Photochemically Produced Aminocyclobutanes as Masked Dienes in Thermal Electrocyclic Cascade Reactions

Article abstract of DOI:10.1021/acs.orglett.9b00211

Cyclobutane products of a triplet sensitized enamide-alkene intramolecular [2 + 2] photocycloaddition have been shown to undergo fragmentation under acidic conditions. This lability has been exploited by inducing a complexity-generating thermal electrocyc

Full text of DOI:10.1021/acs.orglett.9b00211

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photochemically Produced Aminocyclobutanes as Masked Dienes in
Thermal Electrocyclic Cascade Reactions
Luke D. Elliott* and Kevin I. Booker-Milburn*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: Cyclobutane products of a triplet sensitized enamide-
alkene intramolecular [2 + 2] photocycloaddition have been shown to
undergo fragmentation under acidic conditions. This lability has been
exploited by inducing a complexity-generating thermal electrocyclic
cascade sequence involving the in situ formation of a cyclobutene,
followed by electrocyclic ring opening, Diels−Alder cycloaddition, and
subsequent lactamization. This combination of excited state photo-
chemistry and thermal electrocyclic cascade reactions allows simple planar molecules to be rapidly transformed into sp3-rich
scaffolds.
tructural novelty and 3D molecules are generating
increasing interest as potential library scaffolds in drug
Scheme 1. Acid Catalyzed Fragmentation of 2,4-
Methanopyrrolidines and Proposed Capture of Reactive
Intermediates
S
discovery as the pharmaceutical industry explores bioactivity
beyond the constraints of flat polyaryl molecules.1,2 Excited
state photochemistry is unparalleled in its ability to convert
simple planar molecules into complex sp3-rich species.3
Photocycloadditions, in particular, can give rise to exotic
polycyclic species under “reagentless” conditions with 100%
atom economy. Although scalability is often cited as a limiting
factor preventing the more widespread uptake of excited state
photochemistry in pharma, we have recently demonstrated the
scale-up of a wide range of photochemical reactions under
research lab conditions to unprecedented quantities (≥1 kg/
day) using novel flow reactors developed by us.4
The high energies involved in the formation of photochemi-
cally excited states means that the products often possess great
strain.3c Thermal release of this strain often facilitates further
ground state reactivity, e.g. the de-Mayo reaction;5 fragmenta-
tion of cyclobutanols from Norrish−Yang products;6 1,5-H
shifts of photochemically produced aziridines;7 and photo-
isomerization and trapping of trans cycloalkenes.8 The
availability of complex photochemical products by flow
photochemistry means that they can now be considered as
accessible feedstocks processing “masked reactivity” due to
their inherent high strain energy. The general application of
these in synthesis has yet to be exploited. Herein we report an
investigation into the cascade reactivity of one such structure
from photochemically produced 2,4-methanopyrrolidines.
As part of a program involving the scale-up of photo-
chemistry for drug discovery, we were able to synthesize 2,4-
methanopyrrolidine 2a on the kilogram scale4c in a standard
fumehood (Scheme 1). Key to the success of the reaction was
the use of an inexpensive organic triplet sensitizer isopropyl-
thioxanthone (ITX) which has a strong UVA absorption and
so can be used at low loadings (1%) while still harnessing the
intense I-line emission at 365 nm of the medium pressure lamp
used.
Pyrrolidine 2a appeared to be an ideal motif for fragment
libraries being conformationally restricted and possessing
favorable physiochemical properties.9 Unfortunately, attempts
to deprotect the amide under acidic conditions10 resulted in
significant degradation. On closer analysis of the reaction
mixture traces of the alcohol 3 and cyclobutene 4 could be
identified. This indicates that the strained nature of the
molecule makes the C−N bond particularly labile toward
fragmentation upon protonation of the amide carbonyl. We
reasoned that this inherent strain can be exploited by allowing
the 2,4-methanopyrrolidine to undergo fragmentation to
cyclobutene 4 which could then undergo electrocyclic ring
opening to diene 5 under thermal conditions.11 In the presence
of a dienophile, diene 5 should then be trapped out as a Diels−
Alder adduct.12 Furthermore, in the case of maleic anhydride,
the pendant amide is perfectly positioned to undergo
lactamization to 7. This sequence should allow the formation
Received: January 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00211
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of functionalized bicyclic lactams in a single operation from
2,4-methanopyrrolidines with exceptionally high efficiency and
atom economy. Pyrrolidine and its derivatives are found in
numerous natural products and APIs, making this an attractive
scaffold for drug discovery programs.
Table 2. Reagent-Free Thermal Fragmentation/
Electrocyclic Ring Opening/[4 + 2] Cycloaddition/
Lactamization Cascade Reactions of 2(a−j) with Maleic
Anhydride
While the key complexity-generating step in the cascade is a
Diels−Alder cycloaddition,13 this sequence is unique in that
the cascade begins with a photochemically produced cyclo-
butane which acts as a masked diene. It also provides the
required functionality for lactam formation so each structural
feature plays a vital role in the overall cascade.
To explore the scope of the initial triplet sensitized
photochemical reaction, a series of 2,4-methanopyrrolidines
(2a−j) were prepared from some readily available acetophe-
nones (Table 1).
a
entry
lactam
Ar
C6H5-
3-MeOC6H4-
4-MeOC6H4-
4-FC6H4-
3-FC6H4-
2-FC6H4-
4-CF3C6H4-
3-CF3C6H4-
4-MeC6H4-
3-BrC6H4-
yield (%)
1
2
3
4
5
6
7
8
9
10
7a
7b
7c
7d
7e
7f
7g
7h
7i
64
55
12
52
65
59
57
48
42
66
Table 1. Preparation of 2-Aryl-2,4-methanopyrrolidines by
a
Crossed [2 + 2] Photocycloaddition
7j
a
All reaction performed on a 20 mmol scale in a sealed tube.
b
b
entry ketone
Ar
C6H5-
3-MeOC6H4-
4-MeOC6H4-
4-FC6H4-
3-FC6H4-
2-FC6H4-
4-CF3C6H4-
3-CF3C6H4-
4-MeC6H4-
3-BrC6H4-
1(a−j) yield % (g) 2(a−j) yield % (g)
1
2
3
4
5
6
7
8
9
10
8a
8b
8c
8d
8e
8f
8g
8h
8i
81 (426)
80 (426)
85 (125)
78 (441)
78 (158)
95 (48)
77 (488)
69 (121)
72 (74)
89 (93)
tion/lactamization sequence. Reaction times were reduced
from 4 h to just 30 min by heating at 180 °C in a sealed tube.
Remarkably, no added acid was required, as it was likely
provided by a small amount of maleic acid present in the
corresponding anhydride.
87 (102)
88 (10.4)
75 (170)
82 (9.2)
88 (9.9)
94 (249)
79 (21)
The Diels−Alder products were all formed in isolated yields
that represented a greater than 80% yield for each of the four
steps involved in the cascade. Only entry 3, a pyrrolidine with a
para electron-donating aryl substituent, showed a reduced
yield due to formation of an unidentified resinous material.
The only actual reagent used in the whole sequence from
commercially available starting materials is Et3N in the initial
reactions of acetophenones 8 with allyl amine and BzCl. The
only byproducts are water and Et3N·HCl. The subsequent [2 +
2] and four-step cascade sequence reactions are mediated by
light and heat alone. Apart from 1f, all products were isolated
by trituration and no chromatography was needed for the
entire sequence from the starting acetophenones.
73 (8.1)
86 (103)
8j
77 (528)
a
Conditions: (i) Allylamine (1.5 equiv), 3 Å mol. sieves, cyclohexane;
(ii) BzCl (1.0 equiv), Et3N (1.0 equiv), DCM; (iii) 400 W Hg lamp,
ITX (1%), MeCN. Isolated mass of product.
b
The photochemical precursors and product could all be
formed in similar yield and efficiency for both electron-
withdrawing and electron-donating substituents at meta and
para positions. Enamides 1(a−j) were prepared on scales up to
2 mol while the photochemical step could produce around 100
g of 2,4-methanopyrrolidine in 24 h with a conventional batch
reactor and 400 W mercury lamp. These results demonstrate
how an optimized photochemical reaction driven by a carefully
selected triplet sensitizer can be scaled-up using traditional
batch apparatus.
To test the proposed electrocyclic cascade sequence,
pyrrolidine 2a was heated in xylene at reflux with maleic
anhydride. Full conversion was observed after 4 h, and a new
compound was isolated. To our delight, this was confirmed to
be the expected endo Diels−Alder adduct 6 which had
undergone further lactamization from the initial [4 + 2]
adduct to form ( )-7a (Table 2). The structure and relative
configuration were confirmed by single crystal X-ray
crystallography. This single diastereomer was the product of
four sequential reactions and required no additional reagents
or catalystsessentially 90% yield for each of the four steps.
The full range of 2,4-methanopyrrolidines were then heated in
the presence of maleic anhydride to explore the scope of the
proposed fragmentation/electrocyclic rearrangement/addi-
We then investigated the reaction of pyrrolidines 2 with
butyl acrylate in order to ascertain the reactivity of the diene 5
with a monoactivated dienophile (Table 3). Initially the
reaction proved ineffective in xylene at reflux, and so a catalytic
amount of oxalic acid was added (5%) based on its similar pKa
Table 3. One-Pot, Six-Step Cascade Sequence Reactions of
2-Aryl-2,4-methanopyrollidines 2 with Butyl Acrylate
entry
lactam
Ar
yield (%)
mass (g)
1
2
3
4
5
10a
10b
10d
10f
10j
C6H5
3-MeOC6H4-
4-FC6H4-
2-FC6H4-
3-BrC6H4-
71
61
66
64
49
76
14.7
15.4
14.9
14.3
B
DOI: 10.1021/acs.orglett.9b00211
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to maleic acid. During the reaction, NMR analysis showed the
Diels−Alder adduct 9 was formed as a mixture of
diastereomers (endo/exo = 2:1) but as a single regioisomer.
When the crude reaction mixture was refluxed in methanol
with DBU, epimerization occurred (C*) and the endo isomer
conveniently underwent concurrent lactamization and meth-
anol mediated debenzoylation. The overall sequence from 2 to
( )-10 could be carried out as a single one-pot procedure
whereby six discrete reaction steps are telescoped together.
Furthermore, these complex sequences could be carried out on
significant scale producing the final products in 14−76 g
quantities.
in situ, remain scarce.16 More commonly the diene obtained
from ring opening is isolated before further reaction with the
dienophile.17 To the best of our knowledge this is the first
example of a Diels−Alder cascade sequence in which the
starting material is an alkyl cyclobutane. Although it may be
possible to synthesize the key reactive diene 5 by conventional
means, it is hard to envisage a more efficient and scalable route
than the one disclosed.
In order to assess the scope of the reactivity of the in situ
formed diene 5, the isolated cyclobutene 4 was then heated in
the presence of a wide range of dienophiles (Scheme 2).
Maleimide adducts (( )-11 and ( )-12) were formed with
complete endo selectivity. All acrylates gave approximately 2:1
selectivity and tolerated α-substitution well (( )-14 and
( )-15); however, β-substituents proved problematic as in
the case of crotonates and cinnamates which gave no isolable
products. To telescope the process with nonacidic dienophiles,
a further screen of additives was carried out. This identified 5%
tetrabutylammonium bromide (TBAB) as a mild and effective
additive to initiate the fragmentation (Conditions B).
Excellent yields were obtained for other electron-deficient
alkenes such acrylonitrile and methyl vinyl ketone, with
exclusive regioselectivity observed for the Diels−Alder step
(( )-16 and ( )-17). Electron-deficient alkynes also per-
formed well with no aromatized products observed (( )-19
and ( )-21). Although styrene was found to undergo reaction
to the cyclohexene ( )-18, the presence of the dimer ( )-20
indicated that homo-Diels−Alder of diene 5 was competitive
with the reaction of styrene.
To further understand the cascade sequence the individual
steps were studied. Treatment of pyrrolidine 2a with p-
toluenesulfonic acid (10%) in CHCl3 at 60 °C resulted in the
expected fragmentation to cyclobutene 4 (89%). This was
stable when purified but degraded in solution over a period of
days on standing at room temperature. When heated in a
sealed tube at 180 °C, low levels of the diene 5 (Ar = Ph,
1
Scheme 1) were observed by H NMR but the main product
was the Diels−Alder homodimer14 ( )-20 as a mixture of
diastereomers (Scheme 2). Although Diels−Alder cyclo-
addition of o-quinodimethanes15 generated in situ from the
thermolysis of benzocyclobutenes is well-known, examples of
nonaromatic systems, where the ring-opened diene is trapped
Scheme 2. Thermal Electrocyclic Cascade Reactions of
Cyclobutene 4 and 2,4-Methanopyrollidine 2a with a Range
a
of Dienophiles
Regioselectivity was exclusive in all relevant cases although
all monoactivated dienophiles gave epimeric mixtures of initial
Diels−Alder adducts. However, this is conveniently overcome
by epimerization to the more stable exo isomer under basic
conditions. For example, treatment of the crude reaction
mixture of ( )-16 with 10% DBU gave the exo isomer which
precipitated out of MeOH solution when stirred at room
temperature overnight (Scheme 3).
Scheme 3. Epimerization to exo Isomers
The crude butyl acrylate adduct mixture ( )-9a can
similarly be epimerized to the exo isomer by heating with
DBU in ethanol rather than methanol (cf. Table 3). The
isolated product had undergone full transesterification to the
corresponding ethyl ester ( )-13. This result is presumably
due to a slower rate of lactamization of an intermediate ethyl
ester over the methyl ester, and so the reaction outcome can be
controlled by solvent choice.
In summary, we have reported a new and efficient sequence
for the formation of bicyclic lactams and highly substituted
cyclohexenyl-amines. The reaction proceeds from a novel
fragmentation of labile 2,4-methanopyrrolidine derivatives and
involves the in situ formation of cyclobutenes and electrocyclic
ring opening to dienes followed by Diels−Alder cycloaddition.
The reactions have been carried out on scales of over 70 g, and
the 2,4-methanopyrrolidine [2 + 2] adducts can be prepared
a
Conditions: A (cyclobutene 4, no additive); B (2a, 5% TBAB); C
(2a, 5% oxalic acid); endo/exo ratio in parentheses.
C
DOI: 10.1021/acs.orglett.9b00211
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Knowles, J. P.; Stacey, C. S.; Klauber, D. J.; Booker-Milburn, K. I.
React. Chem. Eng. 2018, 3, 86−93.
(5) (a) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95,
2003−2020. (b) Tymann, D.; Tymann, D. C.; Bednarzick, U.;
Iovkova-Berends, L.; Rehbein, J.; Hiersemann, M. Angew. Chem., Int.
Ed. 2018, 57, 15553−15557.
(6) (a) Kanaoka, Y.; Hatanaka, Y. J. J. Org. Chem. 1976, 41, 400−
401. (b) Machida, M.; Oda, K.; Kanaoka, Y. Chem. Pharm. Bull. 1984,
32, 950−956. (c) Mooney, B. M.; Prager, R. H.; Ward, A. D. Aust. J.
Chem. 1981, 34, 2695−2700.
(7) Knowles, J. P.; Booker-Milburn, K. I. Chem. - Eur. J. 2016, 22,
11429−11434.
(8) (a) Dauben, W. G.; Van Riel, H. C. H. A.; Robbins, J. D.;
Wagner, G. J. J. Am. Chem. Soc. 1979, 101, 6383−6389. (b) Day, J. I.;
Singh, K.; Trinh, W.; Weaver, J. D. J. Am. Chem. Soc. 2018, 140,
9934−9941.
(9) Levterov, V. V.; Michurin, O.; Borysko, P. O.; Zozulya, S.;
Sadkova, I. V.; Tolmachev, A. A.; Mykhailiuk, P. K. J. Org. Chem.
2018, 83, 14350−14361.
(10) Varnes, J. G.; Lehr, G. S.; Moore, G. L.; Hulsizer, J. M.; Albert,
J. S. Tetrahedron Lett. 2010, 51, 3756−3758.
(11) (a) Binns, F.; Hayes, R.; Ingham, S.; Saengchantara, S. T.;
Turner, R. W.; Wallace, T. W. Tetrahedron 1992, 48, 515−530.
(b) Booker-Milburn, K. I.; Jimenez, F. D.; Sharpe, A. Tetrahedron
1999, 55, 5889−5902. (c) Ralph, M. J.; Harrowven, D. C.; Gaulier, S.;
Ng, S.; Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2015, 54, 1527−
1531.
(12) Meek, J. S.; Merrow, R. T.; Ramey, D. E.; Cristol, S. J. J. Am.
Chem. Soc. 1951, 73, 5563−5565.
(13) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668−1698.
(14) Hawkins, E. G. E.; Thompson, R. D. J. Chem. Soc. 1961, 0,
370−377.
on scales of up to 1 kg. In the case of many of the examples, no
added acid is required which renders the sequence
“reagentless” as well as highly atom-economic.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00211.
Experimental details and full spectroscopic data for all
new compounds (PDF)
Accession Codes
CCDC 1891842 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: k.booker-milburn@bristol.ac.uk.
*E-mail: luke.elliott@bristol.ac.uk.
ORCID
Kevin I. Booker-Milburn: 0000-0001-6789-6882
Notes
(15) Segura, J. L.; Martin, N. Chem. Rev. 1999, 99, 3199−3246.
(16) Diels−Alder reactions of dienes formed from in situ
electrocyclic ring opening of cyclobutenes: (a) Kaupp, G.; Stark, M.
Chem. Ber. 1977, 110, 3084−3110 (intermolecular) . (b) Jung, M. E.;
Halweg, K. M. Tetrahedron Lett 1981, 22, 2735−2738 (intra-
molecular) .
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC for funding (EP/P013341/1; EP/
L003325/1).
(17) Diels−Alder reactions of isolated dienes formed from
electrocyclic ring opening of cyclobutenes: (a) Trost, B. M.;
Bridges, A. J. J. Am. Chem. Soc. 1976, 98, 5017−5019. (b) Anderson,
D. R.; Koch, T. H. J. Org. Chem. 1978, 43, 2726−2728. (c) Keana, J.
F. W.; Taneja, H. R.; Erion, M. Synth. Commun. 1982, 12, 167−176.
(d) Potman, R. P.; Janssen, N. J. M. L.; Scheeren, J. W.; Nivard, R. J.
REFERENCES
■
(1) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752−6756.
(2) (a) Foley, D. J.; Craven, P. G. E.; Collins, P. M.; Doveston, R.
G.; Aimon, A.; Talon, R.; Churcher, I.; von Delft, F.; Marsden, S. P.;
Nelson, A. Chem. - Eur. J. 2017, 23, 15227−15232. (b) Druzhenko,
T.; Skalenko, Y.; Samoilenko, M.; Denisenko, A.; Zozulya, S.;
Borysko, P. O.; Sokolenko, M. I.; Tarasov, A.; Mykhailiuk, P. K. J.
Org. Chem. 2018, 83, 1394−1401. (c) Chen, T.-G.; Barton, L. M.;
Lin, Y.; Tsien, J.; Kossler, D.; Bastida, I.; Asai, S.; Bi, C.; Chen, J. S.;
Shan, M.; Fang, H.; Fang, F. G.; Choi, H-w.; Hawkins, L.; Qin, T.;
Baran, P. S. Nature 2018, 560, 350−354. (d) Buendia, J.; Chang, Z.;
Eijsberg, H.; Guillot, R.; Frongia, A.; Secci, F.; Xie, J.; Robin, S.;
Boddaert, T.; Aitken, D. J. Angew. Chem., Int. Ed. 2018, 57, 6592−
6596.
̈
F. J. Org. Chem. 1984, 49, 3628−3634. (e) Knolker, H.-J.; Baum, E.;
Schmitt, O. Tetrahedron Lett. 1998, 39, 7705−7708. (f) Nishimura,
A.; Tamai, E.; Ohashi, M.; Ogoshi, S. Chem. - Eur. J. 2014, 20, 6613−
6617.
(3) (a) Hoffmann, N. Chem. Rev. 2008, 108, 1052−1103. (b) Bach,
T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000−1045.
̈
̈
(c) Karkas, M. D.; Porco, J. A., Jr.; Stephenson, C. R. J. Chem. Rev.
̈
2016, 116, 9683−9747. (d) Poplata, S.; Troster, A.; Zou, Y.-Q.; Bach,
T. Chem. Rev. 2016, 116, 9748−9815. (e) Remy, R.; Bochet, C. G.
Chem. Rev. 2016, 116, 9816−9849.
(4) (a) Hook, B. D. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.;
Berry, M. B.; Booker-Milburn, K. I. J. Org. Chem. 2005, 70, 7558−
7564. (b) Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.;
Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I.
R.; Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.; Berry, M. B.; Booker-
Milburn, K. I. Chem. - Eur. J. 2014, 20, 15226−15232. (c) Elliott, L.
D.; Berry, M.; Harji, B.; Klauber, D.; Leonard, J.; Booker-Milburn, K.
I. Org. Process Res. Dev. 2016, 20, 1806−1811. (d) Elliott, L. D.;
D
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