Synthesis of Functionalized Tetrahydropyridines by SnCl4-Mediated [4+2] Cycloaddition between Donor–Acceptor Cyclobutanes and Nitriles

Article abstract of DOI:10.1002/chem.201903833

Cycloadditions of strained carbocycles promoted by Lewis acids are powerful methods to construct heterocyclic frameworks. In fact, the formal [3+2] cycloadditions of donor–acceptor (DA) cyclopropanes with nitriles has seen particular success in synthesis. In this work, we report on the first [4+2] cycloaddition of nitriles with DA cyclobutanes by Lewis acid activation. Tetrahydropyridine derivatives were obtained in up to 91 % yield from various aryl-activated cyclobutane diesters and aliphatic or aromatic nitriles.

Full text of DOI:10.1002/chem.201903833

A Journal of
Accepted Article
Title: Synthesis of Functionalized Tetrahydropyridines by SnCl4-
mediated [4+2] Cycloaddition between Donor–Acceptor
Cyclobutanes and Nitriles
Authors: David Tong, Jackie Wu, Nathan Bazinski, Donghyun Koo,
naresh vemula, and Brian L. Pagenkopf
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201903833
Link to VoR: http://dx.doi.org/10.1002/chem.201903833
Supported by

10.1002/chem.201903833
Chemistry - A European Journal
COMMUNICATION
Synthesis of Functionalized Tetrahydropyridines by SnCl4-
mediated [4+2] Cycloaddition between Donor–Acceptor
Cyclobutanes and Nitriles
David Tong, Jackie Wu, Nathan Bazinski, Donghyun Koo, Naresh Vemula and Brian L. Pagenkopf*
Abstract: Cycloadditions of strained carbocycles promoted by Lewis
acids are powerful methods to construct heterocyclic frameworks. In
fact, the formal [3+2] cycloadditions of donor-acceptor (DA)
cyclopropanes with nitriles has seen particular success in synthesis.
In this work, we report on the first [4+2] cycloaddition of nitriles with
DA cyclobutanes via Lewis acid activation. Tetrahydropyridine
derivatives were obtained in up to 91% yield from various aryl
activated cyclobutane diesters and aliphatic or aromatic nitriles.
Cycloaddition reactions of cyclopropanes with nitriles have
been particularly productive (for example, the pyrrole synthesis
in Scheme 1A).1a,11 Yet, the analogous reaction of cyclobutanes
bearing geminal diesters has not been reported to date. In the
most relevant example, Matsuo recently reported the
cycloaddition between aryl-substituted cyclobutanones and
nitriles (Scheme 1, eq B).12 However, the cyclobutanones were
structurally distinct from the cyclopropanes or cyclobutanes with
exocyclic ester electron withdrawing functionality (e.g., Figure 1).
In this contribution, we describe the formal [4+2]-cycloaddition
reactions between nitriles and aryl-activated DACBs via Lewis
acid promotion (Scheme 1, eq C). The method reported herein
could afford a rich variety of tetrahydropyridine derivatives that
are medicinally privileged constituents in many bioactive natural
products13 thanks to the electronic and structural diversity that
are tolerated across both the cyclobutane and nitrile
components.
Cycloadditions of donor-acceptor cyclopropanes (DACPs) have
emerged as a powerful means to construct heterocycles and
carbocycles, and they thus play pivotal roles in natural product
syntheses.1 Cyclobutanes share a similar degree of bond-strain
to cyclopropanes, 2 but they largely remained unexplored as
reaction partners in cycloaddition chemistry until the last
decade. 3 Generalized DA-cyclobutane (DACB) cycloaddition
reactions were firstly reported in 2009 by Johnson 4 and by
Prichard and Christie 5 with aldehydes as the dipolarophiles
(Figure 1). In the following year we disclosed the first alkoxy-
activated DACB cycloaddition reactions with aldehydes, 6 and
Our previous work (2003):
(A)
Matsuo (2018):
(B)
7
subsequently reported DACB cycloadditions with imines,
nitrones,8 alkynes,9 and nitrosoarenes.10
This work:
(C)
Scheme 1: Cyclobutane cycloaddition reactions with nitriles. (Refs [11], [12]).
Johnson (2009), R = Ph
Christie, Prichard (2009), R = PhC2•Co(CO)6
Our previous work (2010), R = OAlkyl
Figure 1. Pioneering contributions to cycloadditions of donor-acceptor
cyclobutanes activated by geminal diesters (Ref. [4], [5], [6]).
[*]
D. Tong, J. Wu, N. Bazinski, D. Koo, N. Vemula, Prof. Dr. B. L.
Pagenkopf
Department of Chemistry
The University of Western Ontario
1151 Richmond Street
London, Ontario N6A 5B7 (Canada)
E-mail: bpagenko@uwo.ca
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903833
Chemistry - A European Journal
COMMUNICATION
Scheme 2. Cycloaddition of model cyclobutanes 1a-Me and 1a-Et with nitriles. a Acetonitrile used as solvent. General procedure: To a solution of cyclobutane
(1.0 equiv, 0.4 mmol) and nitrile (3.0 equiv, 1.2 mmol) in dichloroethane (DCE) at 55 °C was added dropwise SnCl4 (1.5 equiv, 0.6 mmol) in 2 mL DCE.
3
TMSOTf (0.1)
TMSOTf (1.1)
Pr(OTf)3 (0.05)
Mg(OTf)2 (0.1)
MgI2 (0.5)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeNO2 rt
Toluene rt
DCE
DCE
DCE
DCE
MeCN
rt
rt
18
18
48
12
12
16
4
3
3
3
3
3
3
3
3
3
3
3
trace
18
nr
The cyclobutane 1a-Me and acetonitrile (2a) were chosen as
model reaction partners to firstly establish reactivity and optimize
conditions for their cycloaddition to give 3a-Me (Table 1). The
Lewis acids Yb(OTf)3 and Sc(OTf)3 that were highly effective in
the cycloadditions of aldehydes with aryl4 or alkoxy-activated
DACBs6-8 turned out to be inactive or minimally effective (Table
1, entries 1, 2). Neither was TMSOTf successful, although it
efficiently catalyzed the analogous cycloaddition between
cyclopropanes and nitriles (Scheme 1, eq A; Table 1, entries 3,
4). Other common catalysts often employed in the cycloadditions
of donor-acceptor carbocycle were also not productive (entries
5–8). Ultimately, SnCl4 emerged as the most viable catalyst
(entries 9–18),14 and dichloroethane was identified as the most
effective solvent. Reaction temperature was critical (entries 16–
20) because the formation of the fragmentation / cycloaddition
product 4a became competitive at >55 °C (entry 19).15 Ultimately,
the conditions established for this [4+2] cycloaddition employed
super stoichiometric SnCl4 (1.5 equiv) at 55 °C and gave the
cycloadduct 3a-Me in a modest 52% yield. The yield increased
to 78% (entry 20) when acetonitrile was used as solvent, which
demonstrates that sufficient Lewis acid remained to catalyze the
4d
5
rt – 55
rt – 55
rt - 55
rt - 55
rt - 55
rt
rt
rt
rt
6
7
8
9
nr
dec
Nr
nr
BF3ꞏOEt2 (0.1)
TfOH (0.1)
SnCl4 (0.5)
SnCl4 (1.1)
SnCl4 (1.5)
SnCl4 (2.1)
SnCl4 (1.5)
SnCl4 (1.5)
SnCl4 (1.5)
SnCl4 (1.5)
SnCl4 (1.5)
SnCl4 (1.5)
SnCl4 (1.5)
10
11
12
13
14
15
16
17
18
19
20e
26
39
43
44
36
37
44
33
52
38
78
rt
0
55
85
55
a Reactions were run in the indicated solvent on 0.4 mmol scale with
MeCN (5.0 equivalents). b Isolated yield. c No reaction was observed at 0
°C. d Reaction was conducted in a microwave reactor. DCM =
dichloromethane. DCE = dichloroethane. nr = no reaction. e Acetontrile as
solvent (0.1 M cyclobutane, 192 equiv of acetonitrile).
It is known that increasing the size of the esters, i.e., methyl
cycloaddition although formation of SnCl4 adducts with nitriles,
to
ethyl,
decreases
reactivity
and
helps
reduce
16
decomposition.6,7 Using the diethyl ester 1a-Et gratifyingly
improved the efficiency of the cycloaddition with acetonitrile to
70% from the 52% yield with 1a-Me (Scheme 2). By running the
reaction in acetonitrile as solvent the yield improved to 91%.
Further evaluation of the reaction scope was arbitrarily carried
out with either the dimethyl or the diethyl diester variants of the
cyclobutane, and the results are summarized in Scheme 2. The
[4+2] cycloaddition was accomplished with a broad range of
nitriles, and both saturated straight-chain and branched aliphatic
nitriles were well tolerated (3a–e). Reaction in the presence of a
free 3-hydroxy group was successful (3f), and 3-
methoxyacrylonitrile gave the vinylogous formamide 3g in 35%
yield after hydrolysis.
i.e., SnCl4·(MeCN)2, are known.
Similarly, our previously
reported DA-cyclopropane cycloadditions catalyzed by Me3SiOTf
were also more efficient when ran in acetonitrile solvent.11 The
preliminary conditions optimized for 1a-Me were then attempted
with other substrates, most of which proved more efficient.
Table 1. Reaction optimization with cyclobutane 1a-Me and acetonitrile.
conditionsa
catalyst
(equiv)
Time
(h)
yieldb 3a
(%)
Entry
Solvent temp (°C)
1
2
Yb(OTf)3 (0.1)
Sc(OTf)3 (0.05)
DCM
DCM
rt – 55
55
15
24
Nr
16
This article is protected by copyright. All rights reserved.

10.1002/chem.201903833
Chemistry - A European Journal
COMMUNICATION
Electronically diverse aromatic nitriles were also evaluated,
and as expected, electron rich nitriles such as para-methoxy or
para-methyl benzontrile were more effective (3h, 3i).17 Electron
poor nitriles with electron withdrawing groups such as ester or
trifluoromethyl gave lower yields (3k, 3l). Cycloaddition with
halogenated arenes were successful (3m–o). Alkynyl nitriles
could also engage when provided sufficient electronic donation
(3p). 2-Thienyl nitrile also proved to be an efficient partner (3q).
The electronic trends observed with these aryl nitriles were
consistent with a Ritter-type reaction mechanism.
The structure of the cyclobutanes was then varied (Scheme
4). Both acetonitrile (2a) and benzonitrile (2j) were then used as
model nitriles to explore the generality of the reaction with
various cyclobutanes. A para-bromo substituted aryl cyclobutane
gave the cycloadducts with acetonitrile or benzonitrile in 68%
and 82% yield, respectively (3r-Et, 3s-Et). The adducts 3m–o,
3r-Et and 3s-Et provide a convenient aryl halide for additional
synthetic manipulation on both participants.
Scheme 4. Proposed mechanism for formation of 4a.
The tetrahydropiperidene adduct 3 readily underwent classic
transformations, including dealkoxycarbonylation to the
vinylogous
carbamate
6
and
reduction
from
the
tetrahydropyridine 3j to the piperidene 7j (Scheme 5).
Scheme 5. Krapcho dealkoxycarbonylation and reduction of 3j.
Scheme 3. Scope of cycloaddition with cyclobutanes 1b-1d with acetonitrile
and/or benzonitrile.
In summary, we have developed
a
SnCl4-mediated
cycloaddition between nitriles and donor-acceptor cyclobutanes
that are activated by vicinal aryl donating and geminal-diester
electron withdrawing substituents. The resulting reaction favors
electron rich donors and nitriles, but is also compatible with a
wide range of substituents, particularly on the nitrile.
Halogenated substituents on either the cyclobutane or the nitrile
are compatible and provide a convenient handle for additional
synthetic manipulation. Further studies on asymmetric variants
are underway in our laboratory.
Formation of the fragmentation-cycloaddition product 4a-Me
(Table 1) increased notably when the aryl donors on the
cyclobutane (3t–v) became increasingly electron rich.18 Electron
rich donors likely favor the formation of
a zwitterionic
intermediate 5 (Scheme 4) that can undergo E1cB fragmentation
to give styrene and methylidene malonate, a process faster than
the interception of the relatively stable benzylic cation 5 by the
nitrile. The methylidene malonate can then combine with another
equivalent of DA-cyclobutane to afford 4a. This proposed
mechanism is consistent with our detailed crossover study on
similar products formed in cycloadditions of DA-cyclopropanes.15
Acknowledgements
We thank the University of Western Ontario WSS NSERC
Bridge (grant number 47229) and the Natural Sciences and
Engineering Research Council of Canada (NSERC; grant
number 04891-2014) for financial support.
Keywords: cycloaddition • cyclobutane • donor-acceptor
systems • nitrogen heterocycles • strained molecules
1 (a) B.L. Pagenkopf, N. Vemula, Eur. J. Org. Chem. 2017, 2561–2567. (b)
N.R. O'Connor, J.L. Wood, B.M. Stoltz, Isr. J. Chem. 2016, 56, 431–
444. (c) H.K. Grover, M.R. Emmett, M.A. Kerr, Org. Biomol. Chem.
2015, 13, 655-671. (d) M.A. Cavitt, L.H. Phun, S. France, Chem. Soc.
Rev. 2014, 43, 804–818. (e) T.F. Schneider, J. Kaschel, D. Werz,
This article is protected by copyright. All rights reserved.

10.1002/chem.201903833
Chemistry - A European Journal
COMMUNICATION
Angew. Chem. Int. Ed. 2014, 53, 5504–5523. (f) T.P. Lebold, M.A. Kerr,
Pure Appl. Chem. 2010, 82, 1797–1812. (g) C.A. Carson, M.A. Kerr,
Chem. Soc. Rev. 2009, 38, 3051–3060. (h) M. Yu, B.L. Pagenkopf,
Tetrahedron 2005, 61, 321–347. (i) H.-U. Reissig, R. Zimmer, Chem.
Rev. 2003, 103, 1151–1196. (j) H.-U. Reissig, E. Hirsch, Angew. Chem.
Int. Ed. Engl. 1980, 19, 813–814.
2 (a) Wiberg, K. B. Cyclobutane–Physical Properties and Theoretical Studies.
In The Chemistry of Cyclobutanes, Chichester, England: Rappoport, Z.;
Liebman, J. F., Eds.; John Wiley Sons Ltd., 2005, Part 1, 1–15. (b) T.
Seiser, T. Saget, D.N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011,
50, 7740-7752.
3 (a) N. Vemula, B.L. Pagenkopf, Org. Chem. Front. 2016, 3, 1205-1212. (b)
H.-U. Reissig, R. Zimmer, Angew. Chem. Int Ed. 2015, 54, 5009-5011.
(c) J.-i. Matsuo, Tetrahedron Lett. 2014, 55, 2589. (d) F.D. Nanteuil, F.
Simone, R. Frei, F. Benfatti, E. Serrano, J. Waser, Chem. Commun.
2014, 50, 10912-10928.
4 J.S. Johnson, A.T. Parsons, J. Am. Chem. Soc. 2009, 131, 14202−14203
5
E.A. Allart, S.D.R. Christie, G.J. Pritchard, M.R. Elsegood, J. Chem.
Commun. 2009, 7339–7341
6 M.M.A.R. Moustafa, A.C. Stevens, B.P. Machin, B.L. Pagenkopf, Org. Lett.
2010, 12, 4736–4738.
7 M.M.A.R. Moustafa, B.L. Pagenkopf, Org. Lett. 2010, 12, 4732–4735
8 A.C. Stevens, C. Palmer, B.L. Pagenkopf, Org. Lett. 2011, 13, 1528–1531.
9 B.P. Machin, B.L. Pagenkopf, Synlett 2011, 2799–2802.
10 (a) N. Vemula, A.C. Stevens, T.B. Schon, B.L. Pagenkopf, Chem. Commun.
2014, 50, 1668–1670. (b) N. Vemula, B.L. Pagenkopf, Eur. J. Org.
Chem. 2015, 4900-4906.
11 (a) M. Yu, B.L. Pagenkopf, J. Am. Chem. Soc. 2003, 125, 8122 – 8123. (b)
M. Yu, B.L. Pagenkopf. Org. Lett. 2003, 5, 5099–5101.
12
E. Igarashi, K. Sakamoto, T. Yoshimura, J.-i. Matsuo, Tetrahedron Lett.
2018, 60, 13–15.
13 (a) J.S. Birks, R.J. Harvey, Cochrane Database Syst. Rev. (18 June 2018).
6: CD001190. doi:10.1002/14651858.CD001190.pub3. (b) M.
Lewandowski, K. Gwozdzinski, Int. J. Mol. Sci. 2017, 18, 2490;
doi:10.3390/ijms18112490. (c) S. Levent, Int. J. Pharm. Sci. Invent.
2016, 5, 40-42. (d) O’Hagen, D. Nat. Prod. Rep. 2000, 17, 435-446.
14 V. J. Tamilarasan, K. Srinivasan, J. Org. Chem. 2019, 84, 8782-8787.
15 T. Chidley, N. Vemula, C.A. Carson, M.A. Kerr, B.L. Pagenkopf, Org. Lett.
2016, 18, 2922–2925.
16 (a) M. Webster, H. E. Blayden, J. Chem. Soc. A 1969, 2443–2451. (b) M. A.
I. El-Erian, P. G. Huggett, K. Wade Polyhedron 1991, 10, 2131–2136.
17 A. Kreft, A. Lücht, J. Grunenberg, P.G. Jones, D.B. Werz, Angew. Chem. Int.
Ed. 2019, 58, 1955–1959.
18 A. Kreft, S. Ehlers, P.G. Jones, D.B. Werz, Org. Lett. 2019, 16, 6315-6319.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903833
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
David Tong, Jackie Wu, Nathan
Bazinski, Donghyun Koo, Naresh
Vemula and Brian L. Pagenkopf*
Page No. – Page No.
Synthesis of Functionalized
Tetrahydropyridines by SnCl4-
mediated [4+2] Cycloaddition
between Donor–Acceptor
Cyclobutanes and Nitriles
The Lewis-acid promoted cycloadditions of nitriles with donor-acceptor (DA)
cyclopropanes have proven to be powerful tools for the construction of heterocyclic
frameworks, but the analogous reaction with cyclobutanes has remained elusive.
Here we report the first [4+2] cycloaddition of nitriles with DA cyclobutanes by Lewis
acid activation to provide useful tetrahydropyridine derivatives.
This article is protected by copyright. All rights reserved.