5040
C. W. Barfoot et al. / Tetrahedron Letters 51 (2010) 5038–5040
OAc
N
In conclusion, we have demonstrated that all six aldehydes can
TMS
OAc
N
OTf
a
be accessed from key intermediates that were derived from kojic
acid (8). This has allowed a diverse range of aldehydes to be synthes-
ised and the ability to deliver multi-gram quantities of material.
96%
OPMB
OPMB
14
22
Acknowledgements
Quant.
b
OAc
Acknowledgement is given to Steve Richards and Richard Upton
for NMR support, Bill Leavens for mass spectroscopy support and
all the chemists involved in this work.
TMS
OAc
N
c
X
N
O
OH
24 X=H
27%
25 X=TMS 23%
References and notes
23
1. (a) Sasamoto, M. Chem. Pharm. Bull. 1960, 8, 324–329; (b) Dobrowsky, A.
Monatsh. Chem. 1951, 82, 122–139.
2. Walker, D. P.; Jacobsen, J. E.; Acker, B. A.; Groppi, V. E.; Piotrowski D. W.
WO2003042210; Chem. Abstr. 2003, 138, 385606.
3. Erol, D. D.; Yulug, N. Eur. J. Med. Chem. 1994, 29, 893–897.
4. Davies, D. T.; Jones, G. E.; Markwell, R. E.; Miller, W.; Pearson, N. D.
WO2002056882; Chem. Abstr. 2002, 137, 125092.
d
70%
OH
O
e - f
70% over 2 steps
N
N
5. Selected analytical data. Compound 2: White solid; mp 120–122 °C; 1H NMR
(400 MHz, CDCl3): d = 4.31 (s, 4H), 7.38 (s, 1H), 8.21 (s, 1H), 9.41 (s, 1H). 13C
NMR (100 MHz, CDCl3): d = 64.3, 64.8, 110.9, 139.8, 144.2, 147.6, 149.9, 192.0.
ESI-HRMS: m/z calcd for C8H8NO3: 166.0504; found 166.0503 [M+H]+.
Compound 3: White solid; mp 58–60 °C; 1H NMR (400 MHz, CDCl3): d = 1.97–
2.05 (m, 2H), 2.79 (t, 2H, J = 7 Hz), 4.25 (t, 2H, J = 7 Hz), 7.63 (s, 1H), 8.18 (s, 1H),
9.85 (s, 1H). 13C NMR (100 MHz, CDCl3): d = 20.9, 24.0, 67.0, 123.2, 130.5, 139.8,
145.2, 155.5, 192.2. ESI-HRMS: m/z calcd for C9H10NO2: 164.0712; found
164.0708 [M+H]+.
O
O
26
6
Scheme 5. Synthetic approach to 2,3-dihydrofuro[2,3-c]pyridine-5-carbaldehyde
(6).5 (a) HC„CTMS, PdCl2(PPh3)2, CuI, Et3N, CH3CN, 45 °C, 18 h; (b) Et3SiH, TFA,
CH2Cl2, rt, 18 h; (c) pyridine, CuI, reflux, 18 h; (d) 24, NaOH, 1,4-dioxane, H2O, rt,
18 h; (e) Pd/C, H2, EtOH, rt, 18 h; (f) MnO2, CH2Cl2, reflux, 18 h.
Compound 4: White solid; mp 140–142 °C; 1H NMR (400 MHz, CDCl3): d = 3.17
(t, 2H, J = 7 Hz), 4.48 (t, 2H, J = 7 Hz), 7.62 (s, 1H), 8.13 (s, 1H), 9.83 (s, 1H). 13C
NMR (100 MHz, CDCl3): d = 24.9, 65.1, 120.9, 129.3, 139.8, 145.6, 151.5, 191.8.
ESI-HRMS: m/z calcd for C8H8NO2S: 182.0276; found 182.0273 [M+H]+.
Compound 5: Off-white solid; mp 110–112 °C; 1H NMR (400 MHz, CDCl3):
d = 1.59 (s, 9H), 3.94 (t, 2H, J = 7 Hz), 4.37 (t, 2H, J = 7 Hz), 8.31 (s, 1H), 8.60 (s,
1H), 9.94 (s, 1H). 13C NMR (100 MHz, CDCl3): d = 28.1, 41.8, 65.0, 83.4, 115.4,
133.3, 140.1, 145.1, 146.3, 151.3, 192.1. ESI-HRMS: m/z calcd for C13H17N2O4:
265.1188; found 265.1184 [M+H]+.
OH
OH
SH
OH
a
S
N
N
31%
O
20
27
Compound 6: Light brown solid; mp 83–86 °C; 1H NMR (400 MHz, DMSO-d6):
d = 3.32 (t, 2H, J = 7 Hz), 4.73 (t, 2H, J = 7 Hz), 7.89 (s, 1H), 8.32 (s, 1H), 9.83 (s,
1H). 13C NMR (100 MHz, CDCl3): d = 28.6, 72.4, 119.0, 131.8, 137.2, 146.8, 160.8,
191.8. ESI-HRMS: m/z calcd for C8H8NO2: 150.0555; found 150.0553 [M+H]+.
Compound 7: White solid; mp 108–110 °C; 1H NMR (400 MHz, CDCl3): d = 5.87
(s, 2H), 7.77 (s, 1H), 8.13 (s, 1H), 9.87 (s, 1H). 13C NMR (100 MHz, CDCl3):
d = 76.2, 115.7, 131.3, 139.1, 148.4, 157.1, 191.5. ESI-HRMS: m/z calcd for
C7H6NO2S: 168.0119; found 168.0117 [M+H]+.
64%
b
O
S
N
O
7
6. Axten, J. M.; Brooks, G.; Brown, P.; Davies, D.; Gallagher, T. F.; Markwell, R. E.;
Miller, W. H.; Pearson, N. D.; Seefeld, M. WO2004058144; Chem. Abstr. 2004,
141, 140414.
7. Perchonock, C. D.; McCarthy, M. E.; Erhard, K. F.; Gleason, J. G.; Wasserman, M.
A.; Muccitelli, R. M.; DeVan, J. F.; Tucker, S. S.; Vickery, L. M.; Kirchnert, T.;
Weichman, B. M.; Mongs, S.; Crooke, S. T.; Newton, J. F. J. Med. Chem. 1985, 28,
1145–1147.
Scheme 6. Synthetic approach to [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde
(7).5 (a) K2CO3, DMF, 10 min, rt, then BrCH2Br, 55 °C, 24 h; (b) MnO2, CH2Cl2, rt, o/n.
8. Clark, D. A.; Goldstein, S. W.; Volkmann, R. A.; Eggler, J. F.; Holland, G. F.; Hulin,
B.; Stevenson, R. W.; Kreutter, D. K.; Gibbs, E. M.; Krupp, M. N.; Merrigan, P.;
Kelbaugh, P. L.; Andrews, E. G.; Tickner, D. L.; Suleske, R. T.; Lamphere, C. H.;
Rajeckas, F. J.; Kappeler, W. H.; McDermott, R. E.; Hutson, N. J.; Johnson, M. R. J.
Med. Chem. 1991, 34, 319–325.
9. Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397–7403.
10. Cailleau, N.; Davies, D. T.; Esken, J. M.; Hennessy, A. J.; Kusalakumari Sukumar,
S. K.; Markwell, R. E.; Miles, T. J.; Pearson, N. D. WO2007081597; Chem. Abstr.
2007, 147, 189160.
Both compounds were separated and the desired acetate 24 was
carried onto the next step. This involved acetate deprotection to
give alcohol 26 in 70% yield. Finally, hydrogenation of the double
bond followed by oxidation of the alcohol gave the desired
aldehyde 6 in 70% yield over two steps.
For the final aldehyde 7,6 we used the same general route as for
aldehyde 4, but used dibromomethane instead of 1,2-dibromoeth-
ane for the cyclisation (Scheme 6).
11. Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35–37.
12. Lutjens, H.; Scammells, P. J. Synlett 1999, 1079–1081.