Letterpubs.acs.org/OrgLett

Flow Update for a Cossy Photocyclization
Takahide Fukuyama,* Yuki Fujita, Muhammad Abid Rashid,† and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, JapanS Supporting Information*ABSTRACT: A Cossy 5-exo-dig photocyclization of organohalides (X = Br, I) onto a C−C triple bond was studied using aﬂow photomicroreactor, which proceeded in a minute order ofresidence time. A deuterium labeling study supported thenonchain radical mechanism proposed by the Cossy group, inwhich a hydrogen source originates from a triethylamine cation
radical. Scalable ﬂow synthesis using a larger volume of ﬂow
reactor was also successful, providing 4 g of the product inhigh yield.

RTable 1. Flow Radical Cyclization of Bromoacetal 1a in thePresence of Triethylaminea

adical addition onto an internal C−C triple bond provides apromising strategy for the construction of carbo- andheteroring molecules with an exomethylene moiety.1 Cossy’s
photocyclization2 is unique in this regard, since the system does
not contain a typical H-donating radical mediator such as
tributyltin hydride to achieve the same 5-exo-dig type of
reductive radical cyclization (Scheme 1). The use of superstoichiometric amounts of triethylamine (TEA) is the key, which,with photoirradiation, delivers one electron to organohalides.3
The resultant radical anions undergo homolysis to generate thekey alkyl radicals, which are ready to undergo 5-exo-dig
cyclization with the liberation of halogenide anions. The
hydrogen source of the Cossy reaction is thought to be thecation radical of TEA that arises from the one-electron transferreaction.
By taking advantage of very narrow and shallow reactor
channels, radical reactions are promptly carried out using ﬂow
microreactors.4,5 Thus, we believed that a photomicroreactor6,7
would help the speedy execution of Cossy radical cyclization,
which is typically carried out using a batch reactor for 0.5 to 1 h.2
In this paper, we report that (i) Cossy reaction using ﬂow
microreactors proceeds in residence times on the order ofminutes, (ii) the labeling study using deuterated triethylamine
lends support to the nonchain radical mechanism originallyproposed by Cossy, and (iii) the scalable reaction was carried out

entry

conc. (M)residence time (min)conv. (%)byield (%)b123456 (batch)c0.01
0.01
0.01
0.1
0.1
0.1

53.8
1535100
100599867136090379260
8aThe reactions were conducted with 1a (1 mmol), NEt3 (10 mmol),and CH3CN using a ﬂow photomicroreactor (YMC Co. Ltd., innervolume 0.11 mL, width 1 mm, length 560 mm, depth 200 μm, quartz)
bGC yields using n-decane as an internal standard. cThe reaction wascarried out in a quartz test tube with an i.d. of 1.3 cm.

using a larger-volume ﬂow photoreactor, which allowed a 4 g
synthesis of cyclized product.
As a model to establish a ﬂow Cossy reaction, thephotocyclization of trans-3-bromo-2-(propargyloxy)tetrahydropyran (1a) to give 2a was chosen. An acetonitrile
solution of 1a and TEA was irradiated using a ﬂow photomicroreactor (YMC Co. Ltd.; inner volume 0.11 mL, width 1mm, length 560 mm, depth 200 μm, quartz) and a compact lightsource consisting of a low-pressure Hg lamp (254 nm, 1.2 W).
We tested diﬀerent conditions wherein the residence time andconcentrations were systematically varied (Table 1). The ﬂowreaction ([1a] = 0.01 M) with a residence time of 6 min gave theScheme 1. Cossy Cyclization and Tin Hydride-MediatedCyclization

Received: September 10, 2016
Published: October 13, 2016
© 2016 American Chemical Society

5444

DOI: 10.1021/acs.orglett.6b02727
Org. Lett. 2016, 18, 5444−5446

Letter

Organic Letters
Table 2. Flow Radical Photocyclization of Alkynyl Halides 1aScheme 2. Gram-Scale Synthesis of 2a Using a Large-Volume
Flow Photoreactor

Scheme 3. Deuterium Labeling Experiment To Support aSET-Based Reaction Mechanism

diameter) with the same UV source gave only an 8% yield of 2awith 13% conversion (Table 1, entry 6).
After the initial observation of the eﬀective conversion of 1a
into 2a in times on the order of minutes, we next examined theradical cyclization of various haloacetals under the optimized
conditions (Table 2). Irradiation of a 0.1 M acetonitrile solutionof iodoacetal 1a′ in the presence of TEA at 254 nm proceeded
rapidly to aﬀord the cyclized product 2a in 93% yield (Table 2,entry 1). In a similar manner and under otherwise identicalconditions, irradiation of bromoacetals 1b and 1c resulted in theformation of exocyclic alkenes 2b and 2c in 91 and 75% yield,
respectively (Table 2, entries 2 and 3). In the case of
bromooxanorboranone 1d, the desired tricylic compound 2d
was obtained in 70% yield (Table 2, entry 4). The reaction of
bromoalkyne 1e gave the corresponding tricyclic product 2e in62% yield (Table 2, entry 5). In a similar manner, bromoalkyne
1f was converted to the bicyclic compound 2f in 66% yield(Table 2, entry 6). The reaction of bromoether 1g gave a lower
yield of the product 2g (45%), which was probably due to aNorrish type 1 decomposition that is inherent in a ketone moiety(Table 2, entry 7). The photochemical reaction of bromoalkynes
1h and 1i resulted in the formation of tetrasubstituted alkenes 2ha
The reactions were conducted with 1 (1.0 mmol), Et3N (10 mmol),and CH3CN (10 mL) using a ﬂow photomicroreactor (YMC Co. Ltd.,
inner volume 0.11 mL, width 1 mm, length 560 mm, depth 200 μm,quartz) with residence times of 5−8 min. bIsolated yields after
puriﬁcation by chromatography on SiO2 or Al2O3 (entries 3 and 5).

desired product 2a in 60% yield, whereas starting 1a wascompletely consumed (Table 1, entry 1). A shorter residence
time of 3.8 min gave 2a in 90% yield (Table 1, entry 2). Further
reducing the residence time (1 min) resulted in a low conversionof 1a (Table 1, entry 3). The ﬂow radical cyclization of 1aproceeded well even at a higher 1a concentration (0.1 M) withresidence time of 5 min (Table 1, entry 4). It should be noted thatthe batch reaction using a quartz test tube (1.3 cm internal5445

DOI: 10.1021/acs.orglett.6b02727
Org. Lett. 2016, 18, 5444−5446

Letter

Organic Letters(3) For reviews of photoinduced electron transfer from amines, see:(a) Cossy, J. Photoinduced Electron Transfer in Radical Reactions. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, Germany, 2001; Vol. 1, pp 229−249. (b) Cossy, J.; Belotti,D. Tetrahedron 2006, 62, 6459. (c) Griesbeck, A. G.; Hoffmann, N.;
Warzecha, K.-D. Acc. Chem. Res. 2007, 40, 128.
(4) For selected reviews of ﬂow synthesis, see: (a) Mason, B. P.; Price,K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev.
2007, 107, 2300. (b) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I.
Synlett 2008, 2008, 151. (c) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1,675. (d) Suga, S.; Yamada, D.; Yoshida, J. Chem. Lett. 2010, 39, 404.
(e) Yoshida, J.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4, 331.
(f) Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354,
17. (g) Ley, S. V. Chem. Rec. 2012, 12, 378. (h) Wiles, C.; Watts, P. Green
Chem. 2012, 14, 38. (i) McQuade, D. T.; Seeberger, P. H. J. Org. Chem.
2013, 78, 6384. (j) Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15,1456. (k) Fukuyama, T.; Totoki, T.; Ryu, I. Green Chem. 2014, 16, 2042.
(l) Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem., Int. Ed. 2015,54, 6688. (m) Porta, R.; Benaglia, M.; Puglisi, A. Org. Process Res. Dev.
2016, 20, 2.
(5) For reviews of photoreaction using ﬂow microreactors, see:(a) Matsushita, Y.; Ichimura, T.; Ohba, N.; Kumada, S.; Sakeda, K.;
Suzuki, T.; Tanibata, H.; Murata, T. Pure Appl. Chem. 2007, 79, 1959.
(b) Oelgemöller, M. Chem. Eng. Technol. 2012, 35, 1144. (c) Cambie,D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noel, T. Chem. Rev.
2016, 116, 10276.
(6) For a review of ﬂow radical reactions, see: (a) Fukuyama, T.; Ryu, I.
Radical Chemistry by Using Flow Microreactor Technology. In
Encyclopedia of Radicals in Chemistry, Biology, and Materials; Studer,A., Chatgilialoglu, C., Eds.; Wiley: Chichester, U.K., 2012; Vol. 2, pp1243−1258. Also see our recent work: (b) Fukuyama, T.; Kawamoto,T.; Kobayashi, M.; Ryu, I. Beilstein J. Org. Chem. 2013, 9, 1791.
(c) Manabe, Y.; Kitawaki, Y.; Nagasaki, M.; Fukase, K.; Matsubara, H.;
Hino, Y.; Fukuyama, T.; Ryu, I. Chem. - Eur. J. 2014, 20, 12750.
(7) For our work on photoreactions using microreactors, see:(a) Fukuyama, T.; Hino, Y.; Kamata, N.; Ryu, I. Chem. Lett. 2004, 33,1430. (b) Sugimoto, A.; Fukuyama, T.; Sumino, Y.; Takagi, M.; Ryu, I.
Tetrahedron Lett. 2006, 47, 6197. (c) Sugimoto, A.; Fukuyama, T.;
Sumino, Y.; Takagi, M.; Ryu, I. Tetrahedron 2009, 65, 1593.
(d) Tsutsumi, K.; Terao, K.; Yamaguchi, H.; Yoshimura, S.;
Morimoto, T.; Kakiuchi, K.; Fukuyama, T.; Ryu, I. Chem. Lett. 2010,39, 828. (e) Fukuyama, T.; Kajihara, Y.; Hino, Y.; Ryu, I. J. Flow Chem.
2011, 1, 40. (f) Matsubara, H.; Hino, Y.; Tokizane, M.; Ryu, I. Chem.
Eng. J. 2011, 167, 567. Also see ref 6c.

and 2i in 71 and 63% yield, respectively (Table 2, entries 8 and9). In these cases, an exocyclic double bond was isomerized toform conjugated esters. The internal alkyne 1j gave 2j in 60%
yield as a 53/47 E/Z mixture (Table 2, entry 10).
We next executed the scalable synthesis of 2a using an MiChS
L1 ﬂow photoreactor, which has a large inner volume (6 mL,width 2 mm, depth 1 mm, length 3 m), and two 6 W low-pressure
Hg lamps were used for photoirradiation. The reaction was
carried out with a residence time of 20 min using CH3CN
containing 10% H2O as the solvent to suppress the inﬂuence ofinsoluble material, which stuck to the glass surface during thelong-time operation. After continuous operation for 18 h, weobtained 4 g of 2a in 90% isolated yield after column
chromatography on silica gel (Scheme 2).
As for the mechanism, Cossy and co-workers already proposeda photoelectron-transfer mechanism for the generation of alkyl
radicals, wherein TEA serves as a sacriﬁcial electron source.2
Labeling experiments using deuterated TEA were carried out in abatch reaction. The results reasonably supported Cossy’s
nonchain single electron transfer (SET) mechanism, sincedeuterium incorporation was observed only for the experimentusing deuterated TEA and nonlabeled acetonitrile (Scheme 3).
In summary, we have demonstrated that the Cossy 5-exo-dig
photocyclization of organohalides onto a C−C triple bond can be
successfully carried out using a ﬂow photomicroreactor andrequires a relatively short residence time. Deuterium labelingexperiments supported the nonchain radical mechanism
proposed by Cossy, in which a vinyl radical abstracts hydrogenfrom a triethylamine cation radical. Scalable ﬂow synthesis usinga large-volume ﬂow reactor was also successful.

■ASSOCIATED CONTENT

S Supporting Information*The Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.orglett.6b02727.
General experimental procedures and spectroscopic dataof products (PDF)■

AUTHOR INFORMATION

Corresponding Authors*E-mail: fukuyama@c.s.osakafu-u.ac.jp.
*E-mail: ryu@c.s.osakafu-u.ac.jp.
Present Address†

M.A.R.: Department of Chemistry, University of Agriculture,
38040 Pakistan.
Notes

The authors declare no competing ﬁnancial interest.

■

ACKNOWLEDGMENTS
This work was supported by Grants-in-Aid for ScientiﬁcResearch (A) (26248031) from JSPS and Scientiﬁc Researchon Innovative Areas 2707 Middle Molecular Strategy(15H05850) from MEXT.

■REFERENCES(1) For a leading review, see: Gilmore, K.; Alabugin, I. V. Chem. Rev.
2011, 111, 6513.
(2) (a) Cossy, J.; Ranaivosata, J.-L.; Bellosta, V. Tetrahedron Lett. 1994,35, 8161. (b) Cossy, J.; Bellosta, V.; Ranaivosata, J.-L; Gille, B.
Tetrahedron 2001, 57, 5173.
5446

DOI: 10.1021/acs.orglett.6b02727
Org. Lett. 2016, 18, 5444−5446