N-heterocyclic carbene-catalyzed intramolecular aldehyde-nitrile cross coupling: An easy access to 3-aminochromones

Article abstract of DOI:10.1021/ol9026232

(Figure presented) An immense effort has been made to develop an efficient strategy for the carbon-carbon bond formation between aldehyde and nitrile intramolecularly using an N-heterocyclic carbene catalyst to derive 3-aminochromone derivatives In good to excellent yields (80-95%).

Full text of DOI:10.1021/ol9026232

ORGANIC
LETTERS
2010
Vol. 12, No. 2
352-355
N-Heterocyclic Carbene-Catalyzed
Intramolecular Aldehyde-Nitrile Cross
Coupling: An Easy Access to 3-
Aminochromones†
Seenuvasan Vedachalam, Jing Zeng, Bala Kishan Gorityala, Meraldo Antonio,
and Xue-Wei Liu*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
xuewei@ntu.edu.sg
Received November 22, 2009
ABSTRACT
An immense effort has been made to develop an efficient strategy for the carbon-carbon bond formation between aldehyde and nitrile
intramolecularly using an N-heterocyclic carbene catalyst to derive 3-aminochromone derivatives in good to excellent yields (80-95%).
Chromone is one of the most common heterocyclic motifs
found in pharmaceutically active compounds.1 One of the
most important subfamilies of chromone is 3-aminochromone,
whose derivatives show interesting therapeutic effects.2 From
previous research efforts, a wide variety of functionalized
3-aminochromone derivatives have been identified to possess
anti-inflammatory (T-614) (I),3 antirheumatic (I),4 leukemic
B-cells apoptosis (II),5 and antimutagenic (II) activities.6
They were found to be effective in the selective inhibition
† Dedicated to Professor Charles E. McKenna on the occasion of his
65th birthday.
(1) (a) Gobbi, S.; Cavalli, A.; Rampa, A.; Belluti, F.; Piazzi, L.;
Paluszcak, A.; Hartmann, R. W.; Recanatini, M.; Bisi, A. J. Med. Chem.
2006, 49, 4777–4780. (b) Nutley, B. P.; Smith, N. F.; Hayes, A.; Kelland,
L. R.; Brunton, L.; Golding, B. T.; Smith, G. C. M.; Martin, N. M. B.;
Workman, P.; Raynaud, F. I. Br. J. Cancer. 2005, 93, 1011–1018. (c)
Boumendjel, A.; Nicolle, E.; Moraux, T.; Gerby, B.; Blanc, M.; Ronot, X.;
Boutonnat, J. J. Med. Chem. 2005, 48, 7275–7281. (d) Ahmed-Belkacem,
A.; Pozza, A.; Mun˜oz-Mart´ınez, F.; Bates, S. E.; Castanys, S.; Gamarro,
F.; Di Pietro, A.; Pe´rez-Victoria, J. M. Cancer Res. 2005, 65, 4852–4860.
(e) Morris, J.; Wishka, D. G.; Lin, A. H.; Humphrey, W. R.; Wiltse, A. L.;
Gammill, R. B.; Judge, T. M.; Bisaha, S. N.; Olds, N. L.; Jacob, C. S.;
Bergh, C. L.; Cudahy, M. M.; Williams, D. J.; Nishizawa, E. E.; Thomas,
E. W.; Gorman, R. R.; Benjamin, C. W.; Shebusk, R. J. J. Med. Chem.
1993, 36, 2026–2032. (f) Horie, T.; Tominaga, H.; Kawamura, Y.; Hada,
T.; Ueda, N.; Amano, Y.; Yamamoto, S. J. Med. Chem. 1991, 34, 2169–
2176.
(2) Dauzonne, D.; Folle´as, B.; Martinez, L.; Chabot, G. G. Eur. J. Med.
Chem. 1997, 32, 71–82.
(3) (a) Sawada, T.; Hashimoto, S.; Tohma, S.; Nishioka, Y.; Nagai, T.;
Sato, T.; Ito, K.; Inoue, T.; Iwata, M.; Yamamoto, K. Immunopharmacol.
2000, 49, 285–294. (b) Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.;
Yoshida, C.; Takano, S. Chem. Pharm. Bull. 2000, 48, 131–139.
(4) (a) Tanaka, K.; Yamamoto, T.; Aikawa, Y.; Kizawa, K.; Muramoto,
K.; Matsuno, H.; Muraguchi, A. Rheumatology 2003, 42, 1365–1371. (b)
Kuriyama, K.; Higuchi, C.; Tanaka, K.; Yoshikawa, H.; Itoh, K. Biochem.
Biophys. Res. Commun. 2002, 299, 903–909. (c) Aikawa, Y.; Yamamoto,
M.; Yamamoto, T.; Morimoto, K.; Tanaka, K. Inflammation Res. 2002, 51,
188–194. (d) Kawakami, A.; Tsuboi, M.; Urayama, S.; Matsuoka, N.;
Yamasaki, S.; Hida, A.; Aoyagi, T.; Furuichi, I.; Nakashima, T.; Migita,
K.; Kawabe, Y.; Nakashima, M.; Origuchi, T.; Eguchi, K. J. Lab. Clin.
Med. 1999, 133, 566–574. (e) Aikawa, Y.; Tanuma, N.; Shin, T.; Makino,
S.; Tanaka, K.; Matsumoto, Y. J. Neuroimmunol. 1998, 89, 35–42.
10.1021/ol9026232  2010 American Chemical Society
Published on Web 12/21/2009

of v-abl tyrosine protein kinase (III).7 Thus, facile prepara-
tion of chromone derivatives remains an essential research
topic in organic synthesis.
Our synthetic strategy was acquired from the observation
of two NHC-catalyzed reactions (Scheme 1): the reaction
It is evident from prior research that the synthesis of the
chromone scaffold often suffers lengthy steps, harsh reaction
conditions, and absence of diversified substrate scope. The
potential utility of 3-aminochromones has prompted organic
chemists to look for alternatives to replace conventional
chromone syntheses.8 In this context, the N-heterocyclic
carbene (NHC) catalyzed carbon-carbon bond formation
strategy is, in our opinion, a more attractive and innovative
approach.9 This approach generally facilitates the reactions
such as benzoin condensation,10 aza-benzoin condensation,11
Stetter reaction,12addition reactions to homoenoloate inter-
mediate,13 intramolecular nucleophilic addition of carbonyl
anion,14 etc. These reactions involve an alternating acceptor
and donor reactivity pattern called umpolung,9 which de-
velops a new carbon-carbon bond and shortens the con-
ventional synthetic routes in organic synthesis. Thus we felt
that this umpolung derived strategy would allow the synthesis
of 3-aminochromones in an expeditious manner.
Scheme 1
.
Blueprint for NHC-Catalyzed C-C Bond Formation
Strategy
between two aldehydes (Benzoin condensation, eq 1) and
between an aldehyde and an imine (aza-benzoin condesation,
eq 2). The central core of both the reactions is trivial variation
of polarity of the carbonyl and imine bonds which is
effortlessly attacked by the Breslow intermediate15 to form
a carbon-carbon bond. We envisioned that this umpolung
derived reactivity could be applied to the intramolecular
carbon-carbon bond formation reaction between aldehyde
and nitrile, which would significantly simplify traditional
synthetic routes and allow an easy access to diversity-oriented
3-aminochromones (eq 3).
(5) Quiney, C.; Dauzonne, D.; Kern, C.; Fourneron, J.-D.; Izard, J.-C.;
Mohammad, R. M.; Kolb, J.-P.; Billard, C. Leukemia Res. 2004, 28, 851–
861.
(6) Beudot, C.; De Me´o, M. P.; Dauzonne, D.; Elias, R.; Laget, M.;
Guiraud, H.; Balansard, G.; Dume´nil, G. Mutat. Res. 1998, 417, 141–153.
(7) Geissler, J. F.; Roesel, J. L.; Meyer, T.; Trinks, U. P.; Traxler, P.;
Lydon, N. B. Cancer Res. 1992, 52, 4492–4498.
(8) (a) Fride´n-Saxin, M.; Pemberton, N.; da Silva Andersson, K.;
Dyrager, C.; Friberg, A.; Grøtli, M.; Luthman, K. J. Org. Chem. 2009, 74,
2755–2759. (b) Bauvois, B.; Puiffe, M.-L.; Bongui, J.-B.; Paillat, S.;
Monneret, C.; Dauzonne, D. J. Med. Chem. 2003, 46, 3900–3913. (c)
DeWald, H. A.; Heffner, T. G.; Jaen, J. C.; Lustgarten, D. M.; McPhail,
A. T.; Meltzer, L. T.; Pugsley, T. A.; Wise, L. D. J. Med. Chem. 1990, 33,
445–450.
Our initial efforts were focused on the systematic evalu-
ation of various catalysts and reaction conditions to optimize
(9) (a) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. ReV. 2008, 37,
2691–2698. (b) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2988–3000. (c) Enders, D.; Niemeier, O.; Henseler, A.
Chem. ReV. 2007, 107, 5606–5655. (d) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719–724. (e) Vijay, N.; Santhamma, B.; Vellalath, S. Angew.
Chem., Int. Ed. 2004, 43, 5130–5135. (f) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138–5175. (g) Enders, D.; Balensiefer, T. Acc.
Chem. Res. 2004, 37, 534–541. (h) Grasa, G. A.; Singh, R.; Nolan, S. P.
Synthesis 2004, 971–985. (i) Seebach, D. Angew. Chem., Int. Ed. 1979, 18,
239–258.
(12) (a) DiRocco, D. A.; Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am.
Chem. Soc. 2009, 131, 10872–10874. (b) Rovis, T. Chem. Lett. 2008, 37,
2–7. (c) de Alaniz, J. R.; Kerr, M. S.; Moore, J. L.; Rovis, T. J. Org. Chem.
2008, 73, 2033–2040. (d) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128,
2552–2553. (e) Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368–
6378. (f) Mennen, S. M.; Blank, J. T.; Tran-Dube´, M. B.; Imbriglio, J. E.;
Miller, S. J. Chem. Commun. 2005, 195–197. (g) Mattson, A. E.; Bharadwaj,
A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314–2315. (h) Kerr,
M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876–8877. (i) Barrett,
A. G. M.; Love, A. C.; Tedeschi, L. Org. Lett. 2004, 6, 3377–3380. (j)
Raghavan, S.; Anuradha, K. Synlett 2003, 711–713. (k) Kerr, M. S.; Rovis,
T. Synlett 2003, 1934–1936. (l) Raghavan, S.; Anuradha, K. Tetrahedron
Lett. 2002, 43, 5181–5183. (m) Kerr, M. S.; Read de Alaniz, J.; Rovis, T.
J. Am. Chem. Soc. 2002, 124, 10298–10299. (n) Braun, R. U.; Zeitler, K.;
Muller, T. J. J. Org. Lett. 2001, 3, 3297–3300. (o) Ciganek, E. Synthesis
1995, 1311–1314. (p) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639–
647. (q) Stetter, H.; Kuhlmann, H. Synthesis 1975, 379–380. (r) Stetter,
H.; Schreckenberg, M. Angew. Chem., Int. Ed. 1973, 12, 81.
(10) (a) Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org.
Chem. 2009, 74, 9214-9217. (b) Enders, D.; Niemeier, O.; Raabe, G. Synlett
2006, 2431–2434. (c) Enders, D.; Niemeier, O.; Balensiefer, T. Angew.
Chem., Int. Ed. 2006, 45, 1463–1467. (d) Hachisu, Y.; Bode, J. W.; Suzuki,
K. AdV. Synth. Catal. 2004, 346, 1097–1100. (e) Hachisu, Y.; Bode, J. W.;
Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432–8433. (f) Enders, D.;
Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743–1745. (g) White, M. J.;
Leeper, F. J. J. Org. Chem. 2001, 66, 5124–5131. (h) Heck, R.; Henderson,
A. P.; Ko¨hler, B.; Re´tey, J.; Golding, B. T. Eur. J. Org. Chem. 2001, 2623–
2627. (i) Iding, H.; Du¨nnwald, T.; Greiner, L.; Liese, A.; Mu¨ller, M.; Siegert,
P.; Gro¨tzinger, J.; Demir, A. S.; Pohl, M. Chem.sEur. J. 2000, 6, 1483–
1495. (j) Lo´pez-Calahorra, F.; Rubires, R. Tetrahedron 1995, 51, 9713–
9728. (k) Chen, Y. T.; Barletta, G. L.; Haghjoo, K.; Cheng, J. T.; Jordan,
F. J. Org. Chem. 1994, 59, 7714–7722. (l) Diederich, F.; Lutter, H. D.
J. Am. Chem. Soc. 1989, 111, 8438–8446. (m) Castells, J.; Lo´pez Calahorra,
F.; Domingo, L. J. Org. Chem. 1988, 53, 4433–4436. (n) Matsumoto, T.;
Ohishi, M.; Inoue, S. J. Org. Chem. 1985, 50, 603–606. (o) Lapworth, A.
J. Chem. Soc. 1903, 83, 995–996. (p) Wo¨hler, F.; Lie´big, J. Ann. Pharm.
1832, 3, 249–282.
(13) (a) Chiang, P.-C.; Rommel, M.; Bode, J. W. J. Am. Chem. Soc.
2009, 131, 8714–8718. (b) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2008, 130, 2416–2417. (c) Chan, A.; Scheidt, K. A.
J. Am. Chem. Soc. 2008, 130, 2740–2741. (d) Chiang, P. C.; Kaeobamrung,
J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520–3521. (e) He, M.; Uc
Gerson, J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. (f)
Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006,
128, 8736–8737. (g) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131–3134.
(h) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205–6208.
(14) (a) Hirano, K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc.
2009, 131, 14190–14191. (b) He, J.; Tang, S.; Liu, J.; Su, Y.; Pan, X.; She,
X. Tetrahedron 2008, 64, 8797–8800.
(11) (a) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun. 2007, 852–
854. (b) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J. J. Am.
Chem. Soc. 2005, 127, 1654–1655. (c) Li, W.; Lam, Y. J. Comb. Chem.
2005, 7, 644–647. (d) Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6,
4363–4366. (e) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.;
Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696–9697.
(f) Castells, J.; Lo´pez-Calahorra, F.; Bassedas, M.; Urrios, P. Synthesis 1988,
314–315.
(15) (a) Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996, 37, 8241–
8242. (b) Breslow, R.; Kim, R. Tetrahedron Lett. 1994, 35, 699–702. (c)
Breslow, R.; Kool, E. Tetrahedron Lett. 1988, 29, 1635–1638. (d) Breslow,
R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
Org. Lett., Vol. 12, No. 2, 2010
353

the reaction. To gauge the performance of the reaction, a
simple phenyl (1a) was used as a model substrate. The scope
of this transformation was examined using the NHC catalyst
precursors (A-F) (Table 1, entries 1-6). Among the tested
Table 2. Reaction Scope for 3-Aminochromone Derivatives
Table 1. Optimization of Intramolecular Aldehyde-Nitrile
Cross Coupling
entrya substrate R1
R2
R3
R4 product yieldb (%)
1
2
3
4
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a
26a
27a
28a
29a
30a
H
H
H
H
tBu
-Ph-
Me
H
H
H
OTBS
OMe
OH
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
29b
30b
83
81
88
83
85
81
92
95
91
89
86
95
93
86
91
82
89
93
90
83
83
87
81
88
85
90
81
80
83
85
Me
tBu
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
F
5
H
6c
7
Allyl
OMe
H
H
H
H
H
Cl
H
Br
I
OMe
Br
OMe
H
F
H
F
H
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Cl
Br
Br
I
I
Cl
NO2
NO2
H
H
F
OCF3
F
H
H
F
entrya catalyst (equiv)
baseb
DBU
solvent (0.1 M) yieldc (%)
1
A (0.10)
B (0.10)
C (0.10)
D (0.10)
E (0.10)
F (0.10)
D (0.15)
D (0.05)
D (0.10)
D (0.10)
D (0.10)
D (0.10)
D (0.10)
D (0.10)
D (0.10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
53
trace
65
83
77
67
84
70
59
63
54
72
43
69
53
2
3
4
5
6
7
8
9
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBACO
H
H
H
F
H
H
H
H
H
H
F
H
OMe
OMe
H
10
11
12
13
14
15
CH3CN
Toluene
DMF
Me
Me
Me
Me
Ph
CH2Cl2
CH2Cl2
CH2Cl2
H
H
d
Cs2CO3
LiHMDS
a See Supporting Information for a detailed experimental procedure.
b Isolated yield. c Isolated as an acetamide derivative due to the unstable
nature of amine upon column purification.
a Unless otherwise specified, all of the reactions were carried out with
freshly distilled dry solvents at room temperature for 24 h. b Equal mol %
with respect to catalyst. c Isolated yields. d 3 equiv of base was used with
respect to catalyst.
of the halo-substituted derivatives prompted us to study the
biologically viable7 fluoro derivatives (entries 21-28). For
the fluoro-substituted substrate study, results were equally
good. Further hearten implementation was the inclusion of
methyl phenyl substituents at the R4 position which produced
the desired products in good to excellent yields (entries
26-30). The structure of the 3-amino-chromone motif was
further confirmed by X-ray crystallography (Figure 2, 7b).
On the basis of the results, we propose the reaction
mechanism as illustrated below (Scheme 2). Presumably, the
catalysts, catalyst D was found to be efficient (entry 4). Use
of solvent other than dichloromethane gave diminished yields
(entries 9-12). DBU was found to be the best among the
bases tested (entries 13-15). With this optimized condition,
we ensued to scrutinize the scope and generality of the
method using a variety of substrates.
Our results show that cross coupling could be adapted for
various salicylaldehyde derivatives ranging from electron-
poor to electron-rich aromatic rings (Table 2). The alkyl-
substituted aldehydes (entries 1-6) and employment of the
fused ring aromatic system (entry 4) exhibited prominently
good yields. A variety of methoxy (entries 7-10) and
hydroxy substituents (entry 11) also provided excellent
yields. Notably, halo (entries 12-18) and nitro (entries 19
and 20) substituents were observed to give excellent yields.
Thus, the scope of the reaction is wide, allowing the facile
generation of a variety of 3-aminochromones. The high yields
Figure 1. 3-Aminochromone scaffold.
354
Org. Lett., Vol. 12, No. 2, 2010

3-aminochromone. Compound 1b served as a model to
straightforwardly illustrate this synthetic potential of amine
functionalization (Scheme 3). Delightfully, similar morpho-
Scheme 3. Amine Functionalization
Figure 2
one (7b).
. X-ray structure of 3-amino-8-methoxy-4H-chromen-4-
reaction proceeds through the Breslow intermediate 1 (step
1), which reacts intramolecularly with the nitrile to give imine
3 (steps 2 and 3) which subsequently tautomerizes to form
3-aminochromone 4 (step 4). The second step of the
mechanism is crucial since an imine anion intermediate 2
(step 2) has been formed when the mesomeric carbanion 1′
from Breslow intermediate 1 attacked the sp carbon of the
nitrile. Subsequent proton exchange and NHC elimination
results in imine 3, which further tautomerizes to form
line attached chromones are being synthesized and actively
investigated in our laboratory to evaluate the potent anti-
cancer activity.1
In conclusion, we have developed a novel method for
carbon-carbon bond formation between sp2 carbon (alde-
hyde) and sp carbon (nitrile). This method allows the usage
of salicylaldehyde derivatives to assemble a variety of
heterocycles at room temperature, and good to excellent
yields were obtained. The results herein disclose considerable
extension of the substrate scope for the synthesis of a wide
pool of 3-aminochromones in an expeditious, straightforward,
and efficient manner. This methodology is likely to find
immediate synthetic applications, given that it is the first
example of a carbon-carbon bond formation between
aldehyde and nitrile.
Scheme 2. Plausible Reaction Mechanism
Acknowledgment. Financial support from Nanyang Tech-
nological University (RG50/08) and the Ministry of Health,
Singapore (NMRC/H1N1R/001/2009), is gratefully acknowl-
edged.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9026232
Org. Lett., Vol. 12, No. 2, 2010
355