Photocyclization of enamines to access Spiroindolines and Spirooxindoles in continuous flow

Article abstract of DOI:10.1016/j.tetlet.2020.152111

We report an expedited flow chemistry approach to the catalyst/photosensitizer-free UV photocyclizations of aryl-enamines to afford spiroindolines. The photocyclizations occur under mild conditions and are tolerant to a variety of substituted aryl-enamine

Full text of DOI:10.1016/j.tetlet.2020.152111

Tetrahedron Letters xxx (xxxx± xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photocyclization of enamines to access Spiroindolines
and Spirooxindoles in continuous flow
⇑
Moses Moustakim, Brian Ledford, Jacob A. Garwin, Michael J. Boyd
Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA 02210, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an expedited flow chemistry approach to the catalyst/photosensitizer-free UV photocycliza-
tions of aryl-enamines to afford spiroindolines. The photocyclizations occur under mild conditions and
are tolerant to a variety of substituted aryl-enamines and spirocycle ring sizes. This flow protocol has
a wide substrate scope and addresses the problems of irreproducibility and scalability of batch protocols.
The utility of this reaction is demonstrated in a shortened formal synthesis of (± ±-horsꢀline.
Ó 2020 Published by Elsevier Ltd.
Received 2 March 2020
Revised 29 May 2020
Accepted 3 June 2020
Available online xxxx
Keywords:
Photochemistry
Flow
Spiroindolines
Spirooxindoles
Introduction
scalability and integration with additional parameter control
(
heating/cooling/reagent addition± [5]. We sought to explore the
Spiroindolines and spirooxindoles are featured in the core of
numerous natural products, chemotherapeutics and drug mole-
cules (Scheme 1± [1]. Increasingly, as this scaffold is observed in
molecules with biological signiꢀcance, there is growing value to
develop new practical methods to access such scaffolds.
scope of this UV-photocyclization under flow conditions and its
utility in accessing spiroindolines.
Results and discussion
In 1984, Schultz and co-workers reported the UV promoted 6e-
photocyclization of aryl-enamines to spiroindolines (Scheme 2± [2].
To the best of our knowledge, this is the only known synthesis of
compounds with substructure A [3]. This transformation could be
of great value, especially to medicinal chemistry projects, as it
allows for the generation of diversity at four areas of the scaffold
from readily available starting materials (anilines and keto esters±.
This strategy could also provide a practical way of generating novel
spiro compounds, which are becoming increasing utilized in
medicinal chemistry due to their inherent three dimensionality
and structural novelty [4]. Since Schultz’s early work, there have
been no reports of developing and exploring this reaction further.
In our laboratories, the batch photocyclization of aryl-enamines
to spiroindolines were often hampered by extended reaction times,
batch-to-batch variability and poor conversions, problems that are
very common in batch photochemical reactions. Flow chemistry
offers a number of synthetic advantages when applied to photo-
chemistry in part owing to precise heat control, superior/consis-
tent light penetration, controlled exposure time, inherent
The Schiff base derived from aniline and ethyl-2-cyclopentyl-2-
oxoacetate was used as a model system to optimize the photocy-
clization conditions (1, Table 1±. Initial solvent and light source
screening in batch revealed that dioxane or benzene with either
UV-A or UV-B gave the best yields (Entries 1 (45%±, 2 (42%± and 3
(
38%±±. These reactions required > 16 h to reach full conversion
on a 1 mmol scale and 2 days on 5 mmol scale.
In flow, it was found that the corresponding cyclization
occurred rapidly (<0.5 h irradiation time, 0.3–0.5 mmol±. The
wavelength of light required to facilitate the cyclization seemed
to be critical to reaction progression (Table 1±. Enamine 1 cyclized
smoothly to spiroindoline 2 when irradiated in benzene using a
UV-A LED bulb (365 nm kmax± with excellent isolated yield (82%,
entry 12±. In comparison, the corresponding batch reaction
required > 16 h to proceed to full conversion with a lower overall
yield (45%, entry 1±.
As stated earlier, Schultz’s initial report of this transformation
provided little information on reaction scope. This limited knowl-
edge of reaction scope, as well as other potential difꢀculties such
as scaling issues and reproducibility, makes this batch reaction
unappealing for generating diverse sets of indolines. In order to
make this protocol more attractive for generating diverse
⇑
Corresponding author.
E-mail address: Michael_Boyd@vrtx.com (M.J. Boyd±.
https://doi.org/10.1016/j.tetlet.2020.152111
040-4039/Ó 2020 Published by Elsevier Ltd.
0
Please cite this article as: M. Moustakim, B. Ledford, J. A. Garwin et al., Photocyclization of enamines to access Spiroindolines and Spirooxindoles in con-
tinuous flow, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152111

2
M. Moustakim et al. / Tetrahedron Letters xxx (xxxx) xxx
Finally, we turned our attention to the application of this
method to the formal synthesis of (± ±-horsꢀline (Scheme 1 and
±, a natural product with analgesic properties [7]. It was envisaged
3
that our strategy would likely intercept the route previously
reported by Fuji and co-workers [8] and could potentially allow
for the generation of SAR around four key areas of the scaffold
(Scheme 2±. Horner-Wadsworth-Emmons (HWE± reagent 5 was
prepared according to literature precedent [9]. Treatment of 5
under standard HWE conditions afforded 6 as a mixture of E/Z iso-
mers. Oleꢀn 6 was then deprotected with cesium
fluoride to afford keto-ester 7 in moderate yields. Microwave
assisted condensation of N-benzyl-p-anisidine with 7 furnished
Schiff base 3 l. An initial investigation of the photocyclization using
UV-A (365 nm± under batch conditions to afford spiroindoline 4 l
was unsuccessful, giving poor conversions even with prolonged
reaction times. Interestingly, using the optimal flow conditions,
Scheme 1. Spiroindolines in natural products and drug molecules.
3
l was cleanly converted to protected spiroindoline 4 l in quanti-
tative yield with a 20 min residence time. We observed that basic
hydrolysis of the spiroindolines 4 often yielded oxidatively decar-
boxylated products along with the anticipated acid. It was there-
fore envisaged that ester 4 l could be oxidatively decarboxylated
to furnish spirooxindole 8 and therefore intercept Fuji’s route
towards horsꢀline. Unfortunately, basic hydrolysis of 4 l yielded
only the corresponding carboxylic acid. However, under aerobic
conditions with UV-A irradiation, ester 4 l was converted to
spirooxindole 8 to complete a formal synthesis of (± ±-horsꢀline.
To the best of our knowledge, this is the ꢀrst example of a UV-pro-
moted oxidative decarboxylation to afford spirooxindoles under
mild conditions.
Scheme 2. Photocyclization of enamines to spiroindolines.
spiroindolines, an investigation into the scope of this flow protocol
was carried out. It was found that aryl-enamines 3 were converted
to spiroindolines in good to excellent yields Table 2. Both electron-
donating (OMe± and -withdrawing (-F, -Br, –CN± groups were toler-
ated irrespective of the substitution pattern. N-Substituted aryl
enamines also cleanly underwent cyclization (4 j,l±. A heteroatom
in the spirocycle (4 l± was also tolerated. Interestingly, aryl-enam-
ine 3 l failed to cyclize under batch conditions but was successful
under optimal flow conditions, demonstrating that this flow proto-
col not only increases reaction efꢀciency but it may also expand
the substrate scope of the reaction, an aspect of flow chemistry
that is often overlooked [6]. This protocol may also address the
scalability issues observed in batch (theoretical daily output of this
protocol can exceed 18 g/per day under steady state conditions
Conclusion
In conclusion, we report an expedited flow chemistry approach
to the catalyst/photosensitizer-free UV photocyclizations of aryl-
enamines to afford spiroindolines. The photocyclizations occur
under mild conditions and are tolerant to a variety of substituted
aryl-enamines and spirocycle ring sizes. This flow protocol has a
wide substrate scope and addresses the problems of irreproducibil-
ity and scalability of batch protocols. The utility of this reaction is
demonstrated in a shortened formal synthesis of (± ±-horsꢀline rel-
ative to a previous route described by Fuji and co-workers. Central
(
compound 4 g±±.
Table 1
Reaction optimization for the UV-photocyclization aryl-enamine 1 to spiroindoline 2.
Entry
UV source
Solvent
Batch/Flow rate (mL/min±
Yield 2 (%±
1
2
3
4
5
6
7
9
UV-A
UV-B
UV-A
UV-A
UV-A
UV-A
UV-A
UV-A
450 nm LED
UV-A/B
365 nm LED
PhH
PhH
Batch
Batch
Batch
Batch
Batch
Batch
Batch
45
42
38
36
18
25
16
45
0
Dioxane
Cyclohexane
PhH/MeOH
PhH/MeCN
Dioxane/MeOH
PhH
PhH
PhH
PhH
a
b
0.5
0.5
0.5
b
1
1
1
0
1
2
a
b
56
82
b
0.5
a 100 W medium pressure mercury lamp with Pyrex or 320 nm ꢀlter.
b 0.1 M, 0.5 mL/min, 30 °C, 1 bar, 10 mL reaction coil, 20 min residence time
Please cite this article as: M. Moustakim, B. Ledford, J. A. Garwin et al., Photocyclization of enamines to access Spiroindolines and Spirooxindoles in con-
tinuous flow, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152111

M. Moustakim et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
UV-photocyclization of aryl-enamine 3 to 2-carboxylspiroindoline 4.
Scheme 3. Formal synthesis of (± ±-horsꢀline. Reagents and conditions: a. LiHMDS/ethyl 3-oxopyrrolidine-1-carboxylate, À78 °C to rt, 16 h, 96%. b. CsF/AcOH, 0 °C, 12 h, 79%.
4 2
c. N-benzyl-p-anisidine, TFA, MgSO , 150 °C, PhH, 30 min, 74%. d. UV-A LED (365 nm±, 0.5 mL/min (20 min±/0.2 mmol/ hv, PhH, quant. e. LiOH UV-A bulb, air, MeOH/H O (2:1±,
rt, 4 d, 26%.
to the shortened synthesis of (± ±-horsꢀline is a mild and novel UV-
promoted oxidative decarboxylation converting 2-carboxyspiroin-
dolines to spiroox-2-indoles. This method could be used to gener-
ate structure activity relationship on the analgesic properties of
horsꢀline, since it can easily provide diversity at four areas of the
scaffold. Our expedient UV-photocyclization represents a rapid
method for building complexity from relatively abundant starting
materials for alkaloid synthesis. Furthermore, the beneꢀt in access-
ing synthetically valuable intermediates such as 8 is extended by a
novel UV-promoted oxidative decarboxylation which offers a
chemical segue between spiroindolines and spirooxindoles war-
ranting the attention of the synthetic community. The scope of this
decarboxylative oxidation reaction and application of this method
to the synthesis of natural products will be reported in due course.
Please cite this article as: M. Moustakim, B. Ledford, J. A. Garwin et al., Photocyclization of enamines to access Spiroindolines and Spirooxindoles in con-
tinuous flow, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152111

4
M. Moustakim et al. / Tetrahedron Letters xxx (xxxx) xxx
Meagher, L. Bai, L. Liu, C.G. Hoffman-Luca, J. Lu, S. Shangary, S. Yu, D. Bernard, A.
Declaration of Competing Interest
Aguilar, O. Dos-Santos, L. Besret, S. Guerif, P. Pannier, D. Gorge-Bernat, L.
Debussche, Cancer Res. 74 (2014± 5855–5865.
The authors declare that they have no known competing ꢀnan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[2] a± A.G. Schultz, Acc. Chem. Res. 16 (6± (1983± 210–219;
b± A.G. Schultz, S. Chin-Kang, Tetrahedron 36 (1980± 1757–1761.
[
3] Published strategies for similar compounds: a± V. Estévez, L. Kloeters, N.
Kwietniewska, E. Vicente-García, F. Ruijter F, R.V.A. Orru, Synlett, 28 (2017±
376-380; b± P. Golubev, M. Krasavin, Tetrahedron Lett. 59 (2018±, 3532-3536.
[
[
4] Y. Zheng, C.M. Tice, S.B. Singh, Bioorg. Med. Chem. Lett. 24 (2014± 3637–3682.
5] a± L.D. Elliott, J.P. Knowles,. P.J. Koovits, K.G. Maskill, K.J. Ralph, G. Lejeune, L. J.
Edwards, R.I. Robinson, I.R. Clemens, B. Cox, D.D. Pascoe, G, Koch, M. Eberle, M.B.
Berry, K.I. Booker-Milburn Chem. Eur. J. 20 (2014± 20 15226-15232 (b± D.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152111.
10276-10341. (c± M.B. Plutschack, B. Pieber, K. Gilmore, P.H. Seeberger, Chem.
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Please cite this article as: M. Moustakim, B. Ledford, J. A. Garwin et al., Photocyclization of enamines to access Spiroindolines and Spirooxindoles in con-
tinuous flow, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152111