Gold- and silver-catalyzed intramolecular hydroamination of terminal alkynes: Water-triggered chemo- and regioselective synthesis of fused tricyclic xanthines

Article abstract of DOI:10.1002/adsc.200900505

A simple, convenient and green synthetic approach to diverse fused tricyclic xanthines has been developed via gold(I) complex-catalyzed intramolecular hydroamination or silver(I)-catalyzed isomerization- hydroamination of terminal alkynes under microwave

Full text of DOI:10.1002/adsc.200900505

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DOI: 10.1002/adsc.200900505
Gold- and Silver-Catalyzed Intramolecular Hydroamination of
Terminal Alkynes: Water-Triggered Chemo- and Regioselective
Synthesis of Fused Tricyclic Xanthines
Deju Ye,a Xu Zhang,a,b Yu Zhou,a Dengyou Zhang,a Lei Zhang,a Hengshuai Wang,a
Hualiang Jiang,a,c and Hong Liua,*
a
The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, Peopleꢀs Republic of
China
Fax : (+86) 21-5080-7088; phone: (+86)-21-5080-7042; e-mail: hliu@mail.shcnc.ac.cn
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Peopleꢀs
b
Republic of China
c
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, Peopleꢀs Republic of China
Received: July 20, 2009; Published online: November 13, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900505.
Abstract: A simple, convenient and green synthetic
approach to diverse fused tricyclic xanthines has
been developed via gold(I) complex-catalyzed intra-
molecular hydroamination or silver(I)-catalyzed iso-
merization-hydroamination of terminal alkynes
under microwave irradiation in water. The first syn-
thesis of N9-annelated xanthines has also been re-
ported.
been reported to be potent and selective antagonists
of human A2A adenosine receptors, and have potential
activities as anticonvulsants to treat chemically in-
duced seizures.[7] Although oxygen- or nitrogen-con-
taining annelated xanthine derivatives have been syn-
thesized by bromination of 8-unsubstituted xanthines
and subsequent base-promoted cyclization,[8] it is im-
portant to develop a direct and efficient method fea-
turing mild reaction conditions for the synthesis of
fused tricyclic xanthines.
Keywords: gold; hydroamination; silver; terminal
alkynes; xanthines
Recently, the transition metal-catalyzed intramolec-
ular hydroamination of alkynes has been identified as
an important synthetic reaction that can be used to
synthesize various heterocycles in an efficient and
atom-economic manner.[9] Among the numerous
Xanthines (a) – that belong to an important class of methods available for this reaction, Au-catalyzed syn-
heterocyclic compounds – have gained significance in thesis of various five- and six-membered N-heterocy-
the synthesis of drugs and pharmaceutical products.[1] cles such as indoles,[10] pyrroles,[11] quinolines,[12] and
Various xanthine derivatives and other caffeine-based isoquinolines[13] has received considerable attention.
heterocycles have been suggested to be potential ther- We have previously developed an efficient and green
apeutic agents for intervention in Alzheimerꢀs dis- method – Au(I)-catalyzed regioselective intramolecu-
ease,[2] asthma,[3] diabetes,[4] Parkinsonꢀs disease,[5] and lar hydroamination – for the synthesis of indoles
cancer[6]. Fused tricyclic xanthines (b) (Figure 1) have under microwave irradiation in water.[14] In the light
of our ongoing efforts to develop new methods for
synthesizing heterocycles using transition metal cata-
lysts,[15] in this study, we report the synthesis of fused
tricyclic xanthines by microwave-assisted chemo- and
regioselective cyclization of 8-(but-3-ynyl)-xanthines
1
[16] in water using an Au(I) complex or an Ag(I) cata-
lyst. We found that the cationic Au(I) complex cata-
lyzed the direct intramolecular hydroamination of 1
and a subsequent 6-endo-dig process afforded N7-an-
nelated xanthines 2; on the other hand, the Ag(I)-cat-
Figure 1. The structures of xanthines a and fused tricyclic
xanthines b.
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our knowledge, this is the first report of the synthesis
of N9-annelated xanthines 3 by the aforementioned
method.
Initially, we investigated the effectiveness of various
combinations of catalysts and reaction conditions
using 1,3-dibenzyl-8-(but-3-ynyl)-xanthine 1a as the
model substrate. The results of these experiments are
shown in Table 1 (also see Table S1 in Supporting In-
formation). Under catalyst-free conditions, the reac-
tion could not proceed and only the starting material
1a was recovered (Table 1, entry 1). However, under
microwave heating for 30 min in the presence of 10
mol% AuClACTHNUGTRENUNG(PPh3) in water at 1208C, the desired N7-
annelated product 2a was formed in 27% yield; a
small amount (3%) of the N9-annelated product 3a
was also isolated (Table 1, entry 2). The structures of
2a and 3a were confirmed by X-ray diffraction
Scheme 1. Two different processes to diverse fused tricyclic
xanthines 2 and 3.
alyzed isomerization-hydroamination of 1 afforded (XRD) studies (Figure 2).[17] Subsequently, we opti-
N9-annelated xanthines 3 (Scheme 1). This catalytic mized the reaction conditions to obtain a single prod-
method of synthesizing fused tricyclic xanthines is ef- uct in high yield. When the reaction was carried out
ficient and environmentally friendly. To the best of using 10 mol% AuClACTHNUTRGNEUNG(PPh3) under microwave heating
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst (mol%)
–
T [8C]
Yield [%][b]
3a
2a
4a
5a
1[c]
2
100
120
150
150
150
150
150
150
150
150
150
150
150
150
150
150
0
0
3
10
0
49
0
36
70
36
0
44
69
69
72
8
0
0
0
0
0
0
2
5
3
0
2
5
5
5
0
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
AuCl
AuCl
U
27
86
0
21
trace
54
17
17
0
11
17
17
18
70
13
3
4[c]
5
AuCl3 (10)
AuCl (10)
Au catalyst X (10)
6[d]
7
AuCl
N
8
9
AgSbF6 (10)
Ag2CO3 (10)
AgI (10)
AgNO3 (10)
AgBF4 (10)
AgOTf (10)
AgAsF6 (10)
10[c]
11
12
13
14
15
16
AuCl
ACHTUNGRTEN(NUNG PPh3)(5)
AgAsF6 (5)
60
[a]
Reaction conditions: 1a (0.2 mmol), catalyst (0.02 mmol), H2O (3 mL) for 10–30 min.
Yield of isolated products based on 1a.
100% of 1a was recovered.
[b]
[c]
[d]
Au catalyst X=[Tris(2,4-di-tert-butylphenyl)phosphite]gold chloride.
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Figure 2. X-ray structures of 2a (A) and 3a (B).
for 10 min in water at 1508C, 2a was isolated in an ex- 51% yields after 1 h, along with 40% of 1f and 20%
cellent yield (86%) along with 3a in 10% yield. No 5- of 1e (starting materials), respectively (Table 2, en-
exo-dig product
ACHTUNGTRENNUNG(4a or 5a) was detected in this reac- tries f and e). We also obtained the ketones 6f and 6e
tion (Table 1, entry 3). The reaction carried out using in 15% and 20% yields, respectively. The proposed re-
a combination of 10 mol% AuClACTHNUTRGENUNG(PPh3) and 10 mol% action could also be extended to 8-(but-3-ynyl)-xan-
AgSbF6 afforded 2a and 3a in 54% and 36% yields, thines containing different R1 and R2 groups. For ex-
respectively (Table 1, entry 7). In addition, the yield ample, 1-methyl-3-benzyl-8-(but-3-ynyl)-xanthine 1g
of 3a increased to 72% when the reaction was carried (Table 2, entry g) afforded 2g in 75% yield after 1 h.
out under microwave heating in water for 10 min at Upon replacing the 1-methyl moiety in 1g with the 1-
1508C using 10 mol% AgAsF6 as the catalyst. How- cyclohexylmethyl moiety, we obtained 1h, which
ACHTUNGTRENNUNGever, a reduction of the catalyst [AuClACHTUNTGNER(NUGN PPh3) or could be efficiently transformed into the target com-
AgAsF6] concentration to 5 mol% resulted in incom- pound 2h in 86% yield within 10 min (Table 2, entry
plete consumption of 1a (Table 1, entries 15 and 16). h). A similar result was obtained when using 1-
Furthermore, water was thought to play an important benzyl-3-cyclohexylmethyl-8-(but-3-ynyl)-xanthine 1i
role in this reaction because the reaction did not pro- as the substrate (85% yield, Table 2, entry i). How-
ceed when toluene or absolute ethanol was used as
ACHTUNGTRENeNGNU ver, no reaction occurred even under the optimized
the solvent (Supporting Information, Table S1, en- reaction conditions when an internal alkyne substrate
tries 11 and 12). This water-triggered reaction is simi- like 1j was used, and 100% of the starting material
lar to that reported in literature, in which water was was recovered (Table 2, entry j).
found to play a key role to promote the gold- or
silver-catalyzed reaction of terminal alkynes and alde- conditions (Table 1, entry 14) demonstrated that the
hydes.[18,19]
proposed reaction could be extended to generate N9-
Further experiments under the optimized reaction
To evaluate the scope of the proposed catalytic fused tricyclic xanthines 3 (Table 3); however, the re-
method, we attempted the cyclization of a variety of action was significantly affected by the nature of R1
8-(but-3-ynyl)-xanthines 1 under the above-mentioned and R2 (substituents on the xanthine ring). As ob-
optimized conditions. As shown in Table 2, the reac- served during the synthesis of N7-fused tricyclic xan-
tion proceeded smoothly to afford the corresponding thines 2, 8-(but-3-ynyl)-xanthines 1b–d with bulky ali-
N7-fused tricyclic xanthines 2 in good to excellent phatic substituents were tolerant to the isomerization-
yields (Table 2, entries a–i). The bulky aliphatic sub- hydroamination and afforded the corresponding prod-
stituents in 1b–d (R1 =R2 =cyclohexylmethyl, n-Bu, ucts 3b–d in good yields (Table 3, entries b–d). How-
n-Pr) facilitated the efficient hydroamination, and ever, the presence of small substituents on the xan-
hence, the desired products were obtained in excel- thine scaffold decreased the reaction efficiency, and
lent yields (up to 90%, Table 2, entries b–d). In con- hence, the products 3e and 3f were obtained in low
trast, when 8-(but-3-ynyl)-xanthine substrates with yields (Table 3, entries e and f). Interestingly, 1e and
small substituents such as 1,3-dimethyl or 1,3-diethyl 1f were converted to 2e and 2f in 52% and 80%
were used, the reaction proceeded slowly to afford yields, respectively, in the presence of AgAsF6. Fur-
the corresponding products 2f and 2e in 42% and thermore, xanthines 1g–i containing different R1 and
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Table 2. AuClACHTUNGTRENNUNG
(PPh3)-catalyzed synthesis of N7-fused tricyclic xanthines 2 in water.[a]
Entry
a
Substrate 1
t
Product 2
Yield [%][b]
86
10 min
b
10 min
91
c
10 min
30 min
1 h
93
90
51
42
75
d
e[c]
f[d]
g
1 h
1 h
h
10 min
10 min
86
85
i
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Yield [%][b]
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Table 2. (Continued)
Entry
Substrate 1
t
Product 2
j[e]
10 min
0
[a]
Reaction conditions: 1 (0.2 mmol), AuCl
Yield of isolated products based on 1.
20% of 6e along with 20% of starting material 1e were obtained.
15% of 6f along with 40% of starting material 1f were obtained.
100% of 1j was recovered.
ACHTUNGTRNE(NUNG PPh3) (0.02 mmol), H2O (3 mL), mw, 1508C.
[b]
[c]
[d]
[e]
Table 3. (Continued)
Table 3. AgAsF6-catalyzed synthesis of N9-fused tricyclic
xanthines 3 in water.[a]
Entry Substrate t
Product 3
Yield
[%][b]
1
f[d]
1f
1g
1h
1 h
3f trace
3g 57
Entry Substrate t
Product 3
Yield
[%][b]
g
1 h
1
a
1a
1b
10 min
10 min
3a 72
h
10 min
3h 69
b
3b 72
i
1i
1j
10 min
10 min
3i 70
c
1c
1d
1e
10 min
1 h
3c 70
3d 60
3e 26
j[e]
3j
0
d
[a]
Reaction conditions: 1 (0.2 mmol), AgAsF6 (0.02 mmol),
H2O (3 mL), mw, 150 8C.
Yield of isolated products based on 1.
52% of 2e along with 10% of 6e were obtained.
80% of 2f along with 4% of 6f were obtained.
100% of 1j was recovered.
[b]
[c]
[d]
[e]
e[c]
1 h
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Gold- and Silver-Catalyzed Intramolecular Hydroamination of Terminal Alkynes
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Scheme 2. Labeling studies with D2O or deuterated starting materials.
R2 groups also underwent the cyclization reaction facilitated by the cationic metal. Then, the intermedi-
smoothly, while no reaction was observed when the ate l’ undergoes alkyne-vinylidene isomerization and
internal alkyne substrate 1j was used as the substrate. cyclization, as described above, to afford the desired
To understand the mechanism underlying the pro- product 3. The aforementioned labeling experiments
posed cyclization reaction, we performed labeling revealed that the vinyl protons of the products came
studies using deuterated starting materials or solvents. from the solvent. The direct formation of [D2]-2a or
The reaction of 1a in D2O under the two different [D2]-3a from D2O is consistent with the results report-
conditions afforded 2,3-bideuterated compounds, ed in the literature, according to which hydrogen
namely, [D2]-2a and [D2]-3a. Reaction of the deuterat- atoms that occupy the a-position with respect to the
ed alkyne [D1]-1c in water led to the formation of carbene group can be exchanged with D2O
non-deuterated products 2c and 3c (Scheme 2).
(Scheme 2).[19d,22,23] This proposed reaction mechanism
On the basis of our previous knowledge and the re- can be further confirmed by comparing the products
sults of our present study, we propose several poten- obtained from terminal and internal alkyne substrates
tial mechanisms for the cyclization reaction studied (Table 2 and Table 3). An alternative mechanism has
herein (Scheme 3). One potential mechanism involv- also been proposed for this reaction.[13,24] Accordingly,
ing alkyne-vinylidene isomerization has been dis- the catalyst coordinates with the alkyne to afford a p-
cussed previously for the transition metal-catalyzed complex; this triggers a nucleophilic attack by the
synthesis of heterocycles.[20] In the presence of the amino group in the endo mode. However, this mecha-
Au(I) complex, the terminal alkyne 1 first coordinates nism cannot explain the poor reactivity of internal al-
with the cationic Au(I) complex. Then, a vinylidene kynes.
intermediate I is formed via 1,2-H migration, and this
In summary, we have developed a chemo- and re-
adds to the N7 atom on the xanthine scaffold to gioselective approach for the synthesis of fused tricy-
afford a carbene complex II. Finally, tautomerization clic xanthines via Au(I) complex-catalyzed intramo-
of II and reductive elimination of the metal hydride lecular hydroamination or Ag(I)-catalyzed isomeriza-
complex results in the formation of the desired prod- tion-hydroamination of terminal alkynes under micro-
uct 2 and the active catalyst is regenerated. When wave irradiation in water. This reaction is atom eco-
using a ligand-free catalyst such as AgAsF6, isomeri- nomical and has high functional group tolerance.
zation involving a 1,3-H-shift between N7 and N9 Further studies for the synthesis of biologically impor-
first occurs to afford the intermediate l’;[21] this step is
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Scheme 3. A proposed mechanism.
tant xanthine derivatives and understanding of its
mechanism are currently in progress.
then irradiated for 10 min at 1508C. After the reaction had
cooled to ambient temperature, the crude reaction mixture
was extracted three times with ethyl acetate (15 mL ꢂ 3).
The combined organic phase was washed with saturated
NaHCO3 solution, brine, dried with Na2SO4 and concentrat-
ed. The residue was purified by column chromatography on
combiflash to provide the desired products.
Experimental Section
2a: Compound 2a was obtained after purification by flash
chromatography (SiO2, 300–400 mesh; ethyl acetate:petrole-
um ether, 1:9 to 1:4). 1H NMR (300 MHz, CDCl3): d=
2.461–2.528 (m, 2H, CH2), 3.050 (t, 2H, J=8.7 Hz , CH2),
5.184 (s, 2H, CH2), 5.262 (s, 2H, CH2), 5.592–5.647 (m,1H,
CH), 7.228–7.334 (m, 6H, CH, ArH), 7.402–7.475 (m, 5H,
General Procedure for the Preparation of Fused
Tricyclic Xanthines 2 or 3
A mixture of 1 (0.2 mmol), AuClACHTNUTRGNEUNG(PPh3) (0.02 mmol) or
AgAsF6 (0.02 mmol) was stirred in water (3–5 mL) under an
argon atmosphere. The vial was sealed and the mixture was
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Gold- and Silver-Catalyzed Intramolecular Hydroamination of Terminal Alkynes
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ArH); 13C NMR (75 MHz, CDCl3): d=19.677 (CH2), 22.314
(CH2), 44.403, 46.635, 104.851, 113.213, 122.828, 127.432,
127.765, 128.361, 128.475, 128.676, 136.359, 137.293, 147.873,
148.775 (C=O), 151.220 (C=O), 154.586; ESI-MS: m/z=385
[M + H]+ 100%; HR-MS (ESI): m/z=407.1406, calcd. for
C23H20N4O2Na [M + Na]+: 407.1484.
Chem. Rev. 2005, 105, 1001–1020; d) A. de Meijere, P.
von Zezschwitz, S. BrIse, Acc. Chem. Res. 2005, 38,
413–422; e) A. S. K. Hashmi, Chem. Rev. 2007, 107,
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3a: Compound 3a was obtained after purification by flash
chromatography (SiO2, 300–400 mesh; CH2Cl2:MeOH, 50:1
to 40:1). 1H NMR (300 MHz, CDCl3): d=2.350–2.367 (m,
2H, CH2), 2.984 (t, J=7.2 Hz, 2H, CH2), 5.265 (s, 2H, CH2),
5.345 (s, 2H, CH2), 5.573–5.599 (m, 1H, CH), 6.611 (d, 1H,
J=7.8 Hz, CH), 7.111–7.514 (m, 10H, ArH); 13C NMR
(75 MHz, CDCl3): d=19.659 (CH2), 22.901 (CH2), 44.945
(CH2), 47.751 (CH2), 115.896, 117.148 (CH), 121.857 (CH),
125.210, 127.220, 127.441, 128.106, 128.270, 128.908, 129.436,
134.788, 136.154, 137.088, 144.598 (C=O), 151.321 (C=O),
157.018; ESI-MS: m/z=385.0 [M+H]+ 100%; HR-MS
(ESI): m/z=407.1497, calcd for C23H20N4O2Na [M+Na]+:
407.1484.
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Acknowledgements
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (grants 20721003
and 20872153), International Collaboration Projects (grants
2007DFB30370 and 20720102040) and the 863 Hi-Tech Pro-
gram of China (Grant 2006AA020602).
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[21] In contrast with 1a, no reactions occurred when heating
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conditions.
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Adv. Synth. Catal. 2009, 351, 2770 – 2778