The chameleon-like behaviour of 3-amino-1,2,4-triazole in the Biginelli reaction: Unexpected formation of a novel spiroheterocyclic system

Article abstract of DOI:10.1016/j.tetlet.2010.12.051

A novel Biginelli-like assembly of 3-amino-1,2,4-triazole with methyl acetoacetate and salicylaldehyde has been developed to enable easy access to spiro{[1]benzopyran-2,7′-[1,2,4]triazolo[1,5-a]pyrimidine} compounds as representatives of a new class of sp

Full text of DOI:10.1016/j.tetlet.2010.12.051

Tetrahedron Letters 52 (2011) 1062–1066
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Tetrahedron Letters
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The chameleon-like behaviour of 3-amino-1,2,4-triazole in the Biginelli
reaction: unexpected formation of a novel spiroheterocyclic system
⇑
ˇ
Jan Svetlík , Viktor Kettmann
Department of Pharmaceutical Analysis and Nuclear Pharmacy, Comenius University, Odbojarov 10, SK-832 32 Bratislava, Slovak Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel Biginelli-like assembly of 3-amino-1,2,4-triazole with methyl acetoacetate and salicylaldehyde
has been developed to enable easy access to spiro{[1]benzopyran-2,70-[1,2,4]triazolo[1,5-a]pyrimidine}
compounds as representatives of a new class of spiro-fused heterocycles. A three-component condensa-
tion mechanism is proposed and discussed.
Received 4 October 2010
Revised 29 November 2010
Accepted 10 December 2010
Available online 21 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
Oxaspiro-heterocyclic system
Salicylaldehyde
3-Amino-1,2,4-triazole
There are only a few reports describing regioselectivity in the
Biginelli-like condensation between 3-amino-1,2,4-triazole (1),
aromatic aldehydes 2 and alkyl acetoacetates 3. Although 4,7-dihy-
dro-1,2,4-triazolo[1,5-a]pyrimidines 4 are the commonly accepted
products of this three-component process, the formation of a re-
lated but oppositely oriented fused heterocycle of type 5, formally
being the regioisomeric precursor of 4, has been demonstrated
independently by two research groups.1,2 Van der Eycken and co-
workers2 chose substituted salicylaldehydes and various active
methylene components for their study. They prepared triazolopyr-
imidine 5a under mild conditions (EtOH, HCl catalyst, 40 °C, 16 h);
however, when acetone was used for the heterocyclization, two
different products were formed, depending on the reaction condi-
tions. The expected bicyclic derivative 6 was formed under the
usual reaction conditions, while 5,11-methano[1,2,4]triazolo[1,5-
c][1,3,5]benzoxadiazocine (7) was formed under microwave irradi-
ation in EtOH, in the presence of HCl as the catalyst, at 150 °C for
30 min (Fig. 1).
tants in EtOH was heated at reflux for 20 h with a catalytic amount
of 35% aqueous HCl.6 Surprisingly, the mass spectrum of the
isolated product (m/z 390) was not consistent with the expected
derivative 5b (m/z 304). This was also corroborated by the
1H and 13C NMR spectra which indicated two salicylaldehyde mol-
ecules in the product. Accordingly, upon doubling the equivalents
of salicylaldehyde the yield of the new product 8 improved consid-
erably. Applying 2D NMR homo- (COSY, NOESY) and heteronuclear
correlation (HSQC, HMBC and the hybrid inverse experiment
HSQC-TOCSY) spectroscopy allowed us to determine the structure
of the product. Based on these spectra, we postulated two
reasonable structures, 8a and 80a (Scheme 1) where the former is
a spiroheterocyclic system and the latter an oxygen-bridged triaz-
olopyrimidine. These candidates were resolved by careful analysis
As we have reported aminoazoles in the Biginelli-like reaction,3
and since conformationally restricted oxygen-bridged pyridines
and pyrimidines also fall into our research area,4,5 the above arti-
cle2 attracted our attention. We present herein our interesting
and unexpected results which arose from a re-examination of the
above-mentioned three-component cyclization.
The Biginelli-like reaction of 3-aminotriazole (1), salicylalde-
hyde (2a) and methyl acetoacetate (3) was conducted under
slightly modified conditions. Thus, an equimolar mixture of reac-
⇑
Corresponding author.
E-mail address: svetlik@fpharm.uniba.sk (J. Svetlík).
Figure 1. Known products of the Biginelli-like reaction with 3-amino-1,2,4-
triazole.
ˇ
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.051

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Scheme 1. Biginelli-like condensation of salicylaldehydes with 3-amino-1,2,4-triazole.
of the HMBC measurements. Firstly, the 1H spin–spin connectivi-
ties in both aromatic rings were mapped by COSY and then the
location of the CH2CH unit was determined. In addition, the HMBC
data revealed that the NH functionality (dH 7.82) was attached to
the benzylic methine, indicating a reversed orientation. Finally,
having recognized the ‘benzylic’ phenylene fragment, other crucial
correlations, observed between the OH proton (dH 9.69) and three
aromatic carbons of the benzylic unit (i.e., CH ortho to C–O and
both quaternary 13C atoms), clearly established 8a as the reaction
product. Additional proof of the spiro compound was acquired
from NOESY experiments which revealed the close proximity of
the OH and adjacent ortho aromatic proton belonging to the above
phenylene moiety.
that the 2-hydroxyphenyl adopts an equatorial position on the
pyrimidine ring. Secondly, of the two methylene protons, the equa-
torial one resonating at lower field (dH 2.59) was identified easily
due to its planar ‘W’ coupling with NH.6
In order to confirm the structure of 8a and to determine its rela-
tive stereochemistry, a single-crystal X-ray analysis was under-
taken.7 A perspective view of the molecular conformation is
shown in Fig. 2a. As expected, the partially saturated pyrimidine ring
adopts a flat envelope conformationand the 2-hydroxyphenyl group
occupies the equatorial position and is almost coplanar with the
mean plane of the pyrimidine ring. The molecule as a whole consists
of two nearly planar segments oriented, due to the spiro fusion, per-
pendicular to one another. In the crystal, there are two independent
molecules differing in the conformation of the methoxycarbonyl
substituent bonded to the benzopyran heterocycle.
Moreover, two additional stereochemical features could be de-
duced from the 1H NMR spectrum. Firstly, the large vicinal cou-
pling (3J ꢀ 12 Hz) for the CH2CH segment indicates
a
trans-
It is noteworthy that 50,60-dihydro-40H-spiro{[1]benzopyran-
2,70-[1,2,4]triazolo[1,5-a]pyrimidine}-3-carboxylate (8a) repre-
coplanar relationship between the interacting protons implying
Figure 2. ORTEP views of (a) spiro derivative 8a (left), and (b) pyrimidine 4a (right).

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In the search for a by-product or isomer of 8a, we analysed thor-
oughly the 1H and 13C NMR spectra of the crude reaction product.
While the major fraction of the product precipitated in a pure form,
the second crop showed additional low intensity signals which
were most likely due to the diastereoisomer, 8aA. Since both iso-
mers were produced in a 91:9 ratio, this three-component domino
reaction evidently proceeds in a highly diastereoselective manner.
Attempts to induce isomerization or ring-opening on standing the
product 8a in dimethylsulfoxide for five days (monitored by NMR)
failed.
2-Hydroxybenzaldehydes 2b–d reacted similarly to give the
corresponding spiro-fused heterocycles 8b–d. We did not observe
the appearance of any additional diastereoisomer in these cases.
In particular, cyclization of 3-methoxysalicylaldehyde (2b) pro-
ceeded very cleanly. In addition to spiro derivatives 8c and 8d,
minor by-products identified by 1H NMR as 6-substituted 3-acety-
lcoumarins 9c and 9d were also obtained (Scheme 1). These benz-
Figure 3. Isolated by-product 10.
sents a novel polyheterocyclic monospiro system not previously
described in the literature.
The results of this work provide the first example of the Biginelli
reaction with salicylaldehyde where the aldehyde component
forms the oxaspiro framework instead of an oxygen-bridged het-
erocycle,4,5 or a fused benzopyranone skeleton.3 In addition, the
involvement of the terminal acetoacetate methyl group was also
unexpected.
Scheme 2. Synthesis of triazolopyrimidine derivatives 4a and 11.
Scheme 3. Plausible spirocyclization mechanisms leading to 8a.

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J. Svetlík, V. Kettmann / Tetrahedron Letters 52 (2011) 1062–1066
1065
proposed to rationalize the stereochemical outcome (Fig. 4). In this
case, the s-cis conformation of the diene unit should ensure a ste-
rically favourable arrangement for attack by the phenolic oxygen,
unlike the s-trans form in which the corresponding benzene nu-
cleus and the triazole ring would come closer and generate a desta-
bilizing contact.
Finally, our findings demonstrate, in accordance with the
above-mentioned article,2 that in the case of salicylaldehydes,
the ortho-phenolic hydroxy directs the three-component conden-
sation towards the ‘reversed’ triazolopyrimidine Biginelli products.
By contrast, the reaction employing a substituted benzaldehyde
which lacked this functionality follows a pathway leading to the
‘normal’ isomer. However, Yang and co-workers reported1 that
various benzaldehydes and b-ketoesters often gave rise to a mix-
ture of both regioisomers in an analogous Biginelli cyclization cat-
alysed by p-TsOH in aqueous solution. In this respect 4-
aminotriazole (1) behaves as a chemical chameleon in the Biginelli
reaction in the sense that its reactivity depends upon the reactants
and conditions used.
In conclusion, the acid-catalysed, three-component condensa-
tion of 3-amino-1,2,4-triazole and methyl acetoacetate with vari-
ous substituted salicylaldehydes represents a synthetically useful
route to a new class of spiroheterocycles. The regio- and stereose-
lective cyclization described herein leads to the spiro{[1]benzopy-
ran-2,70-[1,2,4]triazolo[1,5-a]pyrimidine} system and represents
an attractive supplement to the classical Biginelli reaction in terms
of constructing a structurally novel type of product. Further appli-
cation of the reported methodology is currently being investigated.
Figure 4. Transition state conformation leading to product 8a.
opyran-2-ones, formed by condensation of the salicylaldehydes
and acetoacetate, crystallized prior to the spiro compounds and
hence the target heterocycles 8c and 8d could be readily separated.
In contrast, 5-nitrosalicylaldehyde 2e afforded only the corre-
sponding coumarin 9e along with the azomethine derivative 10
(Fig. 3) which arose from simple condensation of 2e with aminotri-
azole 1.
The spiro-pyrimidines 8a–d, obtained from electron-rich sali-
cylaldehydes, were isolated by precipitation as stable crystalline
compounds in yields ranging from 48% to 64%. From these results,
we conclude that the electronic nature of the substituents on the
salicylaldehydes has a significant effect on the reaction outcome.
Next, the three-component cyclization was repeated using the
related benzaldehyde 2f, in order to assess the effect of the alde-
hyde component on the product distribution. Thus, treatment of
4-methoxybenzaldehyde (2f) with triazole 1 and methyl acetoace-
tate (3) provided, under identical conditions, the ‘normal’ Biginelli
triazolo[1,5-a]pyrimidine (4a) accompanied by traces of isomer 11
(8:1 ratio as determined by 1H NMR spectroscopy) (Scheme 2).
Although the spectral data8 offered ample proof of the structure
of 4a, its identity was verified by X-ray diffraction7 (Fig. 2b). The
differences in chemical shift values found for the benzylic proton
Acknowledgements
The NMR experimental part of this work was facilitated by sup-
port of the Slovak National Research and Development Program
No. 2003SP200280203 and VEGA 1/0320/11.
References and notes
1. Chen, Q.; Jiang, L. L.; Chen, C. N.; Yang, G. F. J. Heterocycl. Chem. 2009, 46, 139.
2. Gorobets, N. Yu.; Sedash, Yu. V.; Ostras, K. S.; Zaremba, O. V.; Shishkina, S. V.;
Baumer, V. N.; Shishkin, O. V.; Kovalenko, S. M.; Desenko, S. M.; Van der Eycken,
E. V. Tetrahedron Lett. 2010, 51, 2095.
in 4a and the isomers of type 5, 7 and 8 (
ough to distinguish between them.
D
d ꢀ 1 ppm) are high en-
A plausible mechanism for the formation of spiro derivatives 8
is shown in Scheme 3. Thus, the initially produced precursors,
aldimine A and Knoevenagel adduct B, combine in a condensation
step to yield iminium species C. Intermediate C may exist in equi-
librium with key enamine D which subsequently undergoes a cat-
ionic domino process.9 The postulated ring closure involves
intramolecular C–O and C–C bond formation. Consequently, the
crucial spirocyclization occurs via a geometrically favoured 6-
exo-trig/6-endo-trig sequence, while the final step providing the
product 8 can be formally classified as a Mannich-type reaction.
Nevertheless, due to the acidic conditions, it is quite possible that
another iminium ion, arising from protonation of the azomethine
or triazole nitrogen in structure D, may participate in the domino
reaction. This could parallel the known mechanism of the Biginelli
reaction.10 Another possible mechanistic pathway from enamine D
to product 8 can be envisioned which involves the formation of a
pyrimidine scaffold bearing a conjugated 1-oxatriene moiety (E)
3. Svetlik, J.; Veizerova, L.; Mayer, T. U.; Catarinella, M. Bioorg. Med. Chem. Lett.
2010, 20, 4073.
4. Svetlik, J.; Veizerova, L.; Kettmann, V. Tetrahedron Lett. 2008, 49, 3520.
5. Svetlik, J.; Veizerova, L. Helv. Chim. Acta 2011, 94. doi:10.1002/hlca.201000193.
6. Typical procedure. To a solution of 3-amino-1,2,4-triazole (1) (0.35 g, 4.0 mmol)
in EtOH (20 mL) were added aldehyde 2 (8.0 mmol) and methyl acetoacetate
(3) (0.44 mL, 4.0 mmol). The mixture containing four drops of concd HCl was
refluxed for 20 h. After cooling, the solution was left to crystallize. The crude
product was recrystallized: 8a from MeCN, and 8b–d from MeOH. In the case
of aldehyde 2d, pure coumarin 9d precipitated first whereas aldehyde 2c
afforded a mixture of 9c and 8c in the first crop. Methyl 50-(2-hydroxyphenyl)-
50,60-dihydro-40H-spiro{[1]benzopyran-2,70-[1,2,4]triazolo[1,5-a]pyrimidine}-3-
carboxylate (8a): mp 238–239 °C, isolated yield 51%; IR (KBr) mmax 3422, 1715,
1635, 1539, 1458, 1294, 1264, 1217, 1121, 1038, 754 cmꢁ1 1H NMR (DMSO-d6,
;
600 MHz) d 2.53 (dd, 1H, J = 12.2 and 12.0 Hz, H-60ax), 2.59 (dd, 1H, J = 12.2
and 1.2 Hz, H-60eq), 3.63 (s, 3H, OMe), 5.23 (dd, 1H, J = 12.0 and 3.0 Hz, H-50),
6.82 (dd, 1H, J = 8.4 and 1.2 Hz, H-300), 6.86 (dt, 1H, J = 7.8 and 1.2 Hz, H-500),
6.97 (d, 1H, J = 7.8 Hz, H-8), 7.05 (dt, 1H, J = 7.8 and 1.2 Hz, H-6), 7.12 (dt, 1H,
J = 7.8 and 1.2 Hz, H-400), 7.38 (dt, 1H, J = 7.8 and 1.2 Hz, H-7), 7.42 (dd, 1H,
J = 7.8 and 1.8 Hz, H-600), 7.43 (s, 1H, H-20), 7.50 (dd, 1H, J = 7.8 and 1.8 Hz, H-5),
7.82 (s, 1H, NH), 7.86 (s, 1H, H-4), 9.69 (s, 1H, OH); 13C NMR (DMSO-d6,
00
´
150 MHz) d 38.5 (CH2), 44.4 (CH), 51.9 (OMe), 85.6 (C-2 spiro), 115.1 (CH-3 ),
115.9 (CH-8), 118.3 (C-4a), 119.3 (CH-500), 122.3 (C-3), 122.4 (CH-6), 126.6 (C-
100), 126.7 (CH-600), 128.4 (CH-400), 129.4 (CH-5), 132.9 (CH-7), 136.2 (CH-4),
149.7 (CH-20), 151.5 (C-8a), 154.3 (C-200), 154.6 (C-30a), 163.5 (COO); EI MS (m/
z, %) 390 (M+, 22), 331 (10), 307 (18), 247 (28), 203 (17), 202 (100), 201 (16),
189 (18), 188 (20), 171 (48), 145 (24), 144 (81), 115 (40), 91 (23), 77 (52), 65
(20). Anal. Calcd for C21H18N4O4 (390.39): C, 64.61; H, 4.65; N, 14.35%. Found:
C, 64.38; H, 4.30; N, 14.51%. Product 8b: mp 221–223 °C, yield 64%; 1H NMR
(DMSO-d6, 300 MHz) d 2.53 (d, 2H, J = 7.8 Hz, H-60), 3.63 (s, 3H, ester-OMe),
3.78 (s, 3H, OMe), 3.80 (s, 3H, OMe), 5.30 (t, 1H, J = 7.8 Hz, H-50), 6.81–7.13 (m,
6H, Harom), 7.42 (s, 1H, H-20), 7.81 (s, 1H, NH), 7.84 (s, 1H, H-4), 8.83 (s, 1H,
OH); 13C NMR (DMSO-d6, 75 MHz) d 38.4 (CH2), 44.4 (CH), 51.9 (ester-OMe),
55.9 (OMe), 56.2 (OMe), 85.5 (C-2 spiro), 110.9 (CHarom), 116.6 (CHarom), 118.4
which then undergoes stereoselective spiroannelation via a 6p dis-
rotatory electrocyclic ring closure, furnishing the target benzopy-
ran skeleton. We are currently pursuing further experimental
work to elucidate the detailed reaction mechanism.
As reported by Royer,11 formation of six-membered rings via
iminium ion cyclization usually occurs through highly-ordered
transition states and thereby delivers substituted heterocycles in
a stereocontrolled manner. Accordingly, the above-mentioned
domino process may allow effective stereocontrol. A tentative
model incorporating a sofa–sofa transition state structure has been

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J. Svetlík, V. Kettmann / Tetrahedron Letters 52 (2011) 1062–1066
1066
(CHarom), 118.9 (Carom), 119.1 (CHarom), 121.1 (CHarom), 122.0 (CHarom), 122.2
(C-3), 127.0 (Carom), 136.4 (CH-4), 140.7 (Carom), 143.4 (Carom), 147.3 (Carom),
147.4 (Carom), 149.7 (CH-20), 154.4 (C-30a), 163.5 (COO). Anal. Calcd for
crude product): Yuan, H. J.; Wang, M.; Liu Y. J.; Liu, Q. Adv. Synth. Catal. 2009,
351, 112; compound 9d: mp 217–219 °C (EtOH), yield 10%; mp 217 °C: Linch,
F. W. J. Chem. Soc., Trans. 1912, 101, 1758; compound 9e: mp 195–197 °C
(EtOH), yield 10%; mp 194–195 °C: Wahlberg, E. Chem. Ber. 1932, 65, 1857.
7. Crystallographic data (excluding structures factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 795123 for 8a and 795122 for 4a. Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk.
C23H22N4O6 (450.45): C, 61.33; H, 4.92; N, 12.44%. Found: C, 61.58; H, 5.09; N,
12.51%. Compound 8c: mp 231–232 °C, yield 48%; 1H NMR (DMSO-d6) d 2.43
(t, 1H, J = 12.0 Hz, H-60ax), 2.60 (br d, 1H, J = 12.0 Hz, H-60eq), 3.62 (s, 3H, ester-
OMe), 3.70 (s, 3H, OMe), 3.73 (s, 3H, OMe), 5.16 (dd, 1H, J = 12.0 and 2.7 Hz, H-
50), 6.69–6.76 (m, 2H, Harom), 6.89–6.98 (m, 3H, Harom), 7.13 (d, 1H, J = 2.7 Hz,
Harom), 7.42 (s, 1H, H-20), 7.82 (s, 1H, H-4), 7.83 (s, 1H, NH), 9.21 (s, 1H, OH);
13C NMR (DMSO-d6) d 37.9 (CH2), 44.7 (CH), 51.9 (ester-OMe), 55.4 (OMe), 55.6
(OMe), 85.6 (C-2 spiro), 112.0 (CHarom), 113.3 (CHarom), 113.4 (CHarom), 115.7
(CHarom), 116.8 (CHarom), 118.7 (CHarom), 119.0 (Carom), 123.1 (C-3), 127.4
(Carom), 136.2 (CH-4), 145.4 (Carom), 147.9 (Carom), 149.6 (CH-20), 152.3 (Carom),
154.2 (Carom), 154.5 (C-30a), 163.5 (COO). Anal. Calcd for C23H22N4O6 (450.45):
C, 61.33; H, 4.92; N, 12.44%. Found: C, 61.08; H, 4.81; N, 12.61%. Compound 8d:
mp 239–241 °C, yield 51%; 1H NMR (DMSO-d6) d 2.49 (t, 1H, J = 12.0 Hz, H-
60ax), 2.61 (d, 1H, J = 12.0 Hz, H-60eq), 3.63 (s, 3H, ester-OMe), 5.14 (dd, 1H,
J = 12.0 and 2.7 Hz, H-50), 6.79 (d, 1H, J = 8.7 Hz, Harom), 6.96 (d, 1H, J = 8.7 Hz,
8. Methyl 7-(4-methoxyphenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimi-
dine-6-carboxylate (4a): mp 234–236 °C (MeOH), yield 46%; IR (KBr) mmax
3440, 1700, 1591, 1535, 1256, 1192 cmꢁ1 1H NMR (DMSO-d6) d 2.41 (s, 3H,
;
Me), 3.51 (s, 3H, ester-OMe), 3.70 (s, 3H, OMe), 6.22 (s, 1H, H-7), 6.85 (d, 2H,
J = 8.7 Hz, H-30 and H-50), 7.13 (d, 2H, J = 8.7 Hz, H-20 and H-60), 7.64 (s, 1H, H-
2), 10.79 (s, 1H, NH); 13C NMR (DMSO-d6) d 18.5 (Me), 50.9 (ester-OMe), 55.0
(OMe), 58.8 (CH-7), 97.3 (C-6), 113.7 (CH-30 and CH-50), 128.1 (CH-20 and CH-
60), 134.2 (C-10), 146.6 (C-5), 147.0 (C-3a), 150.0 (CH-2), 158.9 (C-40), 165.7
(COO). Anal. Calcd for C15H16N4O3 (300.32): C, 59.99; H, 5.37; N, 18.66%. Found:
C, 60.22; H, 5.11; N, 18.43%. Isomer 11a: 1H NMR (DMSO-d6) d 2.42 (s, 3H, Me),
3.50 (s, 3H, ester-OMe), 3.71 (s, 3H, OMe), 6.31 (s, 1H, H-5), 6.87 (d, 2H,
J = 8.7 Hz, H-30 and H-50), 7.20 (d, 2H, J = 8.7 Hz, H-20 and H-60), 8.15 (s, 1H, H-
3), 10.78 (s, 1H, NH).
H
arom), 7.29 (dd, 1H, J = 8.7 and 2.4 Hz, Harom), 7.45 (s, 1H, H-20), 7.50–7.54 (m,
2H, Harom), 7.77 (d, 1H, J = 2.4 Hz, Harom), 7.86 (s, 1H, H-4), 7.94 (s, 1H, NH),
10.10 (s, 1H, OH); 13C NMR (DMSO-d6) d 38.0 (CH2), 44.4 (CH), 52.1 (ester-
OMe), 85.6 (C-2 spiro), 110.3 (Carom), 113.6 (Carom), 117.3 (CHarom), 118.3
(CHarom), 120.5 (Carom), 123.4 (C-3), 129.0 (Carom), 129.1 (CHarom), 131.0
(CHarom), 131.3 (CHarom), 134.9 (CHarom), 135.0 (CH-4), 149.9 (CH-20), 150.6
(Carom), 153.7 (Carom), 154.4 (C-30a), 163.2 (COO). Anal. Calcd for C21H16
Br2N4O4 (548.19): C, 46.01; H, 2.94; N, 10.22%. Found: C, 45.88; H, 3.09; N,
10.41%. Compound 9c: Yield 5% (determined from the 1H NMR spectrum of the
9. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic, Synthesis;
Wiley-VCH: Weinheim, 2006. p. 11.
10. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
11. Royer, J.; Bonin, M.; Micoin, L. Chem. Rev. 2004, 104, 2311.