Diphenylammonium triflate: A novel and efficient catalyst for synthesis of spiro-heterocyclic compounds

Article abstract of DOI:10.2174/157017810791130630

A general and practical one-pot synthesis of spiro-heterocyclic compounds using diphenylammonium triflate (DPAT, 5 mol%) as a novel and efficient catalyst is described. The pseudo four-components Biginelli-like reaction of 5,5- dimethyl-1,3-cyclohexanedione, thiourea and aldehydes catalyzed by DPAT in refluxing ethanol produced the corresponding spiro-heterocyclic compounds with moderate to good yields. A possible mechanism is proposed.

Full text of DOI:10.2174/157017810791130630

314
Letters in Organic Chemistry, 2010, 7, 314-318
Diphenylammonium Triflate: A Novel and Efficient Catalyst for Synthesis
of Spiro-Heterocyclic Compounds
Jianjun Li, Jian Sun and Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P.R. China
Received September 21, 2009: Revised February 06, 2010: Accepted February 08, 2010
Abstract: A general and practical one-pot synthesis of spiro-heterocyclic compounds using diphenylammonium triflate
(DPAT, 5 mol%) as a novel and efficient catalyst is described. The pseudo four-components Biginelli-like reaction of 5,5-
dimethyl-1,3-cyclohexanedione, thiourea and aldehydes catalyzed by DPAT in refluxing ethanol produced the
corresponding spiro-heterocyclic compounds with moderate to good yields. A possible mechanism is proposed.
Keywords: Biginelli-type reaction, spiro-heterocyclic compounds, catalyst, diphenylammonium triflate.
INTRODUCTION
RESULT AND DISCUSSION
The classical Biginelli [1] three-component condensation
reaction is typically the acid-catalyzed [2] cyclocondensation
of an aldehyde, a urea or thiourea and a ꢀ-dicarbonyl
compound, result in 3,4-dihydropyrimidin-2(1H)-ones
(DHPMs), which are efficient calcium channel modulators
[3], mitotic kinesine inhibitors [4], antibacterial and antiviral
agents [4,5]. In recent years, Biginelli reaction has been
widely used for generating large collections of molecules in
combinatorial synthesis [6]. In addition, the novel pseudo
four-component Biginelli-type scaffold synthesis, the use of
the cyclic ꢀ-dicarbonyl compounds instead of open-chain
dicarbonyl compounds has attracted a synthetic interest for
the formation of spiro-heterocyclic structure catalyzed by
HCl [7], NaHSO4 [8], H3PW12O40 [9] and TMSCl [10].
However it suffers from harsh reaction conditions,
unsatisfactory yields and unsuitable environment calls.
Moreover, these catalysts are limited to cyclic-diketones and
none of the reports are extended to the use of open-chain
dicarbonyl compounds in classic Biginelli reaction
conditions.
Firstly, we tried to find the optimal catalyst for the
formation of spiro-heterocycles 1. The model reaction of 5,5-
dimethyl-1,3-cyclohexanedione 3, thiourea 4 and benzalde-
hyde 5a (Scheme 1) was performed in the presence of Lewis
catalysts in refluxing EtOH. The results were summarized in
Table 1. According to Table 1, title product 1a was not
obtained with NaHSO4 or no catalyst in the reaction (Table 1,
entries 1, 2), which gave the DHPM 2a in good yield.
Moreover, the reaction was insufficient to afford the target
product 1a catalyzed by CF3CO2H, L-proline and Sr(OTf)2
(Table 1, entries 3-5). The optimal catalyst was DPAT,
which gave the highest yield of target product 1a in 62 %
yield (Table 1, entry 6). Excitedly, only 5 mol% of DPAT
was sufficient for the reaction (Table 1, entry 7).
In order to confirm the optimum reaction conditions for
the model reaction catalyzed by DPAT, various factors
including molar ratio, solvent and reaction temperature were
investigated. The results were listed in Table 2.
Initially, the experiments were performed in various
solvents in the presence of DPAT and the results were
showed in Table 2. It was found that the reaction is affected
remarkably by solvents. We got low yield of 1a in MeCN,
toluene, DMF or CHCl3 (Table 2, entries 1-4) and the best
solvent was EtOH (Table 2, entry 5). Moreover, increasing
the reaction temperature was a benefit to improving the yield
of the product (Table 2, entries 5-7). In addition, the reaction
was influenced greatly by the molar ratio of reagents. The
results indicated that the amount of benzaldehyde 5a was a
key factor to afford the target product 1a compared with
traditional Biginelli reactions. Excessive benzaldehyde 5a
was necessary to afford the title product 1a (Table 2, entries
5, 8) and the best molar ratio of substrates (3 : 4 : 5a) was 1 :
1 : 5. Lower ratio of reagents (3 : 4 : 5a = 1 : 1 : 1.5 or 3)
could not produce the desired product 1a; in contrast, the
classical Biginelli product 2a was obtained in excellent yield
(Table 2, entries 9, 10).
In continuation of our interest in applications of Biginelli
reaction and the metal triflates [11], which were widely used
in organic synthesis, we wish to report a novel and efficient
catalyst diphenylammonium triflate (DPAT) for prompting
the Biginelli-type reaction of aldehydes, thiourea and 5,5-
dimethyl-1,3-cyclohexanedione under mild conditions. The
reaction proceeded smoothly to give the spiro-heterocyclic
compound 1 in moderate to good yield. The catalyst DPAT
[12] had low toxicity, high stability, easy preparation by a
simple acid-base reaction of diphenylamine and
trifluoromethanesulfonic acid in toluene at ice bath.
*Address correspondence to this author at the Key Laboratory of
Pharmaceutical Engineering of Ministry of Education, College of
Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
310014, P.R. China; Fax: (0086)57188320752;
As the results indicated in Table 1 and Table 2, the
E-mail: pharmlab@zjut.edu.cn
optimal conditions for the reaction were in the presence of 5
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Diphenylammonium Triflate
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
315
O
R
S
O
R
O
R
DPAT, 5 mol%
EtOH, reflux
NH
+
R
CHO
+
+
H2N
NH2
O
O
N
H
S
HN
NH
S
3
2
4
5a-o
1a-o
Scheme 1.
Table 1. The Reaction of 5,5-Dimethyl-1,3-cyclohexanedione 3, Thiourea 4 and Benzaldehyde 5a in Presence of Various Acidic
Catalystsa
Entry
Catalyst
Catalyst Amount (mol %)
Product 1a (Yield, %)b
Product 2a (Yield, %)b
1
2
3
4
5
6
7
8
NaHSO4
None
20
--
--
87
72
35
28
46
29
25
28
--
CF3CO2H
L-Proline
Sr(OTf)2
DPAT
20
20
20
20
5
47
53
35
62
62
54
DPAT
DPAT
1
aReactions conditions: 5,5-dimethyl-1,3-cyclohexanedione 3 (1.0 mmol), thiourea 4 (1.0 mmol), benzaldehyde 5a (5.0 mmol) in refluxing EtOH.bIsolated yield.
Table 2. The Influence of the Reaction Conditions on the Product Yield for the Model Reaction Catalyzed by DPATa
Entry
Solvent
Molar Ratiob
Temp. (oC)
Yield of 1a (%)c
Yield of 2a (%)c
1
2
MeCN
Toluene
DMF
1 : 1 : 5
1 : 1 : 5
1 : 1 : 5
1 : 1 : 5
1 : 1 : 5
1 : 1 : 5
1 : 1 : 5
1 : 1 : 4
1 : 1 : 3
1 : 1 : 1.5
reflux
80
40
25
36
10
62
16
25
42
--
43
67
35
76
25
56
72
47
89
92
3
80
4
CHCl3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
reflux
reflux
r. t.
5
6
7
50
8
reflux
reflux
reflux
9
10
--
aAll the reactions was catalyzed by 5 mol% DPAT and were sonicated firstly for dissolving. bThe molar ratio was 3 : 4 : 5a. cIsolated yield.
mol% DPAT in refluxing EtOH with the 1:1:5 of reagents (3
: 4 : 5a).
group (Table 3, entry 2), which gave moderate yield (60%)
of 1b and a small amount of 2b. However, benzaldehyde and
4-methylbenzaldehyde exhibited the different chemical
behaviors to this reaction (Table 3, entries 1, 9), which
afforded a moderate yield of 1 and a little amount of 2.
Moreover, para-substituted benzaldehydes carrying F, Cl
and OMe (Table 3, entries 10-12) got the classical Biginelli
products 2 as the major products and the target product 1
was obtained in low yield (35%-40%). There was no desired
product 1m afforded with ortho-substituted benzaldehyde
due to the steric hindrance (Table 3, entry 13). Based on the
above results, we attempted to extend the methodology to
With the optimal condition in hand, various aldehydes
were examined in this reaction (Scheme 1). The results were
summarized in Table 3. All reactions went smoothly under
mild reaction conditions to produce 1 in moderate to good
yield.
From Table 3, the reaction proceeded very efficiently
with meta-substituted benzaldehydes and disubstituted
benzaldehydes (Table 3, entries 3-8) carrying either electron-
donating or electron-withdrawing group in good yield (75%-
80%), except meta-substituted benzaldehyde with hydroxy
heterocyclo
aldehydes
and
aliphatic
aldehydes.

316 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Li et al.
Unfortunately, trace amount of target product 1n was
obtained with thiophene (Table 3, entry 14) and no product
was detected with aliphatic aldehyde (Table 3, entry 15).
was cyclization to afford classical Biginelli product 2. Path B
involved condensation of aldehyde to form intermediate 8
and ultimately cyclize to the spiro-heterocyclic compound 1.
From the above results and literatures [7, 13], a possible
explanation for the formation of spiro-heterocyclic
compounds 1 is shown in Scheme 2. Firstly, aldehyde and
thiourea would easily form the intermediate acyl imine 6,
followed by a Michael-type addition reacting with a ꢀ-diketo
enolate 9 to give the open chain ureide 7. Subsequently, two
trends for intermediate 7 are presented in Scheme 2. Path A
CONCLUSION
In summary, we have developed an efficient one-pot
synthesis of spiro-fused heterobicyclic compouds (1) by
using a novel catalyst DPAT. Contrary to classic Biginelli
reaction, this methodology showed that the ratio of
substrates was the main reaction factor in these reactions.
Table 3. Synthesis of Spiro-Heterocyclic Compounds 1a
Entry
R
Time (h)
Product (1)
Yield (%)b
1
2
5a: C6H5
5b: 3-HOC6H4
5c: 3-FC6H4
6
5
1a
1b
1c
1d
1e
1f
62c
60c
77
3
4
4
5d: 3-ClC6H4
4
79
5
5e: 3-MeOC6H4
5f: 3-NO2C6H4
5g: 3,4-(CH3)2C6H3
5h: 3-MeO-4-HOC6H3
5i: 4-MeC6H4
5j: 4-MeOC6H4
5k: 4-FC6H4
4
80
6
6
76
7
5
1g
1h
1i
75
8
5
76
9
6
65c
35c
40c
43c
--c
10
11
12
13
14
15
7
1j
8
1k
1l
5l: 4-ClC6H4
8
5m: 2-ClC6H4
5n: Thiophene
5o: t-Bu
7
1m
1n
1o
7
tracec
--d
10
aReactions conditions: 5,5-dimethyl-1,3-cyclohexanedione 3 (1.0 mmol), thiourea 4 (1.0 mmol), aldehyde 5 (5.0 mmol) and DPAT (0.05 mmol, 5 mol%), in refluxing EtOH.
bIsolated yield. cBesides the product 1, there was another product 2 obtained in these reactions. dNo product obtained.
S
R
O
DPAT
-H2O
HN
NH2
DPAT
S
R
O
O
S
O
HN
-H2O
+
H2N
NH2
R
H
N
N
Path A
S
N
H
H2
R
H
2
6
7
O
OH
9
Path B
Excess RCHO
H2O
S
HN
N
O
C
R
H
O
O
R
O
R
R
HN
NH
S
1
8
Scheme 2.

Diphenylammonium Triflate
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
317
1
Moreover, the method offered in this paper had merits of the
present process including good yields, environment friendly
procedure and easy isolation. Therefore, it offers an
important method for ammonium triflate involving Biginelli-
like reaction and further studies are in progress.
cm-1. H NMR (400 MHz, DMSO-d6) ꢁ: 8.74 (s, 2 H), 7.44
(d, J = 8.0 Hz, 4 H), 7.09 (d, J = 8.4 Hz, 4 H), 5.12 (s, 2 H),
1.75 (s, 2 H), 1.70 (s, 2 H), 0.09 (s, 6 H). 13C NMR (100
MHz, DMSO-d6) ꢁ: 208.5, 204.8, 177.0, 134.1, 133.5, 130.6,
128.4, 64.5, 61.7, 55.5, 53.7, 28.6, 27.8. HRMS (ESI-TOF)
calcd. for C23H23Cl2N2O2S ([M + H]+): 461.0857; Found:
461.0851.
EXPERIMENTAL
General
ACKNOWLEDGEMENTS
Analytical grade solvents and commercially available
reagents were used without further purification. Melting
points were determined with a Büchi B-540 capillary melting
point apparatus and are uncorrected. IR spectra were
recorded on a Nicolet Aviatar-370 instrument, spectrometer
We thank the National Science Foundation of China (No.
20806073), Science & Technology Projects of Zhejiang (No.
2008C11046) and the Opening Foundation of Zhejiang
Provincial Top Key Pharmaceutical Discipline for financial
support.
1
using samples as neat liquids or as KBr plates. H NMR and
13C NMR spectra were recorded on Varian (400 MHz)
instrument using TMS as an internal standard. 19F NMR
spectra were measured at Varian (376 MHz) and Anance III
(470.6 MHz) and chemical shifts were given relative to
CF3COOH. Mass spectra were measured with Agilent 6210
TOF LC/MS.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
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White solid. Yield: 62%, mp: 230.0-230.5 °C. IR (KBr)
ꢀ
max: 3360, 3164, 1682, 1558, 1490, 1400, 1196, 763, 702
cm-1. 1H NMR (400 MHz, CDCl3) ꢁ: 7.35-7.34 (m, 6 H), 7.2-
7.21 (m, 4 H), 6.75 (s, 2 H), 5.17 (s, 2 H), 1.80 (s, 2 H), 1.79
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ꢀ
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1
cm-1. H NMR (400 MHz, DMSO-d6) ꢁ: 8.81 (s, 2 H), 7.41
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= 7.6 Hz, 2 H), 6.86 (d, J = 10.0 Hz, 2 H), 5.15 (s, 2 H), 1.76
(s, 2 H), 1.73 (s, 2 H), 0.08 (s, 6 H). 13C NMR (100 MHz,
DMSO-d6) ꢁ: 208.4, 204.9, 177.0, 162.9, 160.5, 137.8,
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C23H23F2N2O2S ([M + H]+): 429.1448; Found: 429.1439.
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