Potassium superoxide as an alternative reagent for Winterfeldt oxidation of beta-carbolines.

Article abstract of DOI:10.1021/ol0271279

Potassium superoxide was examined as an alternative oxidation reagent for the Winterfeldt reaction. KO(2) was found to be superior to the original Winterfeldt protocol for base-sensitive substrates. [reaction--see text]

Full text of DOI:10.1021/ol0271279

ORGANIC
LETTERS
2003
Vol. 5, No. 1
43-46
Potassium Superoxide as an Alternative
Reagent for Winterfeldt Oxidation of
â-Carbolines
Weiqin Jiang,* Xuqing Zhang, and Zhihua Sui
Johnson & Johnson Pharmaceutical Research & DeVelopment, L.L.C.,
1000 Route 202 South, P.O. Box 300, Raritan, New Jersey 08869
Wjiang1@prdus.jnj.com
Received October 17, 2002
ABSTRACT
Potassium superoxide was examined as an alternative oxidation reagent for the Winterfeldt reaction. KO was found to be superior to the
2
original Winterfeldt protocol for base-sensitive substrates.
Phosphodiesterase 5 (PDE5) is the major cGMP-hydrolyzing
enzyme in the human corpus carvernosum. It is well
established that nitric oxide triggers the signal transduction
pathway, and inhibition of PDE5 ultimately leads to enhanced
penis erection.1 Existing therapy by sildenafil, a PDE5
inhibitor for male erectile dysfunction (MED),2 has some
adverse cardiovascular side effects and causes visual distur-
bances due to PDE1 and PDE6 inhibition. It is our goal to
identify more potent and selective PDE5 inhibitors for the
treatment of erectile dysfunction (ED) and female sexual
arousal disorders.3 Recently, we reported a series of pyrim-
idinyl pyrroloquinolones 2 as more potent and selective
PDE5 inhibitors than their nonoxidized precursors, â-car-
bolines 1.3e As part of our continued efforts in this area, we
attempted to use the Winterfeldt protocol7 to oxidize acyl
â-carbolines, such as furoyl derivatives 3 to pyrroloquino-
lones 4 but failed to obtain any products (Scheme 1).
Oxidation of 2,3-disubstituted indole derivatives with
m-CPBA,4 NaIO4,5 or singlet oxygen,6 particularly 1,2,3,4-
tetrahydro-â-carbolines with O2/NaH or KO-t-Bu,7 is well
documented. Among these conditions, Winterfeldt’s biomi-
metic autoxidation7 appeared to be the only method that
worked for the preparation of pyrroloquinolones, such as
compounds 2, for the PDE5 program. However, for substrates
bearing functional groups sensitive to strong bases, i.e., NaH
or KO-t-Bu, such as acyl â-carbolines, 9a and 9b, the
Winterfeldt reaction failed to provide the desired products.
Yet, compounds 10a and 10b, which are very potent PDE5
(1) Corbin, J. D.; Francis, S. H. J. Biol. Chem. 1999, 274, 13729-13732.
(2) Lue, T. F. N. Engl. J. Med. 2000, 342, 1802-1818.
(3) (a) Sui, Z.; Macielag, M. J.; Guan, J.; Jiang, W.; Lanter, J. C. PCT
Int. Appl. WO 0187882, 2001. (b) Sui, Z.; Macielag, M. J. PCT Appl. WO
0187038, 2001. (c) Sui, Z.; Guan, J.; Jiang, W.; Macielag, M. J.; Walsh, S.
P.; Lanter, J. C.; Fiordeliso, J. J.; Alford, V. C., Jr.; Qiu, Y.; Patricia, K.;
Bhattacharjee, S.; Lombardi, E.; Haynes-Johnson, D.; John, T. M.; Clancy,
J. Abstracts of Papers, 224th National Meeting of the American Chemical
Society, Boston, MA, August 18-22, 2002; American Chemical Society:
Washington, DC, 2002; MEDI-278. (d) Zhang, X.; Jiang, W.; Sui, Z.
Abstracts of Papers, 224th National Meeting of the American Chemical
Society, Boston, MA, August 18-22, 2002; American Chemical Society:
Washington, DC, 2002; MEDI-374. (e) Sui, Z.; Guan, J.; Macielag, M. J.;
Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P.; Bhattacharjee, S.; John, T. M.;
Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096. (f)
Jiang, W.; Sui, Z.; Macielag, M. J.; Walsh, S. P.; Fiordeliso, J. J.; Lanter,
J. C.; Guan, J.; Qiu, Y.; Kraft, P.; Bhattacharjee, S.; Craig, E.; Haynes-
Johnson, D.; John, T. M.; Clancy, J. J. Med. Chem. In press. (g) Jiang, W.;
Sui, Z.; Chen, X. Tetrahedron Lett. 2002, 43, 8941-8945.
(4) Guller, R.; Borschberg, H.-J. Tetrhedron: Asymmetry 1992, 3, 1197-
1204.
(5) Dolby, L. J.; Booth, D. L. J. Am. Chem. Soc. 1966, 88, 1049-1051.
(6) Nakagawa, M.; Yokoyama, Y.; Kato, S.; Hino, T. Tetrahedron 1985,
41, 2125-2132.
(7) (a) Winterfeldt, E. Liebigs Ann. Chem. 1971, 745, 23-30. (b)
Warneke, J.; Winterfeldt, E. Chem. Ber. 1972, 105, 2120-2125. (c) Boch,
M.; Korth T.; Nelke, J. M.; Pike, D.; Radunz, H.; Winterfeldt, E. Chem.
Ber. 1972, 105, 2126-2142.
10.1021/ol0271279 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/12/2002

The general synthetic route for the preparation of 1,2,3,4-
tetrahydro-â-carbolines 7 is outlined in Scheme 3. Tryptamine
Scheme 1
Scheme 3
or its derivatives 5 underwent Pictet-Spengler cyclizations
(CH2Cl2, 0.14 M, 2 equiv of TFA, 25 °C) with alkyl or aryl
aldehydes to afford the corresponding 1,2,3,4-tetrahydro-â-
carbolines 6 in 50-89% yields. After N-acylation or N-
alkylation, we turned our attention to the KO2 oxidation of
â-carbolines 7. Generally, the reaction time varied from 2
to 16 h depending on the substrates. Over-oxidation or excess
heat led to decomposition of some substrates. The reaction
could be carried out at room temperature from 10 mg to 200
g scale in DMF, THF, or DMSO. The solvent study showed
that DMF provided the best yield (Table 1). However, due
inhibitors, can be obtained from the â-carboline precursors
9a and 9b upon treatment by KO2/18-crown-6 in 26 and 21%
yields, respectively (Scheme 2). Thus, our interest in finding
Scheme 2
Table 1. Solvent and Phase Transfer Reagent Studya
solvent
phase transfer reagent
time
% yield
THF
18-crown-6
18-crown-6
18-crown-6
Et3BnNCl
Aliquat 336
16 h
16 h
16 h
4 d
41
35
52
41
58
DMSO
DMF
DMF
DMF
42 h
a This is for the transformation of â-carboline 7a to pyrroloquinolones
8a; see footnote 13 for a detailed procedure.
a general method to oxidize 1,2,3,4-tetrahydro-â-carbolines
bearing an amide functional group led us to the discovery
of the inexpensive and commercially available potassium
superoxide, KO2, as an alternative reagent to Winterfeldt
oxidation.
Potassium superoxide (KO2) is known as a synthetically
useful oxygen nucleophile.8 KO2 oxidation of indoles to
quinolone derivatives in DMF in the presence of a phase
transfer reagent is mild and efficient.9 Herein we demonstrate
that KO2 can also successfully convert â-carbolines to
pyrroloquinolones. Potassium superoxide has a pKa of 4.8,
which is similar to that of KOAc (pKa ) 4.75),10 a much
weaker base than KO-t-Bu. We found that KO2 could be
used in many cases when the Winterfeldt oxidation condi-
tions (KO-t-Bu/O2) failed to provide any desired products
(vide infra).
to the exothermicity of the oxidation, for the large-scale
reactions, KO2 is preferably added at 0 °C and then the
reaction mixture is allowed to slowly warm to ambient
temperature. According to the mechanism proposed for the
oxidation of indole derivatives by G. Speier et al.,9a for each
equivalent of substrate, 2 equiv of KO2 are required to
generate the anionic indolyl intermediate. We tested KO2
ratios from 2 to 12 equiv and found that 4.0 equiv of KO2
are sufficient to drive the reaction to completion. We also
compared different phase transfer reagents, i.e., 18-crown-
6,8 Et3BnNCl,9a and Aliquat 33611 (see Table 1). We found
that the addition of 18-crown-6 or Aliquat 336 provided
higher yields than Et3BnNCl. Additionally, 18-crown-6
accelerated the reaction rate greater than Aliquat 336.
Therefore, we chose 18-crown-6 as the phase transfer reagent
and DMF as the solvent for the remaining substrates.
Table 2 summarizes the results of the KO2 oxidation of
1,2,3,4-â-carbolines 7 to quinolones 8. Generally, KO2
(8) Corey, E. J.; Nicolaou, K. C.; Shibasaki, M.; Machide, Y.; Shiner,
C. S. Tetrahedron Lett. 1975, 37, 3183-86.
(9) (a) Balogh-Hergovich, E.; Spier, G. Tetrahedron Lett. 1982 23, 4473-
5. (b) Itakura, K.; Uchida, K.; Kawakishi, S. Tetrahedron Lett. 1992, 33,
2567-2570.
(10) For the physical chemical properties of KO2, see: Lee-Ruff, E.
Chem. Soc. ReV. 1977, 6, 195-214.
(11) Lissel, M.; Dehmlow, E. V. Tetrahedron Lett. 1978, 19, 3689.
Org. Lett., Vol. 5, No. 1, 2003
44

Table 2. KO2 Oxidations of 1,2,3,4-â-Carbolines to Pyrroloquinolonesa,13
a General reaction condition: â-carboline (1 equiv), 18-crown-6 (1 equiv), and KO2 (4 equiv) in DMF (0.16 M) at 25 °C were stirred until the starting
material disappeared. Different protecting groups were compared in entries 2-4. See footnote 13 for a detailed experimental procedure.
oxidation of 7 provided moderate to good yields of quino-
lones 8. The method works for â-carbolines generated from
both aromatic and aliphatic aldehydes with yields ranging
from 48 to 75%.
Org. Lett., Vol. 5, No. 1, 2003
45

Winterfeldt oxidation did not provide any pyrroloquinolone
products from benzoyl- or Boc-protected â-carbolines 7b and
7c (entries 2 and 3). Initially, we tested the KO2 method on
these two substrates, in which R1 is a phenyl group bearing
an electron-donating group. To our delight, we could isolate
the pyrroloquinolone product in moderate yields. In the case
where R1 was a 3,4-methylene-dioxyphenyl group, the
product yield was dependent upon the functional group R2
on the amine (entries 2-4, R2 ) Bz, Boc, and Bn and the
yields were 24, 37 and 53% for substrates 7b, 7c, and 7d
respectively). When R1 was an alkyl group (entries 9 and
10), similar functional groups on the amine (Boc or Bz) led
to slightly higher yields (75 and 48% for substrates 7i and
7j, respectively). When R1 was a phenyl group, â-carboline
7e (entry 5) proceeded to give pyrroloquinolone 8e in good
yield. However, when R1 was a p-NO2 phenyl group,
â-carboline 7f (entry 6) was dehydrogenated upon treatment
with KO2, even at -60 °C. Interestingly, when R1 was a
p-Cl phenyl group, â-carboline 7g (entry 7) proceeded well
to provide pyrroloquinolone 8g. For optically pure starting
material 7h (entry 8), this method provided product 8h
smoothly without any epimerization.
The following cases distinguished the KO2 method more
from the Winterfeldt conditions. For entry 12, the KO2
method provided the desired product 8l in 52% yield without
epimerization, while the KO-t-Bu/O2 method only led to
dehydrogenated or hydrolyzed starting material. Moreover,
the KO-t-Bu/O2 method failed to provide any desired
pyrroloquinolones in entries 13 and 14 for substrates 7m and
7n, due to the fact that KO-t-Bu isomerized the allyl group
(entry 13) and cleaved the N-SO2Ph bond (entry 14). In
entry 14, Winterfeldt oxidation actually generated fully
aromatized â-carboline as the major product. Yet, because
of the mild basicity of KO2, 7m and 7n proceeded well to
pyrroloquinolones 8m and 8n.
provide the desired quinolone probably due to the ring
opening of the epoxide. Judged by HPLC-MS, the product
mixture contained several diol derivatives. Moreover, sub-
strates bearing radical-sensitive functionalities such as aryl
bromide12a or 1,2-diphenol12b should not be used in this
reaction due to the possible side reactions caused by indolyl
radical intermediate generated during the reaction process.
Since Winterfeldt oxidation might go through an anionic
intermediate, in this sense, KO2 oxidation method is comple-
mentary to the Winterfeldt condition.
In conclusion, we have developed a mild and efficient
method for the synthesis of pyrroloquinolones by KO2.
â-Carbolines bearing a variety of functional groups can be
effectively oxidized using inexpensive and widely available
reagents. This is a superior method to Winterfeldt oxidation
for base-sensitive substrates.
Acknowledgment. The authors thank Ms. Mary Evan-
gelisto and Dr. Naresh Jain for technical support and Dr.
Raymond Ng for helpful discussions.
Supporting Information Available: Experimental details
and characterization for all new compounds (1H NMR and
mass spectral data). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0271279
(12) (a) Yamaguchi, Y.; Van der Plas, H. C. Rec. TraV. 1977, 96, 89.
(b) Lee-Ruff, E.; Lever, A. B. P. Can. J. Chem. 1976, 54, 1837.
(13) Typical procedure of KO2 oxidation. Preparation of 1,2,3,4-
tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]-
quinolin-9-one (8a). To a solution of 7a (entry 1 in Table 2) (60 mg, 0.16
mmol) and 18-crown-6 (42 mg, 0.16 mmol) in DMF (1 mL) was added
KO2 (45 mg, 0.63 mmol) in one portion at 25 °C. The reaction mixture
turned red and was stirred for 16 h. Several drops of water were added to
consume the extra KO2. The mixture was then partitioned between ethyl
acetate and water. The aqueous phase was extracted three times with ethyl
acetate. The combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated to give the crude product,
which was purified by silica gel column chromatography using 1:1 EtOAc-
hexane as eluent to give 8a as a white solid (32.5 mg, 52%): 1H NMR 300
MHz (CDCl3) δ 3.21 (t, J ) 8.7 Hz, 2H), 3.51∼3.72 (m, J ) 11.8 Hz,
2H), 4.02 (d, J ) 12.2 Hz, 1H), 4.41 (d, J ) 11.8 Hz, 1H), 4.61 (t, J ) 8.7
Hz, 2H), 4.95 (s, 1H), 6.81 (d, J ) 8.1 Hz, 1H), 7.21-7.41 (m, 8H), 7.55
(t, J ) 8.3 Hz, 1H), 7.91 (s, 1H), 8.41 (d, 1H, J ) 7.56 Hz); MS (m/z) 395
(MH+); HRMS calcd MH+ for C26H22N2O2, 395.1759; found, 395.1743.
Anal. Calcd for C26H22N2O2‚0.6 H2O: C, 77.05; H, 5.77; N, 6.91. Found
C, 77.17; H, 5.50; N, 6.87.
This method also has its limitations. For 3-chloro-1-(6-
methoxy-1,3,4,9-tetrahydro-â-carbolin-2-yl)-propan-1-one 7o,
even the mild basicity of KO2 led to the â-elimination of
HCl and consequently generated the R,â-unsaturated amide,
2-acryloyl-7-methoxy-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quino-
lin-9-one in only 15% yield. KO2 oxidation of 2-oxiranyl-
methyl-2,3,4,9-tetrahydro-1H-â-carboline 7p also failed to
46
Org. Lett., Vol. 5, No. 1, 2003