Expedient approach to novel N-unprotected bicyclic azapyrimidine and pyridine structures

Article abstract of DOI:10.1021/ol3028829

A direct route to novel bicyclic N-unprotected azapyrimidine structures including fused five-, six-, and seven-membered rings is described involving radical addition and cyclization of xanthates; this approach could be partially extended to pyridines.

Full text of DOI:10.1021/ol3028829

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5976–5979
Expedient Approach to Novel
N‑Unprotected Bicyclic Azapyrimidine
and Pyridine Structures
Zhibo Liu, Ling Qin, and Samir Z. Zard*
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652, Ecole Polytechnique, 91128
Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received October 19, 2012
ABSTRACT
A direct route to novel bicyclic N-unprotected azapyrimidine structures including fused five-, six-, and seven-membered rings is described involv-
ing radical addition and cyclization of xanthates; this approach could be partially extended to pyridines.
Heterocyclic and heteroaromatic compounds constitute
by far the largest proportion of drugs in clinical use. It is
therefore not surprising that access to novel heterocyclic
Scheme 1. Divergent Radical Cyclizations
and heteroaromatic derivatives remains at the heart of
research in medicinal chemistry.1 As part of our ongoing
exploration of the scope of the radical addition-transfer of
xanthates, we have established their unique potential for
the construction of very diverse heterocyclic and hetero-
aromatic structures.2,3 In the course of this study, we un-
covered a dramatic effect of the protecting group on
nitrogen on the regioselectivity of the radical cyclization
in the pyridine and pyrimidine series.4
A sample of our observations is displayed in Scheme 1.
When an acetyl (or a sulfonyl) group is present on the
nitrogen of the side chain, as in 1a and 4a, the cyclization
proceeds as expected to give aza- or diazaindolines 2 and 5;
however, in the presence of a carbamate, such as the Boc
group in 1b and 4b, the radical attack takes place on the
ring nitrogen. This hitherto unprecedented reaction path-
(1) (a) Ward, R. A.; Kettle, J. G. J. Med. Chem. 2011, 54, 4670. (b)
way ultimately leads to pyridinone and pyrimidone struc-
tures such as 3 and 6. The remarkable, and totally un-
expected, effect of the nitrogen substituent raised the
question as to what would be the outcome in the absence
of a substituent. Cyclizations on aromatic or heteroaro-
matic rings starting with a naked extranuclear nitrogen,
such as 1 and 4 with R = H, had never been performed as
far as we are aware; we were therefore curious to explore
the regiochemistry of the cyclization.
Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem.
2009, 52, 2952. (c) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.
2009, 52, 6752.
(2) For reviews on the xanthate radical transfer reaction, see: (a)
Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672. (b) Quiclet-Sire, B.;
Zard, S. Z. Chem.;Eur. J. 2006, 12, 6002. (c) Quiclet-Sire, B.; Zard, S. Z.
Top. Curr. Chem. 2006, 264, 201. (d) Zard, S. Z. Aust. J. Chem. 2006, 59,
663. (e) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2011, 83, 519.
(3) For a review, see: El Qacemi, M.; Petit, L.; Quiclet-Sire, B.; Zard,
S. Z. Org. Biomol. Chem. 2012, 10, 5707.
(4) (a) El Qacemi, M.; Ricard, L.; Zard, S. Z. Chem. Commun. 2006, 42,
4422. (b) Laot, Y.; Petit, L.; Zard, S. Z. Chem. Commun. 2010, 46, 5784.
r
10.1021/ol3028829
Published on Web 11/20/2012
2012 American Chemical Society

Previously, the protecting group on the extranuclear
nitrogen (and also the chlorine atoms on the ring) was
introduced to avoid any inter- or intramolecular attack on
thexanthatebya nucleophilicnitrogen, resultinginthe for-
mation of thiols, which are inhibitors of the radical chain.5
It seemed to us, at least in the dichloropyrimidine series,
that the heteroaromatic ring would exert a sufficient elec-
tron pull on the extranuclear nitrogen to obviate the need
for a protecting group, thus allowing both radical addition
and cyclization to be performed directly on the parent
compound.
analogues 4, especially since there was no particular pro-
blem in principle arising from slow rotation and unfavor-
able rotamer population, as in the well-known case of
unsubstitued amides.8 Nevertheless, one positive aspect
of these preliminary experiments is that the feared S- to
N-migration of the alkoxythiocarbonyl group leading to
the unwanted thiol 14, a serious inhibitor of the radical
chain, was indeed not a complicating factor in this case.
Scheme 3. Synthesis of Tetrahydroazanaphthyridines
Scheme 2. Inefficient Route to Diazaindolines (PhthNÀ =
Phthalimido)
Notwithstanding this setback, we explored the homo-
logous series and were pleased to find that a similar
sequence starting with unprotected (N-butenylamino)-
dichloropyrimidine 15 furnished the desired cyclized prod-
ucts in much higher yield (Scheme 3). Thus, addition of
xanthates 8aÀd to 15 gave the corresponding adducts
16aÀd in 59% to 82% yield. Further treatment with stoi-
chiometric amounts of lauroyl peroxide afforded tetrahy-
droazanaphthyridines 17aÀd in synthetically useful yield.
Interestingly, no side products derived from an ipso radical
substitution (cf. 18) were observed in these cyclizations.
Such radical Smiles rearrangements on related structures
are known.9 Even more surprising, unprotected pyrimi-
doazepines 21a,b,e,f could be readily obtained by subject-
ing (N-pentenylamino)dichloropyrimidine 19 to the same
sequence (Scheme 4). In the case of 20f and 21f, the two
diastereoisomers were separable. The formation of a seven-
membered ring by direct radical cyclization on an aromatic
ring is quite rare, and all approaches essentially rely on
xanthate technology.5,10 The fact that the cyclization could
Lauroyl peroxide initiated addition of both S-phthali-
midomethyl- and cyanomethylxanthates 8a an 8b on un-
protected N-allylaminodichloropyrimidine 7 to give 9a
and 9b indeed proceeded in good yield (Scheme 2).6 In
the case of the former, very minor amounts of compounds
10a and 11a were observed, resulting from direct addition
to the heteroaromatic nucleus.7 However, the subsequent
radical cyclization step proved disappointing and furn-
ished only a very modest yield (10À15%) of diazaindolines
12a,b. Varying amounts of prematurely reduced material
13a,b were also isolated from a rather complex reaction
mixture, but no cyclization on the nitrogen atom of the
pyrimidine was observed.
Although the little cyclization that took place proceeded
on the carbon atom of the pyrimidine ring, it was initially
surprising that the cyclization of xanthates 9 should be so
much less efficient in comparison to that of the protected
(8) Yamasaki, R.; Tanatani, A.; Azumaya, I.; Saito, S.; Yamaguchi,
K.; Kagechika, H. Org. Lett. 2003, 5, 1265and references cited therein.
(9) (a) Studer, A. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds; Wiley-VCH: Weinheim, 2001; Vol. 2, p 44. (b) Studer, A.;
Bossart, M. Tetrahedon 2001, 57, 9649. (c) Bacque, E.; El Qacemi, M.;
Zard, S. Z. Org. Lett. 2005, 7, 3817.
ꢁ
ꢁ
(5) Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2004, 6, 3671.
(6) In Schemes 2À7, placing lauroyl peroxide in parentheses indicates
that it is used as the initiator in substoichiometric amounts. No parentheses
means that the peroxide is used both as initiator and as a stoichiometric
oxidant.
(10) (a) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew.
Chem., Int. Ed. Engl. 2000, 39, 731. (b) Petit, L.; Botez, I.; Tizot, A.;
Zard, S. Z. Tetrahedron Lett. 2012, 53, 3220. (c) Charrier, N.; Liu, Z.;
ꢁ
Zard, S. Z. Org. Lett. 2012, 14, 2018. (d) Bacque, E.; El Qacemi, M.;
(7) Osornio, Y. M.; Cruz-Almanza, R.; Jimenez-Montano, V.; Miranda,
L. D. Chem. Commun. 2003, 2316.
Zard, S. Z. Heterocycles 2012, 84, 291. (e) Quiclet-Sire, B.; Tran,
N. D. M.; Zard, S. Z. Org. Lett. 2012, 14, 5514.
Org. Lett., Vol. 14, No. 23, 2012
5977

be accomplished with an unprotected extranuclear nitrogen
atom is certainly not trivial because of the likelihood of an
intramolecular abstraction of the aminyl hydrogen (cf. 22).
The strength of the NÀH in anilines is comparable to that of
a benzylic CÀH, and aniline derivatives are sometimes used
as radical chain inhibitors.11
Scheme 5. Synthesis of a Tetrahydronaphthyridine
Scheme 4. Synthesis of Pyrimidoazepines
We observed a more complicated trend in the pyridine
series. Thus, while the intermolecular addition to N-alke-
nylfluoropyridines 23, 26, and 30 proceeded reasonably
efficiently, treatment of the resulting adductswith stoichio-
metric amounts of peroxide in the usual manner furnished
a moderate yield of tetrahydronaphthyridine 28 from 27
but did not produce any ofthe corresponding azainoline25
or pyridoazepine 32 from adducts 24 and 31a, respectively.
Prematurelyreducedcompounds29and 33a werethe main
side products in the cyclization of xanthates 27 and 31a.
These results are summarized in Scheme 5.
It is unusual for radical cyclizations leading to six- and
seven-membered rings to prove more efficient than those
leading to five-membered rings. The reasons underlying
the inefficiency in the formation of diazaindolines 12 are
not clear but may be related to unfavorable bond angles
resulting in increased strain in the transition state leading
to the fused five-membered ring. The small size of the hydro-
gen atom allows the opening of CÀNÀC bond angle and
thus favors the formation of the larger ring. This phenom-
enon is well documented in radical cyclizations.12 While
no values are available for the compounds at hand, the
CÀNÀC bond angle in the closely related 4-methylamino-
pyridine 34t, even with a small methyl substituent, has been
calculated to be 124.2°. This value is larger than the 120°
expected for a completely sp2-hybridized extranuclear nitro-
gen atom (Scheme 6).13 Interestingly, the trans-rotamer 34t,
with a conformation propitious for cyclization, was found to
be 1.4 kcal/mol more stable than the cis-rotamer 34c.
materialize to any significant extent in the case of the
pyrimidine derivatives, it could nevertheless prevail with
the less electrophilic pyridine ring. Polar effects are known
to influence considerably the rate of hydrogen atom
abstractions.14 We therefore repeated the cyclization ex-
periment with deuterated substrate 31b and indeed ob-
served partial intramolecular deuterium abstraction.
About 20À25% (by MS) of reduced deuterated product
33b was formed (see the Supporting Information for
details). The proportion of intramolecular abstraction in
the case of the nondeuterated analogue 33a must be much
higher because of the kinetic isotope effect (an NÀH bond
is slightly weaker than an NÀD bond).15
The competition with the untoward radical transloca-
tion is further compounded by an intrinsically slower ring-
closure step due to the greater aromaticity and lower
electrophilicity of the 2-fluoropyridine nucleus. With the
more electrophilic dichloropyrimidine, not only is the rate
of ring-closure increased, because of a polarity match with
the mildly nucleophilic carbon radical, but the hydrogen
atom shift is also slowed down. The net result is a clean
formation of the seven-membered ring.
Scheme 6. Bond Angles in 2-(N-Methylamino)pyridine
The lackof cyclization leading toa seven-memberedring
in the pyridine series was nevertheless puzzling. Although
the feared 1,5-hydrogen atom transfer (cf. 22) did not
The present approach is modular, flexible, and concise.
Indeed, both the intermolecular addition and cyclization
can be combined in a one-pot procedure, since the same
(11) Pratt, D. A.; DiLabio, G. A.; Mulder, P.; Ingold, K. U. Acc.
Chem. Res. 2004, 37, 334.
(12) Broeker, J. L.; Houk, K. N. J. Org. Chem. 1991, 56, 3651.
(13) Akai, N.; Ohno, K.; Aida, M. J. Photochem. Photobiol. A 2007,
187, 113.
(14) Tedder, J. M. Angew. Chem., Int. Ed. Engl. 1982, 21, 401.
Org. Lett., Vol. 14, No. 23, 2012
5978

simply diluting the reaction medium, once TLC monitor-
ing indicated that the intermolecular addition of xanthate
8b to alkenes 15 and 19 was essentially complete, and
adding portionwise a stoichiometric amount of lauroyl
peroxide.
Scheme 7. Access to Spirocyclic and Fused Tricyclic Structures
Bicyclic pyrimidine derivatives such as 17 and, espe-
cially, 21 are rare and hitherto not readily available core
structures.16 The expedient access to complex derivatives,
only tediously available by conventional ionic or organo-
metallic routes, is further illustrated by the synthesis of
spiro derivative 38fromxanthate37displayed inScheme 7.
The radical cyclization step proved remarkably efficient in
this case, and the precursor alkenes 35 and 36 are readily
available using known chemistry.17
Finally, the incorporation of various functional groups
contained in the xanthate partner and the presence of the
two chlorines on the pyrimidine ring provide a simple
means for constructing another ring by an ionic process.
Compounds 17a and 21a may thus be converted into the
novel tricyclic compounds 40 and 41 after cleavage of the
phthalimido group with hydrazine. This cyclization failed
with 12a presumably because of increased strain in the
expected product 39.
In summary, apart from highlighting a facile route to
polycyclic pyrimidine and, to a lesser extent, pyridine
derivatives, this study has revealed a relatively rare situa-
tion where the formation of a five-membered ring is much
less efficient than the corresponding ring closure leading to
six- and seven-membered rings.18
peroxide and solvent are used in both steps; only the con-
centration differs. Thus, 17b and 21b were obtained in
comparable overall yield, 41% and 34% respectively, by
(15) The slower abstraction of deuterium, because of the primary
kinetic isotope effect, has been exploited to circumvent synthetic hurdles
caused by unwanted intramolecular hydrogen atom shifts: (a) Wood,
Acknowledgment. This paper is dedicated with respect
to the memory of Professor Alessandro Degl’Innocenti
(University of Florence). We thank Ecole Polytechnique
and Master Ile-de-France/Fudan University for scholar-
ships to Z.L. and L.Q.
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Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and copies of 1H and 13
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
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2005, 41, 5551The modest yield of precursor 36 is due to competing
substitution at the 2-position of the 2,4,6-trichloropyrimidine ring.
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The authors declare no competing financial interest.
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