Oxidation of p-aminophenols and formal radical cyclization onto benzene rings: Formation of benzo-fused nitrogen heterocycles

Article abstract of DOI:10.1021/ol047977j

(Chemical Equation Presented) p-Iodophenol and its O-MOM-protected ether can be converted into iodoamines 2. These give cross-conjugated ketones 3 on oxidation with hypervalent iodides in the presence of methanol, and the ketones undergo radical cyclization. Exposure of the products to acid or sequential treatment with a Grignard reagent and acid effects rearomatization to produce benzo-fused nitrogen heterocycles 4.

Full text of DOI:10.1021/ol047977j

ORGANIC
LETTERS
2005
Vol. 7, No. 1
23-26
Oxidation of p-Aminophenols and
Formal Radical Cyclization onto
Benzene Rings: Formation of
Benzo-Fused Nitrogen Heterocycles†
Stephen P. Fletcher, Derrick L. J. Clive,* Jianbiao Peng, and David A. Wingert
Chemistry Department, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
derrick.cliVe@ualberta.ca
Received October 3, 2004
ABSTRACT
p-Iodophenol and its O-MOM-protected ether can be converted into iodoamines 2. These give cross-conjugated ketones 3 on oxidation with
hypervalent iodides in the presence of methanol, and the ketones undergo radical cyclization. Exposure of the products to acid or sequential
treatment with a Grignard reagent and acid effects rearomatization to produce benzo-fused nitrogen heterocycles 4.
Radical cyclizations onto benzene rings represent an unde-
veloped but potentially useful process, although, at present,
such reactions are often difficult and the mechanism is not
formation of other types of benzo-fused heterocycles by
radical closure would be useful and, in particular, synthesis
of 2,3-dihydrindoles and 1,2,3,4-tetrahydroquinolines, espe-
cially those with chiral centers, could give access to a broad
range of biologically significant compounds.
We now report synthetic methodology that allows the same
principle to be applied to nitrogen heterocycles conforming
to the general structure 2.4 (Scheme 2). These compound
Scheme 1
Scheme 2
fully understood.1 The most reliable procedure appears to
involve the use of xanthates with stoichiometric amounts of
a diacyl peroxide.2,3 A previous publication4 from this
laboratory has described a method for making benzo-fused
oxygen heterocycles by a process that is formally equivalent
to a radical cyclization onto a benzene ring (Scheme 1). This
method was limited to oxygen heterocycles, as it relies on
the oxidative dearomatization of a p-alkoxy phenol. The
classes include many substances reported in recent pharma-
ceutical patents5 as having important biological properties.
The key intermediates of our method are the cross-
conjugated ketones 2.2, and we first evaluated a number of
synthetic routes in order to identify a preparative sequence
† Dedicated to Professor E. Piers in recognition of his contributions to
Chemistry and to the Canadian Chemical Community.
10.1021/ol047977j CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/15/2004

Scheme 3a
a Reagents and conditions: (a) CuI (cat.), L-proline (cat.), K2CO3, DMSO, amino alcohol, heat. (b) CuI (cat.), N,N′-dimethylethylene-
diamine (cat.), Cs2CO3, DMF, amido alcohol, heat. (c) I2, Ph3P, imidazole. (d) PhOCOCl, i-Pr2NEt, CH2Cl2. (e) (i) allylOCOCl (0.6 equiv),
-40 °C; (ii) i-Pr2NEt (0.6 equiv); (iii) allylOCOCl (0.6 equiv), MeCN. (f) (i) MeOCOCl (0.6 equiv), -30 °C; (ii) i-Pr2NEt (0.6 equiv); (iii)
MeOCOCl (0.6 equiv), MeCN. (g) (CF3CO)2O, i-Pr2NEt, CH2Cl2, 0 °C. (h) MeOCOCl, i-Pr2NEt, CH2Cl2. (i) Me3SiBr, CH2Cl2. (j) PhI(OAc)2,
MeOH. (k) Bu3SnH, AIBN, PhMe. (l) TsOH‚H2O (cat.), CHCl3. (m) TsOH‚H2O (cat.), 4 Å molecular sieves.
in which several closely linked requirements are each
satisfied in a mutually compatible way. Access to these
ketones requires preparation and oxidation of the p-ami-
nophenols 2.1 carrying a protecting group on nitrogen and
also an alkyl chain terminating in an iodine atom. Homolysis
of the carbon-iodine bond serves to trigger radical cycliza-
tion (2.2 f 2.3), and the length of the alkyl chain determines
the size of the newly formed ring.
(1) (a) For mechanistic discussion, see: Beckwith, A. L. J.; Bowry, V.
W.; Bowman, W. R.; Mann, E.; Parr, J.; Story, J. M. D. Angew. Chem.,
Int. Ed. 2004, 43, 95-98. (b) Beckwith, A. L. J.; Storey, J. M. D. J. Chem.
Soc., Chem. Commun. 1995, 977-978. (c) Crich, D.; Hwang, J.-T. J. Org.
Chem. 1998, 63, 2765-2770. (d) Cf. Crich, D.; Sannigrahi, M. Tetrahedron
2002, 58, 3319-3322.
The starting amino or amido alcohols (Scheme 3, column
2) were best made by copper-mediated coupling of an
O-protected p-iodophenol, although in some cases the
24
Org. Lett., Vol. 7, No. 1, 2005

reaction was successful even without masking the phenolic
hydroxyl. The modern procedures developed by the groups
of Ma6 and Buchwald7 were tried. It was found that Ma’s
method is very convenient for coupling with amines (7 f
8, 15, 19; 26 f 27), while Buchwald’s procedure was
excellent for coupling with amides (7 f 23; 26 f 32). Under
Ma’s conditions (CuI, L-proline, DMSO, K2CO2, 55-85 °C),
the iodophenol or its MOM ether was converted smoothly
into the corresponding secondary amine, which was then
processed either by N-acylation and formation of the iodide,
or by the reverse sequence, formation of the iodide followed
by N-acylation. Use of Buchwald’s method gave 23 and 32,
which were directly converted into iodides 24 and 33,
respectively. Our experiments demonstrate the compatibility
of these copper-mediated reactions6,7 with unprotected al-
cohols and, in some cases, free phenols, a characteristic that
is clearly a useful feature.
and alkyl groups appear to be unsuitable in this regard, at
least as judged by experiments with 5a-c and 6. However,
MeOCO-, allylOCO-, CF3CO-, and PhOCO- are satis-
factory, and oxidation was easily achieved also in the case
of 25 (Scheme 3), which is equivalent to an intramolecularly
protected amine.
The oxidations were done using PhI(OAc)2, PhI(O-
COCF3)2, or PhIO and were also successful with the amides
33 (see Scheme 3) and 4.1 (Scheme 4).11
Unlike the oxidation of p-alkoxyphenols to quinone acetals
(cf. 1.1 f 1.2, Scheme 1), the corresponding transformation
of p-aminophenols (cf. 2.1 f 2.2, Scheme 2) is not well-
known, the only relevant examples being found in synthetic
work on dynemicin A (Scheme 4, 3.1 f 3.2)8 and in a report
Iodides 2.1 were prepared from the corresponding alcohols
using the Ph3P-I2-imidazole combination,12 and we have
carried out the alcohol f iodide conversion either before (8
f 9, 15 f 16) or after N-acylation (12 f 13, 20 f 21, 28
f 29, 30 f 31). In the case of the conversion 20 f 21,
generation of the iodide was successful only with phenyl
carbamate protection. Where appropriate, MOM protecting
groups were removed with Me3SiBr prior to oxidation.
Radical cyclization under standard high-dilution conditions13
worked well in all cases, except for 33a, which, like 4.2,
was stable only in the solid state or in acidic MeOH but
decomposed under other conditions.
Scheme 4
The aromatization step (cf. 2.3 f 2.4) can, in principle,
proceed in two ways, depending on whether the methoxy
group (2.3 f 2.4, Scheme 2) or the amino unit is expelled;
fortunately, the desired loss of the methoxy group is the only
pathway we observe under our optimized conditions.14
that 4.1 is convertible into 4.2 on treatment with PhI(OAc)2
(Scheme 4).9,10 We evaluated a number of nitrogen protecting
groups and found that not all of them allow the chemical
oxidation 2.1 f 2.2: p-toluenesulfonyl, t-butoxycarbonyl,
Scheme 5a
(2) (a) Axon, J.; Boiteau, L.; Boivin, J.; Forbes, J. E.; Zard, S. Z.
Tetrahedron Lett. 1994, 35, 1719-1722. (b) Liard, A.; Quiclet-Sire, B.;
Saicic, R.; Zard, S. Z. Tetrahedron Lett. 1997, 38, 1759-1762. (c) Cholleton,
N.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 7295-7298. (d) Hoang-Cong,
X.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2125-2126.
(e) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett.
1999, 40, 2533-2536. (f) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S.
Z. Angew. Chem., Int. Ed. 2000, 39, 731-733. (g) Quiclet-Sire, B.; Sortais,
B.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 2002, 1692-1693. (h)
Quiclet-Sire, B.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 2002, 2306-
2307. (i) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672-685.
(3) (a) Menes-Arzate, M.; Mart´ınez, R.; Cruz-Almanza, R. Muchowski,
J. M.; Osornio, Y. M.; Miranda, L. D. J. Org. Chem. 2004, 69, 4001-
4004. (b) For other leading references, see ref 4.
a Reagents and conditions: (a) (i) Allyl-magnesium bromide,
THF; (ii) TsOH‚H2O, 4 Å molecular sieves, CH2Cl2, 71%.
(4) Clive, D. L. J.; Fletcher, S. P.; Liu, D. J. Org. Chem. 2004, 69, 3282-
As in the formation of benzo-fused oxygen heterocycles
(Scheme 1), the present method can be modified to generate
compounds carrying hydrogen or a carbon substituent instead
3293.
(5) For example, see the following. Kinase inhibitors: Smithkline
Beecham, WO 2004043379, 2004. Histamine H3 receptor antagonists: Eli
Lilly, WO 2004026837, 2004. 2,3-Oxidosqualene-lanosterol cyclase inhibi-
tors: Hoffmann-La Roche, WO 2002050041, 2002. Growth hormone release
promoters: Sumimoto Pharmaceuticals, JP 11292894, 1999. Treatment for
dementia: U.S. Department of Health and Human Services, WO 2002048150,
2002. Dopamine D4 receptors: H. Lundbeck A/S, WO 9828293, 1998.
Estrogen receptor modulators: Eli Lilly, WO 2002094788, 2002.
(6) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453-2455.
(7) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421-7428.
(8) (a) Yoon, T.; Shair, M. D.; Danishefsky, S. J. Tetrahedron Lett. 1994,
35, 6259-6262. (b) Shair, M. D., Yoon, T. Y.; Mosnie, K. K.; Chou, T.
C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509-9525. (c) Myers,
A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem.
Soc. 1997, 119, 6072-6094.
(9) Fleck, A. E.; Hobart, J. A.; Morrow, G. W. Synth. Commun. 1992,
22, 179-187.
Org. Lett., Vol. 7, No. 1, 2005
25

especially attractive feature is the opportunity to use chiral
amino alcohols in the first step so as to afford products with
chiral centers, as illustrated by structures 22c and 25c, and
the possibility of modifying the intermediate enones before
rearomatization offers additional synthetic possibilities.
Scheme 6a
Acknowledgment. We thank NSERC for financial sup-
port, a Graduate Fellowship (S.P.F.), and an Undergraduate
Student Research Award (D.A.W.).
Supporting Information Available: Characterization
data for 11c, 14c, 18c, 22c, 25c, 29c, 31c, 35, 37, 39. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL047977J
a Reagents and conditions: (a) allyltributyltin, AIBN, PhMe,
reflux, 61%. (b) TsOH‚H2O, 4 Å molecular sieves, CH2Cl2, 80%.
(c) (i) Allylmagnesium bromide (1.2 equiv), THF; (ii) TsOH‚H2O,
4 Å molecular sieves, CH2Cl2, 39 (48%) and 37 (35%).
(10) Reported experimental procedure did not work in our hands.
However, we were able to make 4.2 (75%) by a modified workup, while a
modified method gave 92% yield: PhIO was added to a solution of 4.1
and then TsOH was added. The mixture was concentrated to a small volume
(not to dryness) and then chromatographed over silica gel, using MeOH-
EtOAc-hexane (the presence of MeOH was essential).
(11) Oxidation of 4.1 was examined as a model for 33.
(12) Garegg, P. J.; Samuelson, B. J. Chem. Soc., Chem. Commun. 1979,
978-980.
(13) Toluene solutions of tributyltin hydride (0.07-0.12 M) and AIBN
(0.005-0.0110 M, 0.1 equiv) were added over 3-5 h to a hot (85 °C)
solution (0.035 M) of the substrate, and heating was continued for an
arbitrary period of 1-10 h after the addition.
(14) In the absence of molecular sieves, with compound 11b, we did
observe the undesired pathway as a minor pathway (we have not tested
other compounds under the same conditions or attempted to optimize this
minor pathway). Conversion of 14b to 14c was arbitrarily done without
molecular sieves.
of a phenolic hydroxyl (see Scheme 5, 29b f 35), and the
intermediate radical can also be intercepted (see Scheme 6,
31a f 36 f 37); in addition, both possibilities can be
combined for a single substrate (see Scheme 6, 31a f 36
f 38 f 39).
The above exploratory studies establish that our indirect
method for cyclization onto a benzene rings is not limited
to the oxygen series but is also a general and flexible route
to a wide range of benzo-fused nitrogen heterocycles. An
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Org. Lett., Vol. 7, No. 1, 2005