2-azabenzonorbornanes from 7-azabenzonorbornanols by a nitrogen-directed neophyl-type radical rearrangement

Article abstract of DOI:10.1021/ol027039o

(equation presented) Barton deoxygenation of 7-azabenzonorbornanols leads to a synthetically useful neophyl-like rearrangement to give 2-azabenzonorbornane derivatives in 64-90% yields.

Full text of DOI:10.1021/ol027039o

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4353-4356
2-Azabenzonorbornanes from
7-Azabenzonorbornanols by a
Nitrogen-Directed Neophyl-Type Radical
Rearrangement
,†
David M. Hodgson,* Magnus W. P. Bebbington,† and Paul Willis‡
Dyson Perrins Laboratory, Department of Chemistry, UniVersity of Oxford,
South Parks Road, Oxford OX1 3QY, U.K., and AstraZeneca, R&D Charnwood,
Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K
daVid.hodgson@chem.ox.ac.uk
Received October 7, 2002
ABSTRACT
Barton deoxygenation of 7-azabenzonorbornanols leads to a synthetically useful neophyl-like rearrangement to give 2-azabenzonorbornane
derivatives in 64−90% yields.
Azabicyclic systems are ubiquitous in natural products and
pharmaceutical agents. New methods for their construction
are therefore important synthetic goals.1 Radical cyclizations
and rearrangements constitute some of the most powerful
methods for the construction of such polycycles.2 Radical
rearrangements are well-known in norbornenyl (bicyclo-
[2.2.1]heptenyl) systems, usually leading to mixtures of bi-
and tricyclic products.3 However, during the course of our
studies in free radical rearrangements of related azabicyclic
systems, we recently demonstrated that clean radical rear-
rangements can occur.4 These latter processes are likely
driven by the stabilizing feature of generating a radical R to
nitrogen.5 For example, radical addition of thiols to 7-aza-
norbornadienes gave rise to homoallylic rearrangement and
2-azabicyclic sulfides as the sole products (Scheme 1).6
Scheme 1. Radical Addition of Thiols to
7-Azanorbornadienes6
† University of Oxford.
‡ AstraZeneca Pharmaceuticals (Charnwood).
(1) For a review of 2-azabicyclo[2.2.1]heptanes, see: Blondet, D.; Morin,
C. Heterocycles 1982, 19, 2155-2182.
(2) (a) Beckwith, A. L. J.; Ingold, K. U. In Rearrangements in Ground
and Excited States; de Mayo, P., Ed.; Academic: New York, 1980; Vol. 1,
pp 161-310. (b) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma,
G.; Kulicke, K. J.; Trach, F. Org. React (N.Y.) 1996, 48, 301-856. (c)
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, Germany, 2001.
(3) (a) Warner, C. R.; Strunk, R. J.; Kuivila, H. G. J. Org. Chem. 1966,
31, 3381-3384. (b) Davies, D. I. Chem. Soc. Spec. Publ. 1970, 24, 201-
237. (c) Wilt, J. W. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York,
1973; Vol. 1, pp 333-502.
Compared with radical rearrangements in norbornenyl
systems, (partial) neophyl-type rearrangements (1,2-shift of
(4) (a) Hodgson, D. M.; Maxwell, C. R.; Matthews, I. R. Synlett 1998,
1349-1350. (b) Hodgson, D. M.; Maxwell, C. R.; Wisedale, R.; Matthews,
I. R.; Carpenter, K. J.; Dickenson, A. H.; Wonnacott, S. J. Chem. Soc.,
Perkin Trans. 1 2001, 3150-3158.
10.1021/ol027039o CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/05/2002

Scheme 2. Neophyl-Type Radical Rearrangement
Scheme 3. Synthesis and Deoxygenation of
7-Azabenzonorbornanola
an aryl group, Scheme 2, X ) CH2) in the corresponding
benzofused systems are much more rare. This applies both
to free radical additions to benzonorbornadiene and to
H-atom abstraction from benzonorbornane.7 Indeed, many
additions to benzonorbornadiene were found to proceed
without any rearrangement. This is presumably due to the
comparatively unfavorable disruption of aromaticity.3c These
early observations, together with our recent studies, suggested
that extending the “aza homoallylic rearrangement” process
to 7-azabenzonorbornyl systems (Scheme 2, X ) NR) would
be challenging, but could provide an attractive entry to
2-azabenzonorbornanes.8 The latter systems are of interest,
for example, as conformationally defined adrenergic agents.9
7-Azabenzonorbornadienes (e.g. 3a, Scheme 3) were
considered to be excellent substrates to examine the chem-
istry in Scheme 2 (X ) NR), since they are readily available
via aryne cycloadditions with pyrroles.10 However, radical
addition of thiols (cf. Scheme 1) to 3a (R ) Boc)11 gave
only simple addition to the double bond, without any
rearrangement. Therefore, hydroboration of 3a followed by
oxidation to the alcohol and then Barton deoxygenation was
thought an attractive alternative method for radical genera-
tion, since hydroboration is known to proceed with good
facial and regioselectivity in substituted alkenes,12 and the
rate of H-atom transfer would be slowed relative to that of
a thiol.13
a Conditions: (a) 9-BBN (1.5 equiv) ,THF, 25 °C, 24 h, then
35% aq H2O2 (15 equiv), 2 M NaOH (4 equiv), THF/H2O (5:1),
25 °C, 5 h; (b) KH (4 equiv), CS2 (4 equiv), MeI (4 equiv), THF,
0-25 °C, 90 min; (c) TTMSS (1.5 equiv), AIBN (0.5 equiv),
toluene, reflux, 2 h.
reduction, and 7a, which was identified as the desired
rearranged product by NMR studies and by comparison with
known alkene 8 (Scheme 3).16,17 We supposed that increasing
the lifetime of the first-formed radical would lead to a higher
proportion of the rearranged product 7a.18 By increasing the
dilution by a factor of 3, and adding a mixture of TTMSS
and AIBN to a preheated solution of xanthate 7a over 100
min, the ratio increased to ∼20:1, and gave a 90% isolated
yield of 7a.
Encouraged by the above results, we undertook a more
detailed study of the effect on the rearrangement of bicyclic
core substitution and also of variation of electronics in the
aromatic ring. Benzyne cycloadditions11 with Boc-protected19
3-ethylpyrrole and 2,4-dimethylpyrrole20 gave adducts 3b and
3c in 56% and 52% yields, respectively (Scheme 4).
Hydroboration then occurred with complete facial and
regioselectivity to produce alcohols 4b and 4c as single
diastereomers.
Hydroboration-oxidation of 3a (R ) Boc) gave alcohol
4a as a single isomer (Scheme 3) in satisfactory yield (67%),
assigned as the exo-product in accordance with previous
work.14 Formation of xanthate 5a then proceeded smoothly
in excellent (95%) yield. We were pleased to find that
treatment of xanthate 5a with tris(trimethylsilyl)silane (TT-
MSS) (1.5 equiv) in boiling toluene with AIBN as initiator
for 2 h gave a 1:1 mixture of 6a,15 the product of direct
Radical deoxygenation of the xanthates 5b and 5c in the
manner previously described for 5a gave good yields of the
rearranged products (Scheme 4). Only traces of directly
(5) Wayner, D. D. M.; Clark, K. B.; Rauk, A.; Yu, D.; Armstrong, D.
A. J. Am. Chem. Soc. 1997, 119, 8925-8932.
(6) Hodgson, D. M.; Bebbington, M. W. P.; Willis, P. Chem. Commun.
2001, 889-890.
1
reduced products were observed in the crude H NMR
spectra.21 Noteworthy is that NOESY experiments revealed
(7) (a) Cristol, S. J.; Nachtigall, G. W. J. Org. Chem. 1967, 32, 3727-
3737. (b) Cristol, S. J.; Sullivan, J. M. J. Am. Chem. Soc. 1971, 93, 1967-
1970. (c) Sonawane, H. R.; Najundiah, B. S.; Kelkar, R. G. Tetrahedron
1986, 42, 6673-6682. (d) For a recent review of radical aryl migrations,
see: Studer, A.; Bossart, M. Tetrahedron 2001, 57, 9649-9667.
(8) For an alternative method, see: Pedrosa, A.; Andre´s, C.; Iglesias, J.
M.; Pe´rez-Encabo, A. J. Am. Chem. Soc. 2001, 123, 1817-1821.
(9) Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med. Chem. 1988, 31,
433-444.
(10) Chen, Z.; Trudell, M. L. Chem. ReV. 1996, 96, 1179-1193.
(11) Carpino, L. A.; Padykula, R. E.; Barr, D. E.; Hall, F. H.; Krause, J.
G.; Dufresne, R. F.; Thoman, C. J. J. Org. Chem. 1988, 53, 2565-2572.
(12) Brown, H. C.; Prasad, J. V. N. V. Heterocycles 1987, 25, 641-
657.
(16) Kasyan, A.; Wagner, C.; Maier, M. E. Tetrahedron 1998, 54, 8047-
8054.
(17) Further support that the rearrangement proceeds in the manner
indicated is provided by rearrangement of 5a (R ) CO2Me) and base
hydrolysis (KOH) of the resulting 7a (R ) CO2Me) to give the free amine
7a (R ) H), which had spectroscopic data matching those given in ref 9
for 7a (R ) H).
(18) Studies on the kinetics of the process are currently underway in
our laboratories.
(19) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl. 1984, 23,
296-301.
(20) Ethylpyrrole was prepared by hydrolysis (KOH) of the known
3-ethyl-1-phenylsulfonylpyrrole, see: Ketcha, D. M.; Carpenter, K. P.;
Atkinson, S. T.; Rajagopolan, H. R. Synth. Commun. 1990, 1647-1655.
2,4-Dimethylpyrrole is commercially available (Aldrich).
(21) Authentic samples of the directly reduced products were prepared
by hydrogenation15 of the benzyne cycloadducts.
(13) Newcomb, M. Tetrahedron 1993, 49, 1151-1176.
(14) Anderson, P. S. Tetrahedron Lett. 1976, 17, 1141-1144.
(15) Ohwada, T.; Miura, M.; Tanaka, H.; Sakamoto, S.; Yamaguchi, K.;
Ikeda, H.; Inagaki, S. J. Am. Chem. Soc. 2001, 123, 10164-10172.
4354
Org. Lett., Vol. 4, No. 24, 2002

Scheme 4. Synthesis and Rearrangement of Substituted 7-Azabenzonorbornanol Xanthatesa
a Conditions: (a)-(c) as in Scheme 3.
that H-atom transfer to form 7c occurs exclusively from the
exo face, leading to a single diastereomer. These studies also
showed that the 7-alkyl substituent in 7b and 7c resides anti
to nitrogen, confirming that the earlier hydroborations were
completely exo-selective.
To determine the effect of arene ring electronics on the
neophyl-like migration, we prepared adducts 3d-f (Scheme
4) by diazotization of the appropriate aromatic amino acid
derivatives in the presence of N-Boc pyrrole.22 Deoxygen-
ation of the derived xanthates 5d-f gave the expected
products 7d-f in good yields. Dimethoxy substitution in 5d
was found to have a retarding effect on the rearrangement,
as shown by a 6:1 ratio of rearranged:directly reduced
products.23 This is consistent with the initial formation of a
nucleophilic secondary alkyl radical and a slower cyclization
onto the more electron-rich aromatic ring than in the
unsubstituted system. This ratio in the reaction of the
difluorinated xanthate 5e did not appear to differ greatly from
that of 7a:6a, which suggests only a mild overall electron-
withdrawing effect due to the fluorine substituents. None of
the directly reduced product was detected in the reaction of
5f, which is in agreement with rate enhancements observed
(compared to phenyl) in studies of other naphthyl group
radical migrations.7d
In summary, a synthetically useful and conceptually
interesting neophyl-type radical rearrangement process has
been established, leading to azabicycles that are not readily
accessible by other means.8,9 Extensions of the process to
provide enantioenriched 2-azabenzonorbornanes as well as
manipulation of the products to targets of biological interest
are under investigation.
(22) See Supporting Information for the preparation of 3d and 3e. Adduct
3f was prepared according to the procedure of Bornstein, see: Remy, D.
E.; Bissett, F. H.; Bornstein, J. J. Org. Chem. 1978, 43, 4469-4472.
(23) % of directly reduced product was isolated from the reaction of 5d.
Acknowledgment. We thank the EPSRC and AstraZen-
eca for an Industrial CASE award (to M.W.P.B.) and the
EPSRC National Mass Spectrometry Service Centre for mass
Org. Lett., Vol. 4, No. 24, 2002
4355

spectra. We also thank Dr. B. Odell for expert assistance
with structure determination using NMR.
3b-e, 4a-f, and 7a-f. This material is available free of
charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures, full characterization data, and13C NMR spectra for
OL027039O
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Org. Lett., Vol. 4, No. 24, 2002