A Novel Two-Carbon Homologation with N-Vinylacetamides and Ethyl Vinyl Ether as Acetaldehyde Anion Equivalents in the Synthesis of 9H-Xanthene, 9H-Thioxanthene, and 9,10-Dihydro-9-acridine Carboxaldehydes

Article abstract of DOI:10.1021/jo0303057

An efficient synthesis of 9H-xanthene-9-carboxaldehyde (3a), 9H-thioxanthene-9-carboxaldehyde (3b), and 9,10-dihydro-10-methyl-9-acridinecarboxaldehyde (3c) by a novel two-carbon homologation of xanthydrol (1a), thioxanthydrol (1b), and 9,10-dihydro-10-methyl-9-acridinol (1c), respectively, using N-vinylacetamides (2a,b) or ethyl vinyl ether (2c) as acetaldehyde anion equivalents, is described.

Full text of DOI:10.1021/jo0303057

SCHEME 1
A Novel Tw o-Ca r bon Hom ologa tion w ith
N-Vin yla ceta m id es a n d Eth yl Vin yl Eth er
a s Aceta ld eh yd e An ion Equ iva len ts in th e
Syn th esis of 9H-Xa n th en e,
9H-Th ioxa n th en e, a n d
9,10-Dih yd r o-9-a cr id in e Ca r boxa ld eh yd es
Mahavir Prashad,* Yansong Lu, and Oljan Repicˇ
Process Research and Development, Chemical and
Analytical Development, Novartis Institute for
Biomedical Research, One Health Plaza,
East Hanover, New J ersey 07936
mahavir.prashad@pharma.novartis.com
Received September 29, 2003
Abstr a ct: An efficient synthesis of 9H-xanthene-9-carbox-
aldehyde (3a ), 9H-thioxanthene-9-carboxaldehyde (3b), and
9,10-dihydro-10-methyl-9-acridinecarboxaldehyde (3c) by a
novel two-carbon homologation of xanthydrol (1a ), thioxan-
thydrol (1b), and 9,10-dihydro-10-methyl-9-acridinol (1c),
respectively, using N-vinylacetamides (2a ,b) or ethyl vinyl
ether (2c) as acetaldehyde anion equivalents, is described.
TABLE 1. Tw o-Ca r bon Hom ologa tion w ith 2a -c
isolated
entry
alcohol
reagent
product
yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1c
1c
2a
2b
2c
2a
2b
2c
2a
2c
3a
3a
3a
3b
3b
3b
3c
3c
90
85
92
95
90
90
68
65
Xanthene-, thioxanthene-, and acridine-containing mol-
ecules are of biological importance.1-3 Unnatural amino
acids containing these tricyclic ring systems may also be
useful in drug discovery.1 Synthesis of alanine analogues
with these moieties would require 9H-xanthene-9-car-
boxaldehyde (3a), 9H-thioxanthene-9-carboxaldehyde (3b),
and 9,10-dihydro-10-methyl-9-acridinecarboxaldehyde (3c)
as important synthons. Our goal was to develop an
efficient and economical synthesis of these aldehydes. In
this paper we describe our results on a new synthesis of
aldehydes 3a -c by a novel two-carbon homologation of
xanthydrol (1a ), thioxanthydrol (1b), and 9,10-dihydro-
10-methyl-9-acridinol (1c), respectively, using N-vinyl-
acetamides (2a ,b) or ethyl vinyl ether (2c) as acetalde-
hyde anion equivalents (Scheme 1). While the reactions
of carbocations with enamides, silyl enol ethers, and enol
ethers are known,4-12 to the best of our knowledge such
SCHEME 2
(1) Pellicciari, R.; Costantino, G.; Marinozzi, M.; Macchiarulo, A.;
Amori, L.; Flor, P. J .; Gasparini, F.; Kuhn, R.; Urwyler, S. Bioorg. Med.
Chem. Lett. 2001, 11, 3179-3182.
(2) Birman, V. B.; Chopra, A.; Ogle, C. A. Tetrahedron Lett. 1996,
37, 5073-5076.
(3) Matsuno, T.; Okabayashi, I. Yakugaku Zassi 1957, 77, 1145-
1148.
(4) Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000, 56, 3817-
a two-carbon homologation of 1a -c with 2a -c is not
reported in the literature.
3856.
(5) Saito, S.; Uedo, E.; Kato, Y.; Murakami, Y.; Ishikawa, T. Synlett
1996, 1103-1105.
(6) Eberson, L.; Malmberg, M.; Nyberg, K. Acta Chem. Scand. 1984,
38, 391-396.
(7) Mahrwald, R. Chem. Rev. 1999, 99, 1095-1120.
(8) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043-1054.
(9) Ishihara, K.; Yamamoto, H. Tetrahedron Lett. 1989, 30, 1825-
1828.
(10) Bruggen, U. V. D.; Lammers, R.; Mayr, H. J . Org. Chem. 1988,
53, 2920-2925.
(11) Nakamura, E.; Horiguchi, Y.; Shimada, J . I.; Kuwajima, I. J .
Chem. Soc., Chem. Commun. 1983, 796-797.
(12) Sakurai, H.; Sasaki, K.; Hosomi, A. Bull. Chem. Soc. J pn. 1983,
56, 3195-3196.
Reaction of xanthydrol (1a ) with N-methyl-N-vinylac-
etamide (2a ) was selected as the representative example
to develop suitable conditions. Thus, reaction of 1a with
2a in the presence of BF3‚Et2O in dichloromethane
yielded a complicated mixture. Interestingly, the same
reaction in trifluoroacetic acid afforded 9H-xanthene-9-
ylidene-acetaldehyde (4)13 in 17% yield along with xan-
thene and 9-xanthenone. The desired aldehyde 3a was
formed only in trace amounts. However, this reaction in
glacial acetic acid at room temperature afforded the
10.1021/jo0303057 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/20/2003
584
J . Org. Chem. 2004, 69, 584-586

SCHEME 3
desired aldehyde 3a in 90% yield (entry 1, Table 1). No
R,â-unsaturated aldehyde (4) could be detected. The
structure of 3a was further confirmed by its oxidation to
9H-xanthene-9-acetic acid, and by comparison of the
spectroscopic data of this acid with those of an authentic
sample.14 Similarly, use of N-vinylacetamide (2b) instead
of 2a furnished aldehyde 3a in 85% yield (entry 2). The
reaction of 1a with ethyl vinyl ether (1c) in acetic acid
also afforded 3a in 92% yield (entry 3). The two-carbon
homologation of thioxanthydrol (1b) and 9,10-dihydro-
10-methyl-9-acridinol (1c) with 2a -c was studied under
these newly developed conditions. The results are listed
in Table 1. In all cases the yields of 3b and 3c were good
to excellent.
The reaction of diphenylmethanol (6) and 2,4,-dimeth-
oxybenzyl alcohol (7) with 2a did not give any of the
expected homologated products. In both cases, O-protect-
ed derivatives 8 and 9 were isolated in 74% and 61%
yield, respectively (Scheme 2). These results suggested
that this method has a limited scope.
The proposed mechanism for the two-carbon homolo-
gation of 1a -c with 2a ,b is illustrated in Scheme 3. An
initial reaction of alcohol (1a -c) with an acid leads to
the cationic intermediate A, which undergoes a nucleo-
philic attack by 2a ,b to N-acyliminium ion B.4 Interme-
diate B is quenched by water to afford C, which hydro-
lyzes to the desired aldehyde. Evidence for this sequence
was obtained by isolation of 5 as a precipitate formed
during reaction of 1a with 2b. Hydrolysis of isolated 5
afforded 3a . The mechanism of the reaction of ethyl vinyl
ether (2c) with 1a -c would be similar.
(3b), and 9,10-dihydro-10-methyl-9-acridinecarboxalde-
hyde (3c) by a novel two-carbon homologation of xanthy-
drol (1a ), thioxanthydrol (1b), and 9,10-dihydro-10-
methyl-9-acridinol (1c), respectively, using N-vinylacet-
amides (2a ,b) or ethyl vinyl ether (2c) as acetaldehyde
anion equivalents, is described.
Exp er im en ta l Section
Gen er a l P r oced u r e. The alcohol (1a -c, 5.0 mmol) and
N-vinylacetamide, N-methyl-N-vinylacetamide, or ethyl vinyl
ether (2a -c, 6.0 mmol) were mixed, and the flask was immersed
in an ice bath. To the mixture was added glacial acetic acid (8.0
mL). The ice bath was removed, and the reaction mixture was
stirred at room temperature for 1 h. The completion of the
reaction was monitored by TLC.
Water (1.0 mL; or 1.0 mL of concentrated HCl in the case of
2b) was added to the mixture, and stirring was continued for
an additonal 1 h. The reaction mixture was poured onto ice (20.0
g) and extracted with ethyl acetate (30.0 mL). The organic layer
was washed with saturated NaHCO3 (3 × 20.0 mL) and brine
(20.0 mL), dried over anhydrous Na2SO4, and concentrated. The
crude product was purified by silica gel chromatography.
9H-Xa n th en e-9-ca r boxa ld eh yd e (3a ): oil; 1H NMR (300
MHz, CDCl3) δ 2.85 (dd, J ) 1.7 and 6.4 Hz, 2H), 4.62 (t, J )
6.4 Hz, 1H), 7.0-7.15 (m, 4H), 7.15-7.30 (m, 4H), 9.69 (t, J )
1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 33.4, 54.2, 116.7, 123.6,
124.3, 128.2, 128.5, 152.1, 200.4. Anal. Calcd for C15 H12O2: C,
80.34; H, 5.39. Found C, 79.92; H, 5.32.
9H-Th ioxa n th en e-9-ca r boxa ld eh yd e (3b): oil; 1H NMR
(300 MHz, CDCl3) δ 2.92 (dd, J ) 1.5 and 7.1 Hz, 2H), 4.70 (t,
J ) 7.1 Hz, 1H), 7.15-7.28 (m, 4H), 7.32-7.46 (m, 4H), 9.64 (t,
J ) 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 43.0, 45.7, 126.8,
126.9, 127.2, 128.8, 132.7, 137.0, 200.7. Anal. Calcd for C15 H12
-
OS: C, 74.97; H, 5.03; S, 13.34. Found: C, 74.70; H, 4.99; S,
13.20.
In summary, an efficient synthesis of 9H-xanthene-9-
carboxaldehyde (3a ), 9H-thioxanthene-9-carboxaldehyde
9,10-Dih yd r o-10-m eth yl-9-a cr id in eca r boxa ld eh yd e (3c):
mp 85-86 °C; 1H NMR (300 MHz, CDCl3) δ 2.67 (dd, J ) 2.1
and 6.8 Hz, 2H), 3.41 (s, 3H), 4.55 (t, J ) 6.8 Hz, 1H), 6.80-
7.10 (m, 4H), 7.15-7.30 (m, 4H), 9.65 (t, J ) 2.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 33.0, 38.7, 50.7, 112.4, 121.0, 126.1,
127.4, 127.9, 142.6, 201.5. Anal. Calcd for C16 H15NO: C, 80.99;
H, 6.37; N, 5.90. Found: C, 81.04; H, 6.43; N, 5.78.
Isola tion of N-[1-(Hyd r oxy)-2-(9H-xa n th en -9-yl)eth yl]-
a ceta m id e (5). Xanthydrol (1a , 5.0 mmol) and N-vinylaceta-
mide (2b, 6.0 mmol) were mixed, and the flask was immersed
in an ice bath. To the mixture was added glacial acetic acid (8.0
mL). The ice bath was removed, and the reaction mixture was
(13) 9H-Xanthene-9-ylidene-acetaldehyde (4): 1H NMR (300 MHz,
CDCl3) δ 6.47 (d, J ) 7.7 Hz, 1H), 7.19-7.36 (m, 4H), 7.42-7.59 (m,
2H), 7.67 (dd, J ) 1.5 and 7.7 Hz, 1H), 7.73 (dd, J ) 1.5 and 7.9 Hz,
1H), 10.05 (d, J ) 7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 117.2,
117.3, 119.0, 120.5, 121.7, 123.7, 124.0, 124.5, 130.1, 131.6, 132.1, 144.4,
151.2, 152.5, 191.9; MS (CI/NH3) 223.0 (MH+). Structure 4 was further
confirmed by its hydrogenation and by comparison of the spectroscopic
data of the resulting hydrogenated product with those of an authentic
sample of 3a .
(14) Okabayashi, I.; Fujiwara, H. J . Heterocycl. Chem. 1984, 21,
1401-1402.
J . Org. Chem, Vol. 69, No. 2, 2004 585

stirred at room temperature for 1 h. The reaction mixture was
filtered and the solid was washed with hexane and dried (it
contained acetic acid). The solid was stirred with aqueous
NaHCO3 and ethyl acetate. The organic layer was separated,
dried over anhydrous Na2SO4, and concentrated to afford 5 (yield
128.16, 129.0, 129.3, 151.98, 152.04, 169.1; MS (ESI) 328 [M +
HCOO]-.
Ack n ow led gm en t. We thank Prof. D. Seebach
(ETH, Zurich, Switzerland) for a helpful discussion.
1
50%): mp 128-129 °C; H NMR (300 MHz, DMSO-d6) δ 1.55-
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR data for compounds 8 and 9. This material is available
free of charge via the Internet at http://pubs.acs.org.
1.70 (m, 1H), 1.72-1.92 (m, 1H), 1.8 (s, 3H), 4.05 (t, J ) 7.3 Hz,
1H), 5.02-5.19 (m, 1H), 5.78 (d, J ) 5.1 Hz, 1H, OH), 7.05-
7.20 (m, 4H), 7.22-7.34 (m, 3H), 7.36-7.45 (m, 1H), 8.28 (d, J
) 9 Hz, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 23.2, 35.5,
47.2, 69.8, 116.52, 116.56, 123.7, 123.8, 125.7, 126.2, 128.09,
J O0303057
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