Radical-mediated divergent cyclization of benzamides toward perfluorinated or cyanated isoquinolinediones

Article abstract of DOI:10.1039/c6ob01550f

A simple and efficient copper-controlled divergent cyclization of benzamides, which leads to perfluorinated or cyanated isoquinolinediones, is developed. In the presence of AIBN, methacryloyl benzamides with perfluoroalkyl iodides undergo cascade radical addition/cyclization to afford perfluoroinated isoquinolinediones as the major product under metal-free conditions, whereas the use of CuI (10 mol%) is able to redirect the cyclization to yield isoquinolinediones bearing an α-cyano quaternary carbon center. The cyclization features controllable divergent synthesis and a broad substrate scope as well as highly practical reaction conditions, thereby making this strategy a highly attractive means to fluorinate or cyanate isoquinolinediones.

Full text of DOI:10.1039/c6ob01550f

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Deng, S. Tang,
G. Ding, M. Wang, J. Li, Z. Li, L. Yuan and R. L. Sheng, Org. Biomol. Chem., 2016, DOI:
10.1039/C6OB01550F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C6OB01550F
Journal Name
ARTICLE
Radical‐mediated divergent cyclization of benzamides toward
perfluorinated or cyanated Isoquinolinediones†
Received 00th January 20xx,
Accepted 00th January 20xx
You‐Lin Deng,a Shi Tang,*a Guo‐Liang Ding,a Ming‐Wei Wang,a Jie Li,a Zeng‐Zeng Li,a Li Yuana and
Rui‐Long Shengb
DOI: 10.1039/x0xx00000x
A simple and efficient copper‐controlled divergent cyclization of benzamides leading to perfluorinated or cyanated
isoquinolinediones was developed. In the presence of AIBN, methacryloyl benzamides with perfluoroalkyl iodides
underwent cascade radical addition/cyclization to give perfluoroinated isoquinolinediones as the major product under
metal‐free conditions, whereas the use of CuI (10 mol %) was able to redirect the cyclization to yield isoquinolinediones
bearing an α‐cyano quaternary carbon center. The cyclization features controllable divergent synthesis and broad
substrates scope as well as highly practical reaction conditions, thereby making such strategy as a highly attractive means
to fluorinated or cyanated isoquinolinediones.
www.rsc.org/
and lipophilicity imparted by the fluorinated groups leading to
better cell membrane fusion and permeability and increased
Introduction
Isoquinoline-1,3(2
bioavailability,3 the introduction of fluorinated substituents
H
,4
H
)-diones are prevalent structural units
into isoquinolinedione skeleton by such strategy has also
presented in naturally occurring products and pharmaceuticals
with important biological functionality.1 In Figure 1, several
representative bioactive isoquinolinedione derivatives are
shown, which exhibit various bioactivities such as antiviral
agent targeting HIV-I enzyme,1a,b 5-HT3 receptor antagonist1c
and TrkA/p75NTR inhibitor.1d Thus, elegant construction of the
modified and functionalized isoquinolinediones are expected to
serve as popularly fundamental processes in organic synthesis
and pharmaceutical industry. Recently, a strategy for the
attracted increasing attention.3a‐d For example, using
commercially available and much less expensive perfluoroalkyl
iodides as the Rf source,4,5 our group recently developed a
rapid
and
efficient
approach
to
perfluorinated
isoquinolinedione via visible‐light photoredox catalysis under
mild conditions (Scheme 1, eq 1).2d Although it represents an
elegant and rare example toward perfluorinated
isoquinolinedione, the expensive iridium‐based photocatalyst6
was, nevertheless, required for good reaction efficiency,
thereby limiting its application in practical organic synthesis to
some extent. Therefore, developing more practically interesting
and green chemistry approaches (e.g. under metal-free
conditions) for such purpose is arguably of high interest by
O
O
O
OH
N
N
N
N
O
O
O
F
F
inhibitor of HIV-I RT
inhibitor of aminopeptidase
anti-cancer agent
H
N
N
O
O
N
HO2C
CF3
N
CO2H
HN
O
N
N
O
inhibitor of ITPKb
inhibitor of TrkA/p75NTR
Figure 1. Selected Examples of Biologically Active Isoquinoline‐1,3‐dione Derivatives.
synthesis of such molecular skeleton via difunctionalization of
alkenes involving cascade addition/cyclization has attracted
great interest.2 In this context, given that the higher solubility
a. College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000
(China). Email: stang@jsu.edu.cn
b. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, 200032 (China).
Scheme 1. Perfluoroalkylation or cyanoalkylation of benzamides toward
†Electronic
Supplementary
Informaꢀon
(ESI)
available,
See
DOI: 10.1039/x0xx00000x
isoquinolinediones
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
ARTICLE
synthetic chemists. On the other hand, cyano-containing other hand, although
Journal Name
a
rapid access to 7-Vteierwt-Aartlikclye lOantleinde
DOI: 10.1039/C6OB01550F
molecules exhibit important functions in synthetically or isoquinolinediones by using AIBN and analogues has
medicinally important intermediates. Undoubtedly, exploration
Table 1 Optimization of reaction conditionsa
of these strategies to construct the cyano-containing
O
isoquinolinedione scaffold through low cost and high efficient
process will be highly valuable, thereby fitting in with the
demand of many promising synthetic or pharmaceutical
applications. As a continuation of our ongoing project on the
synthesis of functionalized isoquinolinediones,2d,2e we herein
want to demonstrate a simple and efficient divergent cyclization
of benzamides toward perfluorinated and cyanated
isoquinolinediones (Scheme 1). In the divergent cascades, with
AIBN (azodiisobutyronitrile) severing as the initiator of
perfluorinated radical,7,8 methacryloyl benzamides along with
perfluoroalkyl iodides as the starting materials, which
underwent perfluorinating cyclization to give the fluoroinated
isoquinolinediones as the major product under metal-free
conditions (eq 2). In contrast, when a catalytic amount of CuI
(10 mol %) was used, the cyanating cyclization of benzamides
with AIBN and analogues occurred with the removal of
perfluoroalkyl iodides, thereby leading to various
isoquinolinediones bearing an α-functionalized quaternary
O
AIBN
O
O
n-C4F9I (2a)
N
N
N
+
cat.
O
O
1a
n-C4F9
CN
3a
4a
yield
3a
(%)b
16
13
9
14
12
11
65
41
22
32
trace
18
29
0
yield
entry
initiator
oxidant solvent
base
4a (%)b
1
2
3
4
5
6
7
8
9
AIBN
AIBN
AIBN
DTBP
TBPB
TBHP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
O2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
dioxane
CH3CN
DCE
―
―
―
―
―
9
7
trace
21
19
7
12
9
7
8
0
9
10
61
67
14
17
29
25
CuI/AIBN
CuBr/AIBN
FeBr2/AIBN
AIBN
―
K3PO4
K2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
AIBN
AIBN
AIBN
10c
11
12d
13e
14f,g
15f,g
16 f,g
17f,g
18f,g
19f,g
―
AIBN
AIBN
CuI/AIBN
CuI/AIBN
AIBN
CuI/AIBN
CuI/AIBN
CuI/AIBN
air
air
air
air
0
0
0
0
carbon center in high efficiency (eq 3)
.
air
0
Results and discussion
a Reaction conditions: 1a (0.3 mmol), n-C4F9I (2 equiv), metal (10 mol % )
and/or initiator (2 equiv.), oxidant (2 equiv ) or O2/air (1 atm), and solvent
(2 mL) at 100 oC for 12 h. DTBP = di-tert-butyl peroxide, AIBN =
azodiisobutyronitrile, TBPB = tert-butylperoxyl benzoate, TBHP = tert-
butyl hydrogenperoxide (70% aqueous solution). b Yield of the isolated
product. c Using 1 equiv. of AIBN. d At 80 oC. e At 120 oC. f With the
removal of n-C4F9I. g At 90 oC.
We began the reaction exploration by optimizing the cascade
cyclization of -methyl-
-methacryloyl benzamide1a with
N
N
n-
C4F9I (Table 1). At the outset, a combination of AIBN/DTBP
described in our former work9a was firstly investigated, and the
reaction, nevertheless, resulted in the perfluorinated
isoquinolinedione 3a in only 16% yield, accompanying a small
amount of cyanated by-product 4a possibly resulting from the
cascade addition/cyclization of benzamide 1a with AIBN (entry
1).9,10 The replacement of DTBP with other similar oxidants
such as TBPB and TBHP did not allow a further increase in 3a
yield (entries 2 and 3). To further improve the 3a yield, several
metal salts were next used in the reactions (entries 4-6).
However, they did not lead to 3a in higher yield, whereas the
by-product 4a appeared to form more efficiently in the presence
of the copper catalysts (entries 4 and 5). Considering that a base
could facilitate the removal of the aryl hydrogen in the catalytic
cycle,3d several bases such as K2CO3, K3PO4 and Cs2CO3 was
next investigated (entries 7-9). As expected, K3PO4 sharply
improve the yield of 3a to 71%, and the formation of the
cyanated by-product 4a was also suppressed efficiently with the
removal of copper catalyst (entry 7). Notably, reducing the
amount of initiator AIBN could exactly suppress the cyclization
resulting in the by-product 4a, but the yield of desired product
3a decreased simultaneously (entry 10). In the control
experiment, the cyclization reactions were found to be
completely restrained with the removal of the AIBN (entry 11).
Further screening disclosed that the optimal temperature for the
fluoroalkylating cyclization was 100 oC, and an elevated
recently disclosed in our group,2e the cyanated skeleton outlined
as 4a was, in our opinion, also of synthetic and medicinal
importance. Therefore, we next set out to optimize the
conditions
for
the
cyclization
toward
cyanated
isoquinolinedione 4a
.
Notably, the copper catalyst was
observed to be important for the formation of 4a, as well as the
use of air as the oxidant turned out to be more efficient to
promote the cyclization than DTBP (entries 14-16). In addition,
a slightly decreased temperature (90 oC) was, compared with
above perfluoroalkylating cyclization, more beneficial for the
cyanating cyclization. Further screening disclosed that the
solvent had important impact on the cyclization, and DMF
proved to be best choice solvent/ media and could efficiently
suppress the formation of another by-product 7-tert-alkylated
isoquinolinedione (entries 17-19).2e
With the optimal conditions for the fluorinating cyclization
in hand, we sequentially turned our attention to investigate the
substrate scope (Scheme 2). Firstly, we embarked on
investigating the compatibility of N-substituents of the
methacryloyl benzamides in this cyclization. A series of
N
-
substituents of methacryloyl benzamides such as Me, Bu and
Bn were observed to be well reactive in the cyclization, but the
CH2CO2Et, unfortunately, led to 3e in only 29% yield (3a-d).
o
temperature (>120 C) would result in some unidentified side-
Next, we set out to evaluate the substitution effect on the
aromatic moiety of the methacryloyl benzamides in the
reactions possibly resulting from the free radicals produced by
AIBN11 or DTBP12 decomposition (entries 12 and 13). On the
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 6
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
cyclization cascades. Gratefully, a wide variety of para- yields irrespective of the electronic and steric character of the
View Article Online
substituents (e.g., Me, MeO, F, Cl, CF3 and Ph) on the aromatic substituent groups on the benzamide scaffold (4a
ring displayed good reactivity irrespective of electronic and different from above fluoroalkylating cyclization, the cyanating
-
DOI: 10.1039/Ck6O).B0B1e55in0gF
steric character of the substituent groups (3e-k). Additionally,
O
O
O
when the meta-methoxyl substituted benzamide was examined
under the reaction conditions, two regioselective products 3l
and 3l’ was observed to form with a moderate regioselectivity
(2:1). Notably, the benzamides bearing ortho-substituents (e.g.,
Me and Cl) appeared to be less subject to steric hindrance, and
be able to undergo the cyclization cascade to give the desired
3m and 3n efficiently. In addition, the 2,4-dichloro or 3,5-
dimethyl benzamides were also viable substrates, thereafter
leading to 3o and 3p in 54% and 51% yields respectively.
AIBN (2 equiv.)
DTBP (2 equiv.)
R2
N
Rf-I
N
R2
1
+
R1
R1
K3PO4, DMF
100oC, 10-12 h
(2 equiv)
O
Rf
3
Rf = n-C3F7, n-C6F13, n-C8F17 and n-C10F21
Me
O
O
O
N
N
N
O
O
Me
O
n-C6F13
n-C3F7
n-C6F13
3q, 55%
Me
3s, 54%
3r, 60%
O
O
O
O
R2
AIBN (2 equiv.)
DTBP (2 equiv.)
O
N
I-C4F9
R1
N
N
R2
+
N
O
R1
K3PO4, DMF
100 oC, 10-12 h
O
C4F9
(2 equiv)
O
Me
1
3
n-C8F17
n-C10F21
3u, 44 %
3t, 45%
O
O
O
Scheme 3 Scope of perfluoroalkyl iodides. Reaction conditions: 1 (0.3 mmol), RfI (2
equiv), AIBN (2 equiv), DTBP (2 equiv), K3PO4 (2 equiv.), and DMF (2 mL) at 100 oC for
10‐12 h.
R
N
N
N
O
n-C4F9
R
O
n-C4F9
O
n-C4F9
R = Me (3e), 75%
MeO (3f),72%
F (3g), 55%b
Cl (3h), 64%
Br (3i), 57%
R = Bu (3b), 73%
Bn (3c), 57%
3a,65%
cyclization of the meta- substituted benzamides mainly gave the
CH2CO2Et (3d), 29%a
isoquinolinediones regioselectively via cyclizing at the para
position of the substituents, albeit with slightly decreased yield
4l ). In addition, the ortho- substituted benzamides, as well as
the 3,5-dimethyl benzamide, were also viable substrates for the
cyanating cyclization (4o ). However, further investigations
-
O
N
O
n-Bu
MeO
+
n-Bu
CF3 (3j), 51%
Ph (3k), 43%b
N
(
-n
O
O
n-C4F9
OMe
n-C4F9
-q
3l (21%)
3l' (39%)
R
O
disclosed that the substituent phenyl group at both the 2 and 3-
position of the acrylamide unit was inefficient for the
cyclization, and failed to yield desired cyanated
isoquinolinediones.
Cl
O
O
N
O
N
O
Me
N
Cl
O
n-C4F9
n-C4F9
n-C4F9
Me
3p, 51%a
R = Cl (3m), 57%
Me (3n), 63%
3o, 54%
Scheme 2. Scope of methacryloyl benzamides in the reaction with n‐C4F9I. Reaction
conditions: 1 (0.3 mmol), n‐C4F9I (2 equiv), AIBN (2 equiv), DTBP (2 equiv), K3PO4 (2
equiv.), and DMF (2 mL) at 100 oC for 10‐12 h. a CH3CN instead of DMF as the solvent. b
With methyl group on the N‐atom.
Subsequently, we also investigated the compatibility of other
perfluoroalkyl iodide in the cyclization, thereby resulting in the
incorporation of perfluoroalkyl moieties with various carbon-
chain lengths into isoquinolinedione skeleton (Scheme 3). To
our delight, a series of perfluoroalkyl iodides including C3F7I,
C6F13I, C8F17I, and etc. were observed to be reactive with the
perfluoroalkylation conditions, thereby leading to the
isoquinolinediones bearing various perfluorinated moieties in
moderate yields (3q-u). Moreover, the perfluoroalkylation
reaction was expected to be employed as an efficient approach
for the synthesis of lipophilic-controllable isoquinolinediones
for the screening of fluoro-based bioactive compounds.
With the identification of cyanoalkylation conditions, we
also investigated the substrate scope in the cyanoalkylation
leading to isoquinolinediones bearing an α-cyano quaternary
centre (Scheme 4). Delightedly, AIBN mediated the
cyanoalkylating cyclization smoothly to afford the
isoquinolinediones bearing a nitrile moiety in moderate to good
Scheme 4. Scope of substrates in cyanoalkylation. Reaction conditions: 1 (0.3 mmol),
CuI (10 mol %), AIBN (2 equiv), air (1 atm), K3PO4 (2 equiv.), and DMF (2 mL) at 90 oC for
10‐12 h. a Diastereomeric ratios (d.r.) was determined by 1H NMR.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
ARTICLE
Journal Name
In addition, we also investigated the reactivity of other alkyl conditions, and then adds onto the C=C bond of VmiewetAhrtaiccleryOlnoliynel
azo-compounds in the cyanoalkylating cyclization (Scheme 5). benzamide 1a leading to radical inDteOrmI: 1e0d.1i0a3te9/C6OB01550F
Next,
Encouragingly, several other azo-compounds containing an a- intramolecular cyclization of intermediate occurs to form
functionalized tert-alkyl groups such as Et(Me)(NC)C and intermediate , and then oxidation of the radical by DTBP
NC(C6H10)C, as well as EtO2C(Me)2C, were also observed to takes place to afford cyclohexadienyl cation . Finally, the
be well reactive under the optimal conditions, leading to abstraction of an aromatic hydrogen of intermediate by
-functionalized K3PO4 occurs to afford perfluorinated isoquinolinedione 3a.
A
.
A
B
B
C
C
various isoquinolinediones bearing bearing an
α
quaternary centre in moderate to good yield (3r
-
x
).
Regarding the cyanoalkylation cyclization of methacryloyl
benzamide 1a with AIBN, a similar mechanism process
involving Cu/air oxidative combination13 is responsible for this
cyclization (path b, Scheme 7).
O
R2
O
O
N
CuI (10 mol%)/air
R1
N
R
+
N
R1
R
N
K3PO4, DMF
90 oC, 10-12 h
O
R
R2
2
4
1
O
O
O
Me
N
N
N
R
O
O
O
Me
CN
Et
NC
R = H (4r), 57% (d.r = 7:3)a
R = F (4s), 50% (d.r. = 1:1)a
NC
4t, 68%
4u, 72%
O
N
O
O
N
O
Me
O
Cl
N
O
Scheme 7. Proposed mechanism for the divergent perfluoroalkylation and
cyanoalkyaltion
CO2Me
4w, 51%
4x, 57%
NC
4v, 57%
NC
Scheme 5. Scope of alkyl azo‐Compounds in the cyanoalkylation. Reaction conditions:
1 (0.3 mmol), azo‐compound 2 (2 equiv), air (1 atm), CuI (10 mol %), K3PO4 (2 equiv.),
and DMF (2 mL) at 90 oC for 10‐12 h. a Diastereomeric ratios (d.r.) was determined by Conclusions
1H NMR
In summary, we have disclosed a simple and efficient
copper-controlled divergent cyclization of methacryloyl
benzamide leading to perfluorinated or cyanated
To further insight into the mechanism, we performed two
control experiments shown as Scheme 6. First, by adding the
isoquinolinediones by using AIBN and analogues for the first
time. The reaction represents a rare and general example of
AIBN-mediated divergent cyclization cascades of methacryloyl
benzamide leading to different functionalized isoquinolinedione
motifs in single step. Under transition-metal-free conditions,
AIBN mainly acts as the initiator of Rf radical from RfI to
mediate the perfluorinating cyclization of benzamides, whereas
the use of CuI may switch the role of AIBN from the radical
initiator to a reactant leading to cyanated isoquinolinedione.
Notably, the successful perfluoroalkylation reaction paves an
efficient way to prepare new perfluoroalkyl-containing
isoquinolinediones with different carbon-chain lengths, which
may bring them versatile lipophilicity and cell permeability.
The use of comparatively low cost RfI as Rf radical sources,
readily available azo-compounds as an initiator or reactant and
naturally abundant air as the oxidant, broad substrate scope, as
well as the copper catalysis or metal-free reaction conditions
and controllable divergent synthesis, arguably make this
protocol a highly attractive means to perfluorinated and
radical
scavenger
TEMPO
(2,2,6,6-tetramethyl-1-
piperidinyloxyl), the perfluoroalkylation cyclization of 1a with
perfluorobutyl iodide was seriously inhibited (eq 4). Being
consistent with the above event, the copper-catalyzed
cyanoalkyalting cyclization of benzamide 1a and AIBN was
also suppressed completely in the presence of excess TEMPO,
thus suggesting that the free radical intermediates might involve
both of the present two divergent reactions (eq 5).
Scheme 6.
cyanoalkyaltion
Control experiments for the perfluoroalkylation and
cyanated isoquinoline-1,3(2H,4H)-diones.
On the basis of above experimental results, we proposed a
possible working mechanism process for the divergent cascades
Experimental
General. All manipulations of oxygen- and moisture-sensitive
materials were conducted with a Schlenk technique under a
nitrogen or argon atmosphere. Solvent were purified and dried
(Scheme 7).2,5,7-13 For the fluoroalkylating cyclization (path a
,
Scheme 7), firstly perfluorinated radical C4F9• is generated
from C4F9I with the initiation of AIBN under heating
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 6
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
in a standard manner. Flash column chromatography was 2015JJ2113), The Research Innovation Program for Graduates
View Article Online
DOI: 10.1039/C6OB01550F
performed using EM Silica gel 60 (300-400 mesh). of Jishou University (No.JGY201636)
.
Visualization was accomplished with UV light (254 nm) and/or
1
an aqueous alkaline KMnO4 solution followed by heating. H
NMR and 13C NMR spectra were recorded on 400 or 500 MHz
NMR spectrometer with trimethylsilane resonance as the
internal standard. Unless otherwise noted, reagents were
commercially available and were used without further
Notes and references
1
For selected examples, see: (a) S. K. V. Vernekar, Z. Liu, E.
Nagy, L. Miller, K. A. Kirby, D. J. Wilson, J. Kankanala, S. T.
Sarafianos, M. A. Parniak and Z. Wang, J. Med. Chem., 2015,
58, 651; (b) Y.‐L. Chen, J. Tang, M. J. Kesler, Y. Y. Sham, R.
Vince, R. J. Geraghty and Z. Wang, Bioorg. Med. Chem., 2012,
20, 467; (c) M. Langlois, J. L. Soulier, V. Rampillon, C. Gallais,
B. Brkmont, S. Shen, D. Yang, A. Giudice and F. Sureau, Eur. J.
Med. Chem., 1994, 29, 925; (d) X. Gui, G. Gill, Z. Gan, Z. Dube
and R. Vohra, Wo2009/39635 A1, 2009.
purification.
N-Alkyl-N-methacryloyl benzamides (1) were
prepared according to literature procedures.2
General procedure for the synthesis of perfluoroalkylatedi
isoquinoline‐1,3(2H,4H)‐diones (products 3a‐u). To a mixture
2
(a) W. Kong, M. Casimiro, N. Fuentes, E. Merino and C.
Nevado, Angew. Chem., 2013, 125, 13324; Angew. Chem. Int.
Ed., 2013, 52, 13086; (b) L. Li, M. Deng, S.‐C. Zheng, Y. P.
Xiong, B. Tan and X.‐Y. Liu, Org. Lett., 2014, 16, 504; (c) L.
Zhang, C. Yang, Z. Xu, F. Gao and W. J. Xia, J. Org. Chem.,
2015, 80, 5730; (d) S. Tang, Y.‐L. Deng, J. Li, W. Wang, G. Ding,
M. Wang, Z. Xiao, Y. Wang and R. Sheng, J. Org. Chem., 2015,
80, 12599; (e) S. Tang, Y.‐L. Deng, J. Li, W. Wang, Y. Wang, Z.‐
Z. Li, L. Yuan, S.‐L. Chen and R. ‐L. Sheng, Chem. Commun.,
2016, 52, 4470; (f) X.‐F. Xia, S.‐L. Zhu, Y. Li and H. Wang, RSC
of methacryloyl benzamide 1a (0.3 mmol), AIBN (0.06 mmol),
DTBP (0.6 mmol), K3PO4 (0.6 mmol) in DMF (2.0 mL) was
added perfluoroalkyl iodine (0.6 mmol) under N2 atmosphere,
and then the resulting solution was stirred at 100 oC for 10-12 h.
Then the resulted mixture was diluted with Et2O, and washed
with water and then brine. The organic layer was dried over
anhydrous MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/ethyl acetate
10:1 as the eluant) on silica gel to afford the corresponding
Adv., 2016, 6, 51703.
3
For selected reports, see: (a) J. Wang, M. Sanchez‐Rosello, J.
Acena, C. L. Pozo, A. E. Sorochinsky, S. Fustero, V. A.
Soloshonok and H. Liu, Chem. Rev., 2014, 114, 2432; (b) G. K.
S. Prakash and S. Chacko, Curr. Opin. Drug Discovery Dev.,
2008, 11, 793; (c) O. A. Tomshenko and V. V. Grushin, Chem.
Rev., 2011, 111, 4475; (d) J. Nie, H.‐C. Guo, D. Gahard and J.‐
A. Ma, Chem. Rev., 2011, 111, 455.
perfluorinated isoquinoline-1,3-diones 3a as yellowish oil (89.7
1
mg, 71%). H NMR (400 MHz, CDCl3) δ: 8.30 (d,
J
= 7.9 Hz,
1H), 7.67 (t,
J = 7.6 Hz, 1H), 7.52 – 7.43 (m, 2H), 3.51– 3.35
(m, 1H), 3.42 (s, 3H), 2.78 (ddd,
J = 28.1, 15.3, 8.2 Hz, 1H),
1.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ:174.7, 163.8,
140.6, 133.8, 129.3, 128.1, 125.7, 124.0, 120.5 – 106.1 (m),
4
5
Price from Alfa Aesar: nonafluoro‐1‐iodobutane, (97%, $45.7
for 25 g); nonafluorobutanesulfonyl chloride (98%, $317 for
5g), and nonafluorobutyl Togni reagent is not commercially
available.
43.3, 40.5 (t,
J = 19.6 Hz), 31.9, 27.5, 23.4; HRMS m/z (ESI-
TOF) calcd for C16H13F9NO2 [M+H]+ 422.0798, found:
422.0796.
For selected examples of reactions of fluoroalkyl iodides, see:
(a) P. V. Pham, D. A. Nagib and D. W. C. MacMillan, Angew.
Chem. Int. Ed., 2011, 50, 6119; (b) A. Hafner, A. Bihlmeier, M.
General procedure for the synthesis of cyanated
isoquinoline-1,3(2
H
,4
H
)-diones
(products 4a-x
).
To
a
mixture of methacryloyl benzamide 1a (0.3 mmol), AIBN (0.06
mmol), CuI (0.003 mmol, 10 mol%), K3PO4 (0.6 mmol) in
DMF (2.0 mL) was added perfluoroalkyl iodine (0.6 mmol),
Nieger, W. Klopper and S. Bräse, J. Org. Chem., 2013, 78
,
7938; (c) R. Zeng, C. Fu and S. Ma, Angew. Chem. Int. Ed.,
2012, 51, 3888; (d) Q. Qi, Q. Shen and L. Lu, J. Am. Chem.
Soc., 2012, 134, 6548; (e) A. T. Herrmann, L. L. Smith and A.
Zakarian, J. Am. Chem. Soc., 2012, 134, 6976; (f) T. Xu, C. W.
Cheung and X. Hu, Angew. Chem. Int. Ed., 2014, 53, 4910; (g)
B. Zhang and A. Studer, Org. Lett., 2014, 16, 3990; (h) Q. Luo,
M. L. Chun, J. J. Tong, Y. Shao, W. Y. Shan, H. H. Wang, H.
Zheng, J. Cheng and X. B. Wan, J. Org. Chem., 2016, 81, 3103.
Price from Sigma‐Aldrich: Ir(ppy)3 (99%, $277.5 for 250 mg),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (98%, $125 for 100 mg).
o
and then the resulting solution was stirred at 90 C for 10-12 h
under air atmosphere. Then the resulted mixture was diluted
with Et2O, and washed with water and then brine. The organic
layer was dried over anhydrous MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography
(petroleum ether/ethyl acetate 5:1 as the eluant) on silica gel to
afford the corresponding cyanated isoquinoline-1,3-diones 4a
as yellowish solid (54.2 mg, 67%). 1HNMR (400 MHz, CDCl3)
δ: 8.33 (dd, J = 8.2, 1.3 Hz, 1H), 7.71 – 7.65 (m, 1H), 7.52 (t, J
= 7.3 Hz, 2H), 3.42 (s, 3H), 2.77 (d, J = 14.5 Hz, 1H), 2.29 (d, J
= 14.5 Hz, 1H), 1.65 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ: 175.6, 163.9, 141.0, 133.8, 129.4,
128.2, 126.6, 124.7, 123.2, 50.4, 45.9, 33.1, 30.6, 29.2, 27.7,
27.3; HRMS m/z (ESI-TOF) calcd for C16H19N2O2 [M+H]+
271.1442, found: 271.1440.
6
7
8
For a review on fluorinated radicals, see: W. R. Dolbier, Chem.
Rev., 1996, 96, 1557.
(a) X. Fang, X. Yang, S. Mao, Y. Wang, G. Chen and F. Wu,
Tetrahedron., 2007, 63, 10684; (b) M. Napoli, C. Fraccaro, L.
Conte, G. P. Cambaretto and E. Legnaro, J. Fluorine Chem.
1992, 57, 219; (c) N. O. Brace, J. Org. Chem., 1663, 28, 2093.
(a) D. Zhou, Z.‐H. Li, S.‐H. Li, M.‐J. Fu, G.‐L. Ding, Y.‐C. Wang,
9
R.‐L. Sheng and S. Tang, Eur. J. Org. Chem., 2015, 7, 1606; (b)
S. Tang, Z.‐H. Li, D. Zhou, S.‐H. Li and R.‐L. Sheng,
Tetrahedron Lett., 2015, 56, 142; (c) W. Wei, J. Wen, D. Yang,
M. Guo, L. Tian, J. You and H. Wang, RSC Adv., 2014, 4, 48535.
10 For selected reviews, see: (a) W. Mai, J. Wang, L. Yang, J.
Yuan, P. Mao, Y. Xiao and L. Qu, China. J. Org. Chem., 2014,
14, 1958; (b) R. J. Song, Y. Liu, Y. X. Xie, J. H. Li and Y.‐X. Xi,
Synthesis., 2015, 47, 1195 and references cited therein.
11 Q. Dai, T. Yu, X. Feng, H. Yang, Y. Jiang and J. Cheng, Chem.
Commun., 2014, 50, 12139.
Acknowledgements
Financial support from the National Natural Science
Foundation of China
Provincial Natural Science Foundation of China (no.
(No.21462017, 21662013), Hunan
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 6
ARTICLE
Journal Name
12 F.‐L. Tan, R.‐J. Song, M. Hu and J.‐H. Li, Org. Lett., DOI:
10.1021/acs.orglett.6b01419.
View Article Online
DOI: 10.1039/C6OB01550F
13 For a review, see: A. E. Wendlandt, A. M. Suess and S. S.
Stahl, Angew. Chem. Int. Ed., 2011, 50, 11062.
6 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins