Synthesis of medium ring heterocycles using an intramolecular Heck reaction

Article abstract of DOI:10.1021/ol0487884

(Equation Presented) Historically, general convergent syntheses of medium ring heterocycles have been difficult to develop. Herein, we describe the synthesis of five classes of heterocycles: dihydrodibenzo[b,f]azepine, -oxocine, and -thiocine and dibenzo[b,f]azepine and -oxepine using a strategy of alkylation followed by highly selective intramolecular Heck arylation reaction. The hetero-tricyclic compounds were available in only two steps starting from commercially available starting materials.

Full text of DOI:10.1021/ol0487884

ORGANIC
LETTERS
2004
Vol. 6, No. 17
3005-3007
Synthesis of Medium Ring Heterocycles
Using an Intramolecular Heck Reaction
Leggy A. Arnold, Wenchen Luo, and R. Kiplin Guy*
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology,
UniVersity of California-San Francisco, 600 16th Street,
San Francisco, California 94143-2280
rguy@cgl.ucsf.edu
Received June 24, 2004
ABSTRACT
Historically, general convergent syntheses of medium ring heterocycles have been difficult to develop. Herein, we describe the synthesis of
five classes of heterocycles: dihydrodibenzo[b,f]azepine, -oxocine, and -thiocine and dibenzo[b,f]azepine and -oxepine using a strategy of
alkylation followed by highly selective intramolecular Heck arylation reaction. The hetero-tricyclic compounds were available in only two steps
starting from commercially available starting materials.
Many natural products, drugs, and preclinical leads contain
medium-size heterocycles fused to aryl rings. For example
carbamazine (Tegretol), a dihydro[b,f]azepine,1 is an impor-
tant antiepileptic drug.2 A general synthesis for seven- and
eight-membered heterotricyclic compounds of these classes
is missing. Therefore we developed a novel alkylation-Heck
reaction sequence giving access to these important pharma-
ceutical building blocks.
The intramolecular Heck reaction has been widely used
for the synthesis of cyclic natural products3 and was therefore
highly attractive. However, whereas intermolecular coupling
between aryl halides and monoaryl-substituted olefins is
highly regio- and stereoselective,4 the intramolecular version
proceeds with a wide range of regioselectivity depending
on ring size and reaction conditions.3,5 Low regioselectivity
is generally observed for the formation dibenzo[a,e]annulene-
like molecules.6 In contrast, the intramolecular Heck coupling
between aryl halides and R-substituted acrylates proceeds
with high regio- and stereoselectivity for seven- and eight-
membered rings to give trisubstituted olefins.7 Herein, we
present an intramolecular Heck coupling between R-aryl-
substituted acrylates and aryl halides using the general
phosphine-free reaction conditions developed by Buchwald
and co-workers8 to synthesize compounds such as dihydro-
benzo[b,f]azocines.
Aniline derivatives (1 and 2) and phenols (3 and 4) were
alkylated in good yield using substituted benzyl bromide 11
to give the products 5-8 (Scheme 1).
The Heck reaction was carried out in N,N-dimethylacet-
amide using Cy2NMe as a base, Et4NCl as a promoter,9 and
(6) (a) Laursen, B.; Denieul, M.-P.; Skrydstrup, T. Tetrahedron 2002,
58, 2231. (b) Prashad, M.; Liu, Y.; Mak, Y.; Har, D.; Repi, O.; Blacklock,
T. J. Tetrahedron Lett. 2002, 43, 8559.
(1) For a review, see: (a) Renfroe, B.; Harrington, C. Chem. Heterocycl.
Compd. (N. Y.) 1984, 43, 1. (b) Kricka, L. J.; Ledwith, A. Chem. ReV.
1974, 74, 101.
(7) (a) Gibson, S. E.; Mainolfi, N.; Kalindjinan, S. B.; Wright, P. T. J.
Chem. Soc., Chem. Commun. 2003, 1568. (b) Gibson, S. E.; Jones, J. O.;
Kalindjinan, S. B.; Knight, J. D.; Steed, J. W.; Tozer, M. J. J. Chem. Soc.,
Chem. Commun. 2002, 1938 and references herein. (c) Aalcaide, B.;
Polanco, C.; Sierra, M. A. Eur. J. Org. Chem. 1998, 2913. (d) Hegedus, L.
S.; Sestrick, M. R.; Michealson, E. T.; Harrington, P. J. J. Org. Chem.
1989, 54, 4141. (e) Gibson, S. E.; Middleton, R. J. J. Chem. Soc., Chem.
Commun. 1995, 1743.
(2) Epilepsy, A ComprehensiVe Textbook, Volume II; Engel, J., Pedley,
T. A., Eds.; Lippincot-Ravens Publishers: Philadelphia, 1998.
(3) For a review, see: Link, J. Org. React. 2002, 60, 157.
(4) For a recent review see: (a) Littke, A. F.; Fu, G. C. Angew. Chem.,
Int. Ed. 2001, 41, 4176. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem.
ReV. 2000, 100, 3009.
(5) For a recent example, see: Geng, X.; Miller, L. M.; Lin S.; Ojima,
I. Org. Lett. 2003, 5, 3733.
(8) Gu¨rtler, C.; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107.
(9) Jeffery, T. Tetrahedron 1996, 52, 10113.
10.1021/ol0487884 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/27/2004

All attempts to apply the new method to the synthesis of
nine-membered rings (17a and 18a) failed (Scheme 3).
Scheme 1. Synthesis of Dibenzo[b,f]azocine and
Dibenzo[b,f]oxocine Derivativesa
Scheme 3. Attempted Synthesis of Nine-Membered Ringsa
a Reagents and conditions: (i) Pd(OAc)2 (0.03 equiv), Et4NCl,
Cy2NMe, N,N-dimethylacetamide, 12 h, 100 °C.
a Reagents and conditions: (i) K2CO3, acetone, 12 h, 50 °C,
yields 72-82%; (ii) Pd(OAc)2 (0.03 equiv), Et4NCl, Cy2NMe, N,N-
dimethylacetamide, 4-12 h, 95 °C.
The standard Heck reaction conditions gave a complex
mixture consisting of intermolecular Heck reaction products,
starting material, and various uncharacterized degradation
products.
In contrast, the synthesis of dibenzo[b,f]azepine and
dibenzo[b,f]oxepine derivatives could be achieved by varying
the reaction sequence (Scheme 4).
Pd(OAc)2 as precatalyst. All reactions gave the 8-endo
products 9 and 10 exclusively in up to 72% yield. Bromo
analogues 6 and 8 required longer reaction times (12 h) in
contrast to the corresponding iodo compounds 5 and 7 (4
h). The Heck reaction with compound 6 gave dibenzo[b,f]-
azocine 9 in only 47% yield as the major product along with
the formation of some uncharacterized compounds.
The sequence described could not be applied to the
synthesis of 6H-dibenzo[b,f]thiocine because thiols undergo
a conjugate addition reaction with the unsaturated esters
under basic conditions.10 Instead, 2-iodobenzenesulfonyl
chloride 1211 and 2-bromobenzenesulfonyl chloride 13 were
alkylated with 11 under reductive conditions12 to give the
products 14 and 15 in 46% and 35% yield, respectively
(Scheme 2).
Scheme 4. Synthesis of Dibenzo[b,f]azepine and
Dibenzo[b,f]oxepine Derivativesa
Scheme 2. Synthesis of
5,5-Dioxo-5,6-dihydro-dibenzo[b,f]thiocine-11-carboxylic Acid
Ethyl Estera
a Reagents and conditions: (i) Pd(OAc)2 (0.03 equiv), Et4NCl,
Cy2NMe, N,N-dimethylacetamide, 12 h, 100 °C; (ii) TFA, CH2Cl2;
(iii) (b) K3PO4, Pd(t-Bu3P)2 (0.03 equiv), toluene, 16 h, 90 °C; (c)
K3PO4 Pd(OAc)2 (0.03 equiv), 2-(di-tert-butylphosphino)biphenyl
(0.06 equiv), toluene, 16 h, 90 °C.
The Heck reaction was carried out first, giving a selective
reaction with the aryl iodide in the presence of an aryl
bromide (20). Very good chemoselectivity was observed,
giving products 21 and 23 exclusively in 82% yield.
Applying the Pd(t-Bu3P)2-catalyzed amination reaction
conditions developed by Hartwig and co-workers13 failed to
a Reagents and conditions: (i) NaH2PO4, Na2SO3, water, 12 h,
60 °C; (ii) 11, acetone, 50 °C, 12 h; (iii) Pd(OAc)2 (0.03 equiv),
Et4NCl, Cy2NMe, N,N-dimethylacetamide, 12 h, 100 °C.
(10) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992.
(11) Chau, M. M.; Kice, J. L. J. Org. Chem. 1977, 42, 3265.
(12) Chen, J. J.; Nugent, T. C.; Lu, C. V.; Kondapally, S.; Giannousis,
P.; Wang, Y.; Wilmot, J. T. Org. Proc. Res. DeV. 2003, 7, 313.
(13) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. J. Org. Chem. 1999, 64, 5575.
Both the iodo and bromo derivatives 14 and 15 afforded
cyclic products in good yield when exposed to the Heck
reaction conditions (67% and 69%), giving a novel cyclic
sulfone 16.
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Org. Lett., Vol. 6, No. 17, 2004

give the seven-membered ring of compound 21. Therefore,
the carbamate 21 was deprotected using TFA to give the
free aniline 22. In contrast to the compound 21, compound
22 gave the dibenzo[b,f]azepine 24 in 74% yield. Phenol 23
was obtained in 82% yield using 2-iodophenol and 20. The
cyclization of 23 using the catalytic conditions developed
by Buchwald and co-workers14 gave 25 in 60% yield.
functional groups. Application of this strategy to the synthesis
of a heterocyclic library is under way and will be reported
in due course.
Acknowledgment. The authors thank the Sidney Kimmel
Foundation for Cancer Research, the HHMI Research
Resources Program grant no. 76296-549901, the NIH (R01
DK58080), and the Sandler Foundation for financial support.
In summary, we have developed a general strategy for the
synthesis of dibenzo[b,f]azepine, -oxocine, -thiocine, -azepine,
and -oxepine using transition metal catalysis. The advantages
of this strategy are (1) a very direct and convergent synthesis
of tricyclic compounds and (2) the tolerance of various
Supporting Information Available: Complete descrip-
tion of the experimental detail and product characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
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