Synthesis of carbamoylpyridine and imidazo[1,5-a]pyridin-1,3-diones via ortho-acetalhydantoin intermediates

Article abstract of DOI:10.1016/j.tetlet.2003.10.200

A new method for preparing carbamoylpyridine and imidazo[1,5-a]pyridin-1,3- dione rings from an ortho-acetalmethylideneimidazolidin-2,4-dione is described.

Full text of DOI:10.1016/j.tetlet.2003.10.200

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 553–556
Synthesis of carbamoylpyridine and imidazo[1,5-a]pyridin-1,3-
diones via ortho-acetalhydantoin intermediates
Jean M. Chezal,a Emmanuel Moreau,a Nicolas Desbois,a Yves Blache,b Olivier Chavignona
and Jean C. Teuladea,*
aFaculteꢀ de Pharmacie UMR-INSERM 484, 28 place Henri-Dunant, BP 38, 63001 Clermont-Ferrand Cedex 1, France
bLaboratoire de Chimie Organique, Faculteꢀ de Pharmacie, 7 boulevard Jeanne d’-Arc, 21079 Dijon Cedex, France
Received 4 September 2003; revised 22 October 2003; accepted 31 October 2003
Abstract—A new method for preparing carbamoylpyridine and imidazo[1,5-a]pyridin-1,3-dione rings from an ortho-acetalmethyl-
ideneimidazolidin-2,4-dione is described.
ꢀ 2003 Published by Elsevier Ltd.
1. Results and discussion
O
O
H3CO
+
Several 5-substituted hydantoins display a wide range
of biological properties,1 and have proved to be use-
ful precursors of a-amino acids after alkaline hydro-
lytic degradation2 or enzymatic reactions.3 Different
approaches have been used for the construction of pyri-
dine (or diazepine) moieties. 5-Substituted hydantoins
have been found to be valuable precursors of a great
variety of heterocyclic systems: 5-methoxy-3-phenyl-
hydantoin reacts with various conjugated dienes to give
Diels–Alder-type adducts 14 (Scheme 1, Eq. 1).
N-Ph
N-Ph
Eq (1)
Eq (2)
Eq (3)
Eq (4)
HN
N
O
O
1
R1
N
NO2
R4
R3
N
R4
R3
O
O
R1
O
N
R2
N
N
R2
2
O
N
O
NH
O
NH
HN
More recently 5-(2-nitrophenylmethylidene)imidazoli-
din-2,4-dione derivatives have been synthesized as key
intermediates for access to imidazo[4,5-b]quinolin-
2-ones 2 after reduction by 10% Pd/C followed by acid-
catalyzed ring closure (Eq. 2).5 This reactivity was
extended by Molina6 with 5-(2-(triphenylphosphoranyl-
idene)phenyl)methylidenehydantoin to afford imidazo[1,5-
c][1,3]benzodiazepines 3 via an aza-Wittig/carbodiimide
mediated annulation process (Eq. 3). Alternatively,
by-product 4 has been observed when a trimethylsilyl-
nucleoside is condensed with 5-(naphthylmethyl-
idene)imidazolidin-2,4-dione7 (Eq. 4).
O
O
N
N
NHR
PPh3
3
O
NH
NH
HN
N
OH
OR
O
O
RO
4
Scheme 1.
Further to our previous work on the heterocyclization
of aromatic rings8 we report a new protocol for the
synthesis of imidazo[1,5-a]pyridine moieties based on
the nucleophilic attack of the more basic9 N-1 hydantoin
ring on an ortho-carbaldehyde function (Scheme 2).
Keywords: Hydantoin; Imidazolidin-2,4-dione; Imidazo[1,5-a]pyridin-
1,3-dione; Carbamoylpyridine.
* Corresponding author. Tel.: +33-4-73-17-80-00; fax: +33-4-73-17-80-
12; e-mail: j-claude.teulade@u-clermont1.fr
0040-4039/$ - see front matter ꢀ 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.10.200

554
J. M. Chezal et al. / Tetrahedron Letters 45 (2004) 553–556
Acetal aldehydes 8b–f were easily prepared by lithiation
OH
O
of bromoacetals 7b–f13;18 with n-BuLi at )70 ꢁC and
subsequent treatment with DMF19 (Table 1, entries 1–
5). Addition of aromatic aldehydes 8b–f to a slight
excess of diethyl 2,4-dioxoimidazolidine-5-phosphonate20
and sodium ethoxide in ethanol at room temperature
gave a mixture of (E)- and (Z)-5-arylidenehydantoins
9b–f.21
CHO
O
N
Ar
H
N
Ar
NH
O
O
NH
6
5
Scheme 2.
First we examined the reactivity of an imidazo[1,2-a]-
pyridine series. The most convenient route to
5-(2-formylimidazo[1,2-a]pyridin-3-yl)methylideneimi-
dazolidin-2,4-dione 6a appeared to involve a Horner–
Wadsworth–Emmons type olefin-forming reaction
between diethyl 2,4-dioxoimidazolidine-5-phosphonate
and 8a followed by acidic deprotection (Scheme 3). The
required compound 8a was prepared from 3-bromo-2-
diethoxymethylimidazo[1,2-a]pyridine 7a by a reported
procedure.10
Under the hydrolysis conditions used previously for 9a,
the pyridine hydantoins gave the stable imidazo[1,5-
a]pyridinic compounds 5b,c in 45% and 87% yields,
respectively (Table 1, entries 1, 2). This direct depro-
tection/cyclization reaction agrees with the mechanism
proposed in Scheme 4. The use of phenyl, naphthalene,
or indole units afforded amides 10b–d in excellent yields
(Table 1, entries 3–5). Similar observations have been
reported for related structures.22 Compounds 5b,c and
10b–d were characterized by 1H, 13C and mass spec-
troscopy.12
Compound 9a was obtained from 8a using MeanwellÕs
procedure11 in 45% yield. Our attempts to hydrolyze the
ketal moiety using catalytic concentrated HCl in
CH3CN/H2O (3/1, v/v)12 gave the unexpected amide 10a
in 80% yield and not the predicted aldehyde 6a, as
shown in Scheme 3. This surprising pyridinization
reaction can be explained by deprotection of 9a, fol-
lowed by intramolecular cyclization to give the imi-
dazo[1,5-a]pyridine intermediate 5a. Once intermediate
5a is formed, it can be converted into 10a after dehy-
dration, hydrolysis and finaly decarboxylation. The
mechanistic details are set out in Scheme 4.
In order to obtain imidazo[1,5-a]pyridin-1,3-dione 5d
from acetal 9d, milder conditions (catalytic AcOH) were
investigated. However no reaction took place at room
temperature and only formation of 10b was observed at
50 ꢁC. Therefore, our attention was focused on conver-
sion of imidazonaphthyridines 5b,c to the corresponding
amides. Attempts to hydrolyze 5b,c under more acidic
conditions CH3CN/HCl concd (3/1, v/v) at room tem-
perature or reflux gave only starting materials. Pre-
sumably, the presence of a second pyridine moiety
increases the stability of hydroxyimidazonaphthyridines
5b,c.
To explore the potential applications of this method, we
set out to generalize the protocol. A wide variety of
aromatic rings possessing acetal and bromo groups in
the ortho position were chosen as starting materials. The
reactions and results are summarized in Table 1.
In conclusion, this procedure offers a new, simple, and
attractive method for the synthesis of carbamoylpyri-
dine or imidazo[1,5-a]pyridin-2,4-dione cores in a one-
pot synthesis from ortho-acetalmethylidenehydantoins.
N
CHO
H
N
N
O
X
iii
6a
N
CH(OEt)2
N
CH(OEt)2
R
NH
ii
H
N
O
N
N
N
N
O
9a (45%)
7a R = Br
NH
N
i
CONH2
O
10a (80%)
8a R = CHO (68%)
Scheme 3. Reagents and conditions: (i) 1/n-BuLi, THF, )60 ꢁC, 2/DMF, rt; (ii) diethyl 2,4-dioxo imidazolidin-5-phosphonate, EtONa; (iii) CH3CN/
H2O (3/1, v/v), concd HCl (three drops).
OH
Cl-
N+
O
O
-H2O
H2O
N
H2O
-CO2
HCl
N
IP
NHCO2H
10a
IP
NH
9a
IP
NH
-H2O
O
O
O
5a
IP = imidazo[1,2-a]pyridine
Scheme 4.

J. M. Chezal et al. / Tetrahedron Letters 45 (2004) 553–556
555
Table 1. Cyclization of arylidenehydantoinsa
OH
O
N
Ar
NH
CH(OEt)2
CH(OEt)2
Ar
iii
ii
5
O
Ar
H
N
O
R
N
Ar
NH
7 R = Br
9
i
CONH2
O
8 R = CHO
10
Entry
Starting material
Yield (%)
Acetaldehydeb
Hydantoin
Product
CH(OEt)2
1
8b14 (42)
9b (46)
5b (45)
N
Br
7b13
CH(OEt)2
2
3
4
8c15 (68)
8d16 (68)
8e (51)
9c (65)
9d (67)
9e (74)
5c (87)
N
Br
7c13
CH(OEt)2
Br
10b17 (81)
7d
CH(OEt)2
Br
10c (83)
7e18
5
8f (54)
9f (15)
10d (43)
7f13
Reagents and conditions: (i) 1/n-BuLi, THF, )70 ꢁC, 2/DMF, rt; (ii) diethyl 2,4-dioxo imidazolidin 5-phosphonate, EtONa; (iii) CH3CN/H2O (3/1,
v/v), concd HCl (three drops).
a All products were characterized by IR, NMR and mass spectroscopy.
b Isolated yields after column chromatography.
5. (a) Meanwell, N. A.; Pearce, B. C.; Roth, H. R.; Smith, E.
C. R.; Wedding, D. L.; Wright, J. J. K.; Buchanan, J. O.;
Baryla, U. M.; Gamberdella, M.; Gillespie, E.; Hayes, D.
C.; Seiler, S. M.; Stanton, H. C.; Zavoico, G. B.; Fleming,
J. S. J. Med. Chem. 1992, 35, 2672–2687; (b) Zhu, Z.;
Lippa, B. S.; Townsend, L. B. Tetrahedron Lett. 1996, 37,
1937–1940.
References and Notes
1. (a) Bharucha, K. R.; Pavilinis, V.; Ajdukovic, D.; Schrenk,
H. M. Ger. Offen. 2329745, 1974; (b) Wessels, F. L.;
Schwan, T. J.; Pong, S. F. J. Pharm. Sci. 1980, 69, 1102–
1104; (c) Mehta, N. B.; Risinger Diuguid, C. A.; Soroko,
F. E. J. Med. Chem. 1981, 24, 465–468.
6. Molina, P.; Tarraga, A.; Curiel, D.; de Arellano, C. R.
Tetrahedron 1997, 53, 15895–15902.
7. El-Barbary, A. A.; Khodair, A. I.; Pedersen, E. B. J. Org.
Chem. 1993, 58, 5994–5999.
8. (a) Chezal, J. M.; Moreau, E.; Delmas, G.; Gueiffier, A.;
Blache, Y.; Grassy, G.; Lartigue, C.; Chavignon, O.;
Teulade, J. C. J. Org. Chem. 2001, 66, 6576–6584; (b)
Dupuy, M.; Pinguet, F.; Chavignon, O.; Chezal, J. M.;
Teulade, J. C.; Chapat, J. P.; Blache, Y. Chem. Pharm. Bull.
2001, 49, 1061–1065; (c) Moreau, E.; Chezal, J. M.;
2. (a) Johnson, T. B.; Bengis, R. J. Am. Chem. Soc. 1913, 35,
1606–1617; (b) White, H. C. U.S. Patent 2,557,920, 1951;
(c) White, H. C. U.S. Patent 2,642,459, 1953.
3. (a) Takahashi, S.; Ohashi, T.; Kii, Y.; Kumagai, H.;
Yamada, H. J. Ferment. Technol. 1979, 57, 328–332; (b)
Hamilton, G. S.; Huang, X. J.; Patch, R. J.; Narayanan,
B. A.; Ferkany, J. W. J. Org. Chem. 1993, 58, 7263–
7270.
4. Goldstein, E.; Ben-Ishai, D. Tetrahedron Lett. 1969, 10,
2631–2634.

556
J. M. Chezal et al. / Tetrahedron Letters 45 (2004) 553–556
Dechambre, C.; Canitrot, D.; Blache, Y.; Lartigue, C.;
Chavignon, O.; Teulade, J. C. Heterocycles 2002, 57, 21–38.
128.6, 130.9, 137.7, 140.1, 141.8, 166.9; MS m=z 225 (Mþ,
100), 182 (95), 181 (85), 127 (18).
9. Tan, S. F.; Ang, K. P.; Fong, Y. F.; Jayachandran, H.
J. Chem. Soc., Perkin Trans. 2 1988, 472–476.
10. Chezal, J. M.; Moreau, E.; Chavignon, O.; Lartigue, C.;
Blache, Y.; Teulade, J. C. Tetrahedron 2003, 59, 5869–
5878.
13. These compounds were obtained by heating the corre-
sponding bromoaldehyde14 for 15 h in anhydrous ethanol
in the presence of ethyl orthoformate (1.1 equiv) and
catalytic ammonium chloride. After evaporation to dry-
ness, the crude product was chromatographed over Al2O3
using CH2Cl2 as eluent.
14. (a) Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis 1999,
2, 306–311; (b) Liu, Y.; Gribble, G. W. Tetrahedron Lett.
2002, 43, 7135–7137.
15. Queguiner, G.; Fugier, C.; Pastour, P. C. R. Hebd. Seances
Acad. Sc. Ser. C 1970, 270, 551–554.
16. Semeraro, C.; Micheli, D.; Pieraccioli, D.; Gaviraghi, G.;
Borthwick, A. D. U.S. Patent 4,801,599, 1989.
11. Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding,
D. L.; Wright, J. J. K. J. Org. Chem. 1991, 56, 6897–6904.
12. Typical procedure for hydrolysis: To a solution of 9
(2.91 mmol) in 40 mL of CH3CN/H2O (3/1, v/v) was added
a small quantity of concentrated HCl (three drops). The
solution was stirred at room temperature. For compounds
9a,d–f the solution was made basic with Na2CO3 (1.00 g,
9.43 mmol) and extracted with CH2Cl2 (3 · 20 mL). The
extract was dried (Na2SO4) and evaporated to give a
yellow precipitate. The product was washed with ether
(5 mL) to give 10a–d. For compounds 9b,c the precipitate
was collected by filtration and dried under vacuum to
afford 5b,c.
17. Langry, K. C. Org. Prep. Proced. Int. 1994, 26, 429–438.
18. Clayden, J.; McCarthy, C.; Westlund, N.; Frampton, C. S.
J. Chem. Soc., Perkin Trans. 1 2000, 1363–1378.
19. Typical procedure for the preparation of aldehydes 8b–f:
n-BuLi (4.26 mL of an 1.6 M hexane solution, 6.81 mmol)
was added dropwise, under argon, to a stirred solution of
the appropriate acetal bromide 7 (6.19 mmol) in THF
(16 mL) at )70 ꢁC. After 30 min, DMF (5.7 mL,
73.4 mmol) was added slowly dropwise keeping the tem-
perature at )70 ꢁC and stirring continued for 30 min. The
solution mixture was cooled to room temperature, stirred
for 30 min, poured into aqueous saturated ammonium
chloride solution (100 mL), and extracted with CH2Cl2
(3 · 30 mL). The organic layer was dried over Na2SO4, and
concentrated. The crude product was purified by column
chromatography Al2O3/CH2Cl2 for 8d,f, Al2O3/AcOEt/
hexanes (1/9, v/v) for 8e, SiO2/AcOEt/hexanes (8/2, v/v)
Compound 5b: mp: 168–170 ꢁC; 1H (400 MHz, DMSO-d6)
d 6.63 (d, 1H, J ¼ 8 Hz), 6.73 (s, 1H), 7.15 (d, 1H,
J ¼ 8 Hz), 7.46 (dd, 1H, J ¼ 4:5, 7.5 Hz), 7.94 (d, 1H,
J ¼ 7:5 Hz), 8.66 (d, 1H, J ¼ 4:5 Hz), 11.74 (br s, 1H); 13
C
(100 MHz, DMSO-d6) d 71.9, 105.5, 123.4, 128.5, 131.5,
136.4, 147.4, 150.3, 153.3, 162.5; MS m/z 217 (Mþ, 9), 199
(34), 157 (68), 129 (100), 102 (30), 75 (19), 63 (20), 51 (25).
Compound 5c: mp: 216–218 ꢁC; 1H (400 MHz, DMSO-d6)
d 5.12 (br s, 1H), 6.79 (s, 1H), 7.09 (s, 1H), 8.12 (d, 1H,
J ¼ 5:5 Hz), 8.90 (d, 1H, J ¼ 5:5 Hz), 9.17 (s, 1H), 11.99 (s,
1H); 13C (100 MHz, DMSO-d6) d 70.4, 99.8, 125.8, 127.5,
131.0, 141.7, 141.8, 145.5, 153.3, 162.1; MS m=z 217 (Mþ,
12), 199 (45), 157 (66), 129 (100), 102 (17), 75 (30), 51 (23).
for
8b,
and
SiO2/AcOEt/CH2Cl2
(9/1,
1
Compound 10a: 245–247 ꢁC; H (400 MHz, DMSO-d6) d
v/v) for 8c. All these compounds were accompanied by
the corresponding dehalogenated compounds.
20. Hamilton, G. S.; Huang, Z.; Yang, X. J.; Patch, R. J.;
Narayanan, B. A.; Ferkany, J. W. J. Org. Chem. 1993, 58,
7263–7270.
21. Typical procedure for the preparation of 5-arylidene-
hydantoin 9: To a solution of sodium (0.18 g, 7.82 mmol)
in anhydrous ethanol (15 mL) was added, under argon,
diethyl 2,4-dioxoimidazolidine-5-phosphonate (1.10 g,
4.66 mmol) and the appropriate aldehyde 8 (3.10 mmol).
The solution was stirred at room temperature for 4 h then
diluted with water (30 mL). The yellow precipitate was
collected via filtration, washed with cold ethanol (10 mL),
and dried under reduced pressure to give 9. The hydan-
toins 9 were generally isolated as mixtures of geometrical
isomers.
7.17 (t, 1H, J ¼ 7 Hz), 7.67 (br s, 1H), 7.75 (m, 1H), 7.83 (d,
1H, J ¼ 9 Hz), 8.24 (br s, 1H), 9.13 (s, 1H), 9.19 (s, 1H),
9.36 (d, 1H, J ¼ 7 Hz); 13C (100 MHz, DMSO-d6) 106.9,
112.0, 117.7, 128.5, 132.9, 134.9, 140.5, 141.0, 142.1, 150.0,
166.4; MS m=z 212 (Mþ, 36), 169 (56), 141 (12), 78 (100), 51
(91).
1
Compound 10c: mp: 275–277 ꢁC; H (400 MHz, DMSO-
d6) d 7.57 (br s, 1H), 7.63 (m, 2H), 7.91 (m, 3H), 8.12 (br s,
1H), 8.74 (m, 1H), 9.07 (s, 1H), 9.16 (s, 1H); 13C (100 MHz,
DMSO-d6) 116.6, 125.5, 126.2, 129.6, 129.7, 129.9, 130.6,
131.1, 131.6, 134.9, 136.2, 147.8, 152.4, 168.0; MS m=z 222
(Mþ, 62), 179 (100), 151 (35).
1
Compound 10d: 223–225 ꢁC; H (400 MHz, DMSO-d6 ) d
4.03 (s, 3H), 7.34 (t, 1H, J ¼ 8 Hz), 7.50 (br s, 1H), 7.67 (t,
1H, J ¼ 8 Hz), 7.74 (d, 1H, J ¼ 8 Hz), 8.10 (br s, 1H), 8.41
(d, 1H, J ¼ 8 Hz), 8.87 (s, 1H), 9.03 (s, 1H); 13C (100 MHz,
DMSO-d6) 26.5, 110.3, 113.8, 120.1, 120.6, 122.2, 127.7,
22. Niopas, I.; Smail, G. A. J. Chem. Soc., Perkin Trans. 1
1991, 113–117.