Bismuth-catalyzed direct substitution of the hydroxy group in alcohols with sulfonamides, carbamates, and carboxamides

Article abstract of DOI:10.1002/anie.200602909

(Figure Presented) No preactivation of the alcohol substrates is required in allylic, propargylic, and benzylic aminations catalyzed by a combination of commercially available Bi(OTf)₃ and KPF₆, mostly at room temperature (see scheme). The substitution reactions of readily accessible allylic, propargylic, and benzylic alcohols with sulfonamides, carbamates, and carboxamides give the desired amine products in up to 99% yield.

Full text of DOI:10.1002/anie.200602909

Angewandte
Chemie
DOI: 10.1002/anie.200602909
Amination Reactions
Bismuth-Catalyzed Direct Substitution of the Hydroxy Group in
Alcohols with Sulfonamides, Carbamates, and Carboxamides**
Hongbo Qin, Noriyuki Yamagiwa, Shigeki Matsunaga,* and Masakatsu Shibasaki*
The importance of amine derivatives for the synthesis of
pharmaceuticals and fine chemicals has aroused considerable
interest in allylic and propargylic amination reactions.[1]
Readily available allylic and propargylic alcohols are desir-
able substrates for the synthesis of allylic and propargylic
amines. Substitution of the hydroxy group in alcohols by
amine nucleophiles generally requires preactivation of the
alcohols because of the poor leaving ability of the hydroxy
group. Alcohols are generally transformed into the corre-
sponding halides,carboxylates,carbonates,phosphonates,or
related compounds with good leaving groups. The process
inevitably produces a stoichiometric amount of salt waste.
The substitution of the halides and related compounds also
produces salt waste and requires a stoichiometric amount of a
base (Scheme 1,path a). In this context,well-established
cases either a high reaction temperature is required or a
promoter is added to enhance the leaving ability of the
hydroxy group. Notable progress was made by using cationic
Pd complexes with diphosphinidenecyclobutene ligands (with
anilines)[4a] and a Pd complex in aqueous media (with aryl and
alkyl amines).[4b] The reactions proceeded smoothly at room
temperature without any additives;[4] however,the use of
amides,which are less nucleophilic,is still quite rare,and a
high reaction temperature is essential.[5] Nishibayashi,Hidai,
Uemura,and co-workers and Toste and co-workers carried
out pioneering studies on propargylic substitutions with
amides in the presence of a catalytic amount of dinuclear
Ru[6] and oxo-Re complexes[7] in a catalytic Nicholas reac-
tion.[8] Good yields were observed with these systems,and a
broad range of amine nucleophiles can be used; however,
there remains room for improvement,as: a) 3–5 equivalents
of the amine nucleophiles were required,b) the reactions
were performed at a relatively high temperature (60–658C),
and c) only secondary propargylic alcohols were used.
Herein,we report that bismuth catalysis is suitable for the
direct substitution of allylic,propargylic,and benzylic alco-
hols with sulfonamides,carbamates,and carboxamides under
mild reaction conditions. A combination of commercially
available Bi(OTf)3 and KPF6 (1–5 mol%) promoted the
amination reactions at room temperature to give the products
in up to 99% yield.
We reported recently the utility of bismuth catalysis[9] in
the hydroamination of 1,3-dienes with amides.[10] In the
hydroamination,a Bi(OTf) 3/MPF6 (M = K or Cu) system
not only acts as a p acid to activate 1,3-dienes, but also acts as
a Lewis acid to control the position of attack of the amide
nucleophile. We hypothesized that bismuth catalysis would
also be suitable for the activation of allylic and propargylic
alcohols,as shown in Scheme 2. [11] To test this hypothesis,the
reaction of 1a with amide 2a was examined. Bi(OTf)3/KPF6
promoted the reaction smoothly,and 3aa was obtained in
94% yield after 0.2 h (Table 1,entry 1). To study the
efficiency of the catalyst,several control experiments were
Scheme 1. Substitution of the hydroxy group of an alcohol by:
a)preactivation and b)direct catalytic substitution.
transition-metal-catalyzed allylic aminations of allylic ace-
tates and their derivatives have intrinsic drawbacks in terms
of atom economy.[2] Therefore,the direct catalytic substitu-
tion of alcohols with amines is desirable. As no stoichiometric
hydroxy-group activator is utilized,the products are produced
with water as the only waste (Scheme 1,path b).
A number of direct allylic aminations catalyzed by late
transition metals have been reported.[3,4] However,in most
performed (Table 1,entries 2–4). Bi(OTf) alone promoted
the reaction,albeit at a lower reaction rate (Table 1,entry 2;
3
[*] H. Qin, Dr. N. Yamagiwa, Dr. S. Matsunaga, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
2 h,76% yield). The reaction was much slower with BiCl
3
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
[**] This work was supported by a Grant-in-Aid for Specially Promoted
Research and a Grant-in-Aid for the Encouragement of Young
Scientists (B)(for S.M.)from the JSPS and MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Working hypothesis for the activation of allylic and
propargylic alcohols by a Bi catalyst.
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Table 1: Optimization of the reaction conditions.
Table 2: Direct catalytic allylic substitution of 1a with amides 2a–2l.[a]
Entry Catalyst
(mol%)
2a
Additive 1 Additive 2
t
[h]
Yield
[%][a]
[equiv] (mol%)
Entry
NuH 2
Prod.
Cat.
[mol%]
t [h] Yield
[%][b]
1
2
3
4
5
6
7
Bi(OTf)3 (10)2
Bi(OTf)3 (10)2
BiCl3 (10)2
KPF
–
(10)–
0.2 94
6
–
2
76
1
2
3
4
5
6
TsNH2
2a
2b
2c
3aa
3ab
3ac
3ad
3ae
3af
2
2
2
2
2
2
0.2
0.2
0.2
0.2
1.5
0.2
96 (94)[c]
o-NsNH2
PhSO2NH2
p-CF3C6H4SO2NH2 2d
TsNMeH
CbzNH2
93 (82)[c]
–
–
12
70
–
–
KPF6 (10)–
12
0
99
97
85
97
Bi(OTf)3 (2)1.5
Bi(OTf)3 (2)1.5
Bi(OTf)3 (1)1.5
KPF
KPF
KPF
(2)–
(2)drierite
(1)drierite
0.2 94
6
[b]
[b]
0.2 96
0.2 95
6
6
2e
2 f
[a] Yield of the isolated product after column chromatography.
[b] A quantity of 45 mg of drierite was used per 0.3 mmol of 1a.
Tf =trifluoromethanesulfonyl, Ts=para-toluenesulfonyl.
7
8
2g
2h
3ag
3ah
2
2
0.2
0.2
99 (91)[c]
99
[12]
(Table 1,entry 3; 12 h,70% yield).
KPF6 alone did not
9
2i
3ai
2
0.2
99
afford any of the product 3aa (Table 1,entry 4). Both
Bi(OTf)3 and KPF6 were required for high reactivity at
room temperature.[13] With the Bi(OTf)3/KPF6 system,the
catalyst loading was successfully decreased to 2 mol%
(Table 1,entry 5; 94% yield after 0.2 h). Compound 3aa
10
11
12
2j
2k
2l
3aj
3ak
3al
5
5
5
0.6
15
16
86 (89)[c]
88
95
was obtained in 96% yield after 0.2 h in the presence of the
[14]
desiccant drierite (CaSO4; Table 1,entry 6).
Under the
optimized conditions with drierite,the catalyst loading was
decreased to 1 mol% without any problems (Table 1,entry 7;
0.2 h,95% yield).
[a] Reaction conditions: 1a (0.3 mmol),
2 (0.45 mmol, 1.5 equiv),
Bi(OTf)3 (0.015 mmol, 5 mol%), KPF6 (0.015 mmol, 5 mol%),
drierite (45 mg), 1,4-dioxane (1.0 mL), room temperature. [b] Yield of
the isolated, analytically pure compound after column chromatography.
[c] The number in parenthesis is the yield of the isolated product when
the reaction was performed in the absence of drierite. Cbz=
carbobenzyloxy, o-Ns=ortho-nitrobenzenesulfonyl.
The scope of the reaction with respect to the amide
substrate was examined with catalyst concentrations of 2–5
mol% (Table 2). When sulfonamides with electron-donating
or electron-withdrawing substituents were used,[15] the reac-
tion was complete within 0.2–1.5 h,and the corresponding
allyl amides were obtained in high yield (Table 2,entries 1–5;
85–99%). Carbamates 2 f–2i were also suitable substrates
and gave the desired products in 97–99% yield (Table 2,
entries 6–9). With carboxamides 2j–2l,the reaction rate
decreased; therefore,the catalyst loading was increased for
these substrates. In the presence of 5 mol% of the catalyst,
carboxamide 2j reacted smoothly,and the product was
obtained in 86% yield (Table 2,entry 10; 0.6 h). Carb-
oxamides 2k and 2l were much less reactive; the products
3ak and 3al were obtained in 88 and 95% yield,respectively,
after 15 or 16 h at room temperature (Table 2,entries 11–12).
The reactions of selected substrates in Table 2 were also
performed in the absence of drierite. The results of these
reactions,which proceeded without any difficulty,are shown
mate 2g (Table 3,entry 8; 84%). With 1j and 2e the reaction
proceeded regioselectively to afford 3je (Table 3,entry 9),
which was also obtained starting from 1k (entry 10). Alcohol
1l also reacted at the less hindered terminal carbon atom to
give 3le (Table 3,entry 11; 60%). The reaction of alcohol 1m
afforded 3me as a mixture of regioisomers in a ratio of 6.7:1
(Table 3,entry 12). Diene 3ne was obtained selectively from
alcohol 1n (Table 3,entry 13) and treatment of the tertiary
alcohol 1o with 2g afforded the regioisomer 3og selectively
(Table 3,entry 14; E isomer). The results in entries 5–14 of
Table 3 suggest that the amides attack selectively the steri-
cally less hindered carbon atom of the allylic alcohol
functionality. On the other hand,the propargylic alcohols
[14]
in parenthesis (Table 2,entries 1,2,7,and 10).
1p–1s reacted regioselectively at the propargylic position
[6,7,16]
The scope of the reaction with respect to the alcohol
substrate is summarized in Table 3. The present catalyst is also
suitable for the reaction of non-benzylic allylic alcohols,such
as the cyclic alcohols 1b–1e (Table 3,entries 1–4; 66–96%
yield) and acyclic alcohols 1 f–1i (Table 3,entries 5–8). The
reaction of 1 f afforded 3 fa regioselectively (Table 3,entry 5;
87%). The desired products were also formed regioselectively
from substrates 1g and 1h,with substituted aromatic rings,
and the N-Ts indole 1i (Table 3,entries 6–8). The reaction of
1i proceeded smoothly with an equimolar amount of carba-
(Table 3,entries 15–18).
Allenic products of amide
attack at the triple bond were not observed for 1p–1s. It is
noteworthy that the desired products were obtained when the
tertiary propargylic alcohols 1r and 1s were used. Previously
reported propargylic-amination catalysts[6,7] were not applied
to tertiary propargylic alcohols,possibly because of a
competitive dehydration reaction to afford enynes. The
addition of drierite was essential for the formation of products
3ra and 3sf in greater than 60% yield (Table 3,entries 17–
18).[14] This Bi catalysis was also applicable to the benzylic
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Table 3: Direct catalytic substitution of allylic, propargylic, and benzylic alcohols 1b–1t with amides 2.[a]
Entry
1
Alcohol 1
NuH (equiv)Product
t [h]
Yield [%][b]
96
1b
1c
2a (2)
3ba
3ce
2
2
3
2e (3)
2e (3)
2
2
80
66
1d
1e
3de
3ee
4
2e (3)
17
74
5
6
1 f
2a (1.5)
2e (3)
3 fa
3ge
17
87
99
1g
0.2
7
8
1h
1i
2e (3)
2g (1)
3he
3ig
0.2
0.2
61
84
9
10
11
1j
1k
1l
2e (3)
2e (3)
2e (3)
3je
3je
3le
7
12
2
63
62
60
12[c]
1m
2e (3)
3me[d]
1
55
13
14
1n
1o
2e (2)
3ne
3og
1
69
60
2g (1.5)
0.1
15
16
17
1p
1q
1r
2a (1.5)
2a (1.5)
2a (2)
3pa
3qa
3ra
18
8
82
78
63
4
18
19
1s
1t
2 f (2)
2e (2)
3sf
3te
5
7
65
60
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.3–0.9 mmol, 1–3 equiv), Bi(OTf)3 (0.015 mmol, 5 mol%), KPF6 (0.015 mmol, 5 mol%), drierite (45 mg),
1,4-dioxane (1.0 mL), room temperature (unless otherwise noted). [b] Yield of the isolated, analytically pure compound after column chromatography.
[c] The reaction was performed at 408C. [d] Major/minor=6.7:1.
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Communications
temperature,then TsNH
(2a; 77.0 mg,0.45 mmol) was added,
alcohol 1t,the reaction of which with 2e gave 3te in 60%
2
followed by 1a (63.1 mg,0.3 mmol). The reaction mixture was stirred
at 23–268C for 10 min. It was then diluted with diethyl ether (5 mL),
and silica gel (ca. 3 g) was added. After filtration and washing with
diethyl ether,the solvent was removed under reduced pressure. The
residue was purified by column chromatography on silica gel (hexane/
ethyl acetate 8:1–6:1) to give 3aa (96%) as a colorless solid.
yield after 7 h at room temperature (Table 3,entry 19).
When the optically active alcohols 1a and 1p and amides
2a and 2g were used,only the racemic products 3aa, 3ag,and
3pa were obtained (Scheme 3). This result suggests a reaction
Received: July 20,2006
Revised: September 20,2006
Published online: December 5,2006
Keywords: amination · bismuth · homogeneous catalysis ·
.
nucleophilic substitution · synthetic methods
[1] For reviews,see: a) J. Tsuji, Transition Metal Reagents and
Catalysis,Wiley-VCH,Weinheim, 2000; b) B. M. Trost,C. Lee in
Catalytic Asymmetric Synthesis,2nd ed. (Ed.: I. Ojima),Wiley-
VCH,Weinheim, 2000; c) B. M. Trost,M. L. Crawley, Chem.
Rev. 2003, 103,2921.
Scheme 3. Allylic and propargylic amination of the optically active
alcohols 1a and 1i.
[2] B. M. Trost, Science 1991, 254,1471.
[3] For a recent review of palladium-catalyzed C N bond formation
À
from alcohols,see: a) J. Muzart, Tetrahedron 2005, 61,4179; for a
review of the palladium-catalyzed activation of allylic alcohols,
see: b) Y. Tamaru, Eur. J. Org. Chem. 2005,2647.
mechanism in which a carbenium intermediate is formed. The
observed racemization could also be ascribed to the reversi-
bility of the reaction. The result shown in Scheme 4 indicates
that the reaction is reversible under the reaction conditions.
When 3aa was treated with Bi(OTf)3/KPF6 (5 mol%) and
carbamate 2g (1 equiv),a mixture of 3aa (28%) and 3ag
(68%) was recovered after 1 h. It appears that Bi(OTf)3/KPF6
[4] For examples of allylic aminations with anilines at room
temperature without an additive,see: a) F. Ozawa,H. Okamoto,
S. Kawagishi,S. Yamamoto,T. Minami,M. Yoshifuji,
J. Am.
Chem. Soc. 2002, 124,10968; for examples of allylic aminations
with aryl and alkyl amines at room temperature without an
additive,see: b) H. Kinoshita,H. Shinokubo,K. Oshima, Org.
Lett. 2004, 6,4085; for allylic aminations with Et 3B (30 mol%) as
an additive at room temperature,see: c) M. Kimura,M.
Futamata,K. Shibata,Y. Tamaru, Chem. Commun. 2003,234;
for allylic aminations without an additive at 808C,see: d) Y.
Kayaki,T. Koda,T. Ikariya, J. Org. Chem. 2004, 69,2595; for
other examples of Pd-catalyzed aminations at high reaction
temperatures and/or in the presence of a stoichiometric or
À
cleaved the C N bond in 3aa,and that 3ag is thermodynami-
cally more stable than 3aa.[17,18]
catalytic amount of an additive,such as an inorganic acid,CO
an organic acid,or a Lewis acid,see ref. [3a] and references
therein.
,
2
[5] Only one example of the Pd-catalyzed allylation of carbox-
amides,sulfonamides,and imides has been reported (in articles
in Japanese). However,a high reaction temperature (120–
1408C) was essential for the allylation: a) J. Qü,Y. Ishimura,N.
Nagato, Nippon Kagaku Kaishi 1996,256; b) J. Qü,Y. Ishimura,
N. Nagato, Nippon Kagaku Kaishi 1996,525.
Scheme 4. Reversibility of the allylic amination.
[6] a) Y. Nishibayashi,I. Wakiji,M. Hidai, J. Am. Chem. Soc. 2000,
122,11019; b) Y. Nishibayashi,M. D. Milton,Y. Inada,M.
Yoshikawa,I. Wakiji,M. Hidai,S. Uemura, Chem. Eur. J. 2005,
11,1433,and references therein; for other applications of the
dinuclear Ru complex in direct propargylic substitutions with
other nucleophiles,see: c) Y. Inada,Y. Nishibayashi,S. Uemura,
Angew. Chem. 2005, 117,7893; Angew. Chem. Int. Ed. 2005, 44,
7715; d) Y. Nishibayashi,A. Shinoda,Y. Miyake,H. Matsuzawa,
M. Sato, Angew. Chem. 2006, 118,4953; Angew. Chem. Int. Ed.
2006, 45,4835,and references therein.
[7] a) R. V. Ohri,A. T. Radosevich,K. J. Hrovat,C. Musich,D.
Huang,T. R. Holman,F. D. Toste, Org. Lett. 2005, 7,2501; for
other applications of the oxo-Re complexes in direct propargylic
substitutions with other nucleophiles,see: b) B. D. Sherry,A. T.
Radosevich,F. D. Toste, J. Am. Chem. Soc. 2003, 125,6076;
c) M. R. Luzung,F. D. Toste, J. Am. Chem. Soc. 2003, 125,15760,
and references therein.
In summary,we have developed a bismuth-catalyzed
direct substitution of allylic,propargylic,and benzylic alco-
hols with sulfonamides,carbamates,and carboxamides. A
combination of commercially available Bi(OTf)3 and KPF6
(1–5 mol%) catalyzed the reactions effectively,mostly at
room temperature,to give the products in 55–99% yield.
Further applications of the Bi(OTf)3/KPF6 system as well as
mechanistic studies of the present reaction are under inves-
tigation.
Experimental Section
1,4-Dioxane (1.0 mL) was added to a mixture of Bi(OTf)3 (3.92 mg,
0.006 mmol),KPF (1.11 mg,0.006 mmol),and drierite (45 mg) in a
test tube. The resulting mixture was stirred for 10 min at room
[8] For other recent examples of direct substitutions of allylic,
propargylic,and/or benzylic alcohols with various nucleophiles
6
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Angew. Chem. Int. Ed. 2007, 46, 409 –413

Angewandte
Chemie
without the use of Pd complexes,see (allylic substitutions): a) M.
Yasuda,T. Somyo,A. Baba, Angew. Chem. 2006, 118,807;
80% yield): Z. Zhan,W. Yang,R. Yang,J. Yu,J. Li,H. Liu,
Chem. Commun. 2006,3352.
[13] A combination of Bi(OTf)3 and Cu(CH3CN)4PF6 was as
effective as Bi(OTf)3 with KPF6. KPF6 was selected for the
present study because KPF6 is less expensive than
Cu(CH3CN)4PF6. On the basis of mechanistic studies on the
Angew. Chem. Int. Ed. 2006, 45,793,and references therein;
b) K. Motokura,N. Fujita,K. Mori,T. Mizugaki,K. Ebitani,K.
Kaneda, Angew. Chem. 2006, 118,2667; Angew. Chem. Int. Ed.
2006, 45,2605; (propargylic substitutions): c) M. Gregory,V.
Boucard,J.-M. Campagne, J. Am. Chem. Soc. 2005, 127,14180;
d) R. Sanz,A. Martínez,J. M. lvarez-GutiØrrez,F. Rodríguez,
Eur. J. Org. Chem. 2006,1383; (benzylic substitutions): e) Z.
Zhu,J. H. Espenson, J. Org. Chem. 1996, 61,324; f) M. Noji,T.
Ohno,K. Fuji,N. Futaba,H. Tajima,K. Ishii, J. Org. Chem. 2003,
68,9340,and references therein. For other examples in which Pd
complexes are used,see ref. [3].
Bi(OTf)3/MPF6 system in ref. [10],we speculate that KPF is
6
required to generate a more reactive cationic Bi(OTf)2·PF6
species by anion exchange.
[14] Although the addition of a desiccant (drierite: CaSO4) is not
essential for reactive substrate combinations,such as 1a with 2a,
the use of drierite is recommended for good reproducibility with
less reactive substrates in Table 3.
[15] For the utility of the o-Ns group in organic synthesis,see the
following review: T. Kan,T. Fukuyama, Chem. Commun. 2004,
353.
[16] For recent catalytic regioselective propargylic substitutions with
sulfonamides,see also: P. A. Evans,M. J. Lawler, Angew. Chem.
2006, 118,5092; Angew. Chem. Int. Ed. 2006, 45,4970,and
references therein.
[17] We assume that the desiccant (drierite) has a positive effect on
the reaction of substrates in Table 3 because of the reversibility
of the reaction.
[9] For a review of the use of Bi(OTf)3 in organic synthesis,see:
a) H. Gaspard-Iloughmane,C. Le Roux, Eur. J. Org. Chem.
2004,2517; for a chiral Bi(OTf) complex,see the following
3
review: b) S. Kobayashi,C. Ogawa, Chem. Eur. J. 2006, 12,5954,
and references therein.
[10] H. Qin,N. Yamagiwa,S. Matsunaga,M. Shibasaki, J. Am. Chem.
Soc. 2006, 128,1611.
[11] For the concept of s–p chelation,see: a) N. Asao,T. Asano,T.
Ohishi,Y. Yamamoto, J. Am. Chem. Soc. 2000, 122,4817; b) N.
Asao,T. Ohishi,K. Sato,Y. Yamamoto, J. Am. Chem. Soc. 2001,
123,6931; see also ref. [8c].
[12] During the preparation of this manuscript,a BiCl 3-catalyzed
direct propargylic substitution of secondary propargyl alcohols
with TsNH2 (2a) and benzamide (2j) was reported; however,a
relatively high reaction temperature was required (60–358C,46–
[18] The possibility that TfOH,generated from Bi(OTf) and H2O,
3
promotes the present reaction (Tables 1–3) can not be excluded
completely,even in the presence of desiccant. However,the
result of the reaction in Scheme 4,in which no H 2O is generated,
supports the hypothesis that Bi(OTf)3/KPF6 functions as a
catalyst.
Angew. Chem. Int. Ed. 2007, 46, 409 –413
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