Regiospecific Synthesis of 1-Trifluoromethylisoquinolines Enabled by Photoredox Somophilic Vinyl Isocyanide Insertion

Article abstract of DOI:10.1002/adsc.201400504

A strategy has been developed for the regiospecific synthesis of 1-trifluoromethylisoquinoline derivatives. This strategy is enabled by a photoredox vinyl isocyanide insertion with the help of Umemoto's reagent. The methodology presented here provides an access to highly fuctionalized 1-trifluoromethylisoquinolines regiospecifically under mild conditions in good-to-excellent chemical yields. A detailed mechanism is proposed, which is supported by experiments and theoretical calculations.

Full text of DOI:10.1002/adsc.201400504

UPDATES
DOI: 10.1002/adsc.201400504
Regiospecific Synthesis of 1-Trifluoromethylisoquinolines Enabled
by Photoredox Somophilic Vinyl Isocyanide Insertion
Yuanzheng Cheng,a Xiangai Yuan,b Heng Jiang,a Ruzhi Wang,a Jing Ma,b,*
Yan Zhang,a,* and Shouyun Yua,*
a
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210093, Peopleꢀs Republic of China
E-mail: njuzy@nju.edu.cn or yushouyun@nju.edu.cn
Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Nanjing
b
University, Nanjing 210093, Peopleꢀs Republic of China
E-mail: majing@nju.edu.cn
Received: May 22, 2014; Revised: June 19, 2014; Published online: September 11, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400504.
Abstract: A strategy has been developed for the re-
giospecific synthesis of 1-trifluoromethylisoquino-
line derivatives. This strategy is enabled by a photo-
redox vinyl isocyanide insertion with the help of
Umemotoꢀs reagent. The methodology presented
here provides an access to highly fuctionalized 1-tri-
fluoromethylisoquinolines regiospecifically under
mild conditions in good-to-excellent chemical
yields. A detailed mechanism is proposed, which is
supported by experiments and theoretical calcula-
tions.
aryl halides, boronic acids, sulfonates or as arenes
bearing a directing group.[4] Direct C H trifluorome-
À
thylation protocols, which obviate the need for pre-
functionalization of the substrates, become the focus
of many researchers.[5] These methods provide
straightforward and efficient routes to aromatic and
heterocyclic trifluoromethylated products. However,
the regioselectivity of these transformations is often
questionable.[6]
In particular, trifluoromethylated isoquinoline de-
rivatives are frequently encountered in pharmaceuti-
cals and natural products.[7] Methods to access these
valuable structures are very limited.[8] Trifluoromethy-
lations of isoquinolines at C-3 (the poorest electron
density) or C-4 (the highest electron density) position
can be achieved regioselectively,[8c–g] while 1-CF3-iso-
quinolines have seldom been accessed. As observed
by Akiyama and co-workers,[8a] direct trifluoromethy-
Keywords: iridium; isocyanides; isoquinolines; pho-
tochemistry; trifluoromethylation
Introduction of the trifluoromethyl (CF3) group into lation of isoquinoline under irradiation of a high-pres-
organic compounds has attracted the attention of sure mercury lamp with gaseous CF3Br led to a mix-
chemists for decades, due to the unique properties of ture of four regioisomers in 13.4% overall yield. 4-
trifluoromethylated molecules, such as elevated elec- CF3-isoquinoline was isolated as a major product in
tronegativity, hydrophobicity, metabolic stability, and 8.2% yield while the 1-CF3-isomer was only produced
bioavailability.[1] Aromatic and heterocyclic com- in 1.5% yield as a minor product (Figure 1, A). The
pounds bearing one or more CF3 groups on the ring Stoltz group reported an elegant synthesis of a 1-CF3-
are important intermediates and building blocks for isoquinoline derivative via aryne annulation.[8b] Only
the synthesis of numerous modern pharmaceuticals, one example was mentioned in this work (Figure 1,
highly efficient crop protection agents, and specialty B). So it remains an unsolved challenge to diversely
materials.[2]
access 1-CF3-isoquinoline derivatives regiospecifically.
Recently, our group became interested in visible
Recently, a variety of processes has been developed
for the incorporation of the CF3 group into diverse ar- light-promoted somophilic triple bond insertions to
omatic compounds.[3] Particularly, transition metal- provide functionalized (hetero)arenes.[9] Comparing
À
mediated or -catalyzed C CF3 bond formation reac- to biphenyl isocyanides, which have frequently been
tions have emerged as powerful synthetic tools in this used to construct phenanthridine derivatives,[9b,c,10] the
area in the past decade.[3b–d] For these methods, the ar- chemistry of vinyl isocyanides remains mainly unex-
omatic rings have to be pre-functionalized, such as plored.[11] Very recently, we reported the synthesis of
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Figure 1. Strategies for the synthesis of 1-CF3-isoquinolines.
1-arylisoquinoline derivatives using the somophilic in- achieved when MeOH was used as
a solvent
sertion of vinyl isocyanides.[9d] Based on this work, we (entry 6). EtOH could not improve the result
speculated that 1-CF3-isoquinoline derivatives could (entry 7). The bases, such as Na2CO3, NaHCO3, and
be accessed with the help of this strategy. When vinyl K2HPO4, were also tested, but none of them gave
isocyanide 1 is employed as a somophile to react with better results (entries 8–10). Other photocatalysts,
the CF3C radical, an imidoyl radical I can be generat- such as II, III and IV, also gave good yields of the iso-
ed. After intramolecular homolytic aromatic substitu- lated products, which showed that the photocatalyst
tion (HAS)[12] and an oxidation and deprotonation se- did not affect this transformation significantly (en-
quence, 1-CF3-isoquinoline derivatives
3 can be tries 11–13). Other CF3C radical precursors, such as
formed ultimately (Figure 1, C). This de novo strategy Togniꢀs reagent (2b) and CF3SO2Cl (2c), were also in-
to access 1-CF3-isoquinolines assisted by somophilic vestigated, but none of them gave better yields (en-
vinyl isocyanide insertion can address the regioselec- tries 14 and 15). Control experiments verified the ne-
tivity issue and can also be realized under mild condi- cessity of the base, irradiation and photocatalyst (en-
tions. Herein, we would like to report a visible light- tries 16–18). Without light and photocatalyst, no de-
promoted trifluoromethylation of vinyl isocyanides as sired product was isolated even if the reaction mix-
a modular approach to 1-trifluoromethylated isoqui- ture was heated up to 608C.
nolines.[13,14]
Having identified the optimal conditions, we pro-
Initially, we examined this hypothesis using methyl ceeded to explore the scope of this reaction (Table 2).
(Z)-2-isocyano-3-phenylbut-2-enoate (1a) and Ume- Firstly, aliphatic aryl ketone-derived vinyl isocyanides
motoꢀs reagent (2a)[15] as model substrates (Table 1). were examined. Generally, the reactions proceeded
When a solution of 1a and 2a in DMF was irradiated quite well and 1-CF3-isoquinolines 3a–h were generat-
by 13 W white LED in the presence of the photocata- ed in 28–89% yields. It was found that the electronic
lyst IrACHTUNGTRENNUNG(ppy)2ACHTUNGTRENNUNG(dtbbpy)PF6 (I) and Na2HPO4 for 3 h, the property of phenyl groups had a significant effect on
desired isoquinoline 3a was isolated in 62% yield this transformation. The isocyanide with an electron-
(entry 1). Several common polar solvents were rich phenyl group is more reactive than the one with
screened, such as DMSO, CH3CN, THF, but they an electron-deficient phenyl group (3b vs. 3c). The
could not give any improved results (entries 2–4). The low yield of the isocyanide with an electron-deficient
non-polar solvents, such as toluene, were not effective phenyl group was due to the decomposition of the
at all (entry 5). To our delight, an 88% yield was isocyanide. The reactions with diaryl ketone-derived
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Regiospecific Synthesis of 1-Trifluoromethylisoquinolines
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
Base
Yield [%][b]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
II
III
IV
I
I
I
DMF
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2CO3
NaHCO3
K2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
none
62
53
56
57
trace
88
84
78
80
68
73
83
84
49
62
47
trace
NR
DMSO
CH3CN
THF
toluene
MeOH
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
9
10
11
12
13
14[c]
15[d]
16
17
18[e]
none
I
Na2HPO4
Na2HPO4
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), base (0.3 mmol) and catalyst (0.002 mmol, 1.0 mol%) in the indicated
solvent (2.0 mL) were irradiated by 13 W white LED for 3 h at room temperature. DMF=N,N-dimethylformamide,
DMSO=dimethyl sulfoxide, THF=tetrahydrofuran.
[b]
[c]
[d]
[e]
Isolated yield.
2b instead of 2a.
2c instead of 2a.
No irradiation.
vinyl isocyanides worked also quite well. The corre- smoothly, the corresponding isoquinolines 3aa–ad
sponding isoquinolines 3i–q could be provided in sat- were generated in good yields (50–93%). The vinyl
isfactory yields (52–94%). Then aryl aldehyde-derived isocyanides without electron-withdrawing groups are
vinyl isocyanides were employed. Generally, the reac- quite unstable, and have thus not prepared successful-
tivity of this type of vinyl isocyanide was lower than ly by us at this stage.
that of the ketone-derived counterparts. The desired
In order to obtain further insights into the reaction
isoquinolines 3r–z could be obtained in acceptable mechanism, a series of TEMPO trapping experiments
yields (35–80%). Ethyl ester- or amide-based vinyl was employed. As shown in Scheme 1, when Umemo-
isocyanides also underwent this transformation toꢀs reagent 2a was treated with the radical scavenger
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Table 2. Substrate scope.[a,b]
<
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), NaHPO4 (0.3 mmol) and I (0.002 mmol,
1.0 mol%) in MeOH (2.0 mL) was irradiated by 13 W white LED for 1-4 h at room temperature.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
Regioisomer ratio: 3.5:1, determined by 19F NMR.
Regioisomer ratio: 1:1, determined by 19F NMR.
Regioisomer ratio: 7.6:1, determined by 19F NMR.
1
Regioisomer ratio: 1:1, determined by H NMR.
TEMPO in the dark, only a trace of trapping product
These experimental observations can be supported
4 was detected based on 19F NMR analysis. Instead, by theoretical calculations. Density functional theory
the adduct 4 was observed in comparable yields when [B3LYP/6-311+ +G (d,p)] calculation indicates that
À
the trapping reactions were carried out under visible the C S bond in 2a is rather weak with a low bond
light irradiation irrespective of whether the photoca- dissociation energy (BDE) (DG298 =82.1 kJmolÀ1)
talyst I was present. When isocyanide 1i was intro- [Eq. (1)], which is located in the infrared area. Visible
duced into the trapping experiments, no obvious light is strong enough to induce the homolytic cleav-
À
changes were observed. These observations strongly age of the C S bond in 2a.
suggests that generation of the CF3C radical from
Umemotoꢀs reagent can be achieved only under visi-
ble light irradiation and is independent of the photo-
catalyst and isocyanide.
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Scheme 1. TEMPO trapping experiments.
Figure 2. Proposed reaction mechanism.
Based on our experimental and theoretical observa-
Another two possible mechanism for generation of
tions, a possible catalytic cycle is proposed for this CF3C radical cannot be ruled out completely at this
transformation (Figure 2). Umemotoꢀs reagent 2a stage. One is enabled by electron donor–acceptor
[E1/2 (2a/2aCÀ)=À0.61 V vs. SCE)[16] is dissociated into (EDA) complexes between the Umemotoꢀs reagent
persistent CF3C radical and sulfur-centered radical 2a and isocyanides.[18] The other is reduction of 2a to
cation 6 assisted by visible light. The radical cation 6 generate CF3C radical directly by excited state
[E1/2 (6/5)=0.06 V vs. SCE] is reduced to sulfide 5 by Ir
excited state Ir(III)*[E1/2 (Ir(IV)/Ir
(III)*)=À0.75 V the latter one was also proposed (Figure 3). Umemo-
vs. SCE], which is generated from ground state Ir(III) toꢀs reagent 2a is reduced into persistent CF3C radical
under visible light. The CF3C radical is trapped by iso- and sulfide 5 by excited state Ir(III)*, which is gener-
cyanide 1a to give imidoyl radical 7, which undergoes ated from ground state Ir(III) under visible light.
(III)*.[14b,d,k,m,o] An alternative mechanism based on
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
intramolecular HAS with the generation of aryl radi- Then isoquinoline 3a is generated following a similar
cal 8. The aryl radical 8 [E1/2 (9/8)=À0.65 V vs. SCE] pathway as the aforementioned.
is then oxidized by Ir(IV) [E1/2 (Ir(IV)/Ir
G
In summary, we have described the regiospecific
1.14 V vs. SCE] to aryl cation 9 and regenerates synthesis of 1-CF3-isoquinoline derivatives. This strat-
Ir(III). Ultimately deprotonation assisted by a base egy is enabled by photoredox vinyl isocyanide inser-
ACHTUNGTRENNUNG
yields 1-CF3-isoquinoline 3a. The structure of 3a was tion with Umemotoꢀs reagent. The methodology pre-
established unambiguously by the single crystal X-ray sented here provides an access to highly-fuctionalized
diffraction analysis.[17]
1-CF3-isoquinolines regiospecifically at room temper-
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Figure 3. Alternative reaction mechanism.
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General Procedure
A 10-mL round-bottom flask was equipped with a rubber
septum and magnetic stir bar and was charged with vinyl
isocyanide 1 (0.2 mmol, 1.0 equiv.), Umemotoꢀs reagent 2a
(0.3 mmol, 1.5 equiv.), IrACHTNURGTENNUG(ppy)2ACHTUNTGRENN(GUN dtbbpy)PF6 (0.002 mmol,
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Financial support from 973 Program (2011CB935800,
2011CB808600), 863 program (2013AA092903), NSFC
(21121091, 21472084, 21372115, 21290190), and the Natural
Science Foundation of Jiangsu Province (BK2012012,
BK20131266) is acknowledged.
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