the
reactions usually employ air-sensitive, preformed noble
metal complexes derived from ruthenium and iridium or
addition of capricious ligands for catalyst activation and
require inert atmosphere protection and sometimes even
special apparatuses such as the glovebox to manipulate the
catalysts and reactions. Therefore, developing greener and
more efficient reactions that can be performed under less
demanding conditions and/or using non-noble metal cat-
alysts are highly desirable.
(1) (a) Brooks, G. T., Roberts, T. R. Pesticide Chemistry and
Bioscience; Royal Society of Chemistry: Cambridge, U.K., 1999. (b)
McGuire, J. L. Pharmaceuticals: Classes, Therapeutic Agents, Areas of
Application; Wiley-VCH: Weinheim, Germany, 2000; Vols. 1À4. (c) Hili,
R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (d) Cox, E. D.; Cook,
J. M. Chem. Rev. 1995, 95, 1797. (e) Humphrey, J. M.; Chamberlin, A. R.
Chem. Rev. 1997, 97, 2243. (f) Hansch, C.; Sammes, P. G.; Taylor, J. B.
Comprehensive Medicinal Chemistry; Pergamon Press: Oxford, 1990; Vol.
2, Chapter 7.1. (g) Connor, E. E. Sulfonamide Antibiotics Prim. Care
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Reichert, D. Pharmaceutical Substances, Synthesis, Patents, Applica-
tions; Thieme: Stuggart, 1999.
Recently, we accidentally found that air can promote a
Rh-catalyzed N-alkylation reaction of sulfonamides with
alcohols,4a which later led to a general and advanta-
geous air-promoted metal-catalyzed aerobic N-alkylation
(2) (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (b) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (c) Evano, G.;
Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (d) Tripathi,
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2007, 36, 1407. (g) Veige, A. S. Polyhedron 2008, 27, 3177. (h) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (i)
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Dalton Trans. 2009, 753 and references therein. (f) Guillena, G.; Ramon,
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r
10.1021/ol202582c
Published on Web 10/31/2011
2011 American Chemical Society

method and discovery of a new mechanism4b that has
never been proposed in metal-catalyzed N-alkylation
reactions.3,4 We also noticed that the more easily disposable
metal oxides were also effective catalysts (Scheme 1a).4b
With an intension to further explore the scope of the
aerobic N-alkylation method and develop more preferable
catalysts, we envisioned that simple metal oxides, espe-
cially those derived from the cheaper, more available, and
less toxic non-noble metals, may also be suitable catalysts
for the reaction.
large excess amounts, 5À50 equiv).7,8 In 2001, Taylor et al.
reported an imine preparation method from alcohols and
amines by using large excess amounts (10 equiv) of MnO2
as the oxidant (Scheme 1b), for which, if followed by a
reduction reaction using polymer-supported cyanoboro-
hydride (PSCBH) or NaBH4 as the reductant, a one-pot,
in situ oxidation-condensation-reduction process could be
achieved for N-alkylated amines (Scheme 1c).9,10 Since
large excess amounts of oxidants and reductants were
required, which may be toxic and hazardous, the reactions
not only were costly and tedious in operation and work-
up but also may result in waste disposal and environ-
mental problems. In contrast with the above-mentioned
methods,3,5,6,9,10 herein we report, using catalytic amounts
of MnO2, a practical and efficient dehydrative N-alkyla-
tion method for sulfonamides and amines with alcohols
that can be readily achieved under air and solvent-free
conditions (Scheme 1d).
Scheme 1. Metal Oxide Mediated CÀN Bond Formations
Initially, various simple metal oxides (10 mol %)
were tested in the model reaction of benzyl alcohol 1a
and benzenesulfonamide 2a (Table 1). Sc2O3, TiO2, V2O4,
MnO, Fe2O3, Co3O4, NiO, and Ni2O3 gave no, trace, or
low yields of the target product, while MnO2 afforded the
product, N-benzyl-benzenesulfonamide 3aa, in 73% yield
and high selectivity under the same conditions (run 1).11
Examination of MnO2 and base loadings showed that 20
and 50 mol % were the best at 120 °C (run 2). Higher
loadings gave no higher yields of the product, but lower
loadings could result in slightly lower yields. No reaction
occurred without MnO2 (run 3), indicating it is essential
for the reaction. Besides, by solvent and base screening, the
reaction was found to be better carried out under solvent-
free conditions using K2CO3 as the base. By running the
reaction at a higher temperature of 135 °C, base load-
ings were further reduced to 20 mol % and the product
yield was enhanced to 96% (89% isolated) (run 4).
More conditions revealed that 10À20 mol % MnO2
and 10À20 mol % K2CO3 were all satisfactory choices
(runs 4À6), but less loadings only led to inefficient
reactions. In contrast, the reaction under nitrogen
was ineffective, affording only a low yield of the prod-
uct (run 7). The reason for this difference is unclear
at present but may be explained by the fact that like
other metal oxides that are good alcohol oxidation7
and effective N-alkylation4b catalysts under aerobic
However, to our knowledge, an efficient reaction cata-
lyzed by a simple metal oxide was not yet known. In the
past, these reactions were carried out under rather harsh
conditions such as high temperature (>200 °C), high
pressure, and/or with long reaction times.3f,5 Recently, a
number of heterogeneous noble metal catalysts (Ru, Ir, Pd,
Pt, Au, Ag) supported by metal oxides (CeO2, ZrO2,
Al2O3, SiO2, MgO, ZnO, TiO2, Fe2O3, Fe3O4, etc.) or
hydroxides were developed,6 but severe drawbacks still
remain. For example, these reactions usually suffer from
the requirement of inert atmosphere protection, high
temperatures (>150 °C), long reaction times, or the use
of solvents, large excess amounts of alcohols, amines, or
bases. Among the usual metal oxides, we found manganese
dioxide (MnO2) had not been used in the reactions yet.3À6
MnO2 is a less toxic, easily handled, readily available,
and recyclable reagent. It has long been known as a mild
oxidant frequently used in alcohol oxidations (usually in
(4) (a) Feng, S. L.; Liu, C. Z.; Li, Q.; Yu, X. C.; Xu, Q. Chin. Chem.
Lett. 2011, 22, 1021. (b) Liu, C.; Liao, S.; Li, Q.; Feng, S.; Sun, Q.; Yu, X.;
Xu, Q.; , J. Org. Chem. 2011, 76, 5759 and references therein.
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(5) (a) Martınez, M.; Ramon, D. J.; Yus, M. Org. Biomol. Chem.
2009, 7, 2176. (b) Gonzalez-Arellano, C.; Yoshida, K.; Luque, L.; Gai,
P. L. Green Chem. 2010, 12, 1281. (c) Valotl, F.; Fachel, F.; Jacquot, R.;
Spagnol, M.; Lemairel, M. Tetrahedron Lett. 1999, 40, 3689.
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(7) (a) Tojo, G.; Fernandez, M. Oxidation of Alcohols to Aldehydes
and Ketones: A Guide to Current Common Practice; Springer Press: New
York, 2006. (b) Mallat, T.; Baiker, A. Chem. Rev. 2004, 104, 3037. (c)
Sheldon, R. A.; Arends, I. W. C. E.; Dijksman, A. Catal. Today 2000, 57,
157. (d) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. Rev. 1998, 98,
2599.
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1976, 133. (c) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem.
Res. 2005, 38, 851.
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(b) Kanno, H.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43, 7337.
(10) More recently, Cossy and coworkers also reported a similar
process using TEMPO-PhI(OAc)2 as the stoichiometric oxidant and
€
(6) (a) Shi, F.; Tse, M. K.; Zhou, S.; Pohl, M. M.; Radnik, J.; Hubner,
€
€
S.; Jahnisch, K.; Bruckner, A.; Beller, M. J. Am. Chem. Soc. 2009, 131,
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1775. (b) Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 5547.
(c) Yamaguchi, K.; He, J.; Oishi, T.; Mizuno, N. Chem.;Eur. J. 2010,
16, 7199. (d) He, J.; Kim, J. W.; Yamaguchi, K.; Mizuno, N. Angew.
Chem., Int. Ed. 2009, 48, 9888. (e) Kim, J. W.; Yamaguchi, K.; Mizuno,
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N. J. Catal. 2009, 263, 205. (f) Corma, A.; Rodenas, T.; Sabater, M. J.
Chem.;Eur. J. 2010, 16, 254. (g) Zhang, Y.; Qi, X.; Cui, X.; Shi, F.;
Deng, Y. Tetrahedron Lett. 2011, 52, 1344. (h) He, L.; Lou, X.-B.; Ni, J.;
Liu, Y.-M.; Cao, Y.; He, H.-Y.; Fan, K.-N. Chem.;Eur. J. 2010, 16,
13965. (i) Shimizu, K.; Nishimura, M.; Satsuma, A. ChemCatChem
2009, 1, 497. (j) Cui, X.; Zhang, Y.; Shi, F.; Deng, Y. Chem.;Eur. J.
2011, 17, 1021. (k) Likhar, P. R.; Arundhathi, R.; Kantam, M. L.;
Prathima, P. S. Eur. J. Org. Chem. 2009, 5383. (l) Yamakawa, T.;
Tsuchiya, I.; Mitsuzuka, D.; Ogawa, T. Catal. Commun. 2004, 5, 291.
(m) He, J.; Yamaguchi, K.; Mizuno, N. Chem. Lett. 2010, 39, 1182.
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NaBH4 or NaBH(OAc)3 as the reductant. See: Guerin, G.; Bellosta, V.;
Guillamot, G.; Cossy, J. Org. Lett. 2011, 13, 3534.
(11) An in situ prepared activated MnO2 (according to refs 7 and 8)
and commercial MnO2 were both examined, showing similar activities.
Org. Lett., Vol. 13, No. 23, 2011
6185

conditions, MnO2 behaved similarly in activities in
both reactions12 (vide infra).
Table 2. MnO2-Catalyzed N-Alkylation of Sulfonamides and
Amines with Alcohols under Air
Table 1. Condition Screeninga
run
1, 2
3%a
1b,c
PhCH2OH (1a), PhSO2NH2 (2a)
1a, p-CH3C6H4SO2NH2 (2b)
1a, o-CH3C6H4SO2NH2 (2c)
1a, p-CH3OC6H4SO2NH2 (2d)
1a, p-ClC6H4SO2NH2 (2e)
1a, o-ClC6H4SO2NH2 (2f)
1a, 2-naphthalenesulfonamide (2g)
1a, 2-(5-chlorothiophene)sulfonamide (2h)
1a, CH3SO2NH2 (2i)
p-CH3C6H4CH2OH (1b), 2a
p-CH3OC6H4CH2OH (1c), 2a
o-CH3OC6H4CH2OH (1d), 2a
p-ClC6H4CH2OH (1e), 2a
m-ClC6H4CH2OH (1f), 2a
1a, 2-aminopyrimidine (2j)
1c, 2j
96 (89)
98
2c,d
MnO2
K2CO3
temp
run
(mol %)
(mol %)
(°C)
3aa%b
3aa/4aab
3c,d
94
4c,d
61
1
10
20
0
50
50
50
20
10
10
10
120
120
120
135
135
135
135
73
99/1
99/1
À
5c,d
76
2
87
6c,d
93
3
NDc
96 (89)
96
7c,d
99
4
20
20
10
20
99/1
99/1
99/1
99/1
8c,d
78
5
9c,d
98
6
7d
96
10c,d
11c,d
12c,d
13c,d
14c,d
15d,e
16d,e
17d,e
18d,e
19d,e
20d,f
21d,f
22d,f
23d,f
24d,f
25d,f
26d,f
27d,f
28b,e
29d,f
30b,f
31b,f
32d,f
33b,f
34b,g
35b,f
76
45
87
a Unless otherwise noted, the mixture of 1a (4 mmol), 2a (3 mmol),
and the metal oxides was heated in a 20 mL sealed Schlenk tube under air
and then heated and monitored by TLC and/or GC-MS. b Yields and 3/4
ratios determined by GC-MS (isolated yield in parentheses) based on 2a.
c No product detected by TLC. d Under nitrogen.
82
99
83
88
93
1d, 2j
95 (82)
95
1e, 2j
The optimized conditions were then applied to various
sulfonamides, amines, and alcohols to extend the scope of
the method (Table 2). As investigated, all the electron-rich
and -deficient sulfonamdies (runs 1À9), including hetero-
aromatic and aliphatic ones, and benzylic alcohols (runs
10À14) gave good to high yields of the products.13 Like
para- and meta-substituted substrates, the sterically more
bulky ortho-substituted ones alsogavegood results (runs 3,
6, 12). Beside the sulfonamides, a variety of electron-rich
and -deficient, aromatic or heteroaromatic amines also
reacted efficiently under similar conditions to give good to
high yields of the products (runs 15À35). In these cases,
like the literature reports,3À6 alkali metal hydroxides were
more effective bases. Although the scope of the method
remains to be fully investigated, these results revealed its
potential utility and the advantages of using MnO2 instead
of other metal catalysts3À6 and the oxidation-condensa-
tion-reduction methods.9,10
As an ongoing study in the aerobic N-alkylation
methods,4 mechanistic aspects of the reaction are there-
fore our interest and next concern. As demonstrated below
based on the studies of the individual reactions, this
reaction most probably proceeds via a process similar to
the mechanism we recently proposed4b (Scheme 2). The
first step is the Mn-mediated alcohol oxidation (step i),
a known process in the literature.12 In our hands, trace
o-ClC6H4CH2OH (1g), 2j
1a, 2-aminopyridine (2k)
1c, 2k
88 (74)
90
85
1d, 2k
76 (63)
66
1e, 2k
1g, 2k
68 (55)
83
1a, 3-aminopyridine (2l)
1a, 5-chloro-2-aminopyridine (2m)
1a, PhNH2 (2n)
89 (79)
90
1b, 2n
77
1c, 2n
76
1a, p-CH3C6H4NH2 (2o)
1a, m-CH3C6H4NH2 (2p)
1a, p-EtOC6H4NH2 (2q)
1a, p-ClC6H4NH2 (2r)
1a, m-ClC6H4NH2 (2s)
1a, o-ClC6H4NH2 (2t)
84
97
92 (85)
97
98
91
a See Table 1 for operation. K2CO3 was used as the base unless
otherwise noted. GC yield (isolated yield in parentheses) based on
2. Byproduct 4 was usually formed in low selectivity (<1%). b 10 mol %
MnO2. c 10 mol % K2CO3. d 20 mol % MnO2. e 40 mol % NaOH used.
f 40 mol % CsOH used. g 40 mol % KOH used.
benzaldehyde 5a was observed when absolute benzyl
alcohol 1a was heated with 15% MnO2 under N2 (Table 3,
run 1). The same reaction under air was more efficient
(run 2), showing that air can promote the oxidation to
some extent even without optimizing the conditions,
consistent with the literature reports.12 These contras-
tive results may also account for the observed different
efficiencies of the aerobic and anaerobic reactions
(Table 1), revealing again that the aerobic condition is a
more effective alcohol activation alternative. In addition,
no deactivation of MnO2 by the ligating amides/amines
was observed, for similar amounts of 5a could be observed
when 2a was added (run 3). In contrast, MnO, found
unable to oxidize the alcohol under N2 (run 4) but able
(12) Unlike other metal oxides (ref 7), Mn-catalyzed aerobic alcohol
oxidations are still rare and less effective. See: (a) Kimura, T.; Fujita, M.;
Sohmiya, H.; Ando, T. Bull. Chem. Soc. Jpn. 1992, 65, 1149. (b) Fu, X.;
Feng, J.; Wang, H.; Ng, K. M. Nanotechnology 2009, 20, 37601. (c) Son,
Y. C.; Makwana, V. D.; Howell, A. R.; Suib, S. L. Angew. Chem., Int.
Ed. 2001, 40, 4280. (e) Makwana, V. D.; Son, Y. C.; Howell, A. R.; Suib,
S. L. J. Catal. 2002, 210, 46. (e) Makwana, V. D.; Garces, L. J.; Liu, J.;
Cai, J.; Son, Y. C.; Suib, S. L. Catal. Today 2003, 85, 225.
(13) (a) Layer, R. W. Chem. Rev. 1963, 63, 489. (b) Sprung, M. M.
Chem. Rev. 1940, 26, 297. (c) Adams, J. P. J. Chem. Soc., Perkin Trans. 1
2000, 125.
6186
Org. Lett., Vol. 13, No. 23, 2011

to under air (run 5), was deactivated by the addition of
2a, giving only trace 5a under air. These results (runs 3
and 6) may account for the reason why MnO2 is much
more active than MnO in the reaction (vide supra).
Since MnO cannot oxidize the alcohol under nitrogen
(run 4), Mn(II) may be generated from Mn(IV) under
nitrogen (Scheme 2, step i), but clearly it is not complete
and not an effective alcohol activation protocol
(Table 3, run 1) as it only led to an ineffective anaerobic
reaction (Table 1, run 7).
(Scheme 2), the originally inefficient anaerobic reaction
(Table 1, run 7) should also be able to be accelerated by
adding intermediate aldehyde or imine instead of running
the reactions under air.17 Indeed, when only catalytic
amounts of either 4aa or 5a (10 mol %) were added to a
standard reaction of 1a and 2a followed by heating under
nitrogen, high yields of the product could be obtained
(80% and 97%, respectively), which should also support
the proposed mechanism. Therefore, as proven above and
supported by corresponding literatures,4,9,10,12À15 Scheme 2
should be the most possible mechanism for the Mn-
catalyzed aerobic N-alkylation reactions.
Scheme 2. Proposed Reaction Path
Table 4. Mn-Catalyzed Transfer Hydrogenation
run
MnOn
time
3aa%a
5a%a
5a/3aaa
1
2
MnO2
MnO
8 h
6 h
8 h
68
72
79
74
72
83
1.09/1.00
1.00/1.00
1.05/1.00
Table 3. Mn-Mediated Alcohol Oxidations
a Yields and ratios were determined by 1H NMR analysis.16
In conclusion, a practical and efficient N-alkylation
method for various sulfonamides and amines using alco-
hols as greener alkylating reagents was developed by
simply carrying out the reactions under air and solvent-
free conditions using only catalytic amounts of MnO2.
Since this method avoids the use of noble metal catalysts,
activating ligands, and both stoichiometric oxidants and
reductants, requires no inert atmosphere protection,
and can greatly simplify the operation and workup proce-
dures, it may be a good alternative for the existing
methods.3À6,9,10 Further extensions of the metal oxide
mediated N-alkylation methods are underway.
run
MnOn
atm
additive (mol %)
5a%a
1
2
3
4
5
6
MnO2
MnO2
MnO2
MnO
MnO
MnO
N2
air
air
N2
air
air
À
0.6
3.6
5.4
0
À
2a (30)
À
À
2.9
0.7
2a (30)
a Yields were determined by 1H NMR analysis based on 1a.
The condensation step (Scheme 2, step ii), also a well-
known standard organic reaction, can proceed in the
absence of any catalysts.13 In present cases, the reaction
of 2a and 5a was also found to proceed smoothly in the
presence of either MnO2 or MnO. Similarly, the transfer
hydrogenation step (Scheme 2, step iii)14,15 could also be
confirmed easily. Thus, in the presence of MnO2 or MnO,
good yields of the product could be obtained in the transfer
hydrogenative reduction of 4aa by 1a in 8 h at only 100 °C
(Table 4). As indicated by the NMR studies (Table 4),16
byproduct aldehyde 5a was analyzed to be regenerated
quantitatively in the transfer hydrogenation step (Scheme 2,
step iii). The regenerated aldehydes should be recovered in
the next condensation reaction to complete the catalytic cycle
(step iv). Moreover, according the proposed mechanism
Acknowledgment. We thank the National Natural
Science Foundation of China (No. 20902070), Natural
Science Foundation (No. Y4100579), and Qianjiang
Talents Program (No. QJD0902004) of Zhejiang Prov-
ince for financial support. X.Y. thanks the Opening
Foundation of Zhejing Provincial Top Key Disciplines
(No. 100061200123).
Supporting Information Available. Experimental pro-
cedures, product characterization, mechanistic studies,
1
and H and 13C NMR spectra of the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) For selected reviews and mechanistic discussions on transfer
hydrogenation: (a) Reference 3b. (b) Gladiali, S.; Alberico, E. Chem.
Soc. Rev. 2006, 35, 226.
(16) See Supporting Information for detail.
(17) We are thankful one of the reviewers for this kind and proper
suggestion.
(14) Transfer hydrogenation of intermediate imines by alcohols to
give product amines was also frequently employed to confirm the N-
alkylation path in borrowing hydrogen reactions, albeit indirectly in our
opinion. See ref 3 and references therein.
Org. Lett., Vol. 13, No. 23, 2011
6187