Recyclable gallium as catalyst precursor for a convenient and solvent-free method for the intermolecular addition of sulfonamides to alkenes

Article abstract of DOI:10.1055/s-0029-1219789

Gallium(III) iodide, which is conveniently formed in situ from gallium and iodine, is a competent catalyst for the inter- and intramolecular addition of p-toluenesulfonamides to alkenes. After each reaction, the metallic gallium can easily be recycled and used for subsequent transformations. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219789

1268
LETTER
Recyclable Gallium as Catalyst Precursor for a Convenient and Solvent-Free
Method for the Intermolecular Addition of Sulfonamides to Alkenes
G
aI -Catalyzed
H
y
a
droaminati
non iel Jaspers, Raphael Kubiak, Sven Doye*
3
Institut für Reine und Angewandte Chemie, Universität Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26111 Oldenburg, Germany
Fax +49(441)7983329; E-mail: doye@uni-oldenburg.de
Received 8 February 2010
of commercially available GaCl3 (Table 1). During this
Abstract: Gallium(III) iodide, which is conveniently formed in situ
study, it was found that best results are obtained when the
reaction is performed in the absence of a solvent with a 2:1
from gallium and iodine, is a competent catalyst for the inter- and
intramolecular addition of p-toluenesulfonamides to alkenes. After
ratio between the alkene and p-TsNH2. Corresponding re-
actions, performed for 16 hours or 2 hours with 5 mol% of
GaCl3 gave the desired sulfonamide 2 in 94% and 86%
yield, respectively (Table 1, entries 7 and 8). Additional
reactions performed for 2 hours under comparable condi-
each reaction, the metallic gallium can easily be recycled and used
for subsequent transformations.
Key words: alkenes, amines, gallium, hydroamination, sulfon-
amides
Table 1 Addition of p-Toluenesulfonamide to Cyclohexene (1) in
the Presence of Various Gallium Catalysts
During the last few years, many metal complexes that cat-
alyze the addition of NH across carbon–carbon multiple
bonds have been identified and used for a wide range of
so-called hydroamination reactions.1 However, the fact
that these reactions are usually performed under homoge-
neous conditions can be regarded as a severe drawback
because catalyst recycling is difficult or even impossible,
for example, in the case of highly sensitive catalysts like
rare earth or group IV metal catalysts. As a consequence,
most of the synthetic procedures published in the litera-
ture do not describe any catalyst recycling at all;2 the cat-
alysts are simply destroyed during the workup procedure
and finally disposed. On the other hand, a number of eas-
ily recyclable heterogeneous hydroamination catalysts ex-
ist but they are usually rather limited in scope.3 In order to
develop a recyclable hydroamination catalyst that com-
bines the advantages of both types of catalysts, we turned
our attention towards an application of simple gallium(III)
halides GaX3 (X = Cl, Br, I) as hydroamination catalysts.
Gallium(III) halides are regarded as soft Lewis acids and
they are soluble in common organic solvents.4,5 Conse-
quently, they can be regarded as promising catalysts for
the addition of less basic amine derivatives to alkenes be-
cause they are supposed to activate the alkene by p-com-
plexation towards a nucleophilic attack of the less basic
N-nucleophile. An additional interesting point is that gal-
lium is a nontoxic metal that easily reacts with halogens at
room temperature to give gallium(III) halides. Corre-
spondingly, it is possible to generate the gallium halide in
situ by a simple reaction of metallic gallium with the cor-
responding halogen (e.g., iodine).6
H
N
cat.
reaction conditions
Ts
+
H2NTs
2
1
Entry Catalyst mol% Alkene/
TsNH2 ratio
Solventa
toluene
Temp Time Yield 2
(°C) (h)
(%)c
1a GaCl3 24
1.2:1
105 24 92
2a
24
24
24
12
6
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
2:1
1,4-dioxane 105 24 <5
3a
THF
105 24 <5
105 24 65
105 24 67
105 24 55
105 16 94
4a
DCE
5a
toluene
6a
toluene
7b
5
–
–
–
–
–
–
–
–
–
8b
5
2:1
105
105
105
105
2
2
2
1
86
84
96
83
5
9b GaBr3
10b GaI3
11b
5
2:1
5d 2:1
5d 2:1
1e
2:1
5d 2:1
2:1
7.5 2:1
12b
105 21
90
13b
2
12
14b Ga
15b I2
5
105 16 <5
105 16 <5
a Reaction conditions: alkene (1.0 mmol), TsNH2 (0.82 mmol), cata-
lyst, solvent (1.0 mL), 105 °C, time.
Initial reactions between cyclohexene (1) and p-
toluenesulfonamide3b,7 were carried out at 105 °C in
sealed Schlenk tubes in the presence of catalytic amounts
b Reaction conditions: alkene (6.0 mmol), TsNH2 (3.0 mmol), cata-
lyst, temp, time.
c Yields refer to isolated compounds.
d GaI3 generated in situ from Ga (0.15 mmol, 5 mol%) and I2 (0.23
mmol, 7.5 mol%).
SYNLETT 2010, No. 8, pp 1268–1272
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.03.2010
DOI: 10.1055/s-0029-1219789; Art ID: G04710ST
© Georg Thieme Verlag Stuttgart · New York
e GaI3 generated in situ from Ga (0.03 mmol, 1 mol%) and I2 (0.05
mmol, 1.5 mol%).

LETTER
GaI3-Catalyzed Hydroamination
1269
tions in the presence of either GaBr3 or GaI3 which was ditions of Table 1, entry 10 for all further reactions of p-
conveniently generated in situ from metallic gallium and TsNH2.8 In each case, the GaI3 catalyst was generated in
iodine6 revealed that the former catalyst does not offer any situ from 5 mol% Ga and 7.5 mol% I2. Final control ex-
advantages over GaCl3 while the latter one gives an im- periments performed with 5 mol% of Ga or 7.5 mol% of
9
proved yield of 96% (Table 1, entry 10). Unfortunately, I2 led to the conclusion that these chemicals do not show
worse results were obtained with in situ generated GaI3 af- any catalytic activity when used alone.
ter a shorter reaction time (1 h), with a decreased catalyst
loading (1 mol%) or at a lower temperature (90 °C,
Table 1, entries 11–13). For that reason, we used the con-
8
Table 2 Intermolecular Addition of Sulfonamides to Alkenes Catalyzed by in situ Generated GaI3
R3
R1
R1
R2
N
R3
N
Ga (5 mol%), I2 (7.5 mol%)
105 °C, t
Ts
+
R2
H
Ts
Entry
Alkene
Time (h)
R3
Product
Yield (%)a
96
H
N
Ts
1
2
3
2
2
2
H
H
H
1
3
2
H
N
Ts
88
87
11
H
N
Ts
4
5
12
H
N
Ts
4
2
H
<5
13
14
H
N
5
6
7
2
2
2
H
H
H
96b
Ts
6
7
Ts
Ts
HN
HN
81 (15a/
15b = 59:41)
+
15a
15b
32
20
HN
Ts
8
9
16
17
H
N
Ts
8
9
2
2
H
H
Ts
HN
80c
10
18
Synlett 2010, No. 8, 1268–1272 © Thieme Stuttgart · New York

1270
D. Jaspers et al.
LETTER
8
Table 2 Intermolecular Addition of Sulfonamides to Alkenes Catalyzed by in situ Generated GaI3 (continued)
R3
R1
R1
R2
N
R3
N
Ga (5 mol%), I2 (7.5 mol%)
105 °C, t
Ts
+
R2
H
Ts
Entry
Alkene
Time (h)
R3
Product
Yield (%)a
87
Me
N
10
11
12
13
24
24
24
24
Me
Ts
1
1
1
1
19
20
21
22
n-Bu
N
n-Bu
Ph
Ts
30
34
27
Ph
N
Ts
p-Tol
N
p-Tol
Ts
a Reaction conditions: alkene (6.0 mmol), sulfonamide (3.0 mmol), Ga (0.15 mmol, 5 mol%), I2 (0.23 mmol, 7.5 mol%), 105 °C, time. Yields
refer to isolated compounds.
b Reaction conditions: norbornene (6, 6.0 mmol), p-toluenesulfonamide (3.0 mmol), Ga (0.15 mmol, 5 mol%), I2 (0.23 mmol, 7.5 mol%), Et2O
(1 mL), 105 °C, 2 h.
c Reaction conditions: styrene (10, 3.0 mmol), p-toluenesulfonamide (9.0 mmol), Ga (0.15 mmol, 5 mol%), I2 (0.23 mmol, 7.5 mol%), THF (3
mL), 105 °C, 2 h.
In alkene scope investigations (Table 2) we found that p- behavior was not observed with easily isomerized allyl-
TsNH2 also reacts with cyclopentene (3) and cyclohep- benzene. In this case, the Markovnikov addition product
tene (4) to give the corresponding products 11 and 12 in 16 was isolated as the single product, albeit with a low
88% and 87% yield, respectively. However, the corre- yield of only 32%. While a comparably poor yield (20%)
sponding reaction of cyclooctene (5) did not yield the ex- was obtained with cyclohexadiene (9) a good result was
pected product 13 in detectable quantities. Obviously, observed with styrene which gave the desired addition
decomposition of cyclooctene occurred under the reaction product 18 in 80% yield. However, it must be noted that
conditions. In contrast, norbornene (6) underwent a in this case it was necessary to use an excess of p-TsNH2
smooth addition reaction with p-TsNH2 that gave the exo- and to add a solvent (THF) to the reaction mixture in order
product 147a in 96% yield. However, in this context it to minimize the amount of polymer side products. Addi-
must be noted that due to the low solubility of iodine in tional reactions of cyclohexene with less reactive second-
norbornene an additional low boiling solvent (diethyl ary sulfonamides (Table 2, entries 10–13) revealed that
ether) was added to the reaction mixture. This change in the size of the N-alkyl or N-aryl substituent of the sulfona-
the experimental protocol was necessary in order to re- mide seems to strongly influence the efficiency of the pro-
move sublimated iodine from the upper parts of the cess. As the result, only the N-methyl-substituted product
Schlenk tube glass walls during the reaction. Interesting- 19 could be obtained in good yield (87%) after a reaction
ly, the reaction of 1-hexene (7) gave an inseparable mix- time of 24 hours and strongly decreased yields were ob-
ture of two regioisomers which were identified to be the tained for the corresponding products 20–22 which have
expected Markovnikov product 15a and the unexpected n-Bu , Ph, or p-Tol substituents bound to the nitrogen at-
product 15b in a ratio of 59:41 (GC-MS, Table 2, entry 6). om.
In the latter product the N atom of the sulfonamide is
bound to the C-3 atom of the n-hexane chain. This obser-
vation indicates that obviously a hydrogen shift takes
During the studies mentioned so far we recognized that
during reactions performed with in situ generated GaI3
liquid gallium precipitates. In order to recycle the gallium
place under the reaction conditions prior to the nucleo-
we diluted a crude reaction mixture obtained from a cor-
philic attack of p-TsNH2. Surprisingly, a corresponding
responding standard reaction of cyclohexene (1) and p-
Synlett 2010, No. 8, 1268–1272 © Thieme Stuttgart · New York

LETTER
GaI3-Catalyzed Hydroamination
1271
TsNH2 with CH2Cl2 and removed the organic layer by sy- which leads to the formation of the cyclic sulfonamide
ringe. From the resulting brown solution, the product 2 24a is the major pathway of the reaction, the piperidine
could be isolated in 96% yield by flash chromatography. derivative 24b was always formed as a side product. As
On the other hand, we subsequently used the gallium that described before, the reaction can be performed in various
remained in the flask for an additional reaction of 1 with solvents (THF, Et2O, CH2Cl2) but again best results were
p-TsNH2 (Table 3). For that reason, we simply added 7.5 obtained under neat conditions. Under these standard con-
mol% iodine and the substrates, and heated the reaction ditions the products 24a and 24b were obtained as an in-
mixture to 105 °C for 2 hours. Interestingly, the product 2 separable mixture with a combined yield of 82% and a
could be isolated after an analogous workup procedure in ratio of 88:12 (GC-MS).
unchanged yield of 96%. While a third run still gave 2 in
In summary, we have shown for the first time that galli-
93% yield, the fourth run which was performed after a
um(III) halides are competent catalysts for the inter- and
break of 3 weeks gave a slightly decreased yield of 81%.
intramolecular addition of p-toluenesulfonamides to al-
kenes. Among the halides investigated, GaI3 which can be
However, even the fifth run still gave 2 in 75% yield. The
fact that during the entire sequence of 5 runs it was not
conveniently formed in situ from metallic gallium, and io-
necessary to add additional gallium to the reaction mix-
dine was identified to be the preferred catalyst. This is
tures strongly indicates that the major amount of gallium
particularly true because the metallic gallium can easily
remains in the flask after the simple removal of the organ-
be recycled after each reaction. For that purpose, it is only
ic reaction mixture. In addition, even after a number of
necessary to remove the resulting crude organic reaction
runs, the remaining gallium is still a convenient catalyst
mixture from the metallic gallium which usually precipi-
precursor for the next in situ formation of GaI3. For that
tates during the course of the reaction.
purpose, only an additional amount of 7.5 mol% of iodine
needs to be added. At the moment, we do not have a plau-
Ga (5 mol%)
sible mechanistic explanation for the observation that the
I2 (7.5 mol%)
Ts
metallic gallium precipitates again during the reactions.
However, GC-MS analysis of crude reaction mixtures ob-
tained from reactions that were performed with cyclohex-
ene (1) always proved that iodocyclohexane is formed as
a side product in significant quantities. This formation of
an alkyl iodide can at least explain the consumption of the
iodine during the course of the reaction.
+
N
105 °C, 2 h
82%
24a/24b = 88:12
N
N
H
Ts
Ts
23
24a
24b
Scheme 1 Gallium-catalyzed cyclization of a p-toluenesulfonyl-
amidoalkene
Acknowledgment
Table 3 Addition of p-Toluenesulfonamide to Cyclohexene (1) Per-
formed with Recycled Gallium
We thank the Deutsche Forschungsgemeinschaft for financial sup-
port of our research.
Ga (5 mol%)
H
(recovered after each run)
N
I2 (7.5 mol%)
105 °C, 2 h
Ts
+
H2NTs
References and Notes
(1) For recent reviews, see: (a) Müller, T. E.; Beller, M. Chem.
Rev. 1998, 98, 675. (b) Haak, E.; Doye, S. Chem. Unserer
Zeit 1999, 33, 296. (c) Brunet, J. J.; Neibecker, D. In
Catalytic Heterofunctionalization; Togni, A.; Grützmacher,
H., Eds.; Wiley-VCH: Weinheim, 2001, 91. (d) Bytschkov,
I.; Doye, S. Eur. J. Org. Chem. 2003, 935. (e) Pohlki, F.;
Doye, S. Chem. Soc. Rev. 2003, 32, 104. (f) Hartwig, J. F.
Pure Appl. Chem. 2004, 76, 507. (g) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
(h) Doye, S. Synlett 2004, 1653. (i) Odom, A. L. Dalton
Trans. 2005, 225. (j) Hultzsch, K. C. Adv. Synth. Catal.
2005, 347, 367. (k) Hultzsch, K. C. Org. Biomol. Chem.
2005, 3, 1819. (l) Severin, R.; Doye, S. Chem. Soc. Rev.
2007, 36, 1407. (m) Brunet, J.-J.; Chu, N.-C.; Rodriguez-
Zubiri, M. Eur. J. Inorg. Chem. 2007, 4711. (n) Aillaud, I.;
Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007,
5105. (o) Lee, A. V.; Schafer, L. L. Eur. J. Inorg. Chem.
2007, 2243. (p) Müller, T. E.; Hultzsch, K. C.; Yus, M.;
Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.
(q) Doye, S. In Science of Synthesis, Vol. 40a; Enders, D.;
Schaumann, E., Eds.; Thieme: Stuttgart, 2009, 241.
(2) A recyclable polymer-supported organolanthanide
hydroamination catalyst has been reported: Zhao, J.; Marks,
T. J. Organometallics 2006, 25, 4763.
1
2
Entry
Runa
Yield 2 (%)b
1
2
3
4
5
1
2
3
4
5
96c
96
93
81d
75
a Reaction conditions: alkene (6.0 mmol), TsNH2 (3.0 mmol), Ga
(0.15 mmol, 5 mol%, recovered after each run), I2 (0.23 mmol, 7.5
mol%), 105 °C, 2 h.
b Yields refer to isolated compounds.
c Run 1 was performed with fresh Ga.
d Run 4 was performed after a break of 3 weeks between runs 3 and 4.
Finally, we turned our attention towards the intramolecu-
lar hydroamination of tosylated amino alkene 23
(Scheme 1). Although the expected 5-exo-trig cyclization
Synlett 2010, No. 8, 1268–1272 © Thieme Stuttgart · New York

1272
D. Jaspers et al.
LETTER
(3) For selected examples of heterogeneous hydroamination
catalysts, see: (a) Jimenez, O.; Müller, T. E.; Sievers, C.;
Spirkl, A.; Lercher, J. A. Chem. Commun. 2006, 2974.
(b) Motokura, K.; Nakagiri, N.; Mori, K.; Mizugaki, T.;
Ebitani, K.; Jitsukawa, K.; Kaneda, K. Org. Lett. 2006, 8,
4617. (c) Neff, V.; Müller, T. E.; Lercher, J. A. Chem.
Commun. 2002, 906. (d) Penzien, J.; Müller, T. E.; Lercher,
J. A. Chem. Commun. 2000, 1753. (e) Hölderich, W.;
Hesse, M.; Näumann, F. Angew. Chem., Int. Ed. Engl. 1988,
27, 226; Angew. Chem. 1988, 100, 232.
(4) Yamaguchi, M.; Matsunaga, S.; Shibasaki, M. In
Encyclopedia of Reagents for Organic Synthesis, 2nd ed.,
Vol. 7; Paquette, L. A.; Crich, D.; Fuchs, P. L.; Molander,
G. A., Eds.; Wiley: New Delhi, 2009, 5209.
(5) For synthetic applications of gallium(III) halides, see:
(a) Amemiya, R.; Yamaguchi, M. Eur. J. Org. Chem. 2005,
5145. (b) Sun, P.; Hu, Z.; Huang, Z. Synth. Commun. 2004,
34, 4293. (c) Zhou, H.; Zeng, C.; Ren, L.; Liao, W.; Huang,
X. Synlett 2006, 3504. (d) Amemiya, R.; Yamaguchi, M.
Adv. Synth. Catal. 2007, 349, 1011. (e) Yadav, J. S.; Reddy,
B. V. S.; Sengupta, S.; Biswas, S. K. Synthesis 2009, 1301.
(f) Nishimoto, Y.; Onishi, Y.; Yasuda, M.; Baba, A. Angew.
Chem. Int. Ed. 2009, 48, 9131; Angew. Chem. 2009, 121,
9295. (g) Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah, B.;
Gupta, M. K.; Biswas, S. K. Tetrahedron Lett. 2005, 46,
1161.
(6) Han, Y.; Huang, Y.-Z. Tetrahedron Lett. 1995, 36, 7277.
(7) For selected examples of acid- or metal-catalyzed additions
of sulfonamides to alkenes, see: (a) Zhang, J.; Yang, C.-G.;
He, C. J. Am. Chem. Soc. 2006, 128, 1798. (b) Schlummer,
B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471. (c) Brouwer, C.;
He, C. Angew. Chem. Int. Ed. 2006, 45, 1744; Angew. Chem.
2006, 118, 1776. (d) Li, Z.; Zhang, J.; Brouwer, C.; Yang,
C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175.
(e) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.;
Prim, D.; Campagne, J.-M. Eur. J. Org. Chem. 2007, 2601.
(j) Huang, J.-M.; Wong, C.-M.; Xu, F.-X.; Loh, T.-P.
Tetrahedron Lett. 2007, 48, 3375. (k) Yang, L.; Xu, L.-W.;
Xia, C.-G. Tetrahedron Lett. 2008, 49, 2882. (l) Yang, L.;
Xu, L.-W.; Zhou, W.; Gao, Y.-H.; Sun, W.; Xia, C.-G.
Synlett 2009, 1167. (m) Giner, X.; Nájera, C. Synlett 2009,
3211.
(8) General Procedure Exemplified by the Reaction of
Cyclohexene (1) with p-Toluenesulfonamide
An oven-dried Schlenk tube equipped with a Teflon
stopcock and a magnetic stirring bar was charged with
gallium (99.9999% from Acros Organics, 11 mg, 0.15
mmol, 5 mol%) and p-toluenesulfonamide (514 mg, 3.0
mmol). Then the tube was evacuated and flushed with argon,
and cyclohexene (1, 493 mg, 6.0 mmol) and iodine (58 mg,
0.23 mmol, 7.5 mol%) were added. The tube was sealed, and
the resulting mixture was heated to 105 °C for 2 h. After the
tube had been cooled to r.t., the reaction mixture was diluted
with CH2Cl2 (20 mL). The resulting solution was separated
from the precipitated gallium by syringe and concentrated
under vacuum. Finally, the crude product was purified by
flash chromatography (light PE–EtOAc, 4:1) to give sulfon-
amide 2 (730 mg, 2.9 mmol, 96%) as a colorless solid; mp
82 °C. 1H NMR (500 MHz, CDCl3): d = 0.97–1.21 (m, 5 H),
1.38–1.47 (m, 1 H), 1.50–1.59 (m, 2 H), 1.63–1.70 (m, 2 H),
2.35 (s, 3 H), 2.98–3.10 (m, 1 H), 4.67 (d, JH,H = 7.4 Hz, 1 H,
NH), 7.22 (d, JH,H = 8.0 Hz, 2 H), 7.70 (d, JH,H = 8.2 Hz, 2 H)
ppm. 13C NMR (125 MHz, DEPT, CDCl3): d = 21.5 (CH3),
24.6 (CH2), 25.1 (CH2), 33.8 (CH2), 52.5 (CH), 126.9 (CH),
129.6 (CH), 138.4 (C), 143.0 (C) ppm. IR (neat): 1/l = 3305,
2931, 2851, 1323, 1156, 662 cm–1. HRMS (70 eV): m/z
calcd. (C13H19NO2S) 253.1136; found 253.1140. For the
next catalytic reaction, the Schlenk tube which still
contained the gallium was evacuated, flushed with argon,
and charged with p-toluenesulfonamide (514 mg, 3.0 mmol),
cyclohexene (1, 493 mg, 6.0 mmol) and iodine (58 mg, 0.23
mmol, 7.5 mol%), and the reaction was run as described
above.
Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
(f) Komeyama, K.; Morimoto, T.; Takaki, K. Angew. Chem.
Int. Ed. 2006, 45, 2938; Angew. Chem. 2006, 118, 3004.
(g) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Chem. Asian. J. 2007, 2, 150. (h) Patil, N. T.; Lutete, L. M.;
Nishina, N.; Yamamoto, Y. Tetrahedron Lett. 2006, 47,
4749. (i) Michaux, J.; Terrasson, V.; Marque, S.; Wehbe, J.;
(9) The I2-catalyzed intermolecular addition of sulfonamides to
vinyl arenes has been described: Yadav, J. S.; Reddy, B. V.
S.; Rao, T. S.; Krishna, B. M. Tetrahedron Lett. 2009, 50,
5351.
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