Synthesis of 2-substituted 2H-chromenes using potassium vinyltrifluoroborates

Article abstract of DOI:10.1016/j.tetlet.2008.01.008

2H-Chromenes were synthesized from salicylaldehyde using potassium vinylic borates in the presence of secondary amines. We synthesized these 2H-chromene derivatives as a part of an ongoing project to develop inhibitors for TGF-β receptors. Potassium vinyl

Full text of DOI:10.1016/j.tetlet.2008.01.008

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1578–1581
Synthesis of 2-substituted 2H-chromenes using potassium
vinyltrifluoroborates
Fei Liu a, Todd Evans b, Bhaskar C. Das a,b,
*
a Department of Nuclear Medicine Albert Einstein College of Medicine, Bronx, NY 10461, United States
b Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States
Received 6 December 2007; revised 28 December 2007; accepted 3 January 2008
Available online 8 January 2008
Abstract
2H-Chromenes were synthesized from salicylaldehyde using potassium vinylic borates in the presence of secondary amines. We
synthesized these 2H-chromene derivatives as a part of an ongoing project to develop inhibitors for TGF-b receptors. Potassium vinyl
trifluoroborates react with salicylaldehydes at 80 °C in the presence of a secondary amine and produced 2-substituted 2H-chromene
derivatives with a 70–90% yield.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Chromenes; Potassium organic trifluoroborate; TGF-b inhibitors; Signal transduction
We have a long-term goal to develop novel chemical
screens capable of analyzing important biological systems
by interfacing libraries of small molecules, in the context
of developing zebrafish embryos. Toward this end, we were
interested in developing potential new inhibitors of TGF-b
signaling using 2-substituted 2H-chromene derivatives.
2H-Chromenes are an important class of oxygenated
heterocyclic compounds.1 Many biologically active natural
products contain a chromene ring system.2 In recent years,
there has been increased interest in the synthesis of 2H-
chromenes due to the number of compounds that possess
this group, and that show a variety of activities including
as antidepresssant, antihypertensive, anti-tubulin, antiviral,
antioxidative, activator of potassium channels and inhibi-
tion of phosphodiesterase IV or dihydrofolate reductase.3
Based on the importance of these compounds, a number
of research groups have developed methodologies to syn-
thesize these compounds. The approaches used include
intramolecular cyclization of Wittig intermediates,4 micro-
wave-assisted reaction of salicylaldehyde with enamines,5
catalytic Petasis reaction of salicylaldehydes,6 ring-closing
olefin metathesis,7 Baylis–Hillman reaction of 2-hydroxy-
benzaldehydes with methyl vinyl ketones,8 Claisen rear-
rangement of propargyl phenol ethers,9 Pd-catalyzed ring
closure of 2-isoprenyl phenols,10 electrocyclic ring closure
of vinylquinone derivatives,11 and the Ylide annulation
reaction.12 Despite the availability of these existing meth-
ods for the synthesis of chromene derivatives, there
remains a demand for general strategies that can more effi-
ciently provide variously substituted chromene systems.
In the context of our goal to generate small molecule
probes to study the biology of key signal transduction
pathways, including transforming growth factor beta
(TGF-b) pathways, we were interested in developing
improved methods for the synthesis of a 2H-chromene
library.
In this Letter, we report a practical and highly efficient
procedure for preparing diverse chromene derivatives using
potassium vinyltrifluoroborate as a substrate for the
Petasis reaction in the presence of catalytic amounts of
dibenzylamine as a secondary base at 80 °C in dimethyl
*
Corresponding author. Tel.: +1 718 430 2422; fax: +1 718 430 8853.
E-mail address: bdas@aecom.yu.edu (B. C. Das).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.008

F. Liu et al. / Tetrahedron Letters 49 (2008) 1578–1581
1579
CHO
OH
BF3K
20% mol, Dibenzylamine
+
80 °C, DMF, 17 h, 51%
O
(1)
(2)
(3)
Scheme 1.
formide. This procedure is complementary to that of Finn
and Kabalka, which in both cases uses boronic acid. The
utility of organoboronic acids in organic synthesis has
flourished in recent years, particularly through develop-
ments in Miyaura–Suzuki coupling,13 allyl-boration,14,15
copper catalyzed arylboronic acid–hetero atom coupling16
and Petasis reaction.17,18 However, these organoboron
derivatives have many limitations:19 (i) quantitative analy-
sis and stoichiometric reactions using boronic acids are
often difficult because of the rapid equilibrium between
the boronic acids and the corresponding cyclic, trimeric
anhydrides (boroxines), (ii) the diols utilized to generate
Table 1
Synthesis of 2-substituted 2H-chromenes from salicylaldehydes in the presence of 20% mol dibenzylamine in DMF at 80 °C
Entry
Aldehydes
Potassium vinylboronic
Producta
Yieldb (%)
O
BF3K
H
OH
1
51
O
(2)
(3)
(1)
O
Cl
Br
BF3K
Cl
H
2
3
4
5
89
71
90
54
O
O
OH
(2)
(5)
(4)
O
BF3K
Br
H
OH
(2)
(6)
(7)
O
O2N
BF3K
O2N
H
O
OH
(2)
(9)
(8)
O
BF3K
H
OH
O
OH
(2)
OH
(10)
(11)
O
Cl
Cl
BF3K
H
6
7
83
O
OH
Cl
(2)
Cl
(12)
(13)
O
H
BF3K
78
O
OH
(2)
(15)
(14)
(continued on next page)

1580
F. Liu et al. / Tetrahedron Letters 49 (2008) 1578–1581
Table 1 (continued)
Entry
Aldehydes
Potassium vinylboronic
Producta
Yieldb (%)
O
O2N
O2N
BF3K
H
8
9
65
(16)
O
OH
(17)
(8)
O
O2N
O2N
BF3K
H
C8H17
85
87
O
(19)
(18)
OH
(8)
O
Cl
Cl
H
BF3K
C8H17
10
O
OH
(18)
Cl
(20)
Cl
(12)
a
All products exhibited 1H NMR and 13C NMR characteristics in accord with assigned structures and literature values (for known compounds) and
high resolution mass spectrometry.
b
Isolated yields.
stable boronate esters such as catechol, pinacol, and
diethanolamine add considerable expense to the overall
process and they must be separated from the final product,
further increasing the cost of synthesis.
methodology, we worked with a variety of substituted
salicylaldehydes and boronic acids, as shown in Table 1.
We purified all products by column chromatography and
the reported yields are the isolated yields. The purity of
the products was subsequently established by thin layer
chromatography, 1H NMR, 13C NMR and by high resolu-
tion mass spectrometry. For all new products, experimental
procedures and analytical data are provided in Ref. 22, and
for all known compounds we compared the analytical data
with our compounds (which were identical).
A somewhat higher yield is obtained in the case of elec-
tron withdrawing groups in the para position of salicyl-
aldehydes, as compared to unsubstituted functional groups.
When we changed from potassium trans-styryltrifluoro-
borate to potassium vinyltrifluoroborate the yields decreased,
except in the case of potassium trans-1-decenyltrifluoro-
borate, where the yield remained similar.
(iii) Boronate esters, as Lewis acids and electrophiles, to
elaborate the functionalization of multistep synthesis using
nucleophiles, hamper the reaction process. To overcome all
these difficulties using organoboron derivatives, the use of
potassium organotrifluoroborates was developed. These
reagents are easily prepared by the addition of inexpensive
KHF2 to various organoboron intermediates,20a–e from
organostannate20f and by C–H activation method.20g For
our reaction, we purchased all alkenyl trifluoroborates from
Aldrich chemicals. All these salts have been described as
being very stable at elevated temperature. Potassium
organotrifluoroborates are more stable and easier to handle
than the corresponding organoboronic acids, and they are
more reactive due to the higher nucleophilicity of the
organic group on the boron atom. Due to these distinctive
features (greater nucleophilicity, ready accessibility, and
remarkable stability in air), organotrifluoroborate have
been used for many organic reactions, as reported by
Kabalka, Molander, Genet and others.21
In summary, we report a practical synthesis of chromene
derivatives using potassium organotrifluoroborate. Experi-
ments are currently underway to test the biological activity
of these 2H derivatives and to determine their utility as
inhibitors of TGF-b receptors.
In this Letter, we report a practical and highly efficient
procedure for preparing diverse chromene derivatives,
and demonstrate the practical utility of potassium organo-
trifluoroborate in chromene synthesis.
As shown in Scheme 1, salicylaldehyde (1 mmol), vinyl
boronic acid (1 mmol) and dibenzylamine (20 mol %) was
added to DMF and the solution was stirred at 80 °C for
3 h. The reaction was monitored through thin layer chro-
matography (solvent system). Unexpectedly we identified
a novel spot, and after workup NMR analysis determined
it that comprised 2-phenyl chromenes.22 To generalize this
Acknowledgments
The author BCD acknowledges Professor M. Donald
Blaufox for his financial support and encouragement and
AECOM for startup funding.
References and notes
1. (a) Hepworth, J. D. Pyrans and Fused Pyrans: Synthesis and
Applications. In Comprehensive Heterocyclic Chemistry; Katrizky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3, p 737; (b)

F. Liu et al. / Tetrahedron Letters 49 (2008) 1578–1581
1581
Milcent, R.; Chau, F. Chimie Organique He’te’rocyclique; EDP
Sciences: Les Ulis, France, 2003; p 434.
Org. Chem. 2002, 67, 8416; (f) Darses, S.; Michaud, G.; Genet, J.-P.
Eur. J. Org. Chem. 1999, 1875; (g) Vedejs, E.; Chapman, R. W.;
Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020;
(h) Darses, S.; Michaud, G.; Genet, J.-P. Tetrahedron Lett. 1998, 39,
5045; (i) Molander, G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867; (j)
Molander, G. A.; Petrillo, D. E. J. Am. Chem. Soc. 2006, 128, 9634–
9635; (k) Molander, G. A.; Ribagorda, M. J. Am. Chem. Soc. 2003,
125, 11148–11149; (l) Molander, G. A.; Figueroa, R. Org. Lett. 2006,
8, 75–78; (m) Stefani, H. A.; Cella, R.; Do¨rr, F. A.; Pereira, C. M. P.;
Zeni, G.; Gomes, M., Jr. Tetrahedron Lett. 2005, 46, 563–567; (n)
Fang, G.-H.; Yan, Z.-J.; Deng, M.-Z. Org. Lett. 2004, 6, 357–360.
22. Experimental details: Synthesis of compound 11: A solution of 2,3-
dihydroxybenzaldehyde (276.2 mg, 2 mmol), potassium trans-styryl-
trifluoroborate (420 mg, 2 mmol), was added with dibenzylamine
(82 mg, 20 mol %) in anhydrous DMF (10 mL). The reaction mixture
was heated at 80 °C overnight. The reaction mixture was quenched
with aqueous saturated NH4Cl (8 mL), extracted with CH2Cl2
(10 mL Â 3), and combined organic layers were washed with water
(10 mL Â 3). The water layer was extracted with CH2Cl2 (5 mL Â 2).
The combined organic layers were dried with Na2SO4, and evapo-
rated. The residue was purified by flash column chromatography
using hexane–ethyl acetate (98:2) as the eluent to give a yellow solid,
242.2 mg (54.0%). 1H NMR (300 MHz, CDCl3): d 7.50–7.39 (m, 5H),
6.87–6.82 (m, 2H), 6.67 (dd, J = 6.9, 2.4 Hz, 1H), 6.60 (dd, J = 9.9,
2.1 Hz, 1H), 5.98 (t, J = 3 Hz, 1H), 5.85 (dd, J = 9.9, 3.3 Hz, 1H),
5.44 (s, 1H). 13C NMR CD3OD: d 145.04, 141.31, 140.65, 128.49,
126.94, 125.20, 123.97, 122.63, 121.14, 117.80, 116.47, 77.10. ESI MS:
calcd for C15H12O2 ([M+H]+ ) 225.088; found: 225.12.
2. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem., Int.
Ed. 2000, 39, 734; (b) Nicolaou, K. C.; Cao, G.-Q.; Pfefferkorn, J. A.
Angew. Chem., Int. Ed. 2000, 39, 739; (c) Trost, B. M.; Trost, F. D. J.
Am. Chem. Soc. 1998, 120, 9074; (d) Varma, R. S.; Dahiya, R. J. Org.
Chem. 1998, 63, 8038; (e) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765;
(f) Maggiani, A.; Tubul, A.; Brun, P. Helv. Chem. Acta 2000, 83, 650.
3. (a) Evans, J. M.; Fake, C. S.; Hamilton, T. C.; Poyser, R. H.; Watts,
E. A. J. Med. Chem. 1983, 26, 1582; (b) Ashwood, V. A.;
Buckingham, R. E.; Cassidy, F.; Evans, J. M.; Faruk, E. A.;
Hamilton, T. C.; Nash, D. J.; Stemp, G.; Willcocks, K. J. Med. Chem.
1986, 29, 2194; (c) Bergmann, R.; Gericke, R. J. Med. Chem. 1990, 33,
492; (d) Gericke, R.; Harting, J.; Lues, I.; Schittenhelm, C. J. Med.
Chem. 1991, 34, 3074; (e) Cassidy, F.; Evans, J. M.; Hadley, M. S.;
Haladij, A. H.; Leach, P. E.; Stemp, G. J. Med. Chem. 1992, 35, 1623;
(f) D: Pinney G. Kevin,; Arthasary, P.; Shirali, A.; Edvardsen, K.;
Chaplin, D.J. U.S. Patent. US2005/024590A1; (g) Wipf, P.; Weiner,
W. S. J. Org. Chem. 1999, 65, 5321; (h) Jankun, J.; Selman, S. H.;
Swiercz, R.; Skrzypczak-Jankun, E. Nature 1997, 387, 561; (i) Van
Lommen, G.; De Bruyn, M.; Schoven, M. J. Pharm. Belg. 1990, 45,
355–360; (j) Covington, A. D. Chem. Soc. Rev. 1997, 111–126.
4. Hanamoto, T.; Shindo, K.; Matsuoka, M.; Kiguchi, Y.; Kondo, M.
J. Chem. Soc., Perkin Trans. 1 2000, 3082.
5. Varma, R. S.; Dahiya, R. J. Org. Chem. 1998, 63, 8038.
6. (a) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063–4065; (b)
Kabalka, G. W.; Venkataiah, B.; Das, Bhaskar. C. Synlett 2004,
2194–2196.
7. Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864.
8. Kaye, P. T.; Nocanda, X. W. J. Chem. Soc., Perkin Trans. 1 2000,
1331.
9. Hlubeck, J.; Ritchie, E.; Taylor, W. C. Tetrahedron Lett. 1969, 1369.
10. Iyer, M.; Trivedi, G. R. Synth. Commun. 1990, 20, 1347.
11. Parker, K. A.; Mindt, T. L. Org. Lett. 2001, 3(24), 3875.
12. Ye, L. Wu.; Sun, Xiu-L.; Zhu, Chun-Y.; Tang, Y. Org. Lett. 2006, 8,
3853–3856.
13. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
14. Roush, W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem.
Soc. 1986, 108, 3422–3434.
15. Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644–
13645.
16. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–
5449.
17. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–
446.
18. Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash, G. K. S.; Olah,
G. A. Synlett 1997, 606–608.
Compound 19:
A
solution of 2-hydroxy-5-nitrobenzaldehyde
(272.92 mg, 1.6 mmol), potassium trans-1-decenyltrifluoroborate
(402 mg, 1.6 mmol), was added with dibenzylamine (82 mg,
20 mol %) in anhydrous DMF (8 mL). The reaction mixture was
heated at 80 °C overnight. The reaction mixture was quenched with
aqueous saturated NH4Cl (8 mL), extracted with CH2Cl2
(10 mL Â 3), and the combined organic layers were washed with
water (10 mL Â 3). The water layer was extracted with CH2Cl2
(5 mL Â 2). The combined organic layers were dried with Na2SO4,
and evaporated. The residue was purified by flash column chromato-
graphy using hexane–ethyl acetate/98:2 as the eluent to give a yellow
solid, 402.15 mg (85.1%). 1H NMR(300 MHz, CDCl3): d 7.99 (dd,
J = 8.85, 2.4 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 6.78 (d, J = 8.7 Hz,
1H), 6.40 (dd, J = 10.8, 1.2 Hz, 1H), 5.79 (dd, J = 12, 1.5 Hz, 1H),
5.04–5.01 (m, 1H), 1.82–1.70 (m, 2H), 1.52–1.31 (m, 2H), 1.26 (br s,
10H), 0.875 (t, J = 6.3 Hz, 3H). 13C NMR CD3COCD3: d 159.56,
141.87, 128.03, 125.64, 122.65, 121.83, 116.48, 77.48, 36.34,32.23,
24.94, 23.04, 14.84. ESI MS calcd for C17H23NO3 ([MÅ+ÀHÅ]+):
288.1521; found: 288.120.
19. Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031–2034.
20. For the synthesis of organotrifluoroborates, see: (a) Vedejs, E.;
Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org.
Chem. 1995, 60, 3020; (b) Vedejs, E.; Fields, S. C.; Hayashi, R.;
Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc.
1999, 121, 2460; (c) Molander, G. A.; Figueroa, R. Aldrichim. Acta
2005, 38, 49; (d) Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2003,
4313; (e) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–
286; (f) Chambers, R. D.; Clark, H. C.; Willis, C. J. J. Am. Chem. Soc.
1960, 82, 5298–5301; (g) Takahashi, M.; Bae, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2004, 126, 15334.
21. Use of BF3K in organic synthesis. (a) Kabalka, G. W.; Venkataiah,
B.; Dong, G. Org. Lett. 2003, 3803–3805; (b) Kabalka, G. W.; Reddy,
M. Organometallics 2004, 23, 4519–4521; (c) Kabalka, G. W.;
Venkataiah, B.; Dong, G. Tetrahedron Lett. 2004, 729–731; (d)
Kabalka, G. W.; Dong, G.; Venkataiah, B. Tetrahedron Lett. 2005,
46, 763–765; (e) Molander, G. A.; Katona, B. W.; Machrouhi, F. J.
Compound 20: A solution of 3,5-dichlorosalicyladehyde (382 mg,
2 mmol), potassium trans-1-decenyltrifluoroborate (492 mg, 2 mmol),
was added with dibenzylamine (82 mg, 20 mol %) in anhydrous DMF
(10 mL). The reaction mixture was heated at 80 °C overnight. The
reaction mixture was quenched with aqueous saturated NH4Cl
(8 mL), extracted with CH2Cl2 (15 mL Â 3), and the combined
organic layers were washed with water (10 mL Â 3). The water layer
was extracted with CH2Cl2 (10 mL Â 2). The combined organic layers
were dried with Na2SO4, and evaporated. The residue was purified by
flash column chromatography using hexane as the eluent to give a
yellow solid, 545.00 mg (87.00%). 1H NMR (300 MHz, CDCl3): d
7.16 (d, J = 2.1 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.33 (dd, J = 9.9,
1.5 Hz, 1H), 5.82 (dd, J = 9.8, 3.6 Hz, 1H), 4.95 (m, 1H), 1.83–1.46
(m, 4H), 1.30 (br s, 10H), 0.93 (t, J = 6.3 Hz, 3H).13C NMR CDCl3: d
148.22, 129.25, 128.41, 125.73, 124.89, 124.52, 122.80, 122.12, 76.67,
35.71, 32.27, 29.75, 25.24, 23.09, 14.52. ESI MS calcd for C17H22Cl2O
([MÅ+ÀHÅ]+): 311.097; found: 311.0903.