Ag(I)-catalyzed aminofluorination of alkynes: Efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[α]isoquinolines

Article abstract of DOI:10.1021/ol3026507

A silver-catalyzed intramolecular oxidative aminofluorination of alkynes has been developed by using NFSI as a fluorinating reagent. This reaction represents an efficient method for the synthesis of various 4- fluoroisoquinolines and 4-fluoropyrrolo[α]isoquinolines.

Full text of DOI:10.1021/ol3026507

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Ag(I)-Catalyzed Aminofluorination
of Alkynes: Efficient Synthesis
of 4‑Fluoroisoquinolines and
4‑Fluoropyrrolo[r]isoquinolines
Tao Xu and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Lingling Road, Shanghai, 200032, China
gliu@mail.sioc.ac.cn
Received September 8, 2012
ABSTRACT
A silver-catalyzed intramolecular oxidative aminofluorination of alkynes has been developed by using NFSI as a fluorinating reagent. This reaction
represents an efficient method for the synthesis of various 4-fluoroisoquinolines and 4-fluoropyrrolo[R]isoquinolines.
The introduction of fluorine into drugs often leads to a
significant improvement of their medicinal properties which
have resulted in a revolution of the pharmaceutical industry
in recent decades.1 So far, more than 20% of commercial
drugs contain fluorine. Heterocycles are often a key core of
bioactive molecules. Thus, exploration of a new synthetic
strategy for the synthesis of fluorinated heterocycles has
attracted attention.2
Isoquinolines and pyrrolo[R]isoquinolines represent
structure moieties which are extensively presented in bio-
logical natural products as well as drug molecules.3 For
example, berberine3d is an antitumor compound that
shows inhibition of HIV replication, and Lamellarin D3e,f
is an anticancer alkaloid for inhibition of human topo-
isomerase I (Figure 1). The oxidation product, such as
4-hydroxyisoquinoline, is the major metabolite of isoquinoline.
(1) (a) Filler, R.; Kobayashi, Y. In Biomedicinal Aspects of Fluorine
Chemistry; Elsevier: Amsterdam, 1982. (b) Welch, J. T.; Eswarakrishman,
S., Eds. In Fluorine in Bioorganic Chemistry; Wiley: New York, 1991.
(2) For some reviews on the synthesis of fluorinated heterocycles, see:
(a) Petrov, V. A. In Fluorinated Heterocyclic Compounds: Synthesis,
Chemistry,and Applications; John Wiley & Sons, Inc.: Hoboken, NJ, 2009.
(b) Nosova, E. V.; Lipunova, G. N.; Charushin, V. N.; Chupakhin, O. N.
J. Fluorine Chem. 2010, 131, 1267–1288. (c) Zhu, S.; Wang, Y.; Peng, W.;
Song, L.; Jin, G. Curr. Org. Chem. 2002, 6, 1057–1096. (d) Silvester, M. J.
Aldrichimica Acta 1991, 24, 31–38. For some selective examples, see:
(e) Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2011, 133, 1738–1741. (f) Kishi, Y.; Nagura, H.; Inagi,
S.; Fuchigami, T. Chem. Commun. 2008, 3876–3878. (g) Fustero, S.;
Catalan, S.; Sanchez-Rosello, M.; Simon-Fuentes, A.; del Pozo, C. Org.
Lett. 2010, 12, 3484–3487.
(3) (a) Bentley, K. W. In The Isoquinoline Alkaloids; Hardwood
Academic: Amsterdam, 1998. (b) Eicher, T.; Hauptmann, S. The Chemistry
of Heterocycles; Wiley-VCH: Weinheim, 2003. (c) Dzierszinski, F.; Coppin,
A.; Mortuaire, M.; Dewally, E.; Slomianny, C.; Ameisen, J.-C.; DeBels, F.;
Tomavo, S. Antimicrob. Agents Chemother. 2002, 46, 3197–3207.
(d) Kong, L.; Cheng, C.; Tan, R. Planta Med. 2001, 67, 74–76. (e) Davis,
R.; Carroll, A.; Pierens, G.; Quinn, R. J. Nat. Prod. 1999, 62, 419–424.
(f) Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi,
F.; Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796–3807.
Figure 1. Representive bioactive isoquinoline and pyrrolo[R]-
isoquinoline and related fluorinated compounds.
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10.1021/ol3026507
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Thus, smuggling fluorine into isoquinoline should be help-
ful to reduce the metabolism of isoquinolines and adjust its
biological activities.4 Recently, fluorinated isoquinolines
have been used as building blocks for the design of
pharmaceutical drugs. For instance, 4-fluoroisoquinolines
1ꢀ3 have been used as antiproliferative drugs, as myosin
inhibitors, and for reducing intraocular pressure.5 How-
ever, the synthesis of 4-fluoroisoquinolines is quite rare.
These compounds are prepared from electrophilic fluo-
rination by using nBuLi as a strong base to generate a
nucleophilic carbanion to attack the Fþ reagent. Such
conditions often result in poor functional group
compatibility.6 For more complex fluorinated heteroar-
enes, 4-fluoropyrrolo[R]isoquinolines, there is no report
for their preparation. As part of our ongoing research
program to develop a fluorine-oriented heterocycles syn-
thetic method,7 we herein report a novel method for the
construction of 4-fluoroisoquinolines and 4-fluoropyrrolo-
[R]isoquinolines with high efficiency. It is worth noting that
all the reactions exhibited excellent regioselectivity favoring
fluorine in the 4° carbon position.
Isoquinoline can be efficiently synthesized from transition-
metal-catalyzed hydroamination of alkyne, in which an
sp2 CꢀM bond is involved and prone to protonolysis.8
In addition, Larock,9a,b Li,9c and Wu9d reported that the
related sp2 CꢀM bond can be oxidized to form the
corresponding halogenated isoquinolines. We envisioned
that if the sp2 CꢀM bond can be directly fluorinated, a
concise pathway should be expected for the synthesis of a
fluoroisoquinoline (Scheme 1).
Scheme 1. Proposed Synhesis of Fluoroisoquinoline and
Fluoropyrrolo[R]isoquinoline
Recently, transition-metal-catalyzed carbonꢀfluorine
bond formation has emerged as a highly desirable but
challenging approach for the synthesis of organofluorines
with high efficiency.10 For instance, Ritter and co-workers
have reported a silver-catalyzed oxidative fluorination of
arylstannanes using SelectFluor as the fluorinating reagent
for arylfluoride synthesis under mild reaction conditions.11
We have discovered a silver-catalyzed oxidative fluoro-
amination of allenes to afford a variety of fluorinated
dihydropyrroles. Among those transformations, the oxi-
dative fluorination of the sp2 CꢀAg bond by the Fþ
reagent have been proposed to address the formation of
sp2 CꢀF bond.7d Inspired by this work, our initial inves-
tigation focused on the oxidative fluorination of 4a by
using a silver catalyst. We were delighted that the reaction
of 4a afforded the
(4) For the studies on the metabolism of isoquinolines, see: (a) Boyd,
D. R.; Sharma, N. D.; Dorrity, M. R. J.; Hand, M. V.; McMordie,
R. A. S.; Malone, J. F.; Porter, H. P.; Dalton, H.; Chima, J.; Sheldrake,
G. N. J. Chem. Soc., Perkin. Trans. 1 1993, 1065–1071. (b) LaVoie, E. J.;
Adams, E. A.; Shigematsu, A.; Hoffmann, D. Carcinogenesis 1983, 4,
1169–1173.
(5) For some recent patents involving fluorinated isoquinolines, see:
(a) Yamada, R.; Seto, M. U.S. Patent 201093789, 2010. (b) Zeng, Q.;
Yuan, C. C.; Yao, G.; Wang, X.; Tadesse, S.; Jean JR, D. J. S.; Reichelt, A.;
Liu, Q.; Hong, F.-T.; Han, N.; Fotsch, C.; Davis, C.; Bourbeau, M. P.; Ashton,
K. S.; Allen, J. G. WO 201083246, 2010. (c) Matsubara, K.; Iesato, A.;
Oomura, A.; Kawasaki, K.; Yamada, R.; Seto, M. U.S. Patent 200948223 A1,
2009.
(6) Only two examples of 4-fluoroisoquinolines were reported from
2-methylaniline by using BuLi; see: Si, C.; Myers, A. G. Angew. Chem.,
Int. Ed. 2011, 50, 10409–10413.
(7) (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.
(8) For some reviews, see: (a) Majumdar, K. C.; Debnath, P.; De, N.;
Roy, B. Curr. Org. Chem. 2011, 15, 1760–1801. (b) Montalban, A. G.
Heterocycl. Nat. Prod. Synth. 2011, 299–339. (c) Yamamoto, Y.;
Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075–5087.
(d) Fulop, F.; Bernath, G. Curr. Org. Chem. 1999, 3, 1–24. For selected
examples, see: (e) Zheng, D.; Chen, Z.; Wu, J.; Liu, J. Org. Biomol.
Chem. 2011, 9, 4763–4765. (f) Gao, H.; Zhang, J. Adv. Synth. Catal.
2009, 351, 85–88. (g) Asao, N.; Salprima, Y. S.; Nogami, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2005, 44, 5526–5528. (h) Huang, Q.; Larock,
R. C. J. Org. Chem. 2003, 68, 980–988.
desired fluorinated isoquinoline 5a in the presence of
fluorinating reagent NFSI. After screening silver catalysts,
solvents, bases, and fluorinating reagents (see the Support-
ing Information), optimum conditions were obtained for a
reaction with 20% AgNO3, 1.5 equiv of NFSI, and 1 equiv
of Li2CO3 in DMA (N,N-dimethylacetamide), and the
desired product 5a was produced in 88% 19F NMR yield
(eq 1). It is worth noting that the addition of Li2CO3 is
crucial to inhibit the formation of hydroamination product
5a0.12 In addition, the desired product 5a was not observed
in the absence of the silver catalyst.
(10) For some recent reviews on the transition-metal-catalyzed fluor-
iantion, 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.
(11) For silver-catalyzed fluorination involving oxidative fluorina-
tion of an aryl CꢀAg bond, see: Tang, P.; Furuya, T.; Ritter, T. J. Am.
Chem. Soc. 2010, 132, 12150–12152 and references therein.
(9) (a) Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68, 920–928.
(b) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437–3444. (c) Zhang, H.-P.; Yu, S.-C.; Liang, Y.; Peng, P.; Tang, B.-X.;
Li, J.-H. Synlett 2011, 2011, 982–988. (d) Yu, X.; Wu, J. J. Comb. Chem.
2009, 11, 895–899.
(12) The hydroamination product 5a0 is resulted from the protono-
lysis Aryl-Ag intermediate by the proton generated from the elimination
of the isobutyl group. The role of Li2CO3 is to neutralize the proton.
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Under our standard conditions, the substrate scope of the
amino-fluorination reaction was then examined (Table 1).
A variety of functional groups on the alkyne were compat-
ible with the reaction conditions. For instance, substrates
possessing alkyl, aryl, vinyl, and cyclopropyl groups exhib-
ited good reactivity to afford the corresponding fluorinated
isoquinolines 5aꢀ5f in good yields. Note that both imide
(4g) and ester (4hꢀ4i) groups, which are sensitive to BuLi,
were tolerated in the reaction. Substrates with different
functional groups in aryl ring were also tested. A series of
substituted groups, such as a halogen (4jꢀ4k) or ether (4l),
were productive in this transformation and gave desired
products in good yields. To our delight, the heterocycle
substrates 4mꢀ4n were also successfully processed to gen-
erate fluorinated heterocycles. But substrate 4o bearing a
tert-butyl group is unable to afford the cyclization product.
Furthermore, reaction of 4a still afforded the product 5a in
excellent yield (85%) when the reaction was enlarged to
1 mmol scale. Finally, the reaction was examined in a short
time, and a satisfactory yield (65% or 77%) was obtained in
the high catalyst loading (1.5 equiv of AgNO3 for 30 min
Scheme 2. Silver-Catalyzed Tandem Fluorination and [3 þ 2]
Dipolar Cycloaddition
Table 2. Silver-Catalyzed Tandem Aminofluorination of
Alkynes and [3 þ 2] Dipolar Cycloadditiona
Table 1. Silver-Catalyzed Aminofluorination of Alkynea,b
a Reaction conditions: substrate 4 (0.2 mmol), AgNO3 (20 mol %),
NFSI (1.5 equiv), Li2CO3 (1 equiv), DMA (3 mL), rt. b Isolated yield.
c NFSI (1.5 equiv) at 30 °C. d 1 mmol scale. e AgNO3 (1.5 equiv), 30 min.
f AgNO3 (20 mol %), NFSI (1.5 equiv), 10 min, 70 °C.
a All reactions were conducted on 0.2 mmol scale, and isolated yields
were given.
at rt) or high temperature (0.2 equiv of AgNO3 for 10 min
at 70 °C). This fast reaction provides the possibility to
synthesize F18 labeled fluoroisoquinolines for application
of PET imaging.13
Isoquinonlines have been extensively used to conduct
[2 þ 3] dipolar cycloadditions for the synthesis of
(13) (a) Littich, R.; Scott, P. J. H. Angew. Chem., Int. Ed. 2012, 51,
1106–1109. (b) Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.;
Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T.
Science 2011, 334, 639–642. (c) Teare, H.; Robins, E. G.; Kirjavainen,
A.; Forsback, S.; Sandford, G.; Solin, O.; Luthra, S. K.; Gouverneur, V.
Angew. Chem., Int. Ed. 2010, 49, 6821–6824.
(14) For reviews on the silver-catalyzed dipolar cycloaddition, see:
(a) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132–3148.
(b) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodirguez-Garcia, I.
Chem. Rev. 2008, 108, 3174–3198.
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In addition, we were delighted to learn that the electron-
deficient ethyl 4,4,4-trifluorobutynate (TFBY) exhibited
good reactivity to afford single product 9 with excellent
regioselectivity (Table 3). The structure of 9b was characterized
by X-ray. This methodology presents one of most efficient
ways to introduce both a fluorine and CF3 group simulta-
neously to heterocycle compounds.
Table 3. Silver-Catalyzed Tandem Reaction 6 with
Trifluoromethyl Butyroatea
Finally, further transformation of compound 8 was ex-
plored via a decarboxylation process. The fluorinated
pyrrolo[R]isoquinolines lacking carboxylates can be pre-
pared. For example, compound 8b was treated by trifluoro-
acetic acid (TFA) to remove the tert-butyl group and then
underwent decarboxylation to give diester 10 in quantitative
yield (eq 2). Meanwhile, 8a was hydrolyzed in aqueous
KOH to give a triacid intermediate, which participated in
sequential decarboxylation with TFA to afford 11 in 71%
yield. Alternatively, the decarboxylation could be accom-
plished with copper at high temperature to generate 12 in
43% yield (eq 3).
a All reactions were conductd on 0.2 mmol scale, and isolated yields
were given.
pyrrolo-[R]isoquinolines.14 Following this principle, we
wondered if the fluorinated pyrrolo[R]isoquinolines 8 could
be generated from fluorinated isoquinolines 5. Unfortunately,
the [2 þ 3] dipolar cycloaddition of 4-fluoroisoquinolines 5a
does not proceed to afford 8because the intermediate 7could
not be generated from 5 due to the weak nucleophilic
ability.15 We hypothesized that the intermediate 7 might be
generated in situ from alkynylenamine 6, followed by dipolar
cycloaddition to achieve a fluorinated pyrrolo[R]isoquinoline
synthesis (Scheme 2, top). We were delighted that the tandem
reaction of 6a with dimethyl acetylene dicarboxylate
(DMAD) could be catalyzed by AgNO3 with a bidental
nitrogen ligand to afford the desired product 8a in 60%
isolated yield (Scheme 2, bottom).16
As shown in Table 2, the reaction has a broad substrate
scope. It was the same with substrate 6a, the reaction of
tert-butyl ester 6b provided the desired product in good
yield (62%). The substrates bearing alkyl, aryl, and vinyl
groups on the alkyne afforded the corresponding cycload-
dition products 8aꢀ8f in moderate to good yields. Among
them, substrate 6f bearing a cyclohexene group gave the
bestyield. Incontrast, a substrate with a cyclopropylgroup
delivered a slightly lower yield (8g). Furthermore, several
functional groups in the aromatic ring, such as a halide
and methoxy, were compatible with the catalytic system to
generate desired products 8hꢀ8k in good yields. It is worth
noting that the bisheteroatom-containing fluorocycle 8l
can be efficiently synthesized.
In conclusion, we have developed a novel silver-catalyzed
intramolecular oxidative aminofluorination of alkynes. This
methodology efficiently provides 4-fluoroisoquinolines and
4-fluoropyrrolo[R]isoquinolines. It enriches the methods
available for the synthesis of these fluoroheterocycles and
potentially promotes their application in drug discovery.
Further efforts on the synthesis of more complex molecules
and exploration of their biological activities are in progress.
Acknowledgment. We are grateful for financial support
from the National Basic Research Program of China (973-
2011CB808700), the National Nature Science Foundation of
China (Nos. 20972175, 20923005, and 21121062), the Science
and Technology Commission of the Shanghai Municipality
(11JC1415000), and the Chinese Academy of Sciences.
Supporting Information Available. Detail experimental
procedures and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The weak nucleophilic ability of the nitrogen atom is the result of
the strong electronegativity of fluorine.
(16) For the screening results, see the Supporting Information.
The authors declare no competing financial interest.
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