Direct substitution of the hydroxy group with highly functionalized nitrogen nucleophiles catalyzed by Au(III)

Article abstract of DOI:10.1039/c1cc12760h

A direct catalytic substitution of various allylic and benzylic alcohols with synthetically useful, but acid-sensitive Boc, Bus, and Dios protected amine nucleophiles, which have not been well utilized for Lewis acid catalysis, with various functionalities (OTBS, OTHP, etc.) was efficiently catalyzed by 1 mol% of Au(iii) under mild conditions.

Full text of DOI:10.1039/c1cc12760h

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COMMUNICATION
Direct substitution of the hydroxy group with highly functionalized
nitrogen nucleophiles catalyzed by Au(III)w
Takashi Ohshima,*a Yasuhito Nakahara,b Junji Ipposhi,b Yoshiki Miyamotob and
Kazushi Mashima*b
Received 11th May 2011, Accepted 31st May 2011
DOI: 10.1039/c1cc12760h
A direct catalytic substitution of various allylic and benzylic
alcohols with synthetically useful, but acid-sensitive Boc, Bus,
and Dios protected amine nucleophiles, which have not been well
utilized for Lewis acid catalysis, with various functionalities
(OTBS, OTHP, etc.) was efficiently catalyzed by 1 mol% of
Au(III) under mild conditions.
these reactions efficiently proceed with electron-rich amines,
electron-deficient nitrogen nucleophiles are not good substrates
due to their low nucleophilicity.2e The reaction with electron-
deficient nitrogen nucleophiles was efficiently catalysed by
various Lewis acids (Re,4 Ru,5 rare earth metals,6 Au,7 In,8
Bi,9 Fe,10 Ag,11 Mo,12 Hg,13 etc.) and Brønsted acids14 via a
carbocation intermediate (path b).15 Thus, acid-catalyzed
direct amination is a counterpart of late transition metal-
catalyzed amination;16 nucleophiles of the reported acid-catalyzed
reaction, however, are limited to rather stable nitrogen compounds
such as 4-nitroaniline, tosylamide, methyl carbamate, and
simple amides. In particular, there is almost no access to
more useful but acid-sensitive nucleophiles such as tert-butyl
carbamate.8b,10e,12a Here, we report that direct substitutions
of allylic and benzylic alcohols with synthetically useful
tert-butoxycarbonyl (Boc), thiophenesulfonyl,17 tert-butylsulfonyl
(Bus),18 and 2-(1,3-dioxan-2-yl)ethylsulfonyl (Dios)19 protected
amine nucleophiles are efficiently catalyzed by 1 mol% of
NaAuCl4ꢀ2H2O under mild conditions (rt to 40 1C). Reactions
with more acid-sensitive functional groups such as TBS and THP
groups were achieved using dichloro(pyridine-2-carbozylato)-
gold (III) (4)20 as a catalyst. Moreover, we found unusual positive
effects of added thiophene in the gold-catalyzed direct amination
reactions.
The development of a direct and reliable synthetic method-
ology to attain a wide variety of amine derivatives has attracted
considerable attention because of their relevance as synthetic
tools for various pharmaceuticals and fine chemicals. Nucleo-
philic substitution of allylic substrates represents one of the
most powerful methods for producing allylamines.1 From
both environmental and economic points of view, the direct
catalytic amination of underivatized allylic alcohols 1, which
forms water as the sole coproduct, is desirable (Scheme 1).
Because of the poor leaving ability of the hydroxyl group, such
direct reactions have been rarely explored except for several
palladium-catalyzed direct aminations of 1 via a p-allylpalladium
intermediate (path a).2 We recently reported that platinum
complexes bearing a DPEphos or Xantphos ligand are efficient
catalysts for direct amination of 1 with high monoallyl-
ation selectivity and broad substrate generality.3 Although
Using the protocol based on Pt–Xantphos,3 substrate generality
was not expandable to electron-deficient amines. The reaction
of 1,3-diphenylprop-2-en-1-ol (1a) with electron-deficient
Boc-amide 2a (eqn (1)) using the Pt catalyst gave product 3aa
in low yield (o14%) (ESIw). We are interested in the use of
Au(I) and Au(III) salts,21 which are, respectively, isoelectronic to
Pt(0) and Pt(II). Both AuCl and AuCl3 became catalysts for the
reaction of 1a with 2a and product 3aa was obtained in 92%
and 94% yield, respectively, after optimization of the reaction
conditions.w The use of NaAuCl4ꢀ2H2O,7a,b,e,f also gave a high
yield (96%) and thus we decided to use more stable and easier
to handle NaAuCl4ꢀ2H2O as the catalyst for further studies.
Scheme 1 Direct catalytic amination of allylic alcohol 1.
a Graduate School of Pharmaceutical Sciences,
Kyushu University and CREST, JST, Fukuoka, Japan.
E-mail: ohshima@phar.kyushu-u.ac.jp; Fax: +81 92 642 6650;
Tel: +81 92 642 6650
b Department of Chemistry, Graduate School of Engineering Science,
Osaka University and CREST, JST, Osaka, Japan.
E-mail: mashima@chem.es.osaka-u.ac.jp; Fax: +81 6 6850 6245;
Tel: +81 6 6850 6245
(1)
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization of the products, and other detailed
results. See DOI: 10.1039/c1cc12760h
Under the optimized conditions, direct amination of 1a with various
N-substituted Boc-amides was examined (Table 1, Entries 1–13).
c
8322 Chem. Commun., 2011, 47, 8322–8324
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Benzyl, allyl, phenethyl, and carbonylmethyl substituted Boc-amides
2b–g were good nucleophiles to give the desired products in
high yield (Entries 1–6), except for the reaction with a sterically
congested 2h (R = cHex) (Entry 7). Under the present reac-
tion conditions, several functionalities such as nitrile (Entry 3),
TBS ether of phenol (Entry 5), and ester (Entry 6) remained
intact. We further examined the compatibility of other functional
groups under the NaAuCl4-catalyzed conditions (Entries 8–13).
Nucleophiles with acetoxy (Entry 8) and MEM ether (Entry 9)
functionalities reacted smoothly to give the product in excellent
yield, whereas TBS (Entry 10) and highly acid-sensitive THP
(Entry 12) ethers of aliphatic alcohol partially decomposed
during the reactions, resulting in only moderate yield of the
products. Such undesired decompositions were successfully
suppressed by the use of milder Au(III)-picolinate complex 420
as the catalyst, affording the products 3ak and 3al in 99%
(Entry 11) and 71% (Entry 13) yields, respectively. We next
examined the reaction of 1a with different types of nitrogen
nucleophiles (Entries 14–24). The reaction with Cbz-amide
2m afforded the corresponding product 3am in 94% yield
(Entry 14). Synthetically useful thiophenesulfonyl (Entry 15),17
Bus (Entry 16),18 and Dios (Entry 17)19 amides, which are
readily deprotected by Mg, TFA with anisole, and aq. TFA,
respectively, to give the corresponding amines, were first
utilized in the direct catalytic amination reaction. They smoothly
reacted with 1a to give the product 3an–ap in 70–95% yield,
leaving thienyl, tert-butyl, and acetal functionalities intact.
When ureas 2q (Entry 18) and 2r (Entry 19) were used, only
mono allylation occurred in both cases. Although amide 2s
was less reactive than the above nucleophiles, the desired
product 2as was obtained in 499% yield (Entry 20). Electron-
deficient aniline derivatives 2t–v were also good nucleophiles
(Entries 21–23). Electron-rich aniline (2w) is a challenging
substrate for the acid-catalyzed direct substitution reaction
with a few excellent exceptions.4a Under the present conditions,
the desired product 3aw was obtained, though the yield was
moderate (Entry 24).
The scope of the reaction with respect to alcohols 1 was
further examined (Table 2). The reactions of 1,3-diphenyl
substituted allylic alcohols with both electron-donating (Entry 1)
and electron-withdrawing (Entry 2) groups proceeded smoothly
to afford products 3ba and 3ca in 96% and 94% yields,
respectively. The reactivity of alkyl substituted allylic alcohols
1d (Entry 3) and 1e (Entry 4) was lower than that of 1a–c due to
the formation of less reactive a-methyl cinnamyl alcohols, and
SN20 products (cinnamylamine derivatives) were obtained
regioselectively. Benzylic alcohols 1f (Entry 6), 1h (Entry 9),
and 1i (Entry 10) smoothly reacted with 2a, though related
benzylic alcohol 1g (Entry 7) was less reactive. This gold
catalysis was also applicable to thiophenemethanol derivatives
1j (Entry 12) and 1k (Entry 13), affording the corresponding
products in high yield. Because the thiophene unit is rarely
utilized in gold catalysis7b,21 due to the high affinity of gold to
the soft sulfur atom, the high yields using 2n (Table 1), 1j, and
1k were interesting. Contrary to our expectation, thiophene (5)
had positive effects on the gold-catalysis and the above-
mentioned unsatisfactory results using 1e and 1g were greatly
improved by the addition of 1 equiv. of 5, giving products 3ea
(Entry 5) and 3ga (Entry 8) in 75% and 499% yields,
respectively. Notably, the addition of 5 prevented the undesired
isomerization of 1e to cinnamyl alcohol derivatives. Positive
effects of added 5 were also observed in the reaction of trityl
alcohol (1i) (Entry 11). Finally, crossover experiments indicated
that the reaction is reversible under the reaction conditions.9bw
The reaction using optically active 1h gave only the racemic
product 3ha, suggesting a carbocation intermediate.w
Table 1 Direct catalytic substitution of 1a with various N-nucleophilesa
Entry Nucleophile 2 (Nu–H)
Time/h Yieldb (%)
1
2
3
4
Boc–NH–CH2Ph (2b)
Boc–NH–CH2C6H4–4-CH3 (2c)
Boc–NH–CH2C6H4–4-CN (2d)
Boc–NH–CH2CHQCH2 (2e)
Boc–NH–CH2CH2C6H4–4-OTBS (2f)
Boc–NH–CH2CO2Et (2g)
Boc–NH–cHex (2h)
Boc–NH–(CH2)4–OAc (2i)
Boc–NH–(CH2)6–OMEM (2j)
Boc–NH–(CH2)6–OTBS (2k)
2k
1
3
1
1
2
1
24
3
1.5
1
7
88
91
92
86
79
90
31
93
99
50
99
44
71
94
5
6
7c
8
9
10
11d
12
13d
14
Boc–NH–(CH2)6–OTHP (2l)
2l
Cbz–NH2 (2m)
1.5
4
1
15
16
17
3
5
1
81
70
95
In summary, we developed a direct catalytic substitution of
various allylic and benzylic alcohols with synthetically useful, but
acid-sensitive Boc, Bus, and Dios-protected amine nucleophiles,
which have not been well utilized for Lewis acid catalysis,
promoted by 1 mol% of NaAuCl4ꢀ2H2O under mild conditions
(rt to 40 1C). The use of a milder Au(III)-picolinate complex as a
catalyst enables reactions with more acid-sensitive functional
groups, such as TBS and THP groups. Furthermore, a thiophene
unit showed unusual positive effects on the present gold catalysis
and improved the yield of less reactive substrates.
18
19
20
21
22
23
24
Ph–NHCONH–Ph (2q)
Ph–NHCONH2 (2r)
PhCONH2 (2s)
4-O2N–C6H4–NH2 (2t)
4-NC–C6H4–NH2 (2u)
4-F3C–C6H4–NH2 (2v)
Ph–NH2 (2w)
1
7
6
0.3
3
84
74
499
92
98
92
48
30
36
a
Reaction conditions: 1a (1 mmol), 2 (1.5 mmol), NaAuCl4ꢀ2H2O
This work was supported by Grant-in-Aid for Scientific
Research (B) and Scientific Research on Innovative Areas
from MEXT and CREST from JST. Y.N. thanks Global COE
b
(0.01 mmol), CH2Cl2, reflux. Isolated yield. Toluene (reflux) was
d
used instead of CH2Cl2. Complex 4 was used as the catalyst.
c
c
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Table 2 Direct catalytic substitution of various alcohols with 2aa
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H.-J. Liu, Chem. Commun., 2006, 3352; (b) H. Qin, N. Yamagiwa,
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Curr. Org. Synth., 2009, 6, 426.
Yieldb
Temp. Time/h (%)
Entry Alcohol 1
(E)-4-MeOC6H4CHQCH
–CH(OH)–Ph (1b)
(E)-4-BrC6H4CHQCH
–CH(OH)–C6H4–4-Br (1c)
(E)-4-MeOC6H4CHQCH
–CH(OH)–CH3 (1d)
1
2
3
Reflux
rt
2
8
3
96c
94
Reflux
77d
4
(E)-PhCH(OH)–CHQCH–CH3 (1e) rt
12
12
44d
75d
5e
1e
4-MeOC6H4CH(OH)–C6H4–4-OMe
(1f)
4-MeOC6H4CH(OH)–CH3 (1g)
1g
rt
6
Reflux 0.3
Reflux 19
99
66
7
8e,f
Reflux
9
499
10 (a) Z.-P. Zhan, J.-L. Yu, H.-J. Liu, Y.-Y. Cui, R.-F. Yang, W.-Z. Yang
and J.-P. Li, J. Org. Chem., 2006, 71, 8298; (b) U. Jana, S. Maiti and
S. Biswas, Tetrahedron Lett., 2008, 49, 858; (c) K. Y. Lee, H. S. Lee and
J. N. Kim, Bull. Korean Chem. Soc., 2008, 29, 1099; (d) F. Shi,
M. K. Tse, S. L. Zhou, M. M. Pohl, J. Radnik, S. Hubner,
K. Jahnisch, A. Bruckner and M. Beller, J. Am. Chem. Soc., 2009,
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S. Reymond and J. Cossy, Org. Lett., 2010, 12, 1808; (f) X. Cui, F. Shi,
Y. Zhang and Y. Deng, Tetrahedron Lett., 2010, 51, 2048.
11 B. Sreedhar, P. S. Reddy, M. A. Reddy, B. Neelima and
R. Arundhathi, Tetrahedron Lett., 2007, 48, 8174.
12 (a) C. R. Reddy, P. P. Madhavi and A. S. Reddy, Tetrahedron
Lett., 2007, 48, 7169; (b) H. W. Yang, L. Fang, M. Zhang and
C. J. Zhu, Eur. J. Org. Chem., 2009, 666; (c) M. Zhang, H. Yang,
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13 (a) K. Namba, Y. Nakagawa, H. Yamamoto, H. Imagawa and
M. Nishizawa, Synlett, 2008, 1719; (b) H. Yamamoto, E. Ho,
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16, 11271.
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(b) K. Motokura, N. Nakagiri, T. Mizugaki, K. Ebitani and
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Y. B. Shen and X. L. Wu, Eur. J. Org. Chem., 2008, 4367;
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15 For recent reviews of direct catalytic amination reaction of
alcohols through redox process, see: (a) M. Hamid, P. A. Slatford
and J. M. J. Williams, Adv. Synth. Catal., 2007, 349, 1555;
(b) T. D. Nixon, M. K. Whittlesey and J. M. J. Williams, Dalton
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Rev., 2010, 110, 1611; (d) G. E. Dobereiner and R. H. Crabtree,
Chem. Rev., 2010, 110, 681.
9
Reflux
5
88
10
11e
Ph3C–OH (1i)
1i
Reflux 10
Reflux
80
91
4
12
rt
24
80
85
13
rt
24
a
Reaction conditions: 1a (1 mmol), 2 (1.5 mmol), NaAuCl4ꢀ2H2O
b
c
(0.01 mmol), CH2Cl2, reflux. Isolated yield. 1 : 1 mixture of regio-
d
isomers was obtained. a-Methyl cinnamylamine derivative was obtained.
The reaction was performed with thiophene (5, 1 mmol). 3 mol% of the
catalyst was used.
e
f
Program of Osaka University. We thank Prof. Tsunoda
(Tokushima Bunri Univ.) for a gift of Dios-amides.
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c
8324 Chem. Commun., 2011, 47, 8322–8324
This journal is The Royal Society of Chemistry 2011