Synthetic and Mechanistic Investigation of an Oxime Ether Electrocyclization Approach to Heteroaromatic Boronic Acid Derivatives

Article abstract of DOI:10.1002/chem.201802350

A range of functionalized heteroaromatic boronic acid derivatives are readily accessed by a diboration/6π-electrocyclization sequence. This study revealed the surprising observation that there is a direct relationship between oxime ether stereochemistry and reactivity towards electrocyclization. Specifically, E-oxime ethers are found to be significantly more reactive than their Z-counterparts (stereochemistry relative to azatriene scaffold). In contrast, the configuration at the azatriene alkene terminus has little impact on reaction rates. Computational analysis offers a rationale for this observation; a N_{lone pair}→C=C π* orbital interaction lowers the energy of the transition state in the electrocyclization of E-oxime ethers. Finally, unreactive Z-oxime ethers can be converted to the corresponding heterocyclic products by a photolytically promoted E→Z isomerization and electrocyclization sequence.

Full text of DOI:10.1002/chem.201802350

A Journal of
Accepted Article
Title: Synthetic and Mechanistic Investigation of an Oxime Ether
Electrocyclization Approach to Heteroaromatic Boronic Acid
Derivatives
Authors: Joseph P.A. Harrity, Helena Mora, Lia Sotorrios, Matthew
Ball-Jones, Laurent Bialy, Werngard Czechtizky, Maria
Mendez, and Enrique Gomez-Bengoa
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To be cited as: Chem. Eur. J. 10.1002/chem.201802350
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Synthetic and Mechanistic Investigation of an Oxime Ether
Electrocyclization Approach to Heteroaromatic Boronic Acid
Derivatives**
Helena Mora-Radó,[a] Lia Sotorríos,[b] Matthew P. Ball-Jones,[a] Laurent Bialy,[c] Werngard
Czechtizky,[c,d] María Méndez,[c] Enrique Gómez-Bengoa,*[b] and Joseph P. A. Harrity*[a]
Abstract: A range of functionalized heteroaromatic boronic acid
derivatives are readily accessed by a diboration/6-electrocyclization
sequence. This study revealed the surprising observation that there
is a direct relationship between oxime ether stereochemistry and
reactivity towards electrocyclization. Specifically, E-oxime ethers are
found to be significantly more reactive than their Z-counterparts
(stereochemistry relative to azatriene scaffold). In contrast, the
configuration at the azatriene alkene terminus has little impact on
reaction rates. Computational analysis offers a rationale for this
observation; a Nlone pair→C=C * orbital interaction lowers the energy
of the transition state in the electrocyclization of E-oxime ethers.
Finally, unreactive Z-oxime ethers can be converted to the
corresponding heterocyclic products by a photolytically promoted E
→Z isomerization and electrocyclization sequence.
presence of a Pt-catalyst led to a diboration-electrocyclization
cascade that delivered thienopyridine boronic ester 2a in poor
yield. Interestingly however, the remaining mass balance
consisted of diborylated alkene 3a which was found to contain
exclusively the Z-configuration at the oxime. This result was
reproduced at higher Z/E-1a ratios. The correlation between
initial oxime ether isomer ratio and the product ratios indicated
that the Z-minor oxime isomer of 1a could undergo diboration,
but was inert to electrocyclization.[6]
Heterocycle fused pyridines are common fragments in
biologically active compounds and azole-containing analogs are
particularly prominent, featuring in compounds such as
nucleosides and carbolenes.[1] These compounds are often
prepared via ring synthesis strategies and a number of catalytic
methods have recently emerged.[2] However, suitably
functionalized variants of these compounds could allow them to
be introduced directly via cross-coupling reactions. In this regard,
the availability of borylated azole-fused pyridine derivatives is
very limited.
Scheme 1. Synthesis of borylated thienopyridines. Estimated yields obtained
by 1H NMR spectroscopy with isolated yields in parentheses. n.d.: Not
determined.
In continuing our scoping studies, we found that the majority of
heterocycles examined provided very high selectivity for E-
oxime stereoisomers and so we were able to demonstrate that
Recent studies in our lab have demonstrated that aromatic
oxime ethers bearing an ortho-alkyne group can be transformed
into isoquinoline boronic esters via
a
diboration/6-
electrocyclization sequence.[3] We therefore began our studies
by investigating the applicability of this transformation for the
synthesis of borylated thienopyridines as this would deliver a
novel class of heteroaromatic boronic ester scaffolds.[4,5] As
shown in Scheme 1, subjection of thiophene 1a to B2pin2 in the
[a]
[b]
H. Mora Radó, Dr. M. Ball-Jones, Prof. J. P. A. Harrity
Department of Chemistry, University of Sheffield
Sheffield, S3 7HF (U.K.)
E-mail: j.harrity@sheffield.ac.uk
L. Sotorríos, Prof. E. Gómez-Bengoa
Departamento de Química Organica I
Universidad del País Vasco
San Sebastian, 20018 (Spain)
E-mail: enrique.gomez@ehu.es
[c]
Dr. L. Bialy, Dr. W. Czechtizky, Dr. M. Méndez
Integrated Drug discovery, R&D, Sanofi Aventis Deutschland GmbH,
Industriepark Höchst, D-65926 Frankfurt Am Main, Germany.
Present address: Respiratory, Inflammation, Autoimmunity IMED
Biotech Unit, AstraZeneca, Gothenburg, Sweden
We are grateful for support from the EPSRC, the FP7 Marie Curie
Actions of the European Commission (via the ITN COSSHNET
network), the Basque Government (GIC15/03, IT1033-16) and
IZO/SGI SGIker of UPV/EHU.
[d]
[**]
Scheme 2. Diboration-electrocyclization approach to heteroaromatic
boronates. [a] B2pin2, 10 mol% Pt(PPh3)4, toluene, 120 oC, 16 h. [b] (i) B2pin2,
10 mol% Pt(PPh3)4, toluene, 120 oC, 16 h; (ii) 1,2-C6H4, 200 oC, 16 h.
Supporting information for this article is given via a link at the end of
the document.
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this method offers a rapid and convenient means for generating
novel heteroaromatic boronic esters from readily available
starting materials. As shown in Scheme 2, Boc-protected
carbolenes were readily assembled by diboration of 1b-c,
although the free indole 1d required further heating to promote
cyclization. The method also allows a convenient means for
accessing constitutional isomers, as exemplified by the
synthesis of azaindazoles 2e,g. Overall, this approach allows a
range of functionalized scaffolds to be generated in good yield
over a one or two step sequence.
Returning to the issue of the dependence of the
electrocyclization step on the oxime stereochemistry we
explored the generality of this observation, targeting substrates
that could deliver significant yields of Z-oxime ethers. We were
able to prepare and isolate individual isomers of thiazole 1i and
ketoximes 1j-k. The diboration-electrocyclization of these
compounds reinforces the observation that the cyclization was
critically dependent on oxime ether stereochemistry with Z-
substrates inert to pyridine ring formation (Scheme 3). E-1i
cleanly provided 65% of pyridine 2i, whilst a sample containing
~90% Z-1i gave <10% of the pyridine and 44% of Z-3i, which
proved unstable with respect to protodeboronation. Similar
observations were found in the synthesis of isoquinolines 2j and
2k.
Figure 1. Calculated Free activation energies for cyclizations of E and Z oxime
ethers, computed at M06-2X/6-311+G(d,p)(IEFPCM, toluene). Values in
kcal/mol.
The Z- and E-isomeric forms of all initial oxime substrates show
very similar relative stabilities, with differences between them of
only 0-0.6 kcal/mol (see SI for details). Surprisingly however, the
activation energies for the cyclization of the Z-oxime isomers
were between 20 and 30 kcal/mol higher than those of their E-
counterparts, which corresponds to ten or more orders of
magnitude lower reaction rate. The reaction barriers for the E-
isomers range from 31 - 33 kcal/mol, and these barriers are
easily surmountable at the experimental temperatures typically
used for the cyclization reaction. In contrast, Z-oximes afford
activation energies over 40 kcal/mol (even as high as 63
kcal/mol), meaning that this general kind of substrate will
probably never react, whatever experimental conditions are
employed. In contrast to the oxime ether moiety, the
computational data predict that the structural features on the
alkene terminus do not exert any significant effect on the
cyclizations. For example, 1E,5Z-4 presents slightly lower
activation energy than 1E,5E-4, suggesting that cis-alkenes can
be as good substrates (or even better) as trans-alkenes in this
specific reaction.[9] Furthermore, increased substitution on the
alkene seems to be well tolerated, and tetrasubstituted
derivative 3i shows comparable, slightly lower activation barrier
than the simplest E-alkene 4. Thus, the incorporation of boronic
esters, and the substitution degree and pattern of the alkene,
appear to have no significant impact on reactivity towards
electrocyclization.
To find an explanation for the above findings, we analyzed the
structures of the four different transition states of compound 4
(Figure 2). As expected, all the cyclizations are disrotatory, and
present very homogeneous C-N bond forming distances (1.90-
1.94 Å). The transition states of the two E-oxime isomers (TS-
1E,5E-4 and TS-1E,5Z-4) are structurally very similar, and differ
only in the relative cis/trans disposition of the methyl group at
the terminal alkene which does not have any effect on their
relative activation barriers (32.8 and 32.0 kcal/mol). Indeed, the
terminal olefinic carbon undergoes partial pyramidalization
during the transition state, releasing part of the steric repulsion
between the eclipsed aryl and methyl substituents in the Z-olefin
containing substrates, providing an explanation for the good
performance of hindered Z-alkenes in this process. Meanwhile,
the geometry of the oxime moiety during the reaction is also very
instructive. We hypothesize that the lone pair of the oxime-
nitrogen actively participates in the electrocyclization, and its
orientation is thus crucial for the reactivity. In TS-1E,5E-4, the
iminic nitrogen lone pair is pointing towards the terminal carbon
of the double bond (see tentative disposition, Figure 2 in red),
whereas in TS-1Z,5E-4, the lone pair is orthogonal to the
forming C-N bond.
Scheme 3. Diboration-electrocyclization efficiency in relation to oxime ether
stereochemistry. (i) B2pin2, 10 mol% Pt(PPh3)4, toluene, 120 oC, 16 h; (ii) 1,2-
C6H4, 200 oC, 16 h. Estimated yields obtained by 1H NMR spectroscopy in
parentheses.
The thermally promoted disrotatory 6-electrocyclization of
conjugated trienes to form cyclohexa-1,3-dienes is an
established transformation that has attracted many theoretical
and experimental studies over the years. The influence of
substituent and geometrical effects in electrocyclization
reactions of trienes has been studied in some detail, and it
appears that the incorporation of groups in a ‘cis’ configuration
at the termini of the triene chain significantly retard the
cyclization rate.[7,8] This has been attributed to a reduced
propensity for the substrate to adopt the reactive s-cis, s-cis
conformation. In order to establish sensitivity of the reaction to
the stereochemistry at the oxime ether, the alkenyl terminus,
and the effect of congested borylated substrates, we computed
the free activation energy of the cyclization of Z and E oxime
ether isomers of a non-borylated substrate 4, and compared this
to 3k (Figure 1).
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in modest yield (Scheme 4). In the case of the reaction of 1Z-3i,
monitoring the reaction progress via LC-MS and 1H NMR
spectroscopic analysis showed the rapid formation of the E-
oxime ether together with product formation. Moreover, a ~1:1
mixture of oxime ether isomers was maintained until complete
consumption of starting materials (See supporting information).
We therefore believe that, in this case, the reaction operates via
a photolytically promoted oxime ether isomerization followed by
a thermally promoted electrocyclization step.
Figure 2. Structural features of the isomeric transition structures of compound
4.
Evidence for donation of the nitrogen lone pair into the alkene
antibonding * orbital at the transition state is revealed in the
plotted orbital interaction diagram for TS-1E,5E-4 (B, Figure 3).
This interaction is lacking in TS-1Z,5E-4, where the lone pair is
not participating in the transition state (C). Also, the
electronegative region (red in the ESP diagrams) of reacting
oxime Z is large around the lone pairs of nitrogen and oxygen (D,
Figure 3), showing that the electron density at nitrogen lies away
from the forming C-N bond forming region. Meanwhile, there is
an absence of negative charge around nitrogen in the E-oxime
(A), since its lone pair is involved in bonding.
Scheme 4. Photochemically promoted electrocyclization reaction of oxime
ethers.
In conclusion, the 6-electrocyclization of conjugated azatrienes
offers a useful method for the synthesis of heterocyclic boronic
acid derivatives. Our experimental studies show that, in the case
of oxime ethers, there is a direct relationship between oxime
stereochemistry and reactivity towards electrocyclization.
Specifically, while the configuration of the alkene at the
azatriene terminus has little impact on reaction rates, E-oxime
ethers are significantly more reactive than their Z-counterparts
(stereochemistry relative to azatriene scaffold). Computational
analysis has identified a Nlone pair→C=C * orbital interaction that
promoted the cyclization in the case of E-oxime isomer by
lowering the energy of the transition state in the
electrocyclization process. Finally, unreactive Z-oxime ethers
can be converted to the corresponding heterocyclic products by
Figure 3. Orbital interaction diagrams (B and C) and Electrostatic Potential
maps (A and D) for the cyclization transition states of the isomeric E- and Z-
oxime ethers.
The fact that ketoxime ethers are commonly formed with
significant proportions of Z-isomer present constitutes
a
limitation of this chemistry given that calculations suggest that Z-
oximes are essentially inert to cyclization. This prompted us to
consider the possibility of using photochemically promoted
cyclization methods as a means to processing these unreactive
azatrienes towards pyridine products. In principle, two pathways
could be envisaged: (1) a photochemically promoted conrotatory
cyclization reaction; (2) a photochemically promoted oxime ether
isomerization followed by thermally promoted disrotatory
cyclization. Regarding the latter pathway, photochemically
promoted stereochemical isomerization of oximes has been
established (Scheme 4).[10] Moreover, Pratt and co-workers have
reported that such processes can operate during
electrocyclization reactions, although they did not identify a
relationship between cyclization efficiency and oxime ether
stereochemistry.[11] This approach is especially attractive in the
case of oxime ethers where the rate of thermal interconversion
is extremely slow.
a
photolytically
promoted
E→Z
isomerization
and
electrocyclization sequence.
Experimental Section
Typical
diboration-electrocyclization
procedure
as
exemplified by the formation of 2e: A mixture of oxime 1e
(1.45 g, 6.10 mmol), B2pin2 (1.70 g, 6.70 mmol) and Pt(PPh3)4
(759 mg, 0.61 mmol) were heated in toluene (60 mL) at reflux for
30 min in a Schlenk tube. Flash chromatography over florisil
provided the diborylalkene as a yellow oil (2.50 g, 83%). 1H NMR
(400 MHz, CDCl3) δ 7.74 (s, 1H), 7.14-7.05 (m, 3H), 7.00-6.96
(m, 3H), 3.89 (s, 3H), 3.81 (s, 3H), 1.31 (s, 12H), 1.30 (s, 12H);
13C NMR (101 MHz, CDCl3) δ 141.0, 139.7, 138.8, 130.2 (2C),
128.8, 127.8 (2C), 126.3, 123.8, 84.3 (2C), 84.1 (2C), 62.0, 40.0,
24.9 (8C), two quaternary missing due to quadrupolar relaxation;
11B NMR (128 MHz, CDCl3) δ 30.2 (br); FTIR:  = 2978, 1459,
In order to establish the potential of the photochemically
promoted cyclization, we subjected substrates 1Z,5E-3a and 1Z-
3i to UV irradiation in o-DCB. Pleasingly, these conditions
successfully furnished the desired heterocyclic substrates, albeit
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1308, 1140, 1052 cm-1; HRMS m/z [M+H]+ C26H3811B2N3O5 calcd.
494.2998, found 494.3021.
[11] M. Austin, O. J. Egan, R. Tully, A. C. Pratt, Org. Biomol. Chem. 2007, 5,
3778.
Diborylalkene (2.50 g, 5.0 mmol) in o-DCB (50 mL) was stirred
at 200 °C for 16 h. The reaction mixture was allowed to cool to
room temperature and was filtered through silica gel. The
residue was purified by flash column chromatography on silica
1
gel to give 2e as a yellow foam (1.60 g, 93%). H NMR (400
MHz, CDCl3) δ 9.02 (s, 1H), 8.23 (s, 1H), 7.68-7.63 (m, 2H),
7.45-7.36 (m, 3H), 4.21 (s, 3H), 1.32 (s, 12H); 13C NMR (101
MHz, CDCl3) δ 154.6, 142.2, 134.6, 134.0, 133.9, 133.1, 129.7
(2C), 127.9 (2C), 127.8, 84.4 (2C), 36.1, 24.8 (4C), one
quaternary missing due to quadrupolar relaxation; 11B NMR (128
MHz, CDCl3) δ 31.6 (br); FTIR:  = 2971, 1725, 1562, 1451,
1319, 1195, 1070 cm-1; HRMS m/z [M+H]+ C19H2211BN3O2 calcd.
336.1878, found 336.1888;
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: electrocyclization · heteroaromic · boronic ester ·
stereochemistry
[1]
(a) A. R. Sherman in Comprehensive Heterocyclic Chemistry II; Vol. 7
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon, Oxford,
1996, p. 167; (b) L. B. Townsend, D. S. Wise in Comprehensive
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There are no examples of 4-borylated thieno[2,3-c]pyridines reported in
the literature, to the best of our knowledge. A single example of a 5-
borylated analog was reported by Glorius and co-workers: H. Wang, C.
Grohmann, C. Nimphius, F. Glorius, J. Am. Chem. Soc. 2012, 134,
19592.
[5]
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[6]
[7]
Subjection of Z-3a to heating at 200 0C in 1,2-dichlorobenzene over
extended periods did not lead to any detectable quantities of
thienopyridine 2a.
(a) E. N.Marvell, G. Caple, C. Delphey, J. Platt, N. Polston, J. Tashiro,
Tetrahedron 1973, 29, 3797; (b) C. W. Spangler, T. P. Jondahl, B.
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6157.
[8]
[9]
Although there are no reports correlating oxime ether stereochemistry
with electrocyclization efficiency,
a
theoretical study of the
corresponding reactions of pentadienimine has been documented: J.
Rodríguez-Otero, J. Org. Chem. 1999, 64, 6842.
Heating 1E,5E-4 at 200 oC in 1,2-Cl2C6H4 generated the corresponding
isoquinoline in 83% yield, whereas subjecting 1Z,5E-4 resulted in <2%
conversion under the same conditions.
[10] (a) A. Padwa, F. Albrecht, J. Am. Chem. Soc. 1972, 94, 100; (b) A.
Padwa, F. Albrecht, J. Am. Chem. Soc. 1974, 96, 2361; (c) Y. Takeda,
H. Misawa, H. Sakuragi, K. Tokumaru, Bull. Chem. Soc. Jpn. 1989, 62,
2213.
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Helena Mora-Radó, Lia Sotorríos,
Matthew P. Ball-Jones, Laurent Bialy,
Werngard Czechtizky, María Mendez
Perez, Enrique Gómez-Bengoa, Joseph
P. A. Harrity*
Page No. – Page No.
It’s not all E/Z! E-oxime ethers are found to be significantly more reactive in
electrocyclizations than their Z-counterparts because of an available transition state
stabilizing orbital interaction in the former case. The scope of this chemistry to
deliver useful heterocyclic products is also described.
Synthetic and Mechanistic
Investigation of an Oxime Ether
Electrocyclization Approach to
Heteroaromatic Boronic Acid
Derivatives
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