“This	document	is	the	Accepted	Manuscript	version	of	a	Published	Work	that	appeared	in	final	form	in	
ACS	Catal.	
copyright	©	American	Chemical	Society	after	peer	review	and	technical	editing	by	the	
publisher.	To	access	the	final	edited	and	published	work	see	[insert	ACS	Articles	on	Request	authordirected	
link	to	Published	Work,	see	https://pubs.acs.org/doi/abs/10.1021%2Facscatal.6b03205%20].”	

Visible Light-Promoted Atom Transfer Radical Cyclization of Unactivated Alkyl Iodides
Yangyang Shen,† Josep Cornella,† Francisco Juliá-Hernández†* and Ruben Martin†§*
†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain.
§ICREA, Passeig Lluïs Companys, 23, 08010, Barcelona, Spain.
ABSTRACT: A visible light-mediated atom transfer radical cyclization of unactivated alkyl iodides is described. This protocol
operates under mild conditions and exhibits high chemoselectivity profile while avoiding parasitic hydrogen atom transfer pathways. Preliminary mechanistic studies challenge the perception that a canonical photoredox catalytic cycle is being operative.

KEYWORDS: visible light, alkyl halide, photocatalysis, atom-economy, radical cyclization.

Photocatalytic ATRA/ATRC of activated organic halides (known)
visible light
e- transfer
X = I, Br, Cl
X

R2

R1

·

In recent years, visible light photocatalysis has arguably
gained considerable momentum for generating carboncentered radical intermediates via single-electron transfer (SET) processes.1 Unlike classical SET protocols
based on radical initiators or metal catalysts initiated by
a chemical activation mode and inner-sphere mechanisms,2 photoredox catalysis offers the opportunity to
promote otherwise analogous processes using simple
visible light via outer-sphere mechanisms.1 Particularly
illustrative is the implementation of redox-neutral atom
transfer radical addition (ATRA) or cyclization reactions
(ATRC),3 enabling elegant bond-disconnection strategies
for rapidly building up molecular complexity in a both
atom- and step-economical fashion.4

R1
R2
carbon-centered
radical

R2 R1

unactivated alkyl halides

activated alkyl halides
X

X

X
X

R2
R1
EWG
Ar
ample precedents

H
unprecedented

This work: visible light-mediated ATRC of unactivated alkyl iodides
parasitic HAT
R1
I
R2

photocatalyst
NR3 (12-100 mol%)

R1

R1

Blue-LEDs
I
broad substrate scope
high chemoselectivity

H
R2

R2
Not observed

Scheme 1. Visible Light-Promoted ATRA/ATRC Reactions

At present, the portfolio of photoredox ATRA/ATRC
reactions remains confined to activated organic halides
possessing weak C(sp3)–X bonds adjacent to p-systems,
heteroatoms or electron-withdrawing groups, thus rapidly triggering SET processes (Scheme 1, top pathways).5
In sharp contrast, visible-light mediated ATRA/ATRC
reactions of unactivated alkyl halides are altogether
absent from the literature. This is likely attributed to the
inherent difficulties for finding photocatalysts able to
match the exceptionally high redox potentials of unactivated alkyl halides (Ered [n-BuI] = -2.5 V vs. SCE in

MeCN).6 Although seminal studies by Stephenson7a and
Lee7b elegantly showcased the ability to trigger unconventional photocatalytic non-redox-neutral reductive
processes via hydrogen atom transfer (HAT), at the outset of our investigations it was unclear whether the inherent propensity of in situ generated carbon-centered
radicals to undergo parasitic HAT could be tackled to
efficiently promote a visible light redox-neutral
ATRA/ATRC of unactivated alkyl halides. If successful,
such strategy would provide rapid access to versatile
products amenable to further functionalization via classical cross-coupling scenarios. As part of our ongoing
interest in SET processes,8 we report herein the successful realization of a design principle capable of promoting, for the first time, a redox-neutral ATRC reaction of
unactivated alkyl iodides under visible light irradiation.
The protocol is distinguished by its mild reaction conditions, ease of execution, wide substrate scope and excellent chemoselectivity profile (Scheme 1, bottom). Preliminary mechanistic studies reveal an intriguing role of
the amine, suggesting that a canonical photoredox cycle
might not come into play, pointing towards a different
scenario in which the photocatalyst is not directly involved in a SET to the corresponding alkyl iodide.

Table 2. Visible Light Photocatalytic ATRC of Unactivated
Alkyl Iodides.a,b

Table 1. Optimization of the Reaction Conditions.a
PF 6N
N

Ir

N

N

2

X

(1 mol%)
1a

I

i-Pr 2NEt (1 equiv), t-BuCN
Blue-LEDs, rt

X = I (3a)
X = H (3a')

Deviation from standard conditions

3a (%) b

1

none

89(87)c

0

2

MeCN instead of t-BuCN

68

25

Entry

substantial amounts of 3a’ (entries 2 and 3).10 Although
the nature of the amine did not have a significant influence on reactivity and selectivity (entries 4 and 5), it is
worth noting that catalytic amounts of i-Pr2NEt delivered 3a in a remarkable 83% yield, but at considerably
lower rates (entry 6). The results shown in entry 1 are
particularly intriguing if one takes into consideration the
remarkable mismatch between redox potentials of 1a
(Ered ≤ -2.5 V vs. SCE in MeCN),9,11 and 2 (Ered [IrIII/IrII]
= -1.51 V vs SCE in MeCN).9,11,12 Indeed, we realized
that stronger reducing complexes such as fac-Ir(ppy)3
(Ered [IrIII/IrII] = -2.19 V vs SCE in MeCN)1f resulted in a
significant erosion in yield, whereas stronger oxidizing
Ir[dF(CF3)ppy]2(dtbbpy)]PF6 (Ered [IrIII/IrII] = -1.37 V vs
SCE in MeCN)1f delivered otherwise identical yields
(83%) (entry 7 vs entry 8), thus challenging the perception that a conventional SET photoredox catalytic cycle
is being operative. Unfortunately, no productive formation of 3a-Br was observed with 1a-Br, recovering
unreactive starting material (entry 9). As expected, control experiments revealed that the presence of both iPr2NEt and 2 under visible-light irradiation was absolutely critical for success (entries 10 and 11).

3a' (%) b

3

i-PrCN instead of t-BuCN

30

11

4

n-Bu3N instead of i-Pr 2NEt

87

0

5

Cy2NMe instead of i-Pr 2NEt

82

0

6

i-Pr 2NEt (12 mol%)

83d

0

7

fac-Ir(ppy) 3 instead of 2

58

0

8

Ir(dfCF 3ppy) 2(dtbbpy)PF 6 instead of 2

83

0

9

Using 1a-Br

0

0

10

No i-Pr 2NEt, no 2 or in the dark

0

0

a

1a (0.20 mmol), 2 (1 mol%), i-Pr2NEt (0.20 mmol) in tBuCN (0.20 M) at rt for 12 h. b GC yields using decane as
internal standard. c Isolated yield. d 48 h reaction time.

Our investigations started with 1a as the model substrate
(Table 1). After considerable experimentation,9 the best
results were accomplished with photocatalyst 2 in the
presence of i-Pr2NEt under blue light-emitting diodes
(LEDs) irradiation, obtaining 87% of 3a. As expected,
the choice of the solvent markedly influenced both yield
and selectivity. While not even traces of 3a’ were observed with a protocol based on t-BuCN (entry 1), solvents susceptible to undergo HAT processes generated

R1

R1

[Ir(ppy) 2(dtbbpy)]PF 6 (2, 1 mol%)
I
R2

I
2
3a-z R

i-Pr 2NEt (1 equiv), t-BuCN
Blue-LEDs, rt

1a-y

R

n

t-Bu
I

I
n = 4, 87% (3a)
n = 1, 79% (3b)

I

R = n-C5H11, 96% (3c)
R = Cp, 91% (3d)
R = Ph, 88% (3e)

Me Me

60% (3f)

CN

R Si
I
R = Me, 81% (3g)
R = Ph, 75% (3h)c

I
78% (3j)

I
66% (3i)
MeO

Br
OR

O

Cl

3o and 3j-k is particularly noteworthy; while the former
indicates that intramolecular 1,5-HAT prior to iodine
transfer does not compete with the efficacy of the reaction, the lack of double cyclization with a pending alcohol (3j) or an alkene motif (3k) leaves a reasonable
doubt about the involvement of transient vinyl cationic
species.5e Moreover, the reaction of 3h could be easily
scaled up, even at 0.1 mol% loadings of 2. Interestingly,
the reaction of secondary alkyl iodides posed no problems, although equimolar E/Z mixtures were obtained
for 3v and 3w.13 As shown for 3x, we found that fused
cyclopentane rings could be equally effective.
R

[Ir(ppy)2(dtbbpy)]PF6 (2, 1 mol%)

I

O

CHO

4a-d

I

I

R = H, 89% (3k)
R = TBS, 93% (3l)

i-Pr2NEt (1 equiv), t-BuCN
Blue-LEDs, rt
12-96 h

I

H
5a-d

2

2

I

R
H

92% (3m)

R=
93% (3n)

Me
Si Me , 70% (5a)
Me

R=

, 72% (5b)
dr = 25:1

HN
S

OMe

R

O

R = CH2Cl, 95% (3p)
R = CH=CH2, 72% (3q)
R = (CH 2)2Si(OEt) 3, 61% (3r)

O
2

I
88% (3o)
HN

Me
R=

O

H

, 63% (5c)

R=
N

I

H

44% (5d)

H

Scheme 2. Atom Transfer Double Radical Cyclization.
CF 3

O

HN

OCF3

O
O Cl

O

I

I

89% (3s)
R

Ph

Ph
I
R = H, 73% (3u)
R = Me, 95% (3v)d

3t

90% (3t)

Et Ph

H

Ph

I
I

I
88%

(3w)d

94% (3x)d

80% (3y)e

a

As for Table 1, entry 1 (12-96 h). b Isolated yields, average of at least two independent runs. c 1h (5.80 mmol scale)
with 2 (0.1 mol%). d E/Z = 1:1. e dr = 10:1.

Encouraged by these results, we next focused our attention on exploring the preparative scope of our ATRC
reaction. As evident from the results compiled in Table
2, our visible light photocatalytic ATRC of unactivated
alkyl iodides turned out to be highly chemoselective, as
alkyl iodides possessing silyl groups (3g, 3h, 3r), nitriles
(3i), alkenes (3j, 3q), free alcohols (3k), silyl ethers (3l),
aldehydes (3n) or carbamates (3p-3t), among others,
could perfectly be accommodated. Notably, aryl or alkyl
halides do not interfere (3m, 3p, 3s), providing an additional handle via iterative metal-catalyzed crosscoupling techniques. Interestingly, aromatic- or aliphatic-substituted alkynes could be coupled with equal ease,
even for particularly challenging hindered substrate
combinations (3f-3h). The successful preparation of 3i-

The successful preparation of 3a-3x tacitly suggested
that our visible light ATRC should by no means be limited to unactivated alkyl iodides bearing alkynes on the
side-chain. Indeed, we found that 1y possessing a pending alkene reacted equally well, obtaining 3y in 80%
yield. As for classical radical-type cyclizations, an excellent diastereoselectivity was observed for 3y, invariably favoring the cis-isomer. In view of the significant
erosion in selectivity found for 3v-3x, we hypothesized
that the utilization of secondary alkyl iodides possessing
an allyl group could trigger a 5-exo-trig cyclization followed by rapid interconversion of the in situ formed
vinyl radicals and a final iodine transfer, thus ultimately
resulting in bicyclic skeletons via formal atom transfer
double radical cyclization. As shown in Scheme 2, this
turned out to be the case and 5a-d were all obtained in
good yields with high levels of diastereoselectivity under otherwise identical reaction conditions to that shown
in Table 2.14 To the best of our knowledge, these results
represent the first atom transfer double radical cyclization performed using photocatalysis under visible light
irradiation.15 Taken together, the results of Table 2 and
Scheme 2 illustrate the prospective impact of visible
light-mediated redox-neutral ATRC reactions with unactivated alkyl iodides.

The large energy mismatch between redox potentials of
2 (Ered [IrIII/IrII] vs Ered [1a] = ~ 1 V) suggested that a

conventional photocatalytic redox cycle might not be
operative. Although quenching experiments16 indicated
the involvement of a simple reductive photoredox cycle,
the quantum yield of the ATRC of 1a was found to be
2.3. While this value might fall into a radical-chain
propagation scenario,17 the existence of alternate lightconsuming events cannot be ruled out.18 Indeed, 12% of
3a could be obtained in the absence of 2 after 48 h.
While higher yields of 3a could be obtained upon increasing the light intensity or by using DMSO as solvent
at higher concentrations of i-Pr2NEt, it is worth noting
that significant amounts of undesired 3a’ were inevitably observed in these cases, making this transformation
less-synthetically attractive in the absence of 2.9 Although an in depth mechanistic study should await further investigations, these results might suggest the formation of a weak charge-transfer complex19 between 1a
and i-Pr2NEt, triggering a SET via in situ formation of
an exciplex.20-22 In line with these results, we speculate
that formation of an exciplex might be accelerated via
energy transfer from the triplet excited state of 2.23,24
Whether chain-processes could be initiated from an
exciplex25 or from in situ generated a-amino radicals,26
or if it has other mechanistic considerations is subject of
ongoing studies.27
In summary, we have described an unconventional photocatalytic redox-neutral ATRC of unactivated alkyl
iodides under visible light irradiation. The salient features of this transformation are the mild conditions,
broad scope and exquisite chemoselectivity, thus enabling the preparation of highly versatile building blocks
susceptible to further functionalization. Preliminary
mechanistic experiments leave some doubt about a canonical photoredox cycle. Further investigations along
these lines are currently underway in our laboratories.

thank E. Escudero/E. Martin for X-Ray crystallographic
data and Prof. E. Palomares for insightful discussions.

REFERENCES
(1)

(2)

(3)

(4)
(5)

AUTHOR INFORMATION
Corresponding Author
* rmartinromo@iciq.es
* fjulia@iciq.es

(6)

Funding Sources

(7)

No competing financial interests have been declared.

ASSOCIATED CONTENT

(8)

Supporting Information. Experimental procedures and spectral
data. This material is available free of charge via the Internet at
http://pubs.acs.org.

ACKNOWLEDGMENT
We thank ICIQ, the European Research Council (ERC277883), MINECO (CTQ2015-65496-R & Severo Ochoa
Excellence Accreditation 2014-2018, SEV-2013-0319) and
Cellex Foundation for support. Y. S., F. J.–H., and J. C.
thank CSC, COFUND and European Union (FP7PEOPLE-2012-IEF-328381) for a fellowship. We also

(9)
(10)

Selected reviews: (a) Fabry, D. C.; Rueping, M. Acc.
Chem. Res. 2016, 49, 1969-1979. (b) Hopkinson, M. N.;
Tlahuext-Aca, A.; Glorius, F. Acc. Chem. Res. 2016, 49,
2261-2272. (c) Skubi, K. L.; Blum, T. R.; Yoon, T. P.
Chem. Rev. 2016, 116, 10035-10074. (d) Kärkäs, M. D.;
Porco, J. A.; Stephenson, C. R. J. Chem. Rev., 2016, 116,
9683-9747. (e) Hopkinson, M. N.; Sahoo, B.; Li, J.; Glorius, F. Chem. Eur. J. 2014, 20, 3874-3886. (f) Prier, C. K.;
Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013,
113, 5322-5363.
Selected reviews: (a) Studer, A.; Curran, D. P. Angew.
Chem. Int. Ed. 2016, 55, 58-106. (b) Focsaneanu, K.-S.;
Scaiano, J. C. Helv. Chim. Acta 2006, 89, 2473-2482. (c)
Fischer, H. Chem. Rev. 2001, 101, 3581-3610.
Selected ATRA/ATRC reactions via chemical activation:
(a) Bergeot, O.; Corsi, C.; Quiclet-Sire, B.; Zard, S. Z. J.
Am. Chem. Soc. 2015, 137, 6762-6765. (b) Monks, B. M.;
Cook, S. P. Angew. Chem. Int. Ed. 2013, 52, 14214-14218.
(c) Liu, H.; Qiao, Z.; Jiang, X. Org. Biomol. Chem. 2012,
10, 7274-7277. (d) Weidner, K.; Giroult, A.; Panchaud, P.;
Renaud, P. J. Am. Chem. Soc. 2010, 132, 17511-17515. (e)
Curran, D. P.; Chen, M.-H.; Spleterz, E.; Seong, C. M.;
Chang, C.-T. J. Am. Chem. Soc. 1989, 111, 8872-8878. (f)
Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945,
102, 128, (g) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am.
Chem. Soc. 1986, 108, 2489-2490. (h) Sukeda, M.;
Ichikawa, S.; Matsuda, A.; Shuto, S. Angew. Chem. Int.
Ed. 2002, 41, 4748-4750. (i) Yanada, R.; Nishimori, N.;
Matsumura, A.; Fujii, N.; Takemoto, Y. Tetrahedron Lett.
2002, 43, 4585-4588. (j) Chakraborty, A.; Marek, I. Chem.
Commun. 1999, 2375-2376.
Courant, T.; Masson, G. J. Org. Chem., 2016, 81, 69456952, and references therein.
For recent ATRA/ATRC photoredox with activated alkyl
halides: (a) Arceo, E.; Montroni, E.; Melchiorre, P. Angew. Chem. Int. Ed. 2014, 53, 12064-12068. (b) Gu, X.;
Li, X.; Qu, Y.; Yang, Q.; Li, P.; Yao, Y. Chem. Eur. J.
2013, 19, 11878-11882. (c) Wallentin, C.; Nguyen, J. D.;
Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc.
2012, 134, 8875-8884. (d) Nguyen, J. D.; Tucker, J. W.;
Konieczynska, M. D.; Stephenson, C. R. J. J. Am. Chem.
Soc. 2011, 133, 4160-4163.
Buldt, L. A.; Guo, X.; Prescimone, A.; Wenger, O. S.
Angew. Chem. Int. Ed., 2016, 55, 11247-11250.
(a) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.;
Stephenson, C. R. J. Nat. Chem. 2012, 4, 854-859. (b)
Kim, H.; Lee, C. Angew. Chem. Int. Ed. 2012, 51, 1230312306.
Selected recent examples: (a) Serrano, E.; Martin, R.
Angew. Chem. Int. Ed. 2016, 55, 11207-11211. (b) Börjesson, M.; Moragas, T.; Martin, R. J. Am. Chem. Soc. 2016,
138, 7504-7507. (c) Wang, X.; Liu, Y.; Martin, R. J. Am.
Chem. Soc. 2015, 137, 6476-6479. (d) Liu, Y.; Cornella,
J.; Martin, R. J. Am. Chem. Soc. 2014, 136, 11212-11215.
See Supporting information for details.
For C–H bond dissociation energies of different organic
molecules: (a) Blanksby, S. J.; Ellison, G. B. Acc. Chem.
Res. 2003, 36, 255-263. For HAT processes using MeCN
as solvent: (b) DeLaive, P. J.; Foreman, T. K.; Giannotti,
C.; Whitten, D. G. J. Am. Chem. Soc. 1980, 102, 56275631.

(11)
(12)
(13)

(14)
(15)

(16)
(17)
(18)

(19)

(20)

An otherwise identical redox potential was observed in
tBuCN. See ref. 9.
A similar redox discrepancy was also observed by Lee
(ref. 7b), but no mechanistic rationale was proposed.
Isomerization of olefins has been previously reported
under visible-light irradiation: Singh, K.; Staig,
S.; Weaver, J. D. J. Am. Chem. Soc., 2014, 136, 52755278.
Stereoselectivities of 5a-5d were assigned by analogy with
the reported structure of 5b (ref. 3b).
For selected non-redox neutral reductive atom transfer
double radical cyclization, see: (a) Tucker, J. W.; Nguyen,
J. D.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson, C.
R. J. Chem. Commun., 2010, 46, 4985-4987. (b) Peng, Y.;
Xiao, J.; Xu, X.-B.; Duan, S.-M.; Ren, L.; Shao, Y.-L.;
Wang, Y.-W. Org. Lett. 2016, 18, 5170-5173.
Triplet-excited state of 2 was effectively quenched by iPr2NEt in contrast to 1a, thus ruling out an energy transfer
between 1a and 2. See ref. 9.
Cismesia, M. A.; Yoon, T. P. Chem. Sci., 2015, 6, 54265434.
Similar conclusions have been reached with similar quantum yields using Eosin Y: Majek, M.; Filace, F.; von
Wangelin, A. J. Beilstein J. Org. Chem. 2014, 10, 981989.
For well-known charge-transfer complexes between electron-rich enamines and electron-poor alkyl halides in photocatalytic reactions: Bahamonde, A.; Melchiorre, P. J.
Am. Chem. Soc. 2016, 138, 8019.
(a) Kropp, P. J. Photobehavior of Alkyl Halides. CRC
Handbook of organic photochemistry and photobiology,
2nd ed.; 2004, Vol. 1, p 1. (b) Lautenberger, W. J.; Jones,

(21)

(22)

(23)

(24)
(25)
(26)

(27)

E. N.; Miller, J. G. J. Am. Chem. Soc. 1968, 90, 11101115.
For selected amine-mediated dehalogenation via exciplex
formation: (a) Cossy, J.; Ranaivosata, J.-L.; Bellosta, V.
Tetrahedron Lett. 1994, 35, 8461-8162. (b) Kropp, P. J.;
Adkins, R. L. J. Am. Chem. Soc. 1991, 113, 2709-2717.
Exciplex formation followed by SET process has been
reported under visible light at high concentrations of
amine: Böhm, A.; Bach, T. Chem. Eur. J. 2016, 22,
15921-15928.
Comprehensive characterization of exciplexes is elusive,
and it has only been accomplished with activated alkyl
halides and electron-rich amines, see for example Biaselle,
C. J.; Miller, J. G. J. Am. Chem. Soc. 1974, 96, 3813-3816.
Unfortunately, we could not obtain clear evidences of its
formation by NMR and UV-Vis spectroscopy.
The observed reactivity seems to correlate better with the
energy of the triplet-excited state of different photocatalysts rather than with their redox potentials. See ref. 9.
For an example of a radical-chain process triggered by the
formation of an exciplex see: Biaselle, C. J.; Miller, J. G.
J. Am. Chem. Soc. 1974, 96, 3813-3816.
Reactions in the presence of thioxanthone-generated a
amino radicals in the absence of 2 resulted in the formation of the ATRC product in lower yields compared to
the optimized conditions. See ref. 9. For reduction processes involving a
-amino radicals, see: (a) Ismaili, H.; Pitre, S. P.; Scaiano, J. C. Catal. Sci. Technol. 2013, 3, 935937. (b) Lanterna, A. E.; Elhage, A.; Scaiano, J. C. Catal.
Sci. Technol. 2015, 5, 4336-4340.
For a mechanistic rationale, see Supporting information.

PF6-

I

N
N

R1
I
R2
Ered ≤ -2.5 V

N

Ir

R1

N

or
Blue-LEDs

Ered [IrIII/IrII] = -1.51 V
Wide scope & cascade scenarios
Large energy mismatch (∼1 V)
High chemoselectivity profile

R2

R
I

H

H

6