Synthesis and hetero-Diels-Alder reactions of enantiomerically pure dihydro-1: H -azepines

Article abstract of DOI:10.1039/d0cc04413j

Thermolysis of enantiomerically pure 3-substituted 7,7-dihalo-2-azabicyclo[4.1.0]heptanes in the presence of K2CO3 gives in good yields 2-alkyl-6-halo-1-tosyl-2,3-dihydro-1H-azepines. These undergo highly stereoselective [4+2] cycloaddition reactions with heterodienophiles and arylation/alkenylation under Suzuki conditions.

Full text of DOI:10.1039/d0cc04413j

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DOI: 10.1039/D0CC04413J
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Synthesis and Hetero-Diels–Alder Reactions of Enantiomerically
Pure Dihydro-1H-azepines
Donald Craig,*a,b Samuel R. J. Spreadburya and Andrew J. P. Whitec
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Thermolysis of enantiomerically pure 3-substituted 7,7-dihalo-2- of more complex N-heterocycles.13 It occurred to us that
azabicyclo[4.1.0]heptanes in the presence of K2CO3 gives in good bicyclo[4.1.0] products of dihalocyclopropanation of
yields
2-alkyl-6-halo-1-tosyl-2,3-dihydro-1H-azepines.
These enantiomerically
pure
N-arylsulfonyl-1,2,3,4-tetrahydro-
undergo highly stereoselective [4+2] cycloaddition reactions with pyridines would undergo electrocyclic ring-opening and
heterodienophiles and arylation/alkenylation under Suzuki deprotonation to give stereodefined dihydroazepines. In this
conditions.
work, we describe base-mediated thermal ring-expansion
reactions of 3-substituted 7,7-dihalo-2-azabicyclo[4.1.0]-
heptanes to give halogenated dihydro-1H-azepines, and
present stereoselective [4+2] cycloaddition and Pd(0)-catalysed
cross-coupling reactions of these novel scaffolds.
Stereodefined azepine and azepane derivatives are valuable
molecular scaffolds present in several bioactive natural
products and pharmaceutically relevant molecules.1 Species
featuring these seven-membered heterocyclic cores and
related compounds have received considerable attention
because of their potential as glycosidase inhibitors2 and
anticancer,3 anti-diabetic4 and anti-viral agents.5 Consequently,
a number of methodologies have been developed for their
preparation, with recent accounts detailing ring-expansion
cascades,6 cycloaddition approaches7 and cyclisation
strategies.8
Table 1 Cyclopropanation of enantiomerically pure 1,2,3,4-tetrahydropyridines
The importance of gem-dihalocyclopropanes in synthesis stems
in large part from their ready accessibility and high reactivity in
a range of transformations.9 More specifically, a number of
synthesis methodologies that have been developed exploit the
reactivity of cyclopropanes bearing nitrogen substituents, most
notably involving ring-opening and rearrangement processes.10
Of particular interest to us were the relatively unexplored
thermal ring-expansion reactions of gem-dihalocyclopropanes
in which the three-membered ring was fused to an N-
heterocycle. These often low-yielding processes required high
temperatures or activation by silver(I) salts to generate the
putative allylic cationic intermediates, which were typically
intercepted by alcohols or hydride reagents to afford vinyl
halides.11 To date, there have been few reports of the successful
isolation of diene products in the absence of a nucleophilic
additive or solvent.12
Our laboratory has previously investigated the synthesis and
chemistry of N-arylsulfonyl-1,2,3,4-tetrahydropyridines, in
particular the utility of these for the stereoselective elaboration
a. Department of Chemistry, Imperial College London, Molecular Sciences Research
Hub, White City Campus, Wood Lane, London W12 0BZ, UK
b. Email: d.craig@imperial.ac.uk; Tel: +44 (0)20 7594 5771
c. Chemical Crystallography Laboratory, Imperial College London, Molecular
Sciences Research Hub, White City Campus, Wood Lane, London W12 0BZ, UK
Electronic Supplementary Information (ESI) available: full experimental procedures,
spectroscopic and X-ray crystallographic data (for 2b/3b, 15, 23, 37
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Table 2 Ring-expansion of 7,7-dihalo-2-azabicyclo[4.1.0]heptanes to give 2,3-dihydro-
The
enantiomerically
pure
2-substituted
1,2,3,4-
View Article Online
1H-azepines 6–14a
DOI: 10.1039/D0CC04413J
tetrahydropyridines 1a–g used in this study were synthesised
according to the procedure of Harrity and co-workers14 from
L-
aminoacid-derived N-tosylaziridines.15 Substrates 1a
subjected to dihalocyclopropanation under conditions reported
by Ma
kosza,16 giving dichloro- and dibromo-substituted 2-
azabicyclo[4.1.0]heptanes 2a 3a and 4a 5a
respectively as anti/syn mixtures in good to excellent yields. For
examples
(R1 = Me), (R1 = TBDPSOCH2), (R1 = Bn), and (R1
= 4-MeOC6H4CH2), compounds (X = Cl) and (X = Br) were
–g were
̧
–g
,
–g
–g
,
–g,
a
d
f
g
2
/3
4/5
obtained as inseparable anti/syn mixtures (Table 1).
Moderate stereoselectivity for the anti diastereoisomers
2
and
4
was observed for all the substrates studied, as was indicated
by 1H NMR analysis and assigned unambiguously by X-ray
crystallographic analysis of 2a and 3a. Similar facial selectivity in
the dichlorocyclopropanation of cyclic enamides has been
reported recently.17 We postulate that the lower anti-
selectivity observed in the dibromocarbene addition reactions
is a consequence of the greater steric interaction of the carbene
with the N-tosyl group, which adopts a conformation anti to the
R substituent.13
Initial ring-expansion experiments involved exposure of the ca.
3:1 mixture of 2a + 3a to varying combinations of base and silver
aCompounds 9, 13, 14 were obtained as inseparable mixtures with unreacted anti
substrates 2f, 4f and 4g, respectively
salts (see Supporting Information for optimisation conditions).
Although no consumption of substrate was observed at
ambient temperature, the use of microwave irradiation at 150
°C resulted in conversion of only the syn diastereoisomer 3a into
The cycloaddition reactivity of the enantiomerically pure
dihydroazepines was investigated next. Combination of
analogues 6, 9,
13 and 1418 at ambient temperature with the
the desired dihydro-1H-azepine
6. Further investigation
highly reactive heterodienophiles 4-phenyl-3H-1,2,4-triazole-
3,5(4H)-dione, and tert–butyl or benzyl nitrosoformate
generated in situ by Bu4NIO4-mediated oxidation of the
corresponding alkyl hydroxycarbamates gave in excellent yields
the products of [4+2] heterocycloaddition, exclusively anti with
respect to the R1 substituent on the seven-membered ring
(Table 3). The stereochemistry of the cycloadducts 15 and 23
was unequivocally established by X-ray crystallographic analysis
(Figure 1), which demonstrated also the complete
regioselectivity of formation of the benzyl nitrosoformate
revealed that Ag(I) additives were unnecessary and that the
addition of one equivalent of potassium carbonate in toluene at
150 °C for 5 hours under microwave irradiation conditions
resulted in improved yields of
diastereoisomer 2a still failed to react under these modified
conditions. Several additional 7,7-dihalo-2-
azabicyclo[4.1.0]heptanes were subjected to the optimised
ring-expansion reaction conditions either as pure syn isomers
3b 5b
3e: R1 = s-Bu, i-Bu) and 5e: R1 = s-Bu, i-Pr) or as
anti/syn mixtures of 3a 5a
3f: R1 = Me, Bn) and
5g: R1 = Me, Bn, 4-MeOC6H4CH2) to give dihydroazepines
14 in good to excellent yields based on the syn isomers and
(Table 2). Dihydroazepines 13 and 14 were inseparable from
4f and 4g, respectively.
The difference in ring-expansion reactivity between the syn
isomers and the anti isomers is striking. Inspection of
6, although the anti
3
(
,
5
(
,
2
/3
(
2
/
,
2
/
4
/5
(
4
/
,
adduct 23
.
4
6
5
/5f, 4/
–
3
Figure 1 The molecular structures of 15 and 23
9
,
the unreacted anti substrates 2f
,
15
3
/5
2/4
the obtained crystal structures for 2a and 3a indicates a greater
degree of nitrogen pyramidalisation in the syn-isomer 3a than
in the anti-isomer 2a (see X-ray Supporting Information). We
speculate that this increases the availability of the nitrogen lone
pair in 3 to participate in cyclopropane ring opening (Scheme 1).
23
Scheme1 Proposed mechanism for ring-opening of 3a
2 | J. Name., 2012, 00, 1-3
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Table 3 Hetero-Diels–Alder reactions of 6-halo-2,3-dihydro-1H-azepinesa
Table
4
Suzuki cross-coupling reactions of 6-bromo-2,3-dihydro-1H-azepinesa
View Article Online
DOI: 10.1039/D0CC04413J
aCompounds 9, 13, 14 were used as inseparable mixtures with unreacted 2f, 4f and 4g,
respectively; yields of 16, 18, 20–23 are based on the calculated amount of the
dihydroazepines in the mixtures (1H NMR)
a2-Benzyl-6-bromo-1-tosyl-2,3-dihydro-1H-azepine 13 was used in these reactions as an
inseparable mixture with unreacted 4f; yields for products 32 and 34 are for the two
steps from the 4f/5f mixture based on the calculated amount of 5f (1H NMR)
The last part of this study looked at the functionalisation of
bromo-substituted 6-bromo-2,3-dihydro-1H-azepines using Pd-
catalysed cross-coupling reactions. Substrates 10–13 were
This selectivity demonstrated the expected greater intrinsic
reactivity of the s-cis cyclic diene in 31 with respect to the
conformationally
more
flexible
styryl-containing
coupled with a range of electron-rich and electron-poor
arylboronic acids under Suzuki–Miyaura conditions to give the
6-arylated analogues in excellent yields (Table 4).19 On
combination with excess 4-phenyl-3H-1,2,4-triazole-3,5(4H)-
dione in CH2Cl2 at ambient temperature, the triene product 31
entered into hetero-Diels–Alder reaction to give in 87% yield a
chromatographically separable mixture of the mono- and bis-
adducts 36 and 37 in a 1:2.5 ratio (Scheme 2). The
stereochemistry of mono-adduct 36 was inferred from the
stereoselectivity observed in the hetero-Diels–Alder reactions
endocyclic/exocyclic moiety.
Scheme 2Formation of 36 and 37
of 6, 9, 13 and 14; that of the bis-adduct 37 was established by
X-ray crystallographic analysis (Figure 2).
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Figure 2 The molecular structure of 37
5
(a) P. Greimel, J. Spreitz, A. E. Stütz and T. M. Wrodnigg,
Curr. Top. Med. Chem., 2003,
3
, 513; (b) H. Li, Y.VBielwérAirotictl,eCO.nline
DOI: 10.1039/D0CC04413J
Chantereau, J. M. Mallet, M. Sollogoub, Y. Zhang, E.
Rodríguez-García, P. Vogel, J. Jiménez-Barbero and P. Sinaÿ,
Org. Biomol. Chem., 2004, 2, 1492; (c) I. Robina, A. J.
Moreno-Vargas, A. T. Carmona and P. Vogel, Curr. Drug
Metab., 2004, , 329.
(a) J. Zhou and Y. Y. Yeung, Org. Lett., 2014, 16, 2134; (b) A.
Nortcliffe and C. J. Moody, Bioorg. Med. Chem., 2015, 23
2730; (c) J. Y. Du, X. T. An, X. H. Zhao, X. Y. Ma, Y. X. Cao and
C. A. Fan, Tetrahedron, 2019, 75, 1760.
(a) C. Hu, R. J. Song, M. Hu, Y. Yang, J. H. Li and S. Luo,
Angew. Chem. Int. Ed., 2016, 55, 10423; (b) C. Z. Zhu, J. J.
Feng and J. Zhang, Angew. Chem. Int. Ed., 2017, 56, 1351; (c)
V. Motornov and P. Beier, J. Org. Chem., 2018, 83, 15195; (d)
D. Singh and H. J. Ha, Org. Biomol. Chem., 2019, 17, 3093; (e)
X. Li, S. Wang, S. Li, K. Li, X. Mo, L. Liu, W. Chang and J. Li, J.
Org. Chem., 2019, 84, 1288.
(a) E. Cini, G. Bifulco, G. Menchi, M. Rodriquez and M.
Taddei, Eur. J. Org. Chem., 2012, 2133; (b) W. Zhu, L. Zhao
and M. X. Wang, J. Org. Chem., 2015, 80, 12047; (c) A.
Barbero, A. Diez-Varga, F. J. Pulido and A. Gonzàlez-Ortega,
Org. Lett., 2016, 18, 1972; (d) G. W. Wang and J. F. Bower, J.
Am. Chem. Soc., 2018, 140, 2743; (e) A. Artigas, J. Vila, A.
Lledó, M. Solà, A. Pla-Quintana and A. Roglans, Org. Lett.,
2019, 21, 6608.
5
6
7
,
8
9
(a) B. Halton and J. Harvey, Synlett, 2006, 1975; (b) A. P.
Thankachan, K. S. Sindhu, K. K. Krishnan and G. Anilkumar,
Org. Biomol. Chem., 2015, 13, 8780.
In conclusion, we have developed an efficient ring-expansion
sequence for the conversion of stereodefined 7,7-dihalo-2-
azabicyclo[4.1.0]heptanes into enantiomerically pure 2,3-
dihydro-1H-azepines. These molecular scaffolds undergo
hetero-Diels–Alder cycloadditions with high stereoselectivity
and complete regioselectivity. Additionally, these entities can
be efficiently elaborated with a range of aromatic substituents
using Suzuki coupling reactions. Further investigation into
dihydroazepine derivatisation and application of this chemistry
to natural and unnatural product synthesis is ongoing.
10 V. A. Rassadin and Y. Six, Tetrahedron, 2016, 72, 4701.
11 (a) C. D. Perchonock, I. Lanos, J. A. Finkelstein and K. G.
Holden, J. Org. Chem., 1980, 45, 1950; (b) H. P. Soetens and
U. K. Pandit, Recl. Trav. Chim. Pay-B, 1980, 98, 271; (c) D.
Dhanak, R. Kuroda and C. B. Reese, Tetrahedron Lett., 1987,
28, 1827.
12 (a) T. Inoue, S. Yokoshima and T. Fukuyama, Heterocyles,
2009, 79, 373; (b) G. Chen, P. Kattanguru, O. A. Tomashenk,
R. Karpowicz, G. Siemiaszko, A. Bhattacharya, V. Calasans
and Y. Six, Org. Biomol. Chem., 2017, 15, 5364.
13 (a) D. Craig, R. McCague, G. A. Potter and M. R. V. Williams,
Synlett, 1998, 55; (b) D. Craig, R. McCague, G. A. Potter and
M. R. V. Williams, Synlett, 1998, 58; (c) J. C. Adelbrecht, D.
Craig, B. W. Dymock and S. Thorimbert, Synlett, 2000, 467;
(d) J. C. Adelbrecht, D. Craig, A. J. Fleming and F. M. Martin,
Synlett, 2005, 2643.
Conflicts of interest
The authors have no conflicts of interest to declare.
14 L. C. Pattenden, R. A. J. Wybrow, S. A. Smith and J. P. A.
Harrity, Org. Lett., 2006, 8, 3090.
Acknowledgements
We thank EPSRC (Doctoral Training Programme: PhD
Studentship to S. R. J. S.) for support.
15 M. B. Berry and D. Craig, Synlett, 1992, 41. Standard
procedures for the synthesis of
provided in the ESI.
1 from -aminoacids are
16 M. Ma
̧kosza and M. Wawrzyniewicz, Tetrahedron Lett., 1969,
10, 4659.
17 T. J. Idzik, Z. M. Myk and J. G. Soꢀnicki, J. Org. Chem., 2019,
84, 8046.
Notes and references
18 In the hetero-Diels–Alder reactions 2,3-dihydro-1H-azepines
1
(a) E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257; (b) G. F. Zha, K. P. Rakesh, H. M.
Manukumar, C. S. Shantharam and S. Long, Eur. J. Med.
Chem., 2019, 162, 465.
(a) F. Moris-Varas, X. H. Qian and C. H. Wong, J. Am. Chem.
Soc., 1996, 118, 7647; (b) G. F. Painter, P. J. Eldridge and A.
Falshaw, Bioorg. Med. Chem., 2004, 12, 225.
9, 13 and 14 were used as inseparable mixtures with the
unreacted anti-7,7-dihalo-2-azabicyclo[4.1.0]heptanes 2f
and 4g, respectively.
, 4f
19 Bromo-substituted hetero-Diels–Alder adducts 18 and 22
also were found to be effective substrates in Suzuki
reactions, giving arylated products in 75–98% yield. Full
2
experimental and spectroscopic details are provided in the
ESI.
3
4
(a) B. Winchester and G. W. J. Fleet, Glycobiology, 1992,
199; (b) Y. Nishimura, Curr. Top. Med. Chem., 2003, , 575.
2,
3
(a) H. Li, Y. Zhang, P. Vogel, P. Sinaÿ and Y. Blériot, Chem.
Commun., 2007, 183; (b) B. Luo, F. Marcelo, J. Désire, Y.
Zhang, M. Sollogoub, A. Kato, I. Adachi, F. Javier Cañada, J.
Jiménez-Barbero and Y. Blériot, J. Carbohyd. Chem., 2011,
30, 641.
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