N-heterocyclic carbene-catalyzed monoacylation of 1,4-naphthoquinones with aldehydes

Article abstract of DOI:10.1021/jo902235h

(Chemical Equation Presented) The NHC-catalyzed conjugate hydroacylation of 1,4-naphthoquinones allows for the synthesis of monoacylated 1,4-dihydroxynaphthalene derivatives. These targets, difficult to prepare selectively by standard protocols, represent

Full text of DOI:10.1021/jo902235h

pubs.acs.org/joc
SCHEME 1
N-Heterocyclic Carbene-Catalyzed Monoacylation
of 1,4-Naphthoquinones with Aldehydes
‡
Marıa Teresa Molina,† Cristina Navarro, ‡ Ana Moreno,
, ‡
ꢀ
and Aurelio G. Csaky*
†
´
Instituto de Quımica Medica (CSIC), C/Juan de la Cierva,
3, 28006-Madrid, Spain and Departamento de Quımica
ꢀ
‡
´
ꢀ
Organica, Facultad de Quımica, Universidad Complutense,
´
28040-Madrid, Spain
csaky@quim.ucm.es
“Breslow intermediates”. These can evolve by several reac-
tion pathways, which allows the synthesis of different types
of compounds. Among these reaction pathways, the genera-
tion of acyl azolium intermediates deserves particular atten-
tion, as these species can behave as acylating reagents for
carbon- and heteronucleophiles (Scheme 1).2,3
Received October 20, 2009
Herein, we report (Scheme 2) the NHC-catalyzed reduc-
tion-acylation of 1,4-naphthoquinones (1) with aldehydes
(2) to give the monoacylated 1,4-dihydroxynaphthalenes
4. In particular, high regioselectivity has been observed
when starting from nonsymmetrical 1,4-naphthoquinones.4
Compounds 4 are difficult to prepare selectively by con-
ventional acylation reactions, and are useful intermediates
in the synthesis of highly substituted 1,4-naphthoquinone
derivatives, which constitute relevant pharmaceutical
scaffolds.5,6
The NHC-catalyzed conjugate hydroacylation of 1,4-naph-
thoquinones allows for the synthesis of monoacylated
1,4-dihydroxynaphthalene derivatives. These targets, dif-
ficult to prepare selectively by standard protocols, repre-
sent important intermediates in the elaboration of highly
substituted 1,4-naphthoquinone derivatives, which con-
stitute relevant pharmaceutical scaffolds. High regios-
electivity has been observed in the hydroacylation
reaction when starting from nonsymmetrical quinones.
We have recently undertaken the study of the addition of
different reagents to quinones.7 In the search of a new type
of acylation of quinones, we began the present study by
screening several commercially available azolium salts as
(3) For NHC-catalyzed acylations under oxidative conditions, see:
(a) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed.
2008, 47, 8727. (b) Zeilter, K.; Rose, C. A. J. Org. Chem. 2009, 74, 1759.
(c) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Tetrahedron 2009,
65, 3102. (d) Maki, B. E.; Patterson, E. V.; Cramer, C. J.; Scheidt, K. A. Org.
Lett. 2009, 11, 3942.
N-Heterocyclic carbene (NHC) organocatalysis has be-
come an increasingly popular field in recent times, as it per-
mits a broad range of useful synthetic transformations.1 The
nucleophilic character of NHCs enables their addition to the
carbonyl group of aldehydes, giving rise to the formation of
(4) For chemoselectivity in esterification reactions (perspective), see:
Nahmany, M.; Melman, A. Org. Biomol. Chem. 2004, 2, 1563.
(5) See for example: (a) Mellidis, A. S.; Papageorgiou, V. P. Tetrahedron
Lett. 1986, 27, 5881. (b) Deshpande, P. P.; Martin, O. R. Tetrahedron Lett.
1990, 31, 6613. (c) Hosoya, T.; Takashiro, E.; Yamamoto, Y.; Matsumoto,
T.; Suzuki, K. Heterocycles 1996, 42, 397. (d) Nunes, R. L.; Bieber, L. W.;
Longo, R. L. J. Nat. Prod. 1999, 62, 1643. (e) Ciuffreda, P.; Casati, S.;
Santaniello, E. Tetrahedron 1999, 56, 317. (f) Qabaja, C.; Jones, G. B. J. Org.
Chem. 2000, 65, 7187. (g) Kumamoto, T.; Aoyama, N.; Nakano, S.; Ishikawa,
T.; Narimatsu, S. Tetrahedron: Asymmetry 2001, 12, 791. (h) de Frutos, O.;
Atienza, C.; Echavarren, A. M. Eur. J. Org. Chem. 2001, 163. (i) Foti, M. C.;
Johnson, E. R.; Vinqvist, M. R.; Wright, J. S.; Barclay, L. R. C.; Ingold, K. U.
J.Org. Chem. 2002, 67, 5190.(j) Wang,X.-Y.; Bu, X.-Z.;Liu, P.-Q.; Ma, L.; Xie,
B.-F.; Liu, Z.-C.; Li, Y.-M.; Chan, A. S. C. Synth. Commun. 2006, 36, 2667.
(k) Kimura, M.; Fukasaka, M.; Tamaru, Y. Synthesis 2006, 3611. (l) Krohn, K.;
Diederichs, J.; Riaz, M. Tetrahedron 2006, 62, 1223. (m) Suhara, Y.; Hirota, Y.;
Nakagawa, K.; Kamao, M.; Tsugawa, N.; Okano, T. Biorg. Med. Chem. 2008,
16, 3108.
(1) For recent reviews, see: (a) Enders, D.; Breuer, K. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, Germany, 1999; Vol. 3, p 1093. (b) Enders, D.; Balensiefer, T. Acc. Chem.
Res. 2004, 37, 534. (c) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632.
(d) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506. (e) Enders, D.; Balensiefer,
T.; Niemeier, O.; Christmann, M. In Enantioselective Organocatalysis: Reac-
tions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
ꢀ
Germany, 2007; p 331. (f) Marion, N.; Díez-Gonzalez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988. (g) Enders, D.; Niemeier, O.; Henseler, A Chem.
Rev. 2007, 107, 5606. (h) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev.
2008, 37, 2691.
(2) For leading examples on the use of in situ generated NHC-derived acyl
azolium species as acylating reagents, see ref 1. For some additional recent
examples, see also: (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 8126. (b) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 9518. (c) Chiang, P.-C.; Kim, Y.; Bode, J. W. Chem. Commun.
2009, 4566. (d) Wang, L.; Thai, K.; Gravel, M. Org. Lett. 2009, 11, 891.
ꢀ
(e) Domingo, L. R.; Aurell, M. J.; Arno, M. Tetrahedron 2009, 65, 3432.
(f) Hirano, K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131,
14190 and references cited therein.
(6) Polysubstituted aroylnaphthalenes have recently been disclosed as
relevant starting materials for biaryl synthesis. See: (a) Quasdorf, K. W.;
Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422. (b) Guan, B. T.;
Wang, Y.; Li, B. J.; Yu, D.-G.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 14468.
(c) Li, Z.; Zhang, S. L.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009,
131, 8815. See also: (d) Gooβen, L. J.; Gooβen, K.; Stanciu, C. Angew.
Chem., Int. Ed. 2009, 48, 3569.
ꢀ
(7) Molina, M. T.; Navarro, C.; Moreno, A.; Csaky, A. G. Org. Lett.
2009, 11, 4938.
DOI: 10.1021/jo902235h
r
Published on Web 11/25/2009
J. Org. Chem. 2009, 74, 9573–9575 9573
2009 American Chemical Society

Molina et al.
JOCNote
SCHEME 2
TABLE 2. Scope of the Acylation Reactiona
entry
1
2
R1
R2 R3
R4 4 (yield, %)b
1
2
3
4
5
6
7
8
9
1a 2b Me
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
4ab (75)
4ac (80)
4ad (70)
4ae (80)c
4af (60)
4ag (65)
TABLE 1. Optimization of Reaction Conditionsa
1a 2c cyclopropyl
1a 2d o-Br-C6H4
1a 2e CHdCHMe
1a 2f CHdC(Me)2
1a 2g CHdCHCHdCHMe
1b 2a iPr
H
H
H
H
H
OMe OMe 4ba (80)
H
H
OMe
OMe
OMe
1c 2a iPr
H
H
H
H
H
H
4ca (75)
4ce (70)
4da (75)
4dd (70)
4de (70)
4ea (65)
1c 2e CHdCHMe
10 1d 2a iPr
11 1d 2d o-Br-C6H4
12 1d 2e CHdCHMe
13 1e 2a iPr
Ph OMe
aAll reactions were performed with 0.1 mmol of quinones 1, 1.25
equiv of aldehydes 2, 0.25 equiv of 3e, and 1.0 equiv of Et3N in CH2Cl2
solution (0.3 mL) at rt. bIsolated yield after chromatography. c10% of
the diacylated product 5ae was also isolated.
entry
3
base
solvent
yield of 4aa (%)
1
2
3a
3b
3b
3c
3d
3d
3d
3d
3d
3d
Et3N
Et3N
DBU
Et3N
Et3N
DBU
Et3N
Et3N
Et3N
Et3N
CH2Cl2
CH2Cl2
DMF
CH2Cl2
CH2Cl2
CH2Cl2
1,4-dioxane
toluene
DMF
0
0
0
0
80
0
70
20
20
60d
SCHEME 3
3b
4
5
6
7
8
9
10c
CH2Cl2
aUnless otherwise stated, all reactions were performed with 0.1 mmol of
quinones 1, 1.25 equiv of aldehyde 2a, 0.25 equiv of azolium salts 3, and 1.0
equiv of base at rt. bReaction carried out at 50 °C. cReaction carried out
with 0.12 equiv of 3d. d10% of the diacylated product 5aa was also isolated.
precatalysts for the reaction between 1,4-naphthoquinone
(1a) and isobutyraldehyde (2a) (Table 1). Whereas no reac-
tion was observed for imidazolium 3a, thiazolium 3b, or
mesityltriazolium 3c salts (entries 1-4), the use of the
pentafluorophenyltriazolium salt 3d8 catalyzed a conjugate
hydroacylation reaction at rt to afford 4aa in good yield
(entry 5). Best results were obtained in CH2Cl2 as solvent
as compared with other solvents of different polarities
(entries 7-9).3d
Under the optimized reaction conditions achieved (Table 1,
entry 5), we examined a variety of aldehydes 2 in their reaction
with naphthoquinone 1a (Table 2, entries 1-6).
We observed that the reaction was general with respect
to 2, admitting aliphatic, alicyclic, aromatic, and unsatu-
rated aldehydes. Also, the reaction was tolerant to the
presence of peri substituents on the quinone system
(Table 2, entry 7).
C2-substituted quinones 1c and 1e, the most hindered acy-
lated products 4 resulted from the reaction. In the case of
quinone 1d, high regioselectivity10 was observed in favor of
the 4-hydroxy-5-methoxy-1-naphthyl esters 4. In one case
(Table 2, entry 4), the corresponding diacylated product 5ae
was also isolated.
With regard to the formulation of a plausible mechanism,
we have observed that reaction of 1a with deuterated acet-
aldehyde (2b-D4) takes place with 52% deuterium incor-
poration at C3 of the product 1ab-D (Scheme 3).
Our experimental results, in particular the obtention of
the most hindered acylated hydroquinones 4 as major reac-
tion products, are in agreement with a hydride transfer
Several nonsymmetrically substituted naphthoquinones 1
were also examined to assess the scope of the reaction with
regard to the regiochemistry (Table 2, entries 8-13).9 We
observed that a single monoacylated compound 4 was
formed in all cases. It is noteworthy that, in the case of the
(10) For regioselective additions to quinone derivatives, see ref 7 and the
following: (a) Kelly, T. R.; Gillard, J. W.; Goerner, R. N. Jr.; Lyding, J. M.
J. Am. Chem. Soc. 1977, 99, 5515. (b) Parker, K. A.; Sworin, M. E. J. Org.
Chem. 1981, 46, 3218. (c) Kelly, T. R.; Parekh, N. D.; Trachtenberg, E. N.
J. Org. Chem. 1982, 47, 5009. (d) Couladouros, E. A.; Plyta, Z. F.;
Haroutounian, S. A. J. Org. Chem. 1997, 92, 6 and references cited therein.
(8) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725.
(9) The regiochemical assignment of compounds 4c-e has been carried
out by 1D-NOE, COSY, HMQC, and HMBC NMR experiments. See the
Supporting Information for further details.
9574 J. Org. Chem. Vol. 74, No. 24, 2009

Molina et al.
JOCNote
SCHEME 4. Plausible Reaction Mechanism
Also, a SET mechanism in which the quinones were acting
as oxidants of the Breslow intermediate3 (Scheme 4, Path B)
could be operative. This would give rise to the acyl azolium
intermediate II and the hydroquinone V. Acylation of V with
II should have furnished the diacylated compounds 5 as
major reaction products, together with the less hindered
monoacylated products 6, and the observed products 4 as
minor components of the reaction mixture. However, this
product distribution is not in agreement with our experi-
mental results.
In summary, we have developed the NHC-catalyzed re-
duction-acylation of 1,4-naphthoquinones with aldehydes
to afford monoacylated 1,4-dihydroxynaphthalene deriva-
tives. This process takes place with high regioselectivity in
agreement with a consecutive hydride transfer-electrophilic
acylation mechanism. Further investigations for the use of
other Michael acceptors in this catalytic reaction are in
progress, and will be reported in due course.
Experimental Section
General Procedure for the Synthesis of 4. With exclusion of
air and humidity, 1,4-naphthoquinone 1 (0.1 mmol) was
dissolved in CH2Cl2 (0.3 mL) in a screw-cap vial containing
a magnetic stirring bar. The azolium catalyst 3 (0.025 mmol)
was added, followed by 0.125 mmol of the aldehyde 2, and
Et3N (0.1 mmol). The vial was capped under Ar. After 18 h of
stirring at rt, the mixture was filtered through a pad of Celite,
which was repeatedly rinsed with Et2O. The solvent was
evaporated under reduced pressure and the products were
isolated by chromatography on silica gel with CH2Cl2 as
eluent.
Isobutyric acid 4-hydroxynaphthalen-1-yl ester (4aa): 1H
RMN (CDCl3, 300 MHz) δ 8.00 (d, 3J = 8.0 Hz, 1H), 7.65 (d,
3J=8.0 Hz, 1H), 7.45-7.32 (m, 2H), 6.83 (d, 3J=8.8 Hz, 1H),
6.43 (d, 3J = 8.8 Hz, 1H), 6.13 (s, 1H), 2.91 (sept, 3J = 6.7 Hz,
1H), 1.36 (d, J = 7.1 Hz, 6H) ppm; 13C RMN (CDCl3, 75.5
3
mechanism from intermediate I (Scheme 4, path A).11,12 In
the presence of 1,4-naphthoquinones 1, which are well-
known both for their redox properties and their ability to
add nucleophiles in a conjugate fashion, 1,4-hydride transfer
from I may take place giving rise to the acyl azolium II and
intermediate III. Rapid acylation of III by II affords IV,
which tautomerizes to 4. Further acylation of 4 with II may
occur to give the diacylated compounds 5 as minor reaction
products. However, redox pathways are not to be excluded,
and the hydride transfer step might take place intramolecularly
from a cation-radical/anion-radical complex between 1 and the
Breslow intermediate, leading to an ion pair complex.
MHz) δ 176.8, 149.7, 139.8, 127.6, 126.8, 125.5, 125.2, 122.3,
120.8, 117.8, 107.9, 34.4, 19.2, 19.2 ppm; HRMS (EI) calcd for
C14H14O3 230,0943 (Mþ), found 230,0944.
Isobutyric acid 4-isobutyroyloxynaphthalen-1-yl ester (5aa):
1H RMN (CDCl3, 300 MHz) δ 7.83-7.76 (m, 2H), 7.50-7.44
(m, 2H), 7.19 (s, 2H), 2.93 (sept, 3J=6.7 Hz, 2H), 1.37 (d, 3J=
7.2 Hz, 12H) ppm; 13C-RMN (CDCl3, 75.5 MHz) δ 173.2, 173.2,
143.4, 143.4, 127.5, 127.5, 125.5, 125.5, 120.5, 120.5, 116.7,
116.7, 33.1, 33.1, 17.7, 17.7, 17.7, 17.7 ppm; HRMS (EI) calcd
for C18H20O4 300,1362 (Mþ), found 300,1362.
Acknowledgment. Projects UCM-BSCH GR58/08-910815
and CTQ2006-15279-C03-01 (both to A.G.C), and SAF2006-
04698 (to M.T.M.), are gratefully acknowledged for financial
support. Prof. J. Plumet (UCM) is thanked for his valuable
support of this work.
(11) For the NHC-catalyzed hydroacylation reaction of non-enolizable
1,2-dicarbonyl compounds (benzil and aroylformates) with aromatic alde-
hydes, see: Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558. No
reaction was shown by other less electrophilic ketones such as fluorenone or
aliphatic aldehydes.
(12) For the reduction of NdN bonds as a secondary reaction in the
NHC-catalyzed reaction of R,β-unsaturated aldehydes with hydrazines, see:
Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740.
Supporting Information Available: Regiochemical assign-
ments and copies of 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 24, 2009 9575