Intermolecular [2 + 2] Cycloaddition of 1,4-Dihydropyridines with Olefins via Energy Transfer

Article abstract of DOI:10.1021/acs.orglett.7b02881

A highly regio- and diastereoselective visible-light-promoted [2 + 2] cycloaddition between readily available 1,4-dihydropyridines and olefins has been developed. This strategy is operationally simple and atom-economical and enables the construction of strained polysubstituted 2-azabicyclo[4.2.0]octanes with three all-carbon quaternary centers with good functional group tolerance. These products can be easily converted to various structurally unique derivatives. The primary mechanistic studies demonstrated that the reaction proceeds through an energy transfer pathway.

Full text of DOI:10.1021/acs.orglett.7b02881

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Intermolecular [2 + 2] Cycloaddition of 1,4-Dihydropyridines with
Olefins via Energy Transfer
Chengfeng Wang and Zhan Lu*
Department of Chemistry, Zhejiang University, Hangzhou 310058, China
S
* Supporting Information
ABSTRACT: A highly regio- and diastereoselective visible-
light-promoted [2 + 2] cycloaddition between readily available
1,4-dihydropyridines and olefins has been developed. This
strategy is operationally simple and atom-economical and
enables the construction of strained polysubstituted 2-
azabicyclo[4.2.0]octanes with three all-carbon quaternary
centers with good functional group tolerance. These products
can be easily converted to various structurally unique
derivatives. The primary mechanistic studies demonstrated that the reaction proceeds through an energy transfer pathway.
trained polycyclic scaffolds containing cyclobutane rings are
common motifs in many natural and artificial products
Scheme 2. Useful Transformations of 1,4-Dihydropyridines
S
(Scheme 1) that have extensively been used in organic
Scheme 1. Cyclobutane-Containing Alkaloids or Bioactive
Structures
synthesis, materials science, and biochemistry.1 The photo-
induced [2 + 2] cycloaddition reaction of olefins2 is one of the
ideal and straightforward methods to obtain multisubstituted
cyclobutanes. Generally, complex intramolecular dienes or
superstoichimetric amounts of olefins have to be used to
guarantee the efficiency of [2 + 2] cycloaddition reactions.
Thus, the development of highly efficient, selective, and atom-
economical strategies for the preparation of strained polycyclic
scaffolds from simple starting materials is continuously
desirable. Additionally, it will be ideal that the obtained
polycycles can easily undergo various derivatizations.
Hantzsch ester (1,4-dihydropyridine, 1,4-DHP) as a
synthetic NADH analogue has been proven to be an efficient
hydrogen donor3 or alkyl radical source4 in various useful
transformations. However, these processes provide stoichio-
metric substituted pyridines as side products (Scheme 2a). The
[2 + 2] photocycloaddition reactions of 1,4-DHPs with olefins
could potentially afford polysubstituted strained 2-
azabicyclo[4.2.0]octanes. The Adembri group reported an
intermolecular [2 + 2] cycloadddition of N-benzyl-1,4-
dihydronicotinamide with acrylonitrile under irradiation with
a low-pressure mercury lamp that resulted in a 2:3 cis/trans
product ratio.5 The reaction has shown some drawbacks such as
the use of a high-energy light source, dimerization of the
starting material, and formation of product mixtures with poor
regio- and stereoselectivities. To the best of our knowledge,
highly regio- and diastereoselective [2 + 2] cycloaddition
reactions of 1,4-DHPs with olefins have not been reported to
date. Herein we present an efficient visible-light-promoted [2 +
2] cycloaddition of readily available 1,4-DHPs and olefins with
high regio- and diastereoselectivities to construct polysubsti-
tuted, strained 2-azabicyclo[4.2.0]octanes (Scheme 2b).
At the beginning of our studies, readily available Hantzsch
ester (1a) and simple styrene (2a) were chosen as model
substrates. In the presence of Ir(ppy)3 (2 mol %) as the
photocatalyst, the reaction of 1a and 2a (1 equiv) was carried
out in a solution of MeCN (0.05 M) under irradiation with an 8
W blue LED and an atmosphere of nitrogen at room
temperature (Table 1, entry 1). Two cyclobutanes, 3a and
3a′, were isolated in 77% combined yield, as confirmed by X-
ray diffraction,6 which showed that the reaction underwent a
head-to-head pathway with a 3:1 exo/endo ratio. When a phenyl
group was introduced at the 4-position of the 1,4-DHP (1b),
Received: September 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02881
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Scheme 3. Substrate Scope
b
entry
R
changes
yield of 4a (%)
c
1
2
H (1a)
−
−
77 (3a )
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
65
0
3
without light
without Ir(ppy)3
with air
4
0
5
0
6
THF
63
55
42
39
54
55
53
57
55
78
7
DMF
8
DMSO
9
CH2Cl2
10
11
12
13
14
acetone
with Et3N (1 equiv)
with K2CO3 (1 equiv)
with water (10 equiv)
with AcOH (1 equiv)
48 h
d
15
a
Conditions: 1 (1 equiv), olefin (1 equiv), Ir(ppy)3 (2 mol %), MeCN
b
(0.05 M), 8 W blue LED, rt, 24 h. Determined by 1H NMR analysis
using TMSPh as an internal standard. The endo/exo ratio was 1:3.
c
d
Ir(ppy)3 (1 mol %).
the reaction of 1b with 2a afforded 4a7 in 65% yield with high
regio- and diastereoselectivities (entry 2). The diastereoconfi-
guration was confirmed by X-ray diffraction, which showed that
the phenyl group of the styrene was seated proximal to the 1,4-
DHP scaffold as a result of steric hindrance of the phenyl group
on the 1,4-DHP scaffold. Control experiments indicated that
both light and the photocatalyst were necessary (entries 3 and
4). No desired product was detected under exposure to air
(entry 5). Various solvents such as THF, DMF, DMSO,
CH2Cl2, and acetone were suitable for this reaction but afforded
4a in slightly lower yields (entries 6−10). The reactions with an
organic base (Et3N) or an inorganic base (K2CO3) proceeded
smoothly to afford 4a in 55% and 53% yield, respectively
(entries 11 and 12). Notably, in the presence of water (10
equiv) or AcOH (1 equiv), no significant changes were
observed (entries 13 and 14). The reaction using 1 mol %
Ir(ppy)3 for 48 h afforded 4a in 78% yield (entry 15). Besides,
the reaction exhibited good biocompatibility (Table S1 in the
Supporting Information). The standard conditions were
identified as follows: 1,4-DHP (1 equiv), olefin (1 equiv),
and Ir(ppy)3 (1 mol %) in MeCN solution (0.05 M) under
irradiation with an 8 W blue LED at room temperature.
a
Standard conditions: 1 (1 equiv), olefin (1 equiv), Ir(ppy)3 (1 mol
b
%), MeCN (0.05 M), 8 W blue LED, rt. The gram-scale reaction was
performed using 0.1 mol % Ir(ppy)3 in MeCN (0.10 M). Isolated by
c
With the established reaction conditions, the scope of olefins
was explored (Scheme 3). The diastereomeric ratios of all
reactions were greater than 10:1 unless otherwise noted. With
3- or 4-bromostyrenes as olefin partners, which were easily
further derivatized, the reactions were carried out smoothly to
afford the corresponding cyclobutanes 4b and 4c in 76% and
direct filtration from the reaction mixture without further purification.
d
endo/exo = 6:1.
82% yield, respectively. Indole-containing 2-azabicyclo[4.2.0]-
octane 4d was obtained in 84% yield with N-methyl-5-
B
DOI: 10.1021/acs.orglett.7b02881
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
vinylindole as an alkene partner. α-Methylsytrenes with both
electron-donating and withdrawing groups were suitable for this
catalytic reaction, giving 4e−g in 72−92% yield. Additionally,
long alkyl chains with ester and free alcohol at the α-position of
the styrene were tolerated, delivering 4j and 4k in 65−66%
yield. Furthermore, sterically hindered α-cyclopropylstyrene
could also participate in the cycloaddition for a long time to
afford 4l in 30% yield without any ring-opening products.
Remarkably, structurally rare spiro[3.4]octane 4m and
spiro[3.6]decane 4n8 can be accessed via this strategy in 69−
86% yield with high regio- and stereoselectivities. Interestingly,
quinolin-2(1H)-one can also participate to afford 4q in 38%
yield, which illustrates that this method could potentially be
used as a late-stage functionalization strategy. The non-phenyl
pyridyl group could also be employed in this reaction to deliver
4o in 82% yield. With 0.1 mol % Ir(ppy)3, the reaction can
easily be scaled up to afford pyridine-containing cyclobutane 4p
in 70% yield (1.86 g) and acetylamide-substituted cyclobutane
4r in 76% yield (2.93 g). Notably, 4r could be directly obtained
by filtration from the reaction mixture without further
purification. So far, aliphatic alkenes were not suitable in this
transformation.
by refluxing in a solution of ethanol with aqueous HCl to afford
the corresponding products in 99% (7), 93% (8), and 66% (9)
yield, respectively. The rare spiro[3.6]decane 8 could be
selectively reduced using LiAlH4 to afford ester reduction
product 10 in 66% yield and using Raney Ni with H2 to afford
imine reduction product 11 in 96% yield.
To provide some insights into the mechanism of this
reaction, control experiments in the presence of various radical
trappers (1 equiv), such as TEMPO, BHT, 1,1-diphenylethene,
and methyl acrylate, were carried out to afford cyclobutane 3 in
a slightly lower yield (Scheme 5). Additionally, the reaction
Scheme 5. Radical Trapping Experiments and Proposed
Mechanism
Then the substituents on the 1,4-DHPs were investigated.
The reaction of 4-(4′-trifluoromethyl)phenyl dihydropyridine
provided the desired cyclobutane 5a in 40% yield and
overoxidized pyridine as a side product in 54% yield.
Electron-rich 4-(4′-methoxy)phenyl dihydropyridine was con-
verted to 5b in 97% yield. The 3-methylphenyl and more
sterically hindered 2-methylphenyl groups at the 4-position of
the dihydropyridine were tolerated (5c and 5d). A heteroaryl
ring (2-thiophenyl) was suitable, affording 5e in 69% yield. It
should be noted that aliphatic 1,4-DHPs participated to give
5f−h in 75−92% yield. Dihydropyridines with various
substituents on the ester group or 2- and 6-positions reacted
under standard conditions to give 5i−k in 78−83% yield. The
reaction of a less sterically demanding dihydropyridine without
substituents at the 2- and 6-positions afforded 5l in 69% yield
with 6:1 dr. The unsymmetrical mono-CN substrate could be
reacted to deliver a mixture of 5m and 5n in 45% yield with a
ratio of 6:1. When oxygen instead of nitrogen on the 1,4-DHP
or N-methyl-protected 1,4-DHP was used, the reaction did not
occur.
could tolerate various solvents and acidic and basic conditions
(Table S1). On the basis of redox potential, neither Ph-DHP
9
red
red
1b (E = +0.85 V vs SCE) nor styrene (E = +1.88 V vs
1/2
1/2
SCE)10 could be oxidized by the photoexcited species
Ir(ppy)3* (E1*/I2II/II = +0.31 V vs SCE).11 These experiments
indicated that a redox radical-initiated cycloaddition pathway
was less possible. The triplet energies of 4-substituted Hantzsch
esters,12 styrenes,13 and Ir(ppy)3* were around 68, 62 and 59
3
kcal/mol.14 These data were quite similar, which demonstrated
that the reaction could proceed via an energy transfer pathway.
A proposed mechanism is shown in Scheme 5. The
photosensitizer Ir(ppy)3 absorbs visible light to generate the
excited state Ir(ppy)3*, which undergoes energy transfer to
styrene to afford excited state styrene* and regenerate Ir(ppy)3.
Then styrene* can be trapped by the Hantzsch ester to afford
to the corresponding [2 + 2] cycloaddition product.
In summary, we have developed a novel regio- and
diastereoselective visible-light-promoted [2 + 2] cycloaddition
of 1,4-DHPs and olefins. This protocol is operationally simple
and atom-economical and uses relatively simple and readily
available starting materials for the efficient synthesis of more
valuable polysubstituted 2-azabicyclo[4.2.0]octanes. Various
derivatizations could be realized for the construction of
structurally unique azabicycles or spiro rings. The primary
studies demonstrated that the reaction proceeds via an energy
transfer pathway. The protocol has also demonstrated great
biocompatibility and could potentially be used in biochemistry.
The photocatalytic synthesis of valuable complex molecules is
ongoing in our laboratory.
With regard to the synthetic utility, various derivatizations
were conducted (Scheme 4). Simple treatment of 4e with
LiAlH4 delivered a 55% yield of the unique and selective
reduction product 6, in which one ester group was reduced to
the alcohol while the other was reduced to the aldehyde. The
de-esterification reactions of 4e, 4n, and 4r could be performed
Scheme 4. Further Derivatization
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02881.
Experimental details, characterization data for all
1
compounds, and copies of H and 13C NMR spectra
(PDF)
Crystallographic data for 3a (CIF)
C
DOI: 10.1021/acs.orglett.7b02881
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
́
2016, 55, 14106. (d) Gutierrez-Bonet, A.; Tellis, J. C.; Matsui, J. K.;
Crystallographic data for 3a′ (CIF)
Vara, B. A.; Molander, G. A. ACS Catal. 2016, 6, 8004.
(5) (a) Adembri, G.; Donati, D.; Fusi, S.; Ponticelli, F. Heterocycles
1985, 23, 2885. (b) Adembri, G.; Donati, D.; Fusi, S.; Ponticelli, F. J.
Chem. Soc., Perkin Trans. 1 1992, 2033. For a dimerization, see:
(c) Adembri, G.; Camparini, A.; Donati, D.; Fusi, S.; Ponticelli, F.;
Scotton, M. Tetrahedron Lett. 1983, 24, 5399.
Crystallographic data for 4a (CIF)
Crystallographic data for 4n (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luzhan@zju.edu.cn.
ORCID
(6) CCDC number for 3a′: 1526041. CCDC number for 3a:
1526039.
(7) CCDC number for 4a: 1526043.
(8) CCDC number for 4n: 1565460.
́
́
(9) (a) Zapata-Urzua, C.; Perez-Ortiz, M.; Acosta, G. A.; Mendoza, J.;
Zhan Lu: 0000-0002-3069-079X
Notes
́
́
́
Yedra, L.; Estrade, S.; Alvarez-Lueje, A.; Nunez-Vergara, L. J.;
̃
Albericio, F.; Lavilla, R.; Kogan, M. J. J. Colloid Interface Sci. 2015,
453, 260. (b) Salazar, R.; Navarrete-Encina, P. A.; Camargo, C.;
The authors declare no competing financial interest.
Squella, J. A.; Nunez-Vergara, L. J. J. Electrochem. Soc. 2008, 155, P103.
́
̃
(10) Park, J.; Lee, Y.; Ohkubo, K.; Nam, W.; Fukuzumi, S. Inorg.
Chem. 2015, 54, 5806.
ACKNOWLEDGMENTS
■
Financial support was provided by the NNSFC (21472162)
and the National 973 Program (2015CB856600). We thank
Prof. Peng Wang and Prof. Hongguang Xia from ZJU for kind
discussions.
(11) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322.
(12) Jimenez, A. J.; Fagnoni, M.; Mella, M.; Albini, A. J. Org. Chem.
2009, 74, 6615.
(13) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617.
(14) Noh, Y.; Lee, C.; Kim, J.; Yase, K. J. Chem. Phys. 2003, 118,
2853.
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DOI: 10.1021/acs.orglett.7b02881
Org. Lett. XXXX, XXX, XXX−XXX