substitute.6 4,4-Difluorotetrahydroisoquinoline derivatives
showed excellent inhibitory activity against TRPM8
(transient receptor potential melastatin 8)7 and voltage-
gated sodium ion channel8 (Figure 1).
program on transition-metal-catalyzed fluorination reac-
tions,12 we recently reported a silver-catalyzed aminofluor-
ination of alkynes to achieve fluorinated isoquinolines
(Scheme 1).13 Further mechanistic studies suggested that
fluorinated intermediate isoquinolinium Int-2, derived
from oxidative fluorination of the sp2 CꢀAg bond of Int-
1 by Fþ, is stable at 0 °C. But this intermediate gradually
decomposed to isoquinoline by releasing isobutene at room
temperature. Inspired by this understanding, we envisioned
that further transformation of active isoquinolinium Int-2
would lead to diverse fluorinated isoquinoline derivatives.
Herein, we report a tandem processes for the efficient
synthesis of 1-(trifluoromethyl)-4-fluoro-1,2-dihydroiso-
quionline and 4,4-difluoro-1,2,3, 4-tetrahydroisoquionline
in one pot.
Because of the special function of the CF3 moiety in
medicinal chemistry, CF3ꢀ was employed as a nucleophile
to test our above hypothesis by combining Ruppert’s
reagent (TMSCF3) and fluoride salts.14,15 To our disap-
pointment, as shown in the Supporting Information, the
sequential process of aminofluorination of 1a and trifluoro-
methylation could not deliver the desired product 2a under
the previous reaction conditions at room temperature.
Instead, 4-fluoroisoquinoine was isolated as a major pro-
duct, which suggests the decomposition of Int-2 is prior to
nucleophilic attack by CF3ꢀ. Considering the thermo-
stability of Int-2 at low temperature, the sequential process
was conducted at 0 °C. We were delighted to find that the
desired product 2a was obtained albeit in low yield (15%) in
the presence of 20 mol % of Ag catalyst. Further optimiza-
tion of reaction conditions revealed that the yield could
be improved by increasing the amount of silver catalyst.
In addition, reduced the amount of NFSI was also bene-
ficial to improve the yield of 2a but resulted in a significant
amount of protonolysis byproduct 2a0 (eq 1).16 Mechanistic
studies revealed that the unsuccessful catalytic amino-
fluorination was resulted from the generation of inactive
AgN(SO2Ph)2 catalyst at 0 °C.17 With this process, a variety
Figure 1. Some prevalent bioactive fluorinated isoquinoline
derivatives.
However, accessto4-fluoroisoquinoline derivatives gen-
n
erally requires a strong base, such as BuLi, to generate
a nucleophilic carbanion to attack the Fþ reagent which
suffers from a poor functional group compatibility.9 Tra-
ditional synthesis of gem-difluorinated (CF2) heterocycles
usually adopt nucleophilic fluorination of carbonyl group
with diethylaminosulfur trifluoride (DAST),10 or double
electrophilic fluorination of carbonyl compounds with
Fþ reagent.7 Similarly, these reactions exhibited limited
substrate scopes. In addition, simultaneously introducing
fluorine and fluorine-containing group into one molecular
is even more challenging.
Scheme 1. Silver-Catalyzed Aminofluorination of Alkynes and
Related Transformations
(10) Jiao, R.; Goble, S. D.; Mills, S. G.; Morriello, G.; Pasternak, A.;
Yang, L.; Zhou, C.; Butora, G.; Kothandaraman, S.; Guiadeen, D.;
Moyes, C. WO 03093231 (A2), 2003.
(11) For some recent reviewers on the transition-metal-catalyzed
fluorination, see: (a) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160–
171. (b) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470–477.
(c) Vigalok, A. Organometallics 2011, 30, 4802–4810. (d) Hollingworth,
C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929–2942. (e) Liu, G.
Org. Biomol. Chem. 2012, 10, 6243–6248.
(12) (a) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354–
16355. (b) Peng, H.; Liu, G. Org. Lett. 2011, 13, 772–775. (c) Xu, T.; Qiu,
S.; Liu, G. Chin. J. Chem. 2011, 29, 2785–2790. (d) Xu, T.; Mu, X.; Peng,
H.; Liu, G. Angew. Chem., Int. Ed. 2011, 50, 8176–8179. (e) Mu, X.; Liu,
G. Chem.;Eur. J. 2011, 17, 6039–6042. (f) Mu, X.; Wu, T.; Wang,
H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878–881.
(13) Xu, T.; Liu, G. Org. Lett. 2012, 14, 5416–5419.
(14) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757–
786. (b) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123–
131. (c) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146. (d) Ma,
J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1–PR43.
(15) (a) Loska, R.; Majcher, M.; Makosza, M. J. Org. Chem. 2007,
72, 5574–5580. (b) Chu, L.; Qing, F.-L. Chem. Commun. 2010, 46, 6285–
6287.
Transition-metal-mediated or -catalyzed fluorinations
have been proven to be efficient strategies to introduce
fluorine into organic compounds.11 As part of our ongoing
(8) Layton, M. E.; Pero, J. E.; Fiji, H.; Kelly, M. J.; Deleon, P.; Rossi,
M. A.; Gilbert, K. F.; Roecker, A. J.; Zhao, Z.; Mercer, S. P.;
Wolkenberg, S.; Mulhearn, J.; Zhao, L.; Li, D. WO 2013063459 (A1), 2013.
(9) Si, C.; Myers, A. G. Angew. Chem., Int. Ed. 2011, 50, 10409–
10413.
(16) For details, see the Supporting Information.
(17) AgN(SO2Ph)2, independently synthesized, was proven to be an
inactive catalyst for aminofluorination of alkyne at 0 °C but active at
room temperature or higher temperature.
Org. Lett., Vol. 15, No. 24, 2013
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