Indium triflate catalyzed one-pot multicomponent synthesis of spiro-hexahydropyrimidines explained by multiple covalent bond formation

Article abstract of DOI:10.1016/j.tetlet.2012.07.079

A mild, efficient, and expeditious method has been developed for the synthesis of spiro-hexahydropyrimidine derivatives via a three-component, one-pot cyclocondensation reaction of aromatic amines, formaldehyde, and cyclic ketones in 4-6 h using In(OTf)₃ as Lewis acid catalyst for the first time. The reaction involving creation of six new covalent bonds was efficiently promoted by 10 mol % In(OTf)₃ and the catalyst could be recovered easily after the reaction and reused without any loss of its catalytic activity. The advantageous features of this methodology are high atom-economy, operational simplicity, shorter reaction time, and easy handling.

Full text of DOI:10.1016/j.tetlet.2012.07.079

Tetrahedron Letters 53 (2012) 5270–5274
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium triflate catalyzed one-pot multicomponent synthesis of
spiro-hexahydropyrimidines explained by multiple covalent bond formation
⇑
Anshu Dandia , Anuj K. Jain, Sonam Sharma
Center for Advance Studies, Department of Chemistry, University of Rajasthan, Jaipur 302004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, efficient, and expeditious method has been developed for the synthesis of spiro-hexahydropyrim-
idine derivatives via a three-component, one-pot cyclocondensation reaction of aromatic amines, form-
aldehyde, and cyclic ketones in 4–6 h using In(OTf)3 as Lewis acid catalyst for the first time. The reaction
involving creation of six new covalent bonds was efficiently promoted by 10 mol % In(OTf)3 and the cat-
alyst could be recovered easily after the reaction and reused without any loss of its catalytic activity. The
advantageous features of this methodology are high atom-economy, operational simplicity, shorter reac-
tion time, and easy handling.
Received 30 May 2012
Revised 13 July 2012
Accepted 18 July 2012
Available online 27 July 2012
Keywords:
Multicomponent reaction
Indium triflate
Ó 2012 Elsevier Ltd. All rights reserved.
Spiro-hexahydropyrimidines
The importance of Lewis acid catalysis in organic synthesis has
been well documented in the literature.1a–e The majority of the
strong and efficient Lewis acids such as AlCl3, FeCl3, ZnCl2, SbF5,
TiCl4, and SnCl4 used in various organic transformations2a–e are
prone to fast hydrolysis by atmospheric moisture, and therefore
they should be treated strictly in dry conditions to prevent the loss
of their catalytic activities. Quite often, they are required in stoichi-
ometric amounts, are not reusable, and lead to secondary reac-
tions, making the reaction work-up and product isolation
tedious. Because of the increasing awareness of environmental
problems in chemical research and industry, the search for a more
efficient Lewis acid catalyst still continues.
Indium(III) compounds have evolved as mild and water-toler-
ant Lewis acids, imparting high regio-, stereo-, and chemoselectiv-
ities in various organic transformations.3a–d In contrast to classical
Lewis acids, which are often required in stoichiometric quantities,
Indium(III) compounds readily promote a wide variety of organic
reactions in catalytic quantities soluble both in organic solvents
and in aqueous media.4a,b Particularly, in accordance with the
recent surge of interest in moisture-stable metal triflates, In(OTf)3
has emerged as a promising catalyst for various types of organic
reactions.5–14
drugs for the treatment of A549 lung carcinoma.20 They form struc-
tural units in trypanothione reductase inhibiting ligands for the reg-
ulation of oxidative stress in parasite cells.21 N-(4-Aminobutyl)
hexahydropyrimidine and N-(3-aminopropyl) hexahydropyrimi-
dine are shown to compete with spermidine for uptake by L1210
cells.22 Due to their significant biological activity, hexahydropyrim-
idines have received a great deal of attention in recent years.
Hexahydropyrimidines are classically prepared by condensa-
tion between substituted propane-1,3-diamines and aldehydes or
ketones.23a–f This method, however, limits the range of substitution
at 5-position of the hexahydropyrimidines, being restrained by the
availability of appropriately functionalized 1,3-diamines. There are
also a few reports in the literature describing the synthesis of
substituted hexahydropyrimidine derivatives by using a,b-unsatu-
rated nitriles, by the reaction of substituted alanine and carbam-
ide24a,b or by the reaction of 1,3-dicarbonyl compounds or cyclic
ketones, aromatic amines, and formaldehyde.25a,b Thus each of
the known procedure has its own merits; however, further studies
are still necessary for the versatile, simple, environmental, and eco-
nomical multi component methodology.
Inspired by the initial investigation of the metal triflate
catalyzed Mannich reaction26a–d and the classical method for the
synthesis of hexahydropyrimidines, and in continuation of our
aim to develop novel and highly efficient synthetic reaction meth-
odologies for the synthesis of spiroheterocycles,27a–f we report
herein a straightforward one-pot three-component method for
the synthesis of substituted spiro-hexahydropyrimidine deriva-
tives by multiple covalent bond formation at room temperature.
To the best of our knowledge, this is the first report for the synthe-
sis of spiro-hexahydropyrimidine scaffolds using In(OTf)3 as a
reusable Lewis acid catalyst.
The hexahydropyrimidine skeleton is present in a number of
alkaloids, eudistomidines H and I,15 tetraponerines,16 verbame-
trine,17 andverbamethine.18 Hexetidineis aformaldehyde-releasing
antimicrobialagentemployedin mouthwashes and numerousprod-
ucts of veterinary and human drugs.19 Different N-substituted hexa-
hydropyrimidines are synthones for spermidine-nitroimidazole
⇑
Corresponding author. Tel.: +91 9414073436; fax: +91 141 2609549.
E-mail address: dranshudandia@yahoo.co.in (A. Dandia).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.079

A. Dandia et al. / Tetrahedron Letters 53 (2012) 5270–5274
5271
Cl
R
NH2
O
O
N
O
In(OTf)3
(10 mol %)
O
NH2
O
O
2
N
N
+
H
+
H
DCM, 4-6 h
r.t.stirring
Catalyst
r.t.stirring
R
N
+
H
R
+
H
1
4
3
2
Cl
Cl
3a
Scheme 2. Synthesis of spiro-hexahydropyrimidines 4a–p.
4a
1a
Scheme 1. Synthesis of spiro-hexahydropyrimidine 4a.
final product in aqueous medium may be attributed to low solubil-
ity of the substrate in water.
Performing the reaction with a higher catalyst loading 20 mol %
had no significant effect on yield. However, if the amount of the
catalyst was reduced to 5 and 1 mol %, the product yield was
reduced to 48% and 23% respectively. To our delight, the reaction
worked very well in CH2Cl2 at room temperature under the catal-
ysis of 10 mol % In(OTf)3 to give spiro-hexahydropyrimidine (4a)
in 78% yield.
With these encouraging results in hand, we turned to explore
the scope of the reaction using different aromatic amines as sub-
strate under the optimized reaction conditions (Scheme 2). It was
observed that the aromatic amine with electron donating as well
as electron withdrawing groups reacted successfully to furnish
the final product in good yields. In addition, we have also explored
the reactivity of cyclic ketones (1a–c, Fig. 1) for this transforma-
tion. From the results, it is clear that cyclohexanone showed better
reactivity than 4-methylcyclohexanone and slightly higher yields
were obtained, while, 1,4-dioxaspiro[4.5]decan-8-one is found to
be less active than cyclohexanone (Table 2).
To explore an appropriate reaction condition is of crucial impor-
tance for the targeted synthesis. Initially, the three-component
condensation reaction of cyclohexanone, formaldehyde, and
4-chloroaniline as a simple model substrate was investigated to
establish the feasibility of the strategy and to optimize the reaction
conditions (Scheme 1). In the beginning, the model reaction was
carried out in the absence of catalyst in CH2Cl2 at room tempera-
ture. The reaction yielded the desired product 4a in poor yield after
running the reaction for 18 h (Table 1, entry 1). To improve the
yield, a representative selection of Lewis acids, including Sc(OTf)3,
In(OTf)3, Bi(OTf)3, Cu(OTf)2, and Ag(OTf) were tested. Catalysts
such as Sc(OTf)3, Bi(OTf)3, Cu(OTf)2, and Ag(OTf), have low effi-
ciency as compared to In(OTf)3. The promising activity of indium
triflate as compared to triflate of other metals and halide salts
can be explained due to the soft character of indium as compared
to other metals,28a–c which shows strong affinity for soft Lewis
bases such as enol moiety on the basis of the hard and soft acids
and bases (HSAB) principle.29 The catalytic activity of other In(III)
complexes such as InCl3, InF3, and InBr3, was significantly lower
than that of In(OTf)3. Possibly, the triflate anion coordinates with
cyclohexenol better than other halide ions such as ClÀ, BrÀ, and F
The proposed mechanism for the formation of spiro-hexahy-
dropyrimidine derivatives is shown in Scheme 3. It is clear from
the sequence of steps that the role of indium triflate is to
À
ions and helps in promoting the reaction.
With In(OTf)3 as catalyst, we next investigated the effect of
solvents and found that less coordinating solvent CH2Cl2 was supe-
rior to strong coordinating solvents such as THF, nitromethane, and
acetonitrile, perhaps because the interaction between the indium
catalyst and the substrate was disturbed by its strong coordinating
ability as observed by other workers.28b,c Moreover, in proton
releasing solvent like ethanol, protonation of secondary amine
prior to attack may retard the nucleophilicity of the amine moiety
thus resulting in lower yields. Further, the formation of traces of
O
O
O
O
O
1b
1a
1c
Figure 1.
Table 1
Table 2
Synthetic results of spiro-hexahydropyrimidine derivatives 4a–p
Optimization for the synthesis of 4a
Entry
Solvents
Catalysts
Mol (%)
Time (h)
Yield⁄ (%)
Entry Products Ketone
R
Time (h) Yielda (%) Mp (°C)
1
2
3
4
5
6
7
8
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
THF
Ethanol
Water
Acetonitrile
Nitromethane
Dichloromethane
Dichloromethane
Dichloromethane
—
—
18
4
8
11
7
8
10
10
8
5
7
12
10
9
4
5
14
78
63
56
62
42
48
53
58
32
47
Trace
42
Trace
78
48
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1c
1c
4-Cl
4-CH3
4
4
5
4
5
6
5
5
5
6
6
6
5.5
5
5.5
6
78
74
72
78
80
66
71
73
72
61
58
50
54
63
68
50
160–162
124–126
248–250
96–98
In(OTf)3
Sc(OTf)3
Bi(OTf)3
Cu(OTf)2
Ag(OTf)
InCl3
10
10
10
10
10
10
10
10
10
10
10
10
10
20
5
3-Cl,4-F
3,4-diCH3
4-OCH3
4-Br
4-N(CH3)2
4-Cl
4-CH3
3-Cl,4-F
4-Cl
106–108
154–156
106–108
166–168
104–106
236–238
132–134
126–128
206–208
120–122
118–120
134–136
InBr3
InF3
9
9
10
11
12
13
14
15
16
17
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
10
11
12
13
14
15
16
4-CH3
3-Cl,4-F
3,4-diCH3
4-OCH3
4-Br
1
6
23
a
*
Isolated yield.
Isolated yield.

5272
A. Dandia et al. / Tetrahedron Letters 53 (2012) 5270–5274
In(OTf)3
HO
HN
H
In(OTf)3
H
NH2
Cl
NH2
Cl
N
O
CH2
(TfO)3In OH
HCHO
+
H
+
Cl
Cl
Imine formation
Cl
Cl
O
OH
NH
O
N
H
Cl
N
Cl
H
N
NH
O
HCHO
A
N
N
CH2
B
4a
Cl
Cl
Cl
Scheme 3. Plausible mechanism for the reaction of 4-chloroaniline and formaldehyde with cyclohexanone.
reused in the reaction and it showed the same activity as a fresh
catalyst without any loss of its activity. After four recycles, the cat-
alyst still had a high activity and gave the desired product in fairly
good yield.
All the products were well characterized by IR, 1H, 13C NMR,
mass spectra and elemental analyses.30 The final structure was
confirmed by single crystal X-ray analysis of 2,4-bis-(4-chloro-
phenyl)-2,4-diazaspiro[5.5]undecan-7-one (4a) (Fig. 2).31
In conclusion, we have described an efficient three-component
reaction for the synthesis of a series of substituted spiro-hexahy-
dropyrimidine derivatives catalyzed by indium triflate from simple
and readily available starting materials in one pot operation with
good yields. In the present investigation six molecules of reactants
are involved and six new covalent bonds are generated, and only
water is generated as waste, thus, atom economy of the reaction
is high.
Acknowledgements
Figure 2. Single crystal X-ray structure of 2,4-bis-(4-chlorophenyl)-2,4-diazaspi-
ro[5.5]undecan-7-one (4a).
Financial assistance from the Council for Scientific and Indus-
trial Research (CSIR) New Delhi is gratefully acknowledged. We
are also thankful to the Central Drug Research Institute (CDRI), Luc-
know, for the elemental and spectral analyses.
activate carbonyl group of formaldehyde to generate carbonium
ion, facilitating nucleophilic attack by aromatic amine resulting
in imine formation. After the imine formation, in situ generated
enolate attacks imine to afford b-amino carbonyl derivative A as
observed by earlier workers in metal triflate catalyzed Mannich
reaction.26a,26b Intermediate A reacts further in the same manner
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.79.
to form substituted propane-1,3-diamine
B involving double
Mannich reaction at the same position. Finally the
condensation of the resulting substituted propane-1,3-diamine
References and notes
B
with
formaldehyde
furnishes
the
desired
spiro-
hexahydropyrimidines.
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C
23H28N2O3: C, 72.60; H, 7.42; N, 7.36. Found: C, 72.46; H, 7.54; N, 7.45.
(4f) 2,4-bis(4-bromophenyl)-2,4-diazaspiro[5.5]undecan-7-one.25b White
Solid; (Yield: 66%); mp 154–156 °C; IR (KBr): 2936, 2858, 1700, 1592, 1490,
1236, 1222, 814 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.70–1.67 (m, 2H), 1.88–
;
1.78 (m, 4H), 2.37 (t, J = 6.8 Hz, 2H), 3.54 (l, 4H), 4.21 (d, J = 11.6 Hz, 1H), 4.74
(d, J = 11.6 Hz, 1H), 6.88 (d, J = 9.4 Hz, 4H), 7.36 (d, J = 9.2 Hz, 4H), 13C NMR
(75 MHz, CDCl3): 21.0, 27.8, 35.7, 39.6, 50.3, 55.2, 68.4, 113.5, 119.3, 132.8,
148.8, 212.7; MS (ESI) m/z: 478 [M]+. Anal. Calcd for C21H22Br2N2O: C, 52.74: H,
4.64; N, 5.86. Found: C, 52.89; 4.77; N, 5.99.
(4g)
Yellow Solid, (Yield: 71%); mp 106–108 °C; IR (KBr): 2928, 1702, 1522, 1450,
1216, 946, 818, 736 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.72–1.68 (m, 2H),
2,4-Bis(4-dimethylaminophenyl)-2,4-diazaspiro[5.5]undecan-7-one.25b
;
1.88–1.80 (m, 2H), 1.96–1.90 (m, 2H), 2.38 (t, J = 6.8 Hz, 2H), 2.88 (s, 12H),
3.38–3.32 (m, 4H), 3.98 (d, J = 10.8 Hz, 1H), 4.56 (d, J = 10.8 Hz, 1H), 6.73 (d,
J = 8.6 Hz, 4H), 7.03 (d, J = 8.6 Hz, 4H), 13C NMR (75 MHz, CDCl3): 21.7, 27.9,
35.7, 39.4, 41.8, 50.7, 56.4, 72.5, 114.8, 119.7, 141.9, 146.2, 213.5; MS (ESI) m/z:
406 [M]+. Anal. Calcd for C25H34N4O: C, 73.85; H, 8.43; N, 13.78. Found: C,
73.96; H, 8.51; N, 13.66.
(4h) 2,4-Bis-(4-chlorophenyl)-10-methyl-2,4-diazaspiro[5.5]undecan-7-one.
White Solid, (Yield: 73%); mp 166–168 °C; IR (KBr): 2960, 2928, 2860, 1704,
25. (a) Mukhopadhyay, C.; Rana, S.; Butcher, R. J. Tetrahedron Lett. 2011, 52, 4153;
(b) Wei, H.-L.; Yan, Z.-Y.; Niu, Y.-N.; Li, G.-Q.; Liang, Y.-M. J. Org. Chem. 2007, 72,
8600.
1618, 1502, 1462, 1240, 1126, 1014, 910, 814, 736 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d 0.85 (d, J = 6.3 Hz, 3H), 1.09 (t, J = 12.6 Hz, 1H), 2.04–1.98 (m, 3H),
2.35–2.28 (m, 2H), 2.51–2.49 (m, 1H), 3.14 (d, J = 12.9 Hz, 1H), 3.39 (d,
J = 12.6 Hz, 1H), 3.71 (d, J = 12.6 Hz, 1H), 3.84 (d, J = 12.9 Hz, 1H), 4.25 (d,
J = 11.4 Hz, 1H), 4.75 (d, J = 11.7 Hz, 1H), 7.06–6.98 (m, 4H), 7.27–7.23 (m, 4H),
13C NMR (75 MHz, CDCl3): 21.2, 27.4, 35.6, 38.6, 42.9, 49.4, 55.0, 56.1, 68.1,
118.0, 118.6, 125.0, 125.6, 129.1, 129.2, 148.3, 212.6; MS (ESI) m/z: 403 [M]+.
Anal. Calcd for C22H24Cl2N2O: C, 65.51; H, 6.00; N, 6.95. Found: C, 65.42; H,
6.07; N, 6.82.
26. (a) Guangliang, Z.; Zhihao, H.; Jianping, Z. Chin. J. Chem. 2009, 27, 1967; (b)
Ollevier, T.; Nadeau, E.; Guay-Begin, A.-A. Tetrahedron Lett. 2006, 47, 8351; (c)
Marigo, M.; Kjaersgaard, A.; Juhl, K.; Gathergood, N.; Jorgensen, K. A. Chem. Eur.
J. 2003, 9, 2359; (d) Lee, S.; Park, J. H. Bull. Korean Chem. Soc. 2002, 23, 1367.
27. (a) Dandia, A.; Laxkar, A. K.; Singh, R. Tetrahedron Lett. 2012, 53, 3012; (b)
Dandia, A.; Jain, A. K.; Bhati, D. S. Tetrahedron Lett. 2011, 52, 5333; (c) Dandia,
A.; Parewa, V.; Jain, A. K.; Rathore, K. S. Green Chem. 2011, 13, 2135; (d) Dandia,
A.; Singh, R.; Bhaskaran, S.; Samant, S. D. Green Chem. 2011, 13, 1852; (e)
Dandia, A.; Singh, R.; Bhaskaran, S. Ultrason. Sonochem. 2011, 18, 1113; (f)
Dandia, A.; Jain, A. K.; Bhati, D. S. Synth. Commun. 2011, 41, 2905.
28. (a) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67, 1414; (b) Kiyokawa,
K.; Yasuda, M.; Baba, A. Org. Lett. 2010, 12, 1520; (c) Tsuchimoto, T.;
Matsubayashi, H.; Kaneko, M.; Nagase, Y.; Miyamura, T.; Shirakawa, E. J. Am.
Chem. Soc. 2008, 130, 15823.
(4i) 10-Methyl-2,4-di-p-tolyl-2,4-diazaspiro[5.5]undecan-7-one.25b White
Solid, (Yield: 72%); mp 104–106 °C; IR (KBr): 2962, 2926, 1710, 1614, 1520,
1456, 1388, 1224, 1136, 918, 816, 732, 524 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
0.79 (d, J = 5.6 Hz, 3H), 1.03 (t, J = 12.8 Hz, 1H), 1.42–1.25 (m, 1H), 1.99–1.94
(m, 2H), 2.28–2.22 (l, 7H), 2.42–2.38 (m, 1H), 2.60–2.49 (m, 1H), 3.16 (d,
J = 12.6 Hz, 1H), 3.21 (d, J = 12.6 Hz, 1H), 3.56 (d, J = 12.6 Hz, 1H), 3.82 (d,
J = 12.6 Hz, 1H), 4.10 (d, J = 11.4 Hz, 1H), 4.78 (d, J = 11.4 Hz, 1H), 6.88–6.83 (m,
4H), 7.11 (d, J = 9.2 Hz, 4H), 13C NMR (75 MHz, CDCl3): 20.5, 21.0, 27.3, 35.4,
37.1, 43.1, 49.8, 55.0, 56.9, 70.3, 116.7, 117.6, 129.5, 130.3, 147.9, 212.8; MS
(ESI) m/z: 362 [M]+. Anal. Calcd for C24H30N2O: C, 79.52; H, 8.34; N, 7.73.
Found: C, 79.63; H, 8.26; N, 7.62.
29. Ho, T.-L. Chem. Rev. 1975, 75, 1.
30. General procedure for the synthesis of compounds 4(a–p)
To
a solution of cyclic ketones (1 mmol), aromatic amines (2 mmol),
formaldehyde (3.3 mmol, 36% aqueous solution), and a catalytic amount of
In(OTf)3 (10 mol %) in CH2Cl2 (5 mL) was stirred at room temperature for the
stipulated times. After completion of the reaction, as indicated by TLC, the
reaction mixture was diluted with cold water (5 mL) and extracted with EtOAc
(3 Â 10 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuum to give pure spiro-hexahydropyrimidine derivatives.
(4a) 2,4-Bis-(4-chlorophenyl)-2,4-diazaspiro[5.5]undecan-7-one. White Solid;
(Yield: 78%); mp 160–162 °C; IR (KBr): 2948, 2782, 1708, 1592, 1488, 1232,
(4j) 2,4-Bis-(3-chloro-4-fluorophenyl)-10-methyl-2,4-diazaspiro[5.5]undecan-
7-one. White Solid, (Yield: 61%); mp 236–238 °C; IR (KBr): 2960, 2928, 2860,
1704, 1618, 1502, 1462, 1240, 1126, 1014, 910, 814, 736 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 0.91 (d, J = 6.9 Hz, 3H), 1.03 (t, J = 12.6 Hz, 1H), 1.68–1.61
(m, 1H), 2.04–1.98 (m, 2H), 2.51–2.45 (m, 3H), 3.29 (d, J = 12.3 Hz, 2H), 3.54 (d,
J = 12.3 Hz, 1H), 3.83 (d, J = 12.3 Hz, 1H), 4.21 (d, J = 11.1 Hz, 1H), 4.73 (d,
J = 11.1 Hz, 1H), 6.81–6.74 (m, 2H), 6.91(s, 2H), 7.19 (d, J = 8.4 Hz, 2H), 13C NMR
(75 MHz, CDCl3): 21.9, 27.8, 36.2, 39.7, 42.9, 50.3, 55.1, 56.8, 67.4, 115.3, 118.8,
120.5, 124.1, 130.5, 136.7, 151.3, 212.6; MS (ESI) m/z: 439 [M]+. Anal. Calcd for
1216, 828 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.71–1.67 (m, 2H), 1.90–1.86 (m,
;
4H), 2.37 (t, J = 6.3 Hz, 2H), 3.51 (m, 4H), 4.22 (d, J = 11.4 Hz, 1H), 4.74 (d,
J = 11.4 Hz, 1H), 6.98 (d, J = 7.2 Hz, 4H), 7.24 (d, J = 10.2 Hz, 4H), 13C NMR
(75 MHz, CDCl3): 20.8, 27.6, 34.7, 39.1, 49.9, 55.2, 67.9, 118.2, 125.2, 129.1,
148.3, 212.5; MS (ESI) m/z: 389 [M]+. Anal. Calcd for C21H22Cl2N2O: C, 64.79; H,
5.70; N, 7.20. Found: C, 64.88; H, 5.77; N, 7.08.
C
22H22Cl2F2N2O: C, 60.15; H, 5.05; N, 6.38. Found: C, 60.03; H, 5.14; N, 6.27.
(4k) 2,4-Bis(4-chlorophenyl)-10-(1,1-dioxa-2,2-dimethylene)-2,4-diazaspiro
[5.5]undecan-7-one. White Solid, (Yield: 58%); mp 132–134 °C; IR (KBr):
2954, 1708, 1512, 1456, 1244, 1042, 918, 826, 726 cmÀ1 1H NMR (300 MHz,
;
(4b) 2,4-di-p-Tolyl-2,4-diazaspiro[5.5]undecan-7-one.25b White Solid; (Yield:
CDCl3): d 2.02 (t, J = 6.9 Hz, 2H), 2.11 (s, 2H), 2.58 (t, J = 6.9 Hz, 2H), 3.37 (d,
J = 12.6 Hz, 2H), 3.85–3.74 (m, 4H), 3.93–3.88 (m, 2H), 4.08 (d, J = 11.1 Hz, 1H),
4.84 (d, J = 11.4 Hz, 1H), 6.98 (d, J = 9.0 Hz, 4H), 7.23 (d, J = 9.0 Hz, 4H), 13C NMR
(75 MHz, CDCl3): 34.9, 36.3, 40.4, 48.7, 56.0, 64.4, 67.7, 106.9, 118.3, 125.2,
129.1, 148.4, 211.2; MS (ESI) m/z: 447 [M]+. Anal. Calcd for C23H24Cl2N2O3: C,
61.75; H, 5.41; N, 6.26. Found: C, 61.84; H, 5.47; N, 6.18.
74%); mp 124–126 °C; IR (KBr): 2932, 1708, 1546, 1460, 1234, 1210, 816 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.68–1.66 (m, 2H), 1.88–1.86 (m, 4H), 2.29 (s, 6H),
2.39 (t, J = 6.0 Hz, 2H), 3.40 (d, J = 12.3 Hz, 2H), 3.52 (d, J = 12.6 Hz, 2H), 4.10 (d,
J = 11.4 Hz, 1H), 4.79 (d, J = 11.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 4H), 7.10 (d,
J = 8.1 Hz, 4H), 13C NMR (75 MHz, CDCl3): 20.4, 20.8, 27.7, 29.6, 34.6, 39.1, 50.0,
55.4, 69.4, 117.4, 129.7, 147.8, 213.3; MS (ESI) m/z: 348 [M]+. Anal. Calcd for
C23H28N2O: C, 79.27; H, 8.10; N, 8.04. Found: C, 79.41; H, 8.21; N, 7.95.
(4l) 10-(1,1-Dioxa-2,2-dimethylene)-2,4-di-p-tolyl-2,4-diazaspiro[5.5]undec
an-7-one.25b White Solid, (Yield: 50%); mp 126–128 °C; IR (KBr): 2928, 1710,
(4c)
White Solid; (Yield: 72%); mp 248–250 °C; IR (KBr): 2948, 2782, 1708, 1592,
1488, 1232, 1216, 828 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.72–1.69 (m, 2H),
2,4-Bis-(3-chloro-4-fluorophenyl)-2,4-diazaspiro[5.5]undecan-7-one.
1522, 1108, 914, 734, 652 cmÀ1 1H NMR (300 MHz, CDCl3): d 2.02 (t, J = 7.6 Hz,
;
2H), 2.16 (s, 2H), 2.27 (s, 6H), 2.62 (t, J = 6.6 Hz, 2H), 3.24 (d, J = 12.8 Hz, 2H),
3.79–3.72 (l, 4H), 3.88–3.82 (m, 2H), 3.93 (d, J = 11.1 Hz, 1H), 4.92 (d,
J = 10.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 4H), 7.08 (d, J = 8.6 Hz, 4H), 13C NMR
(75 MHz, CDCl3): 20.7, 35.3, 36.4, 40.1, 49.6, 56.4, 64.3, 69.7, 107.2, 117.4,
;
1.99–1.81 (m, 4H), 2.46 (t, J = 6.9 Hz, 2H), 3.35 (d, J = 12.6 Hz, 2H), 3.59 (d,
J = 12.6 Hz, 2H), 4.28 (d, J = 11.4 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H), 6.87 (d,

5274
A. Dandia et al. / Tetrahedron Letters 53 (2012) 5270–5274
129.3, 149.7, 212.4; MS (ESI) m/z: 406 [M]+. Anal. Calcd for C25H30N2O3: C,
73.86; H, 7.44; N, 6.89. Found: C, 73.75; H, 7.54; N, 6.74.
ro[5.5] undecan-7-one.25b White Solid, (Yield: 68%); mp 118–120 °C; IR (KBr):
2954, 1702, 1518, 1454, 1248, 1112, 1042, 912, 834, 738 cmÀ1 1H NMR
;
(4m) 2,4-Bis(3-chloro-4-fluorophenyl)-10-(1,1-dioxa-2,2-dimethylene)-2,4-
diazaspiro[5.5]undecan-7-one. White Solid, (Yield: 54%); mp 206–208 °C; IR
(300 MHz, CDCl3): d 2.01 (t, J = 6.9 Hz, 2H), 2.21 (s, 2H), 2.58 (t, J = 7.2 Hz, 2H),
3.24 (d, J = 12.4 Hz, 2H), 3.63 (d, J = 12.8 Hz, 2H), 3.82–3.76 (l, 8H), 3.94–3.84 (l,
(KBr): 2954, 1708, 1512, 1456, 1244, 1042, 918, 826, 726 cmÀ1
;
1H NMR
3H), 4.72 (d, J = 11.4 Hz, 1H), 6.84 (d, J = 9.6 Hz, 4H), 7.02 (d, J = 9.6 Hz, 4H), 13
C
(300 MHz, CDCl3): d 2.09 (t, J = 7.5 Hz, 2H), 2.23 (s, 2H), 2.64 (t, J = 6.9 Hz, 2H),
3.38 (d, J = 12.3 Hz, 2H), 3.84–3.72 (m, 4H), 3.92–3.88 (m, 2H), 4.21 (d,
J = 11.7 Hz, 1H), 4.85 (d, J = 11.7 Hz, 1H), 6.91 (s, 2H), 6.99 (d, J = 9.0 Hz, 2H),
7.29 (d, J = 9.0 Hz, 2H), 13C NMR (75 MHz, CDCl3): 21.1, 34.8, 37.5, 40.3, 48.6,
56.3, 65.3, 68.8, 106.5, 115.3, 119.7, 124.5, 130.2, 137.2, 147.9, 213.4; MS (ESI)
m/z: 483 [M]+. Anal. Calcd for C23H22Cl2F2N2O3: C, 57.15; H, 4.59; N, 5.80.
Found: C, 57.26; H, 4.70; N, 5.63.
NMR (75 MHz, CDCl3): 35.7, 37.1, 40.8, 49.3, 55.8, 57.3, 64.7, 71.9, 109.1, 115.3,
119.8, 144.5, 154.9, 212.6; MS (ESI) m/z: 438 [M]+. Anal. Calcd for C25H30N2O5: C,
68.47; H, 6.90; N, 6.39. Found: C, 68.62; H, 6.73; N, 6.48.
(4p) 2,4-Bis(4-bromophenyl)-10-(1,1-dioxa-2,2-dimethylene)-2,4-diazaspiro
[5.5] undecan-7-one.25b White Solid, (Yield: 50%); mp 134–136 °C; IR (KBr):
1712, 1498, 1136, 1122, 914, 732, 642 cmÀ1 1H NMR (300 MHz, CDCl3): d 2.16–
;
2.11 (m, 4H), 2.61 (t, J = 7.6 Hz, 2H), 3.43 (d, J = 12.4 Hz, 2H), 3.80–3.72 (l, 4H),
3.96–3.82 (m, 2H), 4.11 (d, J = 11.8 Hz, 1H), 4.92 (d, J = 12.0 Hz, 1H), 6.84 (d,
J = 9.4 Hz, 4H), 7.28 (d, J = 8.6 Hz, 4H), 13C NMR (75 MHz, CDCl3): 35.7, 36.9, 40.4,
48.8, 56.2, 64.8, 66.9, 107.3, 111.6, 118.1, 132.8, 149.7, 212.1; MS (ESI) m/z: 536
[M]+. Anal. Calcd for C23H24Br2N2O3: C, 51.51; H, 4.51; N, 5.22. Found: C, 51.62;
H, 4.41; N, 5.15.
(4n) 2,4-Bis(3,4-dimethylphenyl)-10-(1,1-dioxa-2,2-dimethylene)-2,4-diaza
spiro[5.5] undecan-7-one.25b White Solid, (Yield: 63%); mp 120–122 °C; IR
(KBr): 3416, 2928, 1712, 1608, 1506, 1452, 1246, 1118, 1032, 918, 742 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d 2.07 (t, J = 7.6 Hz, 2H), 2.25–2.22 (l, 14H), 2.65 (t,
J = 7.6 Hz, 2H), 3.19 (d, J = 12.8 Hz, 2H), 3.86–3.78 (l, 4H), 3.92–3.84 (l, 3H), 4.91
(d, J = 10.8 Hz, 1H), 6.86–6.78 (m, 2H), 6.89 (s, 2H), 7.06 (d, J = 8.4 Hz, 2H), 13C
NMR (75 MHz, CDCl3): 19.1, 20.4, 35.5, 36.8, 40.3, 48.9, 56.4, 65.1, 68.9, 108.9,
115.7, 118.4, 128.5, 130.9, 137.3, 147.8, 211.2; MS (ESI) m/z: 434 [M]+. Anal.
Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C, 74.70; H, 7.71; N, 6.34.
(4o) 2,4-Bis(4-methoxyphenyl)-10-(1,1-dioxa-2,2-dimethylene)-2,4-diazaspi
31. The crystal structure (4a: CCDC 858922) has been deposited at the Cambridge
Crystallographic Data Center and is available on request from the Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (Fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk/deposit).