Intermolecular Aryne Ene Reaction of Hantzsch Esters: Stable Covalent Ene Adducts from a 1,4-Dihydropyridine Reaction

Article abstract of DOI:10.1021/acs.orglett.7b02272

The reaction of arynes with 1,4-dihydropyridines affords 2-aryl-1,2-dihydropyridines or 2-methylene-3-aryl-1,2,3,4-tetrahydropyridines via a regioselective C-2 or C-3 arylation. These compounds are the first series of isolable and bench-stable covalent ene adducts formed between dihydropyridines and unsaturated substrates. Experimental studies and DFT calculations provide mechanistic support for a concerted intermolecular aryne ene process, which may have implications for NAD(P)H model reactions.

Full text of DOI:10.1021/acs.orglett.7b02272

Letter
pubs.acs.org/OrgLett
Intermolecular Aryne Ene Reaction of Hantzsch Esters: Stable
Covalent Ene Adducts from a 1,4-Dihydropyridine Reaction
Piera Trinchera, Weitao Sun, Jane E. Smith, David Palomas, Rachel Crespo-Otero,
and Christopher R. Jones*
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, U.K.
S
* Supporting Information
ABSTRACT: The reaction of arynes with 1,4-dihydropyr-
idines affords 2-aryl-1,2-dihydropyridines or 2-methylene-3-
aryl-1,2,3,4-tetrahydropyridines via a regioselective C-2 or C-3
arylation. These compounds are the first series of isolable and
bench-stable covalent ene adducts formed between dihydro-
pyridines and unsaturated substrates. Experimental studies and
DFT calculations provide mechanistic support for a concerted
intermolecular aryne ene process, which may have implications
for NAD(P)H model reactions.
study by Erb involving NADPH-dependent enzymes,6 as well as
1,4-Dihydropyridines (1,4-DHPs) have been widely exploited as
reports from Iqbal7a and Libby7b using NADH model DHPs,
support the fundamental possibility of an ene mechanism for HT.
Using in situ spectroscopy, unstable covalent ene adducts P.YH
were successfully characterized prior to their decomposition to
ionic species YH− and P+, then eventual product YH2. It follows
that the relative stability of adduct P.YH is key to the outcome of
DHP-driven reductions. Therefore, we reasoned that careful
selection of substrate Y could reverse the established equilibrium
between P.YH and YH−/P+, revealing a new approach to
functionalized DHPs, as well as providing bench-stable DHP−
ene adducts for the first time; a significant development toward
the full comprehension of 1,4-DHP-mediated reductions.
reducing agents in synthesis1 and comprise the core of the
biological redox cofactors, NAD(P)H. As a result, the precise
nature of the overall hydride transfer (HT) between 1,4-DHPs
(PH) and substrates (Y) has been the subject of numerous
mechanistic investigations (Scheme 1a).2 One-step ionic HT has
prevailed,3 in part due to a lack of experimental evidence for
intermediates that would arise from alternative single electron
transfer4 or pericyclic ene pathways.5 However, a recent seminal
Scheme 1. 1,4-Dihydropyridine Reaction Pathways
We envisioned that the use of arynes (Z) as substrates for 1,4-
DHP reactions should result in the formation of stable 2-aryl-1,2-
DHP adducts P.ZH, as decomposition would be disfavored due
to the instability of aryl anion ZH− (Scheme 1b). Arynes are
particularly versatile reactive intermediates that have enjoyed a
remarkable renaissance in recent years.8 This can be attributed to
the development of mild and convenient methods to access
arynes, such as 2-(trimethylsilyl)aryl triflates9 and the hexadehy-
dro-Diels−Alder reaction of polyalkynes,10 which have led to the
discovery of exciting new aryne reactivity motifs.8 Utilizing 1,4-
DHPs and reactive aryne intermediates, herein we describe the
synthesis of the first series of bench-stable covalent ene adducts
from a DHP reaction with an unsaturated substrate. While
removed from a true biological model, the stable ene adducts
obtained offered a unique opportunity to study the competing
HT and pericyclic mechanisms identified in previous NADH
model reactions. To this end, experimental and computational
Received: July 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
evidence is presented that supports a concerted ene reaction.
From a synthetic perspective, direct arylation of readily available
1,4-DHPs represents a new method to prepare 1,2-DHPs bearing
a challenging all-carbon quaternary stereogenic center.11,12
Hantzsch esters (HEs) are readily accessible 1,4-DHPs that
have been widely exploited in synthesis1 and as pharmaceutical
targets.13 As a result, we selected HEs as the DHP component in
our investigations,14 which began with HE 1a (R = Ph) and o-
silylaryl triflate 2a (R1 = H) (Scheme 2). Following a survey of
Scheme 3. C-3 Arylation of C-4 HE Derivatives
a
Scheme 2. C-2 Arylation of HE Derivatives
a
Reaction conditions are as shown in Scheme 2. Yields of isolated
b
1
products throughout. Ratio determined by analysis of the H NMR
spectrum.
corresponding quaternary C-3 arylated THPs 4fb and 4fc
(generated as a 1:1 mixture of meta and para regioisomers). The
reaction with benzyne precursor 2a was equally effective for
substrates with electron-rich (p-OMe, 1g) and electron-poor (p-
NO2, 1h) C-4 aryl substituents, affording THPs 4ga and 4ha
respectively. Aliphatic C-4 substitution of the HE (Me, 1i) was
also tolerated, affording C-3 arylated adduct 4ia in lower yield
(30%) but still no trace of the C-2 product.15 Interestingly, the C-
3 arylation of all 1,4-DHP derivatives 1f−i afforded a single
product diastereoisomer. NOESY experiments conducted on
THP 4ia indicated an anti relationship between the C-3 phenyl
group and the C-4 methyl substituent,16 consistent with the
aryne approaching from the opposite face of the HE to the C-4
substituent. There are very few reports describing the synthesis
of highly functionalized 2-methylene-1,2,3,4-THPs,17 and
adducts 4f−i are the first examples to contain aryl groups at an
all-carbon C-3 quaternary center.
With a selective synthesis of stable and isolable C-2 and C-3
covalent ene adducts in hand, we sought to gain insight into the
mechanisms in operation. There are two main pathways by which
the C-2 arylation of HEs is likely to occur: two-step hydride
transfer−recombination (via either radical or ionic intermedi-
ates) or a concerted aryne ene reaction (see Scheme 1b). To this
end, an equimolar mixture of 2,6-dimethyl HE 1e and a
bisdeuterated analogue, 2,6-dimethyl-4,4-d2 HE 1e-d2, was
treated with benzyne precursor 2a (Scheme 4). Analysis of the
reaction mixture revealed only “concerted products” 3ea and
3ea-d2.18 While this is not definitive proof of a concerted process,
the absence of monodeuterated “cross-products” 3ea-dH and
3ea-Hd does appear to support this hypothesis, as the formation
of ionic intermediates P+ and ZH− from hydride transfer (see
Scheme 1b) would be expected to result in at least trace amounts
of crossover. Similarly, adducts from potential 1,4-addition to P+
have never been detected. With a view to providing more
mechanistic detail, we performed DFT calculations (B3LYP-D3/
def2-TZVP in acetonitrile)19 on HE 1e. A low activation barrier
to the concerted reaction (7.5 kcal/mol) was found, whereas no
transition structure (TS) for either stepwise process (radical or
a
Reaction conditions: HE 1 (1.0 equiv), 2 (2.5 equiv), CsF (6.0 equiv)
in acetonitrile (0.1 M), 70 °C for 15 h. Yields of isolated products
throughout. Ratio determined by analysis of the H NMR spectrum.
b
1
solvents and fluoride sources we were pleased to observe that
cesium fluoride in acetonitrile at 70 °C led to the complete
consumption of 1a and formation of the desired covalent ene
adduct 3aa, which was bench-stable and isolated in 75% yield.
The reaction was equally viable with electron-rich (p-OMe,
1b) and electron-poor (p-F, 1c and p-Br, 1d) 2,6-diaryl HE
derivatives, generating the quaternary C-2 arylated 1,2-DHPs
3ba−da in good yields (60−65%). Incorporation of halogen
atoms in 3ca and 3da is particularly noteworthy, as these groups
can be problematic in organometallic-based approaches to
heterocycle arylation. Next we turned our attention to HE
derivative 1e (R = Me) and again observed exclusive formation of
the desired ene adduct 3ea. Treatment of 1e with methyl-
enedioxy aryne precursor 2b produced the corresponding 2-aryl-
1,2-DHP 3eb in 47% yield, while unsymmetrical 4-methyl-
benzyne precursor 2c provided 3ec as a 1:1 mixture of meta and
para regioisomers.
We continued our investigations into the scope of the DHP−
aryne reaction by introducing alkyl and aryl substituents to the C-
4 position of the HEs (1f−i). Surprisingly, none of the expected
C-2 ene adduct was observed when 2,6-dimethyl-4-phenyl HE 1f
was subjected to the standard arylation conditions; instead an
alternative bench-stable covalent ene adduct was isolated in 52%
yield, the highly substituted 2-methylene-3-aryl-1,2,3,4-tetra-
hydropyridine (THP) 4fa (Scheme 3). Similarly, exposure of 1f
to substituted aryne precursors 2b and 2c resulted in the
B
DOI: 10.1021/acs.orglett.7b02272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Mechanistic Studies
a
Reaction conditions are as shown in Scheme 2.
ionic) could be located, suggesting that the arylation proceeds via
a concerted reaction and is in agreement with the experimental
evidence. Arynes are well-established enophiles, and a number of
intramolecular aryne alkene−ene reactions have been devel-
oped,10a,20 as well as intermolecular hetera−ene21 and
propargylic−ene reactions.22 Intermolecular aryne alkene−ene
processes analogous to our hypothesis have been reported;
however, they are typically limited to simpler substrates.23,24
Similar mechanistic considerations surrounded the formation
of the C-3 adducts 4f−i, as they could arise either from an
alternative aryne ene reaction (involving C-3 and a C−H from
the exocyclic methyl group of 1f−i) or via stepwise addition of
aryne at C-3, followed by α-deprotonation of an intermediate
iminium ion. Again, experimental evidence tentatively favored an
ene process, as arylation of HE 1f in acetonitrile-d3 afforded 4fa
with no trace of any deuterium incorporation that would be
expected from an intermediate zwitterion deprotonating
acetonitrile.25 To further probe the mechanism, DFT
calculations (B3LYP-D3/def2-TZVP in acetonitrile)19 were
conducted using HE 1f. Once more these provided support for
a concerted reaction (ΔG‡ = 9.7 kcal/mol), and again no TS for a
stepwise process was found.
Figure 1. (a) Calculated C-2 and C-3 arylation reaction profiles of HE 1f
at B3LYP-D3/def-TZVP level of theory. (b) Computed transition
structures TS-3fa and TS-4fa.
found in comparison to C-2 adduct 3fa (11.9 kcal/mol), in
agreement with the experimental observations. Analysis of the
two TSs (TS-3fa and TS-4fa) reveals that the C-4 substituent
causes the adjacent ethyl ester groups to project onto the
opposite face of the 1,4-DHP ring and thus hinder the aryne
approach (Figure 1b). This affects C-2 arylation more
significantly than C-3, as evidenced by the increased Caryne
−
C
DHP bond length in TS-3fa (3.34 Å) compared to TS-4fa (2.27
Å), resulting in a more asynchronous distribution of charge and a
higher energy TS.
In summary, we have prepared a range of covalent ene adducts
formed between 1,4-DHPs and unsaturated substrates, the first
bench-stable examples of model intermediates from the ene
mechanism for NAD(P)H redox reactions first proposed by
Hamilton.5 DFT calculations and experimental analyses provide
support for the generation of the adducts by an intermolecular
aryne ene mechanism. Control of the arylation reaction course is
achieved through the substitution pattern around the HEs,
rendering this a flexible approach to highly functionalized 2-aryl-
1,2-DHP or 3-aryl-1,2,3,4-THP derivatives bearing all-carbon
quaternary stereogenic centers.
Finally we turned our attention to understanding the origin of
the divergent C-2/C-3 arylation. Using C-4 substituted HEs
incapable of forming the exocyclic alkene within THPs 4, no
reaction occurred with 2,4,6-triphenyl HE 1j; however, the less
hindered C-4 methyl analogue 1k did afford a small amount of C-
2 ene adduct 3ka (11%) (Scheme 5). This suggests that bulkier
a
Scheme 5. C-2 Arylation of C-4 HE Derivatives
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02272.
a
Reaction conditions are as shown in Scheme 2.
Experimental details for the preparation of new com-
pounds; spectroscopic data for their characterization,
including copies of 1H and 13C NMR spectra; LC-MS and
GC-MS data for deuterium competition experiments
(PDF)
C-4 groups lead to greater suppression of C-2 arylation.
Additional DFT calculations (B3LYP-D3/def2-TZVP in aceto-
nitrile)19 were performed on 2,6-dimethyl-4-phenyl HE 1f to
compare the theoretical reaction energy profiles for C-2 and C-3
arylation (Figure 1a). First, the large exothermic character and
low activation energies of both processes are consistent with the
proposed involvement of the aryne 1,2-pseudodiradical vinyl
resonance structure in ene reactions.26 Second, a lower activation
barrier for the formation of C-3 adduct 4fa (9.7 kcal/mol) was
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: c.jones@qmul.ac.uk.
C
DOI: 10.1021/acs.orglett.7b02272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
Chem. 1986, 64, 556. (d) Patterson, J. W. J. Heterocycl. Chem. 1986, 23,
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(18) See Supporting Information for full details of isotope studies.
(19) See Supporting Information for full details; calculations were
performed using Queen Mary MidPlus computational facilities
supported by QMUL Research-IT.
David Palomas: 0000-0003-2674-6831
Christopher R. Jones: 0000-0002-3420-658X
Notes
The authors declare no competing financial interest.
(20) (a) Candito, D. A.; Panteleev, J.; Lautens, M. J. Am. Chem. Soc.
2011, 133, 14200. (b) Karmakar, R.; Mamidipalli, P.; Yun, S. Y.; Lee, D.
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ACKNOWLEDGMENTS
■
We are grateful to the EPSRC (EP/M026221/1, C.R.J. and P.T.;
EP/K000128/1, R.C.-O.), Ramsay Memorial Trust (C.R.J.),
China Scholarship Council (W.S.), and the RSC Research Fund
for financial support. We thank the EPSRC UK National Mass
Spectrometry Facility at Swansea University. Nada Kurdi,
Gregory Craven, and Gregory Coates (QMUL) are thanked
for early experimental assistance.
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Org. Lett. XXXX, XXX, XXX−XXX