A convenient procedure for the synthesis of fused fluoro isoquinolines

Article abstract of DOI:10.1016/j.tet.2005.10.025

A base-promoted conversion of ortho-trifluoromethyl benzyl derivatives of NH-heterocycles into a respective fluorinated isoquinolines (38-57% isolated yields) is reported. The reaction is general for the benzylated derivatives of the electron-rich NH-hete

Full text of DOI:10.1016/j.tet.2005.10.025

Tetrahedron 62 (2006) 543–548
A convenient procedure for the synthesis of fused
fluoro isoquinolines
*
Alexander S. Kiselyov
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Rd, Suite 5; San Diego, CA 92121, USA
Received 10 August 2005; revised 27 September 2005; accepted 12 October 2005
Available online 3 November 2005
Abstract—A base-promoted conversion of ortho-trifluoromethyl benzyl derivatives of NH-heterocycles into a respective fluorinated
isoquinolines (38–57% isolated yields) is reported. The reaction is general for the benzylated derivatives of the electron-rich NH-
heterocycles and the respective derivatives of pyrazole. The outcome of the reaction could be explained by an intermediate formation of a
highly reactive quinone methide species.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The anionically activated trifluoromethyl group has
attracted considerable interest due to its synthetic utility.
A wide variety of aromatic, heteroaromatic, and aliphatic
compounds could be accessed from the commercially
available substrates containing CF3 functionality that is
conjugated with the ionizable NH or CH group.1 These
include syntheses of 2-(substituted 1-alkenyl) anilines (i),2
2-substituted benzothiazoles and benzoxazoles (ii),3 4(5)-
dihydro-1H-imidazole (iii),4 triazines (iv),5 and isoxazoles,5
1,3-disubstituted naphthalenes (v),6 2,4-di- or 2,3,4-tri-
substituted quinolines (vi),7 7-(substituted amino)-5,6-
dihydrobenz[c]acridines (vii),8 aza-analogues of tacrine9
(viii), fluoronaphthalenes (ix),10 4-fluoroquinolines and
fluoroolefins (x),11 and 4-fluoroquinolones (xi).12 A solid
support synthesis of fluorinated aromatics using this
protocol has been reported.10 Representative examples of
the chemistry of anionically activated CF3 group are
summarized in Scheme 1. It has been suggested that all of
the above transformations proceed via the initial abstraction
of the acidic proton from the XH moiety, followed by
elimination of FK, to afford the quinone methide
intermediate QM (Scheme 1). The subsequent reaction of
this intermediate with various nucleophiles may lead to the
observed array of products.
In our attempt to further expand the synthetic potential of the
anionically activated CF3 group, we studied the reaction of
N-benzylated heterocycles 2a–j, easily available from the
respectiveNH-heterocycles and ortho-trifluoromethyl benzyl
chloride, with LDA (Scheme 2). Under the optimized
reaction conditions, the reaction afforded fused fluoro
isoquinolines in good isolated yields (38–57%). Notably,
this introduction offluorine substituent into isoquinoline ring
system from the respective CF3 derivatives is unprecedented.
We studied the effect of both (i) nature of base as well as (ii)
the ratio of substrate 2: base on the reaction outcome.
Freshly prepared LDA was found to be the optimal base for
the conversion. NaH and Li-piperidide afforded somewhat
lower yields (by ca. 10–20%), as found for the conversions
of 2a, 2d, and 2g to a respective derivatives 3 of the targeted
isoquinolines. Application of the Grignard reagents
(MeMgBr and EtMgBr) as bases resulted in a complex
reaction mixtures including extensive formation of high-
molecular weight products. The yields of 3 in these cases
did not exceed 15%. No reaction was observed with tBuOK
and EtONa in THF and EtOH, respectively. The optimal
ratio of 2: base (LDA) for the reaction was found to be 2.5.
Lower ratios (!2 equiv) resulted in incomplete conversions
of 2, namely unreacted starting material was isolated from
the reaction mixtures. Higher ratios did not affect the
reaction yields. Structures of 3 were further confirmed by
NOE experiments for the selected compounds.13
Keywords: Fluorine and compounds; Condensations; Quinone methide;
Isoquinolines; Anionically activated trifluoromethyl group.
The outcome of the reported reaction could be explained by
an initial abstraction of the acidic methylene proton from
*
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0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.025

544
A. S. Kiselyov / Tetrahedron 62 (2006) 543–548
N
Ph
N
N
N
N
N
N
O
H
N
Ph
NHCOR
NH2
NH2
COPh
NH2
(v)
(i)
(iv)
(iii)
(ii)
N
N
F
CF3
CF2
X
R
B:
(vi)
(xi)
XH - HF
N
H
O
X = NH, CHCN
QM
(x)
(vii)
(x)
F
(viii)
(ix)
N
HN
O
F
F
N
N
R
N
NHCOR
N
NH2
N
CN
Scheme 1.
R
X
N
H
CF3
F
LDA (2.5 eq), THF
-70oC - RT, 3 h
CF3
Cl
NaH, DMF, 2 h
N
N
38-57% yield
X R
85-90% yield
X
R
3a-i
2a-i
1
Heterocycle
Heterocycle
R
R
Yield of
2a-ia, %
Yield of
3a-ia, %
Yield of
2a-ia, %
Yield of
3a-ia, %
X
N
H
X
N
H
f
a
89
90
87
48
51
44
86
85
44
43
N
H
N
H
MeO
b
g
N
N
H
N
H
Cl
c
h
i
88
87
52
38
39
N
N
H
N
H
d
N
H
e
86
89
57
N
N
H
N
H
aYields refer to isolated analytically pure materials
Scheme 2.

A. S. Kiselyov / Tetrahedron 62 (2006) 543–548
545
F
F
F F
H
F
CF2
B:
2d
3d
N
N
- BH
- F
- HF
N
QM
F F
CF2
CF2
B:
- BH
3g
2g
N
N
N
N
- F
N
N
-
QM
QM
Scheme 3.
the CH2 group of the N-benzylated heterocycle (Scheme 3).
This intermediate undergoes conversion to quinone methide
QM by elimination of FK. The highly reactive species QM
are likely to cyclize to afford, after elimination of another
HF molecule and aromatization, the observed fluorinated
isoquinoline 3d. Alternatively, second equivalent of LDA
could further abstract acidic C5 proton from the intermedi-
ate QM, as shown for the pyrazole derivative, to yield
anionic species QMK. These undergo intramolecular
cyclization and elimination of FK to yield 3g.
(50–60% yields) presumably resulting from the SN2
reaction of the respective anion with 2j followed by the
elimination of benzimidazole moiety as shown at Scheme 4.
Varying amounts of 4 (5–15%) were detected in all reaction
mixtures.
Notably, reaction of 2g with potassium hexamethyl
disilazide (KHMDS) under the experimental conditions
described above yielded the nitrile 5g as a major product
(44% isolated yield), instead of the anticipated fluoro
isoquinoline 3g. Possible mechanism for this conversion is
summarized below (Scheme 5).
The postulated intermediacy of the quinone methide
intermediate QM is in agreement with the lack of formation
of the respective derivatives 3 in an attempted reaction of
ortho-trifluoromethyl benzylated derivatives of 2,5-
dimethylpyrrole and 5-methylpyrazole with LDA. The
targeted analogues of 3 were not detected in the crude
mixtures by 19F NMR. Instead, both reactions resulted in
complex mixtures of products, none of them major (LC MS
analysis). Furthermore, attempts to convert benzimidazole
derivative 2j into a respective fluoro isoquinoline were
unsuccessful under a variety of experimental conditions.
The main product isolated from the reaction mixture was 4
In summary, we discovered a base-promoted conversion of
ortho-trifluoromethyl benzyl derivatives of NH-hetero-
cycles into a respective fluorinated isoquinolines (38–57%
isolated yields). The reaction is general for the benzylated
derivatives of the electron-rich NH-heterocycles and the
respective derivatives of pyrazole. Similar reaction for the
benzimidazole derivative yields a product of dimerization,
instead of the expected fluoro isoquinoline. The outcome
of the reaction could be explained by an intermediate
formation of a highly reactive quinone methide species.
CF3
CF3
CF3
CF3
CF3
2j
Base
LDA
N
N
N
N
N
N
N
N
-
-
CF3
N
N
2j
4
Scheme 4.
Me3Si
SiMe3
N
N
CF3
N
CF2
N
CF2
KHMDS
KHMDS
2g
-F-
- Me3SiF
N
N
N
N
N
N
5g, 44% yield
Scheme 5.

546
A. S. Kiselyov / Tetrahedron 62 (2006) 543–548
3. Experimental
7.6 Hz, 1H), 7.26 (d, JZ6.4 Hz, 1H), 7.42 (d, JZ8.0 Hz,
1H), 7.63 (s, 1H); 13C NMR: 52.2, 102.3, 113.1, 117.4,
118.8, 120.9, 124.7, 125.9, 126.7, 127.2, 128.0, 129.2,
129.6, 131.7, 133.3, 134.5; ESI MS: (MC1) 311, (MK1)
309; HR ESI MS: Exact mass calcd for C16H11ClF3N
309.0532, found: 309.0526. Elemental analysis, calcd for
C16H11ClF3N: C, 62.05; H, 3.58; N, 4.52. Found: C, 61.88;
H, 3.44; N, 4.36.
All NMR spectra recorded on a Bruker 400 MHz instrument
in DMSO-d6, chemical shifts reported in ppm. MS analyses
(ESI mode) were performed on a Perkin Elmer API 165
instrument. Melting points were measured with a Bu¨chi 535
melting point apparatus. Elemental analyses were per-
formed by Atlantic Microlab Inc, Norcrosss, GA. HPLC
analyses were performed on a Beckman Gold Analytic 126
apparatus with a diode array detector model 168 at the
wavelengths of 220 and 254 nm. The column employed was
a YMC Pak ProC18 column, 50 mm!4.6 mm. The solvent
system was MeCN–H2O (start: 20/80; finish: 100:0; 3 min
runs; 0.1% TFA added), with a flow rate of 3 mL/min.
3.2.4. 1-(2-(Trifluoromethyl)benzyl)-1H-pyrrole (2d).
1
Yield 87%, oil; H NMR d: 4.99 (s, 2H), 5.98 (dd, J1Z
8.0 Hz, J2Z4.0 Hz, 2H), 6.64 (d, JZ4.0 Hz, 2H), 6.87 (d,
JZ8.0 Hz, 1H), 6.97 (m, 1H), 7.13 (m, 1H), 7.35 (d, JZ
8.0 Hz, 1H); 13C NMR: d 49.7, 106.8, 117.5, 123.0, 124.8,
125.7, 127.6, 130.1, 131.6, 133.2; ESI MS: (MC1) 226,
(MK1) 224; HR ESI MS: Exact mass calcd for C12H10F3N
225.0765, found: 225.0761. Elemental analysis, calcd for
C12H10F3N: C, 64.00; H, 4.48; N, 6.22. Found: C, 63.75; H,
4.31; N, 6.03.
3.1. A typical protocol for the synthesis of 2a–j
A suspension of 60% NaH (2.5 mmol) was washed with dry
hexanes and transferred via cannula to a vigorously stirred
dry DMF (5 mL) under Ar. A solution of NH-heterocycle
(2 mmol) in the same solvent was added at 0 8C (ice bath)
and the resulting mixture was stirred for additional 15 min.
A solution of ortho-trifluoromethyl benzyl chloride (2 mmol
in 5 mL of DMF) was added at 0 8C (ice bath), the mixture
was stirred for 2 h, diluted with aq NH4Cl (25 mL) and
extracted with EtOAc (2!15 mL). The organic phase was
washed with saturated NaHCO3, dried over anhydrous
Na2SO4 and concentrated in vacuo. The resulting solid
residue was purified by flash chromatography (silica, eluent
hexanes/EtOAc, 2:1) to yield the respective N-benzylated
heterocycles 2a–j in 85–90% isolated yields.
3.2.5.
1-(2-(Trifluoromethyl)benzyl)-2-methyl-1H-
pyrrole (2e). Yield 89%, oil; 2.05 (s, 3H), 5.02 (s, 2H),
5.72 (d, JZ6.8 Hz, 1H), 6.01 (dd, J1Z6.8 Hz, J2Z4.4 Hz,
1H), 6.28 (d, JZ4.4 Hz, 1H), 7.02 (d, JZ8.0 Hz, 1H), 7.05
(m, 1H), 7.19 (m, 1H), 7.39 (d, JZ8.0 Hz, 1H); 13C NMR:
d 10.8, 46.8, 105.9, 107.8, 117.4, 121.7, 124.7, 125.9, 128.1,
128.3, 129.0, 131.6, 133.5; ESI MS: (MC1) 240, (MK1)
238; HR ESI MS: Exact mass calcd for C13H12F3N
239.0922, found: 239.0917. Elemental analysis, calcd for
C13H12F3N: C, 65.27; H, 5.06; N, 5.85. Found: 65.04; H,
4.89; N, 5.62.
3.2. Analytical data for 2a–j
3.2.6. 1-(2-(Trifluoromethyl)benzyl)-2,4-dimethyl-1H-
pyrrole (2f). Yield 89%, oil; H NMR d: 1.99 (s, 3H),
1
3.2.1. 1-(2-(Trifluoromethyl)benzyl)-1H-indole (2a).
Yield 86%, oil; H NMR d: 5.05 (s, 2H), 6.55 (d, JZ
2.18 (s, 3H), 4.89 (s, 2H), 5.57 (s, 1H), 5.88 (s, 1H), 6.89 (d,
JZ7.6 Hz, 1H), 6.98 (m, 1H), 7.11 (m, 1H), 7.35 (d, JZ
8.0 Hz, 1H); 13C NMR: d 11.5, 19.6, 45.1, 108.7, 113.6,
117.3, 120.4, 124.5, 125.7, 128.2, 128.7, 129.3, 131.9,
133.0; ESI MS: (MC1) 254, (MK1) 252; HR ESI MS:
Exact mass calcd for C14H14F3N 253.1078, found:
253.1072.
1
7.6 Hz, 1H), 6.85 (d, JZ7.6 Hz, 1H), 6.98 (m, 1H), 7.05 (m,
1H), 7.09 (d, JZ8.4 Hz, 1H), 7.12 (m, 1H), 7.18 (m, 1H),
7.28 (d, JZ8.4 Hz, 1H), 7.36 (d, JZ8.0 Hz, 1H), 7.62 (d,
JZ7.6 Hz, 1H); 13C NMR: 51.9, 101.8, 111.3, 118.2, 119.1,
119.8, 122.3, 125.4, 125.7, 127.4, 128.3, 129.0, 129.3,
131.7, 133.5, 137.1; ESI MS: (MC1) 276, (MK1) 274; HR
ESI MS: Exact mass calcd for C16H12F3N 275.0922, found:
275.0917. Elemental analysis, calcd for C16H12F3N: C,
69.81; H, 4.39; N, 5.09. Found: C, 69.66; H, 4.47; N, 4.89.
3.2.7. 1-(2-(Trifluoromethyl)benzyl)-1H-pyrazole (2g).
1
Yield 90%, oil; H NMR d: 5.04 (s, 2H), 6.54 (dd, J1Z
8.0 Hz, 1H, J2Z6.8 Hz, 1H), 7.02 (d, JZ8.0 Hz, 1H), 7.05
(m, 1H), 7.19 (m, 1H), 7.31 (d, JZ6.8 Hz, 1H), 7.41 (d, JZ
8.0 Hz, 1H), 7.55 (d, JZ8.0 Hz, 1H); 13C NMR: d 51.6,
104.3, 117.5, 124.6, 125.8, 127.7, 129.1, 129.6, 132.1,
133.4, 140.2; ESI MS: (MC1) 227, (MK1) 225; HR ESI
MS: Exact mass calcd for C11H9F3N2 226.0718, found:
226.0712. Elemental analysis, calcd for C11H9F3N2: C,
58.41; H, 4.01; N, 12.38. Found: C, 58.26; H, 3.82; N, 12.12.
3.2.2. 1-(2-(Trifluoromethyl)benzyl)-5-methoxy-1H-
indole (3b). Yield 85%, oil; H NMR d: 3.66 (s, 3H), 5.01
1
(s, 2H), 6.38 (d, JZ7.2 Hz, 1H), 6.55 (d, JZ6.4 Hz, 1H),
6.91 (d, JZ7.2 Hz, 1H), 6.98 (d, JZ8.0 Hz, 1H), 7.03 (m,
1H), 7.08 (s, 1H), 7.11 (m, 1H), 7.26 (d, JZ6.4 Hz, 1H),
7.38 (d, JZ8.0 Hz, 1H); 13C NMR: 52.1, 56.2, 101.9, 102.4,
109.0, 113.2, 117.4, 125.4, 125.8, 127.6, 128.7, 129.1,
129.5, 129.7, 131.9, 133.2, 155.9; ESI MS: (MC1) 306,
(MK1) 304; HR ESI MS: Exact mass calcd for
C17H14F3NO 305.1027, found: 305.1023. Elemental
analysis, calcd for C17H14F3NO: C, 66.88; H, 4.62; N,
4.59. Found: C, 66.71; H, 4.45; N, 4.37.
3.2.8. 1-(2-(Trifluoromethyl)benzyl)-4-cyclopropyl-1H-
pyrazole (2h). Yield 87%, oil; H NMR d: 0.35–0.65 (m,
1
4H), 1.46 (m, 1H), 4.89 (s, 2H), 6.88 (d, JZ7.6 Hz, 1H),
6.96 (m, 1H), 7.09 (m, 1H), 7.21 (s, 1H), 7.26 (s, 1H), 7.37
(d, JZ8.0 Hz, 1H); 13C NMR: d 7.9, 8.3, 117.6, 124.8,
125.1, 125.7, 127.5, 129.6, 131.7, 132.8, 133.0, 133.7,
138.4; ESI MS: (MC1) 267, (MK1) 265; HR ESI MS:
Exact mass calcd for C14H13F3N2 266.1031, found:
266.1026. Elemental analysis, calcd for C14H13F3N2: C,
63.15; H, 4.92; N, 10.52. Found: C, 62.96; H, 4.75; N, 10.34.
3.2.3. 1-(2-(Trifluoromethyl)benzyl)-5-chloro-1H-indole
(2c). Yield 88%, oil; 1H NMR d: 5.08 (s, 2H), 6.45 (d, JZ
7.2 Hz, 1H), 6.88 (d, JZ7.2 Hz, 1H), 7.02 (d, JZ8.0 Hz,
1H), 7.09 (m, 1H), 7.15 (d, JZ7.6 Hz, 1H), 7.27 (d, JZ

A. S. Kiselyov / Tetrahedron 62 (2006) 543–548
547
3.2.9. 1-(2-(Trifluoromethyl)benzyl)-4-phenyl-1H-pyrazole
(2i). Yield 86%, mp 134–135 8C; 1H NMR d: 4.95 (s, 2H),
6.95 (d, JZ8.0 Hz, 1H), 7.02 (m, 1H), 7.12 (m, 1H), 7.19
(m, 1H), 7.25–7.33 (m, 3H), 7.51 (d, JZ8.0 Hz, 2H), 8.06
(s, 1H), 8.22 (s, 1H); 13C NMR: d 53.7, 117.6, 124.9, 125.6,
126.4, 127.4, 127.8, 128.1, 128.5, 129.2, 129.8, 131.6,
132.3, 133.4, 137.1; ESI MS: (MC1) 303, (MK1) 301; HR
ESI MS: Exact mass calcd for C17H13F3N2 302.1031, found:
302.1027. Elemental analysis, calcd for C17H13F3N2:
C, 67.54; H, 4.33; N, 9.27. Found: C, 67.36; H, 4.19;
N, 9.13.
264; HR ESI MS: Exact mass calcd for C17H12FNO
265.0903, found: 265.0896. Elemental analysis, calcd for
C17H12FNO: C, 76.97; H, 4.56; N, 5.28. Found: C, 76.82; H,
4.10; N, 5.12.
3.4.3. 2-Chloro-11-fluoroindolo[1,2-b]isoquinoline (3c).
Yield 52%, mp 236–238 8C; 1H NMR d: 6.25 (s, 1H), 6.98
(d, JZ7.6 Hz, 1H), 7.32 (d, JZ7.6 Hz, 1H), 7.44 (m, 1H),
7.51 (s, 1H), 7.55 (m, 1H), 7.66 (d, JZ8.4 Hz, 1H), 7.84 (d,
JZ8.4 Hz, 1H), 8.89 (s, 1H); 19F NMR: K112.9; 13C NMR:
99.3, 112.2, 114.0, 118.6, 119.5, 120.1, 120.9, 125.6, 126.0,
126.7, 127.4, 128.3, 130.7, 131.2, 148.2, 152.2; ESI MS:
(MC1) 271, (MK1) 269; HR ESI MS: Exact mass calcd for
C16H9ClFN 269.0408, found: 269.0402. Elemental analysis,
calcd for C16H9ClFN: C, 71.25; H, 3.36; N, 5.19. Found: C,
71.37; H, 3.52; N, 5.02.
3.2.10. 1-(2-(Trifluoromethyl)benzyl)-1H-benzo[d]-
imidazole (2j). Yield 87%, mp 122–123 8C; 1H NMR
d: 5.05 (s, 2H), 6.92 (d, JZ8.0 Hz, 1H), 7.04 (m, 1H), 7.14
(m, 1H), 7.22–7.25 (m, 2H), 7.41 (d, JZ8.0 Hz, 1H), 7.62
(d, JZ8.4 Hz, 1H), 7.76 (d, JZ8.4 Hz, 1H), 8.12 (s, 1H);
13C NMR d: 49.8, 114.6, 115.1, 117.4, 122.3, 122.8, 124.8,
125.7, 127.0, 129.1, 131.8, 133.4, 133.8, 138.5, 144.2; ESI
MS: (MC1) 277, (MK1) 275; HR ESI MS: Exact mass
calcd for C15H11F3N2 276.0874, found: 276.0868.
3.4.4. 10-Fluoropyrrolo[1,2-b]isoquinoline (3d). Yield
38%, mp 156–157 8C; 1H NMR d: 6.22 (d, JZ6.8 Hz,
1H), 6.61 (m, 1H), 7.10 (d, JZ7.0 Hz, 1H), 7.42 (m, 1H),
7.50 (m, 1H), 7.62 (d, JZ8.0 Hz, 1H), 7.77 (d, JZ8.0 Hz,
1H), 8.81 (s, 1H); 19F NMR: K111.5; 13C NMR: 105.2,
112.6, 114.3, 119.4, 126.1, 126.5, 127.8, 128.3, 130.5,
131.1, 147.6, 150.9; ESI MS: (MC1) 186, (MK1) 184; HR
ESI MS: Exact mass calcd for C12H8FN 185.0641, found:
185.0633. Elemental analysis, calcd for C12H8FN: C, 77.82;
H, 4.35; N, 7.56. Found: C, 77.95; H, 4.51; N, 7.41.
3.3. A typical protocol for the synthesis of 3a–i
A solution of the respective N-benzylated heterocycle 2a–j
(1 mmol) in 5 mL of dry THF was added to a vigorously
stirred solution of freshly prepared LDA (2.5 mmol,
diisopropyl amine and n-BuLi (2.5 M solution in hexanes))
in the same solvent (20 mL) at K70 8C (dry ice bath) under
Ar. The resulting pale yellow mixture was slowly brought to
rt (2 h) and stirred for additional 1 h. At this time, the TLC
of the reaction mixtures (hexanes/ether, 4:1) indicated
presence of highly fluorescent non-polar product and the
complete consumption of the starting material. The reaction
mixture was quenched with NH4Cl (15 mL) and extracted
with 2!20 mL of Et2O. The organic layer was washed with
saturated NaHCO3 (20 mL), dried over anhydrous Na2SO4,
concentrated and purified by flash chromatography (Silica,
hexanes/ether, 5:1) to yield analytically pure fused fluoro
isoquinolines 3a–i.
3.4.5. 10-Fluoro-3-methylpyrrolo[1,2-b]isoquinoline
(3e). Yield 39%, mp 137–138 8C; 1H NMR d: 2.16 (s,
3H), 6.08 (d, JZ6.4 Hz, 1H), 6.42 (d, JZ6.4 Hz, 1H), 7.50
(m, 1H), 7.53 (m, 1H), 7.75 (d, JZ8.4 Hz, 1H), 7.89 (d, JZ
8.4 Hz, 1H), 8.83 (s, 1H); 19F NMR: K112.1; 13C NMR:
17.0, 106.1, 114.6, 120.1, 125.4, 126.1, 126.7, 128.2, 128.9,
130.5, 131.7, 149.1, 152.0; ESI MS: (MC1) 200, (MK1)
198; HR ESI MS: Exact mass calcd for C13H10FN 199.0797,
found: 199.0788. Elemental analysis, calcd for C13H10FN:
C, 78.37; H, 5.06; N, 7.03. Found: C, 78.48; H, 5.24; N,
6.81.
3.4. Analytical data for 3a–i
3.4.6. 10-Fluoro-1,3-dimethylpyrrolo[1,2-b]isoquinoline
(3f). Yield 48%, mp 151–152 8C; 1H NMR d: 1.99 (s, 3H),
2.21 (s, 3H), 6.05 (s, 1H), 7.39 (m, 1H), 7.46 (m, 1H), 7.65
(d, JZ8.0 Hz, 1H), 7.73 (d, JZ8.0 Hz, 1H), 8.82 (s, 1H);
19F NMR: K112.1; 13C NMR: 15.9, 16.4, 108.8, 117.9,
119.3, 125.6, 125.9, 126.5, 127.6, 128.0, 130.3, 131.1,
147.6, 151.2; ESI MS: (MC1) 214, (MK1) 212; HR ESI
MS: Exact mass calcd for C14H12FN 213.0954, found:
213.0942. Elemental analysis, calcd for C14H12FN: C,
78.85; H, 5.67; N, 6.57. Found: C, 78.66; H, 5.81; N, 6.33.
3.4.1. 11-Fluoroindolo[1,2-b]isoquinoline (3a). Yield
44%, mp 184–185 8C; H NMR d: 6.33 (s, 1H), 7.02 (m,
1
1H), 7.09 (m, 1H), 7.35 (d, JZ8.4 Hz, 1H), 7.51 (m, 1H),
7.55 (d, JZ8.0 Hz, 1H), 7.61 (m, 1H), 7.74 (d, JZ7.6 Hz,
1H), 7.88 (d, JZ8.0 Hz, 1H), 9.01 (s, 1H); 19F NMR:
K112.7; 13C NMR: 99.8, 112.2, 113.5, 118.8, 119.6, 120.0,
120.5, 122.4, 125.9, 126.7, 128.1, 128.9, 130.8, 131.1,
149.0, 151.6; ESI MS: (MC1) 236, (MK1) 234; HR ESI
MS: Exact mass calcd for C16H10FN 235.0797, found:
235.0788. Elemental analysis, calcd for C16H10FN: C,
81.69; H, 4.28; N, 5.95. Found: C, 81.55; H, 4.19; N, 5.84.
3.4.7. 4-Fluoro-pyrazolo[1,5-b]isoquinoline (3g). Yield
51%, mp 165–166 8C; 1H NMR d: 6.32 (d, JZ8.8 Hz, 1H),
7.47 (m, 1H), 7.61 (m, 1H), 7.73 (d, JZ8.4 Hz, 1H), 7.82 (d,
JZ8.8 Hz, 1H), 7.90 (d, JZ8.4 Hz, 1H), 8.99 (s, 1H); 19F
NMR: K113.7; 13C NMR: 97.5, 119.5, 125.8, 126.7, 128.3,
129.1, 130.4, 131.9, 135.0, 149.3, 152.2; ESI MS: (MC1)
187, (MK1) 185; HR ESI MS: Exact mass calcd for
C11H7FN2 186.0593, found: 186.0584. Elemental analysis,
calcd for C11H7FN2: C, 70.96; H, 3.79; N, 15.05. Found: C,
70.73; H, 3.86; N, 14.87.
3.4.2. 11-Fluoro-2-methoxyindolo[1,2-b]isoquinoline
(3b). Yield 43%, mp 214–216 8C; 1H NMR d: 3.65 (s,
3H), 6.23 (s, 1H), 6.49 (d, JZ7.6 Hz, 1H), 6.95 (s, 1H), 7.33
(d, JZ7.6 Hz, 1H), 7.44 (m, 1H), 7.54 (m, 1H), 7.69 (d, JZ
8.4 Hz, 1H), 7.83 (d, JZ8.4 Hz, 1H), 8.85 (s, 1H); 19F
NMR: K112.2; 13C NMR: 56.1, 99.1, 101.8, 110.2, 111.5,
113.2, 119.0, 119.9, 126.1, 126.4, 128.2, 128.5, 130.4,
131.3, 148.2, 150.8, 155.37; ESI MS (MC1) 266, (MK1)

548
A. S. Kiselyov / Tetrahedron 62 (2006) 543–548
3.4.8. 3-Cyclopropyl-4-fluoro-pyrazolo[1,5-b]isoquino-
line (3h). Yield 44%, mp 203–205 8C; 1H NMR d:
0.4–0.65 (m, 4H), 1.45 (m, 1H), 7.51 (m, 1H), 7.58 (m,
1H), 7.66 (s, 1H), 7.72 (d, JZ8.4 Hz, 1H), 7.88 (d, JZ
8.4 Hz, 1H), 8.90 (s, 1H); 19F NMR: K113.2; 13C NMR:
6.3, 8.9, 114.9, 119.7, 125.9, 126.7, 128.3, 127.5, 130.8,
131.1, 132.5, 148.0, 152.0; ESI MS: (MC1) 227, (MK1)
225; HR ESI MS: Exact mass calcd for C14H11FN2
226.0906, found: 226.0894. Elemental analysis, calcd for
C14H11FN2: C, 74.32; H, 4.90; N, 12.38. Found: C, 74.21;
H, 4.78; N, 12.22.
References and notes
1. (a) Kiselyov, A. S.; Strekowski, L. Org. Prep. Proced. Int.
1996, 28, 289–318 and references cited therein. (b)
Strekowski, L.; Kiselyov, A. S. Trends Heterocycl. Chem.
1993, 73–82.
2. Hojjat, M.; Kiselyov, A. S.; Strekowski, L. Synth. Commun.
1994, 24, 267–272.
3. Kiselyov, A. S.; Hojjat, M.; Van Aken, K.; Strekowski, L.
Heterocycles 1994, 37, 775–782.
4. Wydra, R. L.; Patterson, S. E.; Strekowski, L. J. Heterocycl.
Chem. 1990, 27, 803–805.
5. Strekowski, L.; Lin, S.-Y.; Nguyen, J.; Redmore, N. P.;
Mason, J. C.; Kiselyov, A. S. Heterocycl. Commun. 1995, 1,
331–334.
3.4.9. 4-Fluoro-3-phenyl-pyrazolo[1,5-b]isoquinoline
(3i). Yield 57%, mp 236–238 8C; H NMR d: 7.18 (m,
1
1H), 7.28 (m, 2H), 7.50–7.55 (m, 3H), 7.58 (m, 1H), 7.69 (d,
JZ8.4 Hz, 1H), 7.88 (d, JZ8.4 Hz, 1H), 8.70 (s, 1H), 8.94
(s, 1H); 19F NMR: K113.8; 13C NMR: 119.2, 125.0, 125.9,
126.7, 127.4, 128.2, 128.4, 128.7, 129.2, 130.6, 130.9,
131.3, 136.2, 147.8, 152.3; ESI MS: (MC1) 263, (MK1)
261; HR ESI MS: Exact mass calcd for C17H11FN2
262.0906, found: 262.0888. Elemental analysis, calcd for
C17H11FN2: C, 77.85; H, 4.23; N, 10.68. Found: C, 77.64;
H, 4.12; N, 10.52.
6. Strekowski, L.; Wydra, R. L.; Kiselyov, A. S.; Baird, J. H.;
Burritt, A.; Coxon, J. M. Synth. Commun. 1994, 24, 257–266.
7. (a) Strekowski, L.; Patterson, S. E.; Janda, L.; Wydra, R. L.;
Harden, D. B.; Lipowska, M.; Cegla, M. T. J. Org. Chem.
1992, 57, 196–201. (b) Strekowski, L.; Wydra, R. L.; Cegla,
M. T.; Czarny, A.; Harden, D. B.; Patterson, S. E.; Battiste, M. A.;
Coxon, J. M. J. Org. Chem. 1990, 55, 4777–4779. (c) Janda, L.;
Nguyen, J.; Patterson, S. E.; Strekowski, L. J. Heterocycl.
Chem. 1992, 29, 1753–1756.
8. Strekowski, L.; Wydra, R.; Harden, D. B.; Honkan, V. A.
Heterocycles 1990, 31, 1565–1569.
3.4.10. Synthesis of 2-((1H-pyrazol-1-yl)methyl)benzo-
nitrile (5g). A solution of KHMDS in toluene (2.5 mmol)
was added to a vigorously stirred solution of 2g (1 mmol) in
dry degassed THF at K78 8C (acetone/dry ice bath). The
resulting pale yellow mixture was stirred at this temperature
for an additional 30 min, slowly brought up to 0 8C (2 h) and
stirred at 0 8C for an additional 1 h, until LC MS of the
reaction mixture revealed the absence of a starting material.
The resulting dark red homogenous solution was concen-
trated in vacuo at rt, and the residue was partitioned between
EtOAc (20 mL) and 10% aq NH4Cl. Aqueous phase was
extracted with an addl 10 mL of EtOAc, the organic phases
were combined, dried over Na2SO4, concentrated and
purified by flash-chromatography (hexanes/Et2O, 1:1) over
Silica to yield analytically pure 5g in 44% yield, mp
131–132 8C; 1H NMR d: 5.02 (s, 2H), 6.38 (dd, J1Z7.6 Hz,
J2Z6.4 Hz, 1H), 7.21–7.24 (m, 2H), 7.32 (d, JZ7.6 Hz,
1H), 7.40 (d, JZ8.0 Hz, 1H), 7.45 (m, 1H), 7.56 (d, JZ
6.4 Hz, 1H); ESI MS: (MC1) 184, (MK1) 182; HR ESI MS:
Exact mass calcd for C11H9N3 183.0796, found: 183.0791.
9. Smith, L.; Kiselyov, A. S. Tetrahedron Lett. 1999, 40,
5643–5646.
10. (a) Kiselyov, A. S. Tetrahedron 2001, 57, 5321–5326. (b)
Kiselyov, A. S. Tetrahedron Lett. 2001, 42, 3053–3056. (c)
Kiselyov, A. S.; Strekowski, L. Tetrahedron Lett. 1994, 35,
7597–7600.
11. Strekowski, L.; Kiselyov, A. S.; Hojjat, M. J. Org. Chem.
1994, 59, 5886–5890.
12. Kiselyov, A. S.; Piatnitski, E. L.; Doody, J. Org. Lett. 2004, 6,
4061–4063.
13. Regiochemistry of substitution was further confirmed by NOE
experiments:
F
F
N
N
2.16
9.01
8.83
CH3
H
H
H 7.35
.