Synthesis of benzylisoquinoline derivatives possessing electron-withdrawing substituents on the benzene ring of the isoquinoline skeleton

Article abstract of DOI:10.3987/com-07-s(w)54

3,4-Dihydrobenzylisoquinolines and 1,2,3,4-tetrahydrobenzyl-isoquinolines possessing electron withdrawing substituents on the benzene ring of the isoquinoline framework are easily accessible by a synthetic approach that takes advantage of a Sonogashira coupling to build up the C1-C8a bond of the isoquinoline skeleton and a Ti-catalyzed intramolecular hydroamination of an alkyne to close the heterocyclic ring.

Full text of DOI:10.3987/com-07-s(w)54

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HETEROCYCLES, Vol. 74, 2007, pp. 683 - 700. © The Japan Institute of Heterocyclic Chemistry
Received, 30th August, 2007, Accepted, 5th October, 2007, Published online, 12th October, 2007. COM-07-S(W)54
SYNTHESIS OF BENZYLISOQUINOLINE DERIVATIVES POSSESSING
ELECTRON-WITHDRAWING SUBSTITUENTS ON THE BENZENE
RING OF THE ISOQUINOLINE SKELETON
René Severin, Didin Mujahidin, Jessica Reimer, and Sven Doye*
Institute of Pure and Applied Chemistry, University of Oldenburg,
Carl-von-Ossietzky-Str. 9-11, D-26111 Oldenburg, Germany
E-mail: doye@uni-oldenburg.de
Dedicated to Professor Ekkehard Winterfeldt on the occasion of his 75th birthday.
Abstract
–
3,4-Dihydrobenzylisoquinolines and 1,2,3,4-tetrahydrobenzyl-
isoquinolines possessing electron withdrawing substituents on the benzene ring of
the isoquinoline framework are easily accessible by a synthetic approach that
takes advantage of a Sonogashira coupling to build up the C1-C8a bond of the
isoquinoline skeleton and a Ti-catalyzed intramolecular hydroamination of an
alkyne to close the heterocyclic ring.
INTRODUCTION
Benzylisoquinoline alkaloids and related synthetic derivatives represent a class of compounds with a wide
range of interesting pharmaceutical properties, including analgesic, sedative, narcotic, anesthetic,
antitussive, spasmolytic, and sympathomimetic activity.1,2 Consequently, the isolation, the therapeutic use,
and the synthesis of corresponding molecules have attracted much attention during the past 200 years.3
The most important synthetic approaches towards benzylisoquinoline derivatives are based on the
Pictet-Spengler, Bischler-Napieralski, or Pommeranz-Fritsch synthesis.4 Since all these methods rely on a
typical electrophilic aromatic substitution reaction for the formation of the C1-C8a (or the C4-C4a) bond
of the benzylisoquinoline skeleton (Scheme 1), best results are obtained with substrates possessing an
electron-rich benzene ring. In this case, benzylisoquinoline derivatives possessing an electron-rich
aromatic A-ring are formed. Not surprisingly, benzylisoquinolines with an electron-poor A-ring which
may show improved pharmaceutical properties are rare in the literature.5 However,
3,4-dihydrobenzylisoquinoline building blocks can also be obtained by Ti-catalyzed intramolecular
hydroamination reactions of suitable aminoalkynes (Scheme 1).6-8 The major advantage of this synthetic
approach is the fact that in this case, the C1-C8a bond can easily be formed by a Sonogashira coupling9

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684
between a suitable, ortho-functionalized aryl halide and a terminal alkyne. Correspondingly, the typical
electrophilic aromatic substitution reaction which is usually employed for the formation of the C1-C8a
bond can be avoided. Since the Pd-catalyzed Sonogashira coupling is facilitated by electron-withdrawing
substituents (R1) located at the benzene ring of the aryl halide, the Sonogashira coupling/hydroamination
approach is somehow complementary to the common electrophilic substitution approach and should be
particularly useful for the synthesis of benzylisoquinoline derivatives possessing an electron-poor
benzene ring as part of the isoquinoline unit. To demonstrate this possibility, we planned to convert a
number of (2-bromophenyl)acetonitriles bearing electron-withdrawing substituents R1 into corresponding
3,4-dihydrobenzylisoquinoline building blocks. From these reactive intermediates, biologically
interesting norlaudanosine or papaverine analogues should be easily accessible by either reduction10 or
dehydrogenation.11 In addition, an alternative oxidation of the benzylic position of the side chain would
give access to 1-benzoyl-3,4-dihydroquinolines, a class of new antitumor agents.12
R1
R1
Pictet-Spengler Synthesis
A
B
NH
R2
NH
R2
8a
Electrophilic Aromatic
Substitution
8a
1
1
R1
R1
Bischler-Napieralski Synthesis
1
N
HN
Electrophilic Aromatic
Substitution
R2
8a
8a
8a
1
1
O
R2
R1
R1
NH2
Hydroamination
1
N
8a
R2
R2
1) Sonogashira Coupling
2) Reduction
R1
CN
1
+
R2
8a
X
Scheme 1. Retrosynthesis of the benzylisoquinoline skeleton
RESULTS AND DISCUSSION
The synthesis of the trifluoromethyl- or fluoro-substituted (2-bromophenyl)acetonitriles 5, 12 and 13 was
accomplished as depicted in Scheme 2. Regioselective iodination of commercially available
4-bromotrifluorotoluene 1 under oxidative conditions13 gave 1-bromo-2-iodo-4-trifluoromethylbenzene
(2) in 96% yield. Subsequently, a selective I/Mg exchange reaction of 2 using Knochel´s mixed Mg/Li

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685
reagent i-PrMgCl·LiCl14 and trapping of the formed arylmagnesium compound with monomeric
formaldehyde15 gave the benzylic alcohol 3 in 62% yield. The final introduction of the missing cyano
group was then achieved in two steps using standard procedures. Initial reaction of 3 with PBr3 gave the
corresponding dibromide 4 in 79% and a subsequent nucleophilic substitution performed with sodium
cyanide in DMSO gave access to the desired (2-bromophenyl)acetonitrile 5 in 61% yield.
.
I2, NaIO4
H2SO4, AcOH, Ac2O
25 °C, 21 h
1) i-PrMgCl LiCl
THF, -20 °C, 2 h
F3C
F3C
I
F3C
2) CH2O, -20 °C, 1 h
OH
96 %
62 %
Br
Br
Br
1
2
3
PBr3, CH2Cl2
25 °C, 24 h
79 %
NaCN
DMSO, 90 °C
F3C
F3C
CN
Br
Br
61 %
Br
5
4
.
NaBH4, BF3 Et2O
PBr3, CH2Cl2
25 °C, 24 h
R1
R2
COOH
Br
R1
R2
R1
R2
diglyme, 25 °C, 4 h
OH
Br
Br
Br
6: R1 = F, R2 = H
7: R1 = R2 = F
8: R1 = F, R2 = H
9: R1 = R2 = F
73 %
77 %
10: R1 = F, R2 = H 87 %
11: R1 = R2 = F
94 %
NaCN
DMSO, 90 °C
R1
12: R1 = F, R2 = H 60 %
13: R1 = R2 = F
58 %
CN
R2
Br
Scheme 2. Synthesis of (2-bromophenyl)acetonitriles 5, 12 and 13
The fluoro- and difluoro-substituted (2-bromophenyl)acetonitriles 12 and 13 were easily accessible in
three steps from commercially available carboxylic acids 6 and 7. Simple reductions to the benzylic
alcohols 8 and 9 using NaBH4 in the presence of BF3·Et2O16 took place in 73% and 77% yield,
respectively. The same transformation could also be achieved with LiAlH4 but in this case, the yields
were below 60%. As described above, the desired acetonitriles 12 and 13 were obtained from the alcohols
8 and 9 using standard procedures in two steps via the dibromides 10 and 11.
With (2-bromophenyl)acetonitriles 5, 12 and 13 in hand, attention was now directed towards the synthesis
of aminoalkynes 18-20, as shown in Scheme 3. The substrates 5, 12 and 13 were reacted with alkyne 147

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under Sonogashira coupling conditions. Using 4 mol% Pd(PPh3)2Cl2, 8 mol% PPh3, and 8 mol% CuI as
the catalyst system, a mixture of i-Pr2NH and DMF was found to be the best solvent for the cross
coupling reactions. Under optimized conditions, the alkynes 15, 16, and 17 were obtained in 96%, 87%,
and 79% yield, respectively. In this context, it is particular important to mention that the best yield for
this formation of the C1-C8a bond was observed with substrate 5 which has the strongest
electron-acceptor (the CF3-group) bound to the benzene ring. This fact strongly supports the idea that our
synthetic approach is particularly suitable for the synthesis of electron-acceptor substituted
benzylisoquinoline derivatives. Subsequent reductions of the cyano groups present in the alkynes 15-17
with LiAlH4 in the presence of AlCl3 gave accesss to the desired aminoalkynes 18-20 in excellent yields
(90-93%).
R1
4 mol % Pd(PPh3)2Cl2
CN
8 mol % PPh3, 8 mol% CuI
i-Pr2NH, DMF, 80 °C, 16 h
R1
R2
R2
CN
+
OMe
Br
OMe
OMe
5: R1 = CF3, R2 = H
12: R1 = F, R2 = H
13: R1 = R2 = F
14
OMe
15: R1 = CF3, R2 = H 96 %
16: R1 = F, R2 = H
87 %
17: R1 = R2 = F
79 %
R1
R2
NH2
LiAlH4, AlCl3
Et2O, 25 °C, 2 h
18: R1 = CF3, R2 = H 93 %
19: R1 = F, R2 = H
90 %
20: R1 = R2 = F
91 %
OMe
OMe
Scheme 3. Synthesis of aminoalkynes 18-20
The aminoalkynes 18-20 were then subjected to intramolecular hydroamination reactions at 105 °C in
toluene in the presence of 5 mol% Ind2TiMe2 (Ind = indenyl).17 After a reaction time of 16 h (not
minimized), the initially formed 3,4-dihydrobenzylisoquinolines (Scheme 4) were directly reduced by the
addition of NaBH3CN, ZnCl2, and methanol to the crude reaction mixtures. After stirring at room
temperature for 24 h, the racemic norlaudanosine analogues rac-21-23 were finally isolated by
chromatography in pure form. The efficiency of the two-step process is clearly underlined by the
excellent yields (≥ 94%) obtained for all products. For future applications, it is also important to keep in
mind that corresponding reductions can be performed enantioselectively with high ee values following
Noyori´s protocol.7,18 Furthermore, the norlaudanosine derivatives are suitable starting materials for

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687
further transformations to more complex 1,2,3,4-tetrahydrobenzylisoquinolines, e.g. of the berberine- or
the laudanosine type.1-3,7 To verify this idea, rac-21-23 were simply converted into the laudanosine
analogues rac-24-26 by reductive amination (CH2O, NaBH4) in 68%, 81%, and 84% yield, respectively.
R1
R1
R2
NH2
5 mol % Ind2TiMe2
toluene, 105 °C, 16 h
N
R2
OMe
OMe
OMe
OMe
18: R1 = CF3, R2 = H
19: R1 = F, R2 = H
20: R1 = R2 = F
10 mol % Pd/C
tetraline, 190 °C
1-6 h
NaBH3CN, ZnCl2
MeOH, 25 °C, 24 h
R1
R2
R1
R2
R1
R2
CH2O, NaBH4
MeOH, H2O
25 °C, 16 h
N
NH
N
Me
OMe
OMe
OMe
OMe
OMe
OMe
rac-24: R1 = CF3, R2 = H 68 %
rac-21: R1 = CF3, R2 = H 96 %
27: R1 = CF3, R2 = H
28: R1 = F, R2 = H
29: R1 = R2 = F
rac-25: R1 = F, R2 = H
rac-26: R1 = R2 = F
81 %
84 %
rac-22: R1 = F, R2 = H
rac-23: R1 = R2 = F
94 %
96 %
Scheme 4. Synthesis of laudanosine and norlaudanosine analogues from aminoalkynes
Alternatively, it was tried to combine the initial hydroamination reaction with a subsequent
dehydrogenation11 to obtain isoquinolines of the papaverine type (27-29). For that purpose, tetraline was
added together with a dehydrogenation catalyst (10 mol% Pd/C) to the crude reaction mixtures obtained
from the hydroamination reactions. Unfortunately, heating of these mixtures to 190 °C for 1-6 hours
always resulted in the formation of several products as determined by GC. As a consequence, the
papaverines 27-29 could not be isolated in pure form yet. Interestingly, GC-MS analysis suggested that
under the reaction conditions the desired aromatization is accompanied by a loss of one or more F-atoms
probably caused by Pd-catalyzed C-F activation. However, alternative protocols for the dehydrogenation
of the 3,4-dihydroisoquinolines are presently under investigation in our laboratories.

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In summary, we have presented
a
highly flexible method for the synthesis of
1,2,3,4-tetrahydroisoquinolines possessing electron-withdrawing substituents on the benzene ring of the
isoquinoline skeleton. The key-steps of the synthesis are a Sonogashira coupling of a
(2-bromophenyl)acetonitrile and a terminal alkyne as well as an intramolecular hydroamination reaction
that forms a 3,4-dihydroisoquinoline system. This key-intermediate can directly be reduced to
biologically interesting 1,2,3,4-tetrahydroisoquinolines. An alternative dehydrogenation of the
3,4-dihydroisoquinolines that would result in the formation of electron-acceptor substituted papaverine
analogues has failed so far. For future studies, it is also planned to oxidize the benzylic position of the
side chain of the electron-acceptor substituted 3,4-dihydroisoquinolines to get access to corresponding
α-ketoimines, a class of new antitumor agents.12 Further synthetic studies employing other aryl bromides
and other terminal alkynes for the Sonogashira coupling are presently underway in our laboratories. This
will lead to the formation of a library of electron-acceptor substituted benzylisoquinoline derivatives for
pharmaceutical studies.
EXPERIMENTAL
All reactions were performed under an inert atmosphere of argon in oven dried Duran glassware. Toluene
was distilled from molten sodium under argon or purchased (toluene extra dry with molecular sieves)
from Acros Organics. CH2Cl2 and triethylamine were distilled from calcium hydride. All other reagents
were purchased from commercial sources and were used without further purification. Unless otherwise
noted, yields refer to isolated yields of pure compounds as gauged by thin layer chromatography (TLC),
13
1
13
1H and C NMR. All products were characterized by H NMR, C NMR, infrared (IR) spectroscopy,
and mass spectrometry (MS). Additional characterization data were obtained by CHN elemental analysis
and/or high-resolution mass spectrometry (HRMS). NMR spectra were recorded on the following
spectrometers: Bruker Avance DPX 300, Bruker Avance DRX 500. All 1H NMR spectra are reported in δ
units ppm downfield from tetramethylsilane internal standard. All 13C NMR spectra are reported in δ
units ppm relative to the central line of the triplet for CDCl3 at 77.0 ppm. Infrared spectra were recorded
on a Bruker Vector 22 or a Bruker Tensor 27 spectrometer using an attenuated total reflection (ATR)
method. Mass spectra were recorded on a JEOL JMS-700, a Finnigan TSQ 700 or a Finnigan MAT 95
spectrometer (EI) with an ionization potential of 70 eV or a Waters Micromass Q-Tof Premier
spectrometer (ESI, 8 eV). Elemental analyses were carried out on an Elementar Vario EL or a Fisons
Instruments 1108 machine. Melting points are uncorrected. PE: light petroleum ether, b.p. 40-60 °C.
MTBE: methyl tert-butyl ether.
Preparation of a solution of monomeric formaldehyde in THF: A mixture of dry paraformaldehyde

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(3.00 g, dried for two days in a dry oven under vacuum at 80 °C), THF (100 mL) and a few drops of
BF3·Et2O was refluxed at 70 °C for 2 h. Then, the mixture was slowly distilled and collected in a
two-necked flask cooled to −70 °C. The concentration of the solution is approximately 0.8 mol/L.
1-Bromo-2-iodo-4-trifluoromethylbenzene (2): Concentrated H2SO4 (75.0 mL) was added dropwise to
a solution of NaIO4 (12.83 g, 60.0 mmol) and I2 (15.23 g, 60.0 mmol) in a 2:1 mixture of AcOH and
Ac2O (75 mL) at 5-10 °C. Then, 4-bromotrifluorotoluene 1 (11.25 g, 50.0 mmol) was added dropwise at
the same temperature. After this had been stirred at 25 °C for 21 h, the mixture was poured into ice-water
containing Na2SO3. After extraction with CH2Cl2 (3 × 50 mL), the combined organic layers were dried
with MgSO4 and concentrated under vacuum. Purification of the residue by flash chromatography (SiO2,
PE) gave aryl halide 2 (16.92 g, 48.2 mmol, 96%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.45
(br d, J = 8.2 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 8.09 (br s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
101.4 (C), 122.6 (CF3, q, J = 273 Hz), 126.1 (CH, q, J = 4 Hz), 130.6 (C, q, J = 34 Hz), 133.0 (CH),
134.1 (C), 137.0 (CH, q, J = 4 Hz) ppm. IR (neat): υ̃ = 1591, 1459, 1377, 1317, 1257, 1173, 1132, 1102,
1074, 1012, 893, 825, 800, 705 cm-1. MS (EI): m/z (%) = 352 (100) [M+ (81Br)], 350 (99) [M+ (79Br)], 333
(6), 331 (5), 225 (19), 223 (19), 144 (29). Anal. Calcd for C7H3BrF3I: C, 23.96; H, 0.86. Found: C, 23.81;
H, 0.90.
(2-Bromo-5-trifluoromethylphenyl)methanol (3): At −20 °C, a solution of i-PrMgCl·LiCl in THF (12.5
mL, c = 2.0 mol/L, 25.0 mmol) was slowly added to a solution of 2 (8.75 g, 25.0 mmol) in THF (12.5
mL). After the mixture had been stirred at −20 °C for 2 h, a solution of monomeric formaldehyde in THF
(35.0 mL, c ≈ 0.8 mol/L, 28.0 mmol) was added. Then, the mixture was stirred for additional 1 h and
water (50 mL) was subsequently added. After extraction with Et2O (5 × 30 mL), the combined organic
layers were dried with MgSO4 and concentrated under vacuum. Purification of the residue by flash
chromatography (SiO2, PE/EtOAc, 9:1) gave alcohol 3 (3.95 g, 15.5 mmol, 62%) as a colorless solid, mp
66-67 °C. 1H NMR (300 MHz, CDCl3): δ = 2.37 (br s, 1 H), 4.78 (s, 2 H), 7.40 (dd, J = 1.9, 8.3 Hz, 1 H),
7.65 (d, J = 8.3 Hz, 1 H), 7.79 (d, J = 1.3 Hz, 1 H). 13C NMR (75 MHz, DEPT, CDCl3): δ = 64.3 (CH2),
123.8 (CF3, q, J = 272 Hz), 125.1 (CH, q, J = 4 Hz), 125.5 (CH, q, J = 4 Hz), 125.7 (C), 130.1 (C, q, J =
33 Hz), 132.9 (CH), 140.8 (C) ppm. IR (KBr): υ̃ = 3300, 2913, 1605, 1583, 1474, 1413, 1372, 1330, 1257,
1184, 1120, 1083, 1057, 1023, 897, 834, 829, 745, 716 cm-1. MS (EI): m/z (%) = 256 (36) [M+ (81Br)],
254 (34) [M+ (79Br)], 237 (15), 235 (13), 175 (100), 145 (41), 127 (52), 113 (7). HRMS: calcd.
(C8H6O79BrF3) 253.9554; found 253.9559. Anal. Calcd for C8H6OBrF3: C, 37.68; H, 2.37. Found: C,
37.49; H, 2.41.

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1-Bromo-2-bromomethyl-4-trifluoromethylbenzene (4): PBr3 (677 mg, 2.50 mmol) was added
dropwise to a solution of alcohol 3 (1.27 g, 5.00 mmol) in CH2Cl2 (25 mL). After the solution had been
stirred at 25 °C for 24 h, saturated aqueous Na2CO3 solution (50 mL) was added. The mixture was
extracted with CH2Cl2 (5 × 30 mL). The combined organic layers were dried with MgSO4 and
concentrated under vacuum. After purification by flash chromatography (SiO2, PE), dibromide 4 (1.25 g,
3.93 mmol, 79%) was isolated as a colorless oil. 1H NMR (300 MHz, CDCl3): δ = 4.61 (s, 2 H), 7.42 (dd,
J = 1.0, 8.4 Hz, 1 H), 7.70-7.74 (m, 2 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 32.0 (CH2), 123.4
(CF3, q, J = 272 Hz), 126.6 (CH, q, J = 4 Hz), 127.9 (CH, q, J = 4 Hz), 128.3 (C), 130.5 (C, q, J = 33 Hz),
134.0 (CH), 138.1 (C) ppm. IR (neat): υ̃ = 2934, 1780, 1605, 1580, 1479, 1440, 1409, 1333, 1276, 1220,
1198, 1173, 1131, 1081, 1032, 949, 908, 829, 748, 728 cm-1. MS (EI): m/z (%) = 320 (8) [M+ (81Br/81Br)],
318 (16) [M+ (81Br/79Br)], 316 (10) [M+ (79Br/79Br)], 285 (17), 239 (100), 237 (100), 158 (42), 151 (12),
79
113 (8). HRMS: calcd. (C8H5 Br2F3) 315.8710; found 315.8703. Anal. Calcd for C8H5Br2F3: C, 30.22; H,
1.59. Found: C, 30.68; H, 1.76.
(2-Bromo-5-trifluoromethylphenyl)acetonitrile (5): A solution of NaCN (490 mg, 10.0 mmol) in
DMSO (2.5 mL) was heated to 90 °C. The oil bath was removed and dibromide 4 (1.59 g, 5.00 mmol)
was slowly added. After the mixture had been allowed to reach 50 °C, water (25 mL) was added. The
mixture was extracted with CH2Cl2 (5 × 40 mL) and the combined organic layers were dried with MgSO4.
After concentration under vacuum and purification by flash chromatography (SiO2, PE/EtOAc, 95:5),
nitrile 5 (810 mg, 3.07 mmol, 61%) was isolated as a colorless solid, mp 61-62 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.90 (s, 2 H), 7.50 (dd, J = 1.5, 8.3 Hz, 1 H), 7.76 (d, J = 8.7 Hz, 1 H), 7.78 (s, 1 H) ppm. 13C
NMR (75 MHz, DEPT, CDCl3): δ = 25.0 (CH2), 116.0 (C), 123.3 (CF3, q, J = 273 Hz), 126.5 (CH, q, J =
4 Hz), 126.7 (CH, q, J = 4 Hz), 127.6 (C), 130.8 (C, q, J = 33 Hz), 131.2 (C), 133.8 (CH) ppm. IR (KBr):
υ̃ = 3080, 2914, 2252, 1607, 1476, 1425, 1403, 1331, 1322, 1286, 1263, 1187, 1167, 1129, 1085, 1032,
937, 877, 839, 747, 715 cm-1. MS (EI): m/z (%) = 265 (75) [M+ (81Br)], 263 (78) [M+ (79Br)], 246 (9), 244
(11), 184 (100), 183 (21), 157 (13), 134 (11), 114 (6). HRMS: calcd. (C9H5N79BrF3) 262.9557; found
262.9533. Anal. Calcd for C9H5NBrF3: C, 40.94; H, 1.91; N, 5.30. Found: C, 40.71; H, 1.96; N, 5.20.
(2-Bromo-5-fluorophenyl)methanol (8): 2-Bromo-5-fluorobenzoic acid 6 (7.00 g, 32.0 mmol) was
added in portions to a stirred suspension of NaBH4 (1.09 g, 28.8 mmol) in dry diglyme (40 mL). Then, a
solution of freshly distilled BF3·Et2O (4.80 mL, 38.4 mmol) in diglyme (10 mL) was added over a period
of 1 h. After this had been stirred at rt for 4 h (TLC control) the reaction mixture was poured on ice. The
precipitate was suction filtered and dried under vacuum to give alcohol 8 (4.80 g, 23.3 mmol, 73%) as a
colorless solid, mp 92 °C. 1H NMR (500 MHz, CDCl3): δ = 2.02 (t, J = 5.5 Hz, 1 H), 4.65 (d, J = 4.8 Hz,

HETEROCYCLES, Vol. 74, 2007
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2 H), 6.81 (dt, J = 3.1, 8.4 Hz, 1 H), 7.19 (dd, J = 3.3, 8.8 Hz, 1 H), 7.41 (dd, J = 5.3, 8.8 Hz, 1 H) ppm.
13C NMR (126 MHz, DEPT, CDCl3): δ = 64.5 (CH2), 115.6 (CH, d, J = 24 Hz), 115.7 (C), 115.8 (CH, d,
J = 23 Hz), 133.6 (CH, d, J = 8 Hz), 142.0 (C, d, J = 7 Hz), 162.3 (CF, d, J = 247 Hz) ppm. IR (neat): υ̃ =
3272, 3180, 2357, 2338, 1580, 1464, 1439, 1410, 1361, 1266, 1219, 1149, 1106, 1065, 1025, 984, 950,
874, 809 cm-1. MS (EI): m/z (%) = 206 (44) [M+ (81Br)], 204 (47) [M+ (79Br)], 175 (15), 125 (100), 123
(18), 97 (89), 96 (64), 95 (55), 94 (26), 77 (74), 75 (56). HRMS: calcd. (C7H6BrFO) 203.9586; found
203.9586. Anal. Calcd for C7H6BrFO: C, 41.01; H, 2.95; Br, 38.97. Found: C, 41.15; H, 3.10; Br, 38.99.
(2-Bromo-4,5-difluorophenyl)methanol (9): 2-Bromo-4,5-difluorobenzoic acid 7 (2.00 g, 8.4 mmol)
was added in portions to a stirred suspension of NaBH4 (287 mg, 7.6 mmol) in dry diglyme (6.0 ml).
Then, a solution of freshly distilled BF3·Et2O (1.30 mL, 10.1 mmol) in dry diglyme (3.8 mL) was added
over a period of 0.5 h. After this had been stirred at room temperature for 4 h the mixture was poured on
ice. The precipitate was suction filtered and dried under vacuum to give alcohol 9 (1.50 g, 6.5 mmol,
77%) as a colorless solid, mp 70-71 °C. 1H NMR (300 MHz, CDCl3): δ = 2.08 (t, J = 5.8 Hz, 1 H), 4.68
(d, J = 5.3 Hz, 2 H), 7.34-7.42 (m, 2 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 63.9 (CH2), 114.9
(C, dd, J = 4, 8 Hz), 117.0 (CH, d, J = 19 Hz), 121.3 (CH, d, J = 20 Hz), 136.8 (C, dd, J = 4, 5 Hz), 149.3
(CF, dd, J = 13, 251 Hz), 149.8 (CF, dd, J = 12, 249 Hz) ppm. IR (neat): υ̃ = 3303, 3061, 2917, 1614,
1600, 1494, 1474, 1443, 1399, 1362, 1293, 1219, 1185, 1138, 1066, 981, 881, 809 cm-1. MS (EI): m/z (%)
= 224 (72) [M+ (81Br)], 222 (72) [M+ (79Br)], 207 (11), 203 (10), 193 (12), 162 (10), 143 (100), 141 (22),
126 (14), 125 (14), 115 (69), 114 (72), 113 (37), 112 (20), 95 (27), 63 (18). HRMS: calcd. (C7H5O79BrF2)
221.9492; found 221.9491. Anal. Calcd for C7H5OBrF2: C, 37.70; H, 2.26. Found: C, 37.75; H, 2.39.
1-Bromo-2-bromomethyl-4-fluorobenzene (10): PBr3 (1.90 g, 7.05 mmol) was added dropwise to a
solution of alcohol 8 (2.89 g, 14.1 mmol) in CH2Cl2 (55 mL). After the mixture had been stirred at 25 °C
for 24 h, saturated aqueous Na2CO3 solution (50 mL) was added. The mixture was extracted with CH2Cl2
(5 × 30 mL). The combined organic layers were dried with MgSO4 and concentrated under vacuum. After
purification by flash chromatography (SiO2, PE), dibromide 10 (3.29 g, 12.2 mmol, 87%) was isolated as
a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 4.53 (s, 1 H), 6.90 (dt, J = 3.0, 8.3 Hz, 1 H), 7.18 (dd, J
13
= 3.0, 9.0 Hz, 1 H), 7.51 (dd, J = 5.3, 8.8 Hz, 1 H) ppm. C NMR (126 MHz, DEPT, CDCl3): δ = 32.4
(CH2), 117.3 (CH, d, J = 22 Hz), 118.1 (CH, d, J = 24 Hz), 118.4 (C, d, J = 3 Hz), 134.5 (CH, d, J = 8
Hz), 138.8 (C, d, J = 8 Hz), 161.8 (CF, d, J = 248 Hz) ppm. IR (neat): υ̃ = 3072, 2976, 1603, 1580, 1473,
1439, 1408, 1271, 1237, 1214, 1157, 1126, 1100, 1032, 960, 871, 813, 739, 713 cm-1. MS (EI): m/z (%) =
270 (6) [M+ (81Br/81Br)], 268 (14) [M+ (81Br/79Br)], 266 (7) [M+ (79Br/79Br)], 189 (83), 188 (13), 187
79
(100), 108 (25), 107 (24), 81 (13). HRMS: calcd. (C7H5 Br2F) 265.8742; found 265.8742.

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1-Bromo-2-bromomethyl-4,5-difluorobenzene (11): PBr3 (1.49 g, 5.50 mmol) was added dropwise to a
solution of alcohol 9 (2.45 g, 11.0 mmol) in CH2Cl2 (55 mL). After the mixture had been stirred at 25 °C
for 24 h, saturated aqueous Na2CO3 solution (50 mL) was added. The mixture was extracted with CH2Cl2
(5 × 30 mL). The combined organic layers were dried with MgSO4 and concentrated under vacuum. After
purification by flash chromatography (SiO2, PE), dibromide 11 was isolated as a colorless oil (2.96 g,
1
10.3 mmol, 94%). H NMR (300 MHz, CDCl3): δ = 4.51 (s, 2 H), 7.32 (dd, J = 7.9, 10.4 Hz, 1 H), 7.42
(dd, J = 7.4, 9.6 Hz, 1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 31.7 (CH2), 117.9 (C, dd, J = 4, 8
Hz), 119.5 (CH, d, J = 18 Hz), 122.2 (CH, d, J = 20 Hz), 133.9 (C, dd, J = 4, 5 Hz), 149.6 (CF, dd, J = 13,
250 Hz), 150.0 (CF, dd, J = 14, 255 Hz) ppm. IR (neat): υ̃ = 3051, 2977, 2590, 1736, 1602, 1499, 1441,
1395, 1306, 1289, 1218, 1193, 1152, 1115, 994, 883, 815, 737, 703 cm-1. MS (EI): m/z (%) = 288 (7) [M+
(81Br/81Br)], 286 (11) [M+ (81Br/79Br)], 284 (6) [M+ (79Br/79Br)], 207 (97), 205 (100), 126 (33), 125 (19),
79
113 (8). HRMS: calcd. (C7H4 Br2F2) 283.8648; found 283.8633. Anal. Calcd for C7H4Br2F2: C, 29.41; H,
1.41. Found: C, 29.31; H, 1.46.
(2-Bromo-5-fluorophenyl)acetonitrile (12): A solution of NaCN (1.76 g, 36.0 mmol) in DMSO (10 mL)
was heated to 90 °C. The oil bath was removed and dibromide 10 (4.82 g, 18.0 mmol) was slowly added.
After the mixture had been allowed to reach 50 °C, water (100 mL) was added. The mixture was
extracted with CH2Cl2 (5 × 200 mL) and the combined organic layers were dried with MgSO4. After
concentration under vacuum and purification by flash chromatography (SiO2, PE/EtOAc, 9:1), nitrile 12
(2.30 g, 10.75 mmol, 60%) was isolated as a colorless solid, mp 57-58 °C. 1H NMR (300 MHz, CDCl3): δ
= 3.83 (s, 2 H), 6.97 (dt, J = 2.9, 8.4 Hz, 1 H), 7.30 (dd, J = 3.0, 8.7 Hz, 1 H), 7.57 (dd, J = 5.4, 8.7 Hz, 1 H)
ppm. 13C NMR (126 MHz, DEPT, CDCl3): δ = 24.9 (CH2), 116.3 (C), 117.0 (CH, d, J = 24 Hz), 117.1 (CH,
d, J = 22 Hz), 117.6 (C, d, J = 3 Hz), 131.9 (C, d, J = 7 Hz), 134.3 (CH, J = 8 Hz), 162.0 (CF, d, J = 249 Hz)
ppm. IR (neat): υ̃ = 3096, 3075, 2939, 2916, 2264, 2247, 1898, 1727, 1608, 1576, 1465, 1416, 1398, 1321,
1266, 1212, 1151, 1102, 1030, 965, 934, 926, 851, 815, 741 cm-1. MS (EI): m/z (%) = 215 (71) [M+
(81Br)], 213 (76) [M+ (79Br)], 135 (17), 134 (100), 133 (45), 132 (22), 108 (17), 107 (69), 106 (17), 94 (5).
HRMS: calcd. (C8H5N79BrF) 212.9589; found 212.9590. Anal. Calcd for C8H5NBrF: C, 44.89; H, 2.35; N,
6.54; Br, 37.33. Found: C, 44.99; H, 2.48; N, 6.42; Br, 37.08.
(2-Bromo-4,5-difluorophenyl)acetonitrile (13): A solution of NaCN (980 mg, 20.0 mmol) in DMSO
(5.0 mL) was heated to 90 °C. The oil bath was removed and dibromide 11 (2.86 g, 10.0 mmol) was
slowly added. After the mixture had been allowed to reach 50 °C, water (25 mL) was added. The mixture
was extracted with CH2Cl2 (5 × 40 mL) and the combined organic layers were dried with MgSO4. After
concentration under vacuum and purification by flash chromatography (SiO2, PE/EtOAc, 9:1), nitrile 13

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(1.34 g, 5.78 mmol, 58%) was isolated as a colorless solid, mp 53-54 °C. 1H NMR (300 MHz, CDCl3): δ
= 3.79 (s, 2 H), 7.41 (dd, J = 7.7, 10.1 Hz, 1 H), 7.47 (dd, J = 7.3, 9.4 Hz, 1 H) ppm. 13C NMR (75 MHz,
DEPT, CDCl3): δ = 24.3 (CH2), 116.1 (C), 117.1 (C, dd, J = 4, 7 Hz), 118.5 (CH, d, J = 20 Hz), 122.2
(CH, d, J = 20 Hz), 126.8 (C, dd, J = 4, 6 Hz), 149.8 (CF, dd, J = 11, 252 Hz), 149.9 (CF, dd, J = 12, 255
Hz) ppm. IR (KBr): υ̃ = 3055, 2972, 2939, 2257, 1719, 1602, 1586, 1502, 1412, 1399, 1286, 1206, 1177,
1149, 993, 915, 887, 859, 805, 756 cm-1. MS (EI): m/z (%) = 233 (96) [M+ (81Br)], 231 (97) [M+ (79Br)],
152 (100), 125 (47), 113 (7). HRMS: calcd. (C8H4N79BrF2) 230.9495; found 230.9488. Anal. Calcd for
C8H4NBrF2: C, 41.41; H, 1.74; N, 6.04. Found: C, 42.14; H, 1.97; N, 5.87.
[2-(3,4-Dimethoxyphenylethynyl)-5-trifluoromethylphenyl]acetonitrile (15): Pd(PPh3)2Cl2 (85 mg,
0.12 mmol, 4 mol%), CuI (46 mg, 0.24 mmol, 8 mol%), PPh3 (63 mg, 0.24 mmol, 8 mol%) and a 3:1
mixture of i-Pr2NH/DMF (12.0 mL) were placed in a round-bottomed flask. After the addition of aryl
bromide 5 (789 mg, 3.00 mmol), the mixture was stirred at 25 °C for 1 h and alkyne 14 (486 mg, 3.00
mmol) was then added. After the mixture had been stirred at 80 °C for additional 16 h, saturated aqueous
NH4Cl solution was added. The mixture was extracted with MTBE (3 × 50 mL). The combined organic
layers were dried with MgSO4 and concentrated under vacuum. After purification by flash
chromatography (SiO2, PE/EtOAc, 9:1), alkyne 15 (994 mg, 2.88 mmol, 96%) was isolated as a colorless
1
solid, mp 79-80 °C. H NMR (300 MHz, CDCl3): δ = 3.92 (s, 6 H), 4.01 (s, 2 H), 6.87 (d, J = 8.3 Hz, 1
H), 7.06 (d, J = 1.9 Hz, 1 H), 7.20 (dd, J = 1.9, 8.3 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.67 (d, J = 8.1 Hz,
13
1 H), 7.74 (s, 1 H) ppm. C NMR (75 MHz, DEPT, CDCl3): δ = 22.9 (CH2), 56.0 (CH3), 56.0 (CH3),
83.6 (C), 98.7 (C), 111.1 (CH), 113.8 (C), 114.2 (CH), 116.6 (C), 123.5 (CF3, q, J = 272 Hz), 125.1 (CH,
q, J = 4 Hz), 125.4 (CH), 127.0 (C), 130.4 (C, q, J = 33 Hz), 132.3 (C), 132.5 (CH), 149.9 (C), 150.4 (C)
ppm. IR(KBr): υ̃ = 3079, 2972, 2942, 2915, 2842, 2249, 2208, 1600, 1578, 1518, 1499, 1463, 1442, 1426,
1320, 1273, 1251, 1229, 1165, 1137, 1105, 1075, 1020, 871, 834, 817 cm-1. MS (EI): m/z (%) = 345 (100)
[M+], 330 (6), 302 (8), 275 (13), 259 (4), 258 (3), 190 (6), 173 (3), 151 (5). HRMS: calcd. (C19H14NO2F3)
345.0977; found 345.1010. Anal. Calcd for C19H14NO2F3: C, 66.09; H, 4.09; N, 4.06. Found: C, 65.91; H,
4.16; N, 4.03.
[2-(3,4-Dimethoxyphenylethynyl)-5-fluorophenyl]acetonitrile (16): Pd(PPh3)2Cl2 (62 mg, 0.09 mmol,
4 mol%), CuI (34 mg, 0.18 mmol, 8 mol%), PPh3 (46 mg, 0.18 mmol, 8 mol%), i-Pr2NH (10 mL) and
DMF (8 mL) were placed in a round-bottomed flask. After the addition of aryl bromide 12 (942 g, 4.40
mmol), the mixture was stirred at 25 °C for 1 h and alkyne 14 (714 mg, 4.40 mmol) was then added. After
the mixture had been stirred at 80 °C for additional 16 h, saturated aqueous NH4Cl solution was added.
The mixture was extracted with MTBE (3 × 50 mL). The combined organic layers were dried with

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MgSO4 and concentrated under vacuum. After purification by flash chromatography (SiO2, PE/EtOAc,
5:1), alkyne 16 (1.12 g, 3.81 mmol, 87%) was isolated as a colorless solid, mp 117-118 °C. 1H NMR (500
MHz, CDCl3): δ = 3.91 (s, 6 H), 3.96 (s, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 7.02-7.07 (m, 2 H), 7.15 (dd, J = 1.8,
8.3 Hz, 1 H), 7.23 (dd, J = 2.4, 8.9 Hz, 1 H), 7.53 (dd, J = 5.6, 8.5 Hz, 1 H) ppm. 13C NMR (126 MHz,
DEPT, CDCl3): δ = 22.8 (CH2), 55.9 (CH3), 55.9 (CH3), 83.6 (C), 95.6 (C), 111.1 (CH), 114.1 (CH),
114.4 (C), 115.4 (CH, d, J = 22 Hz), 115.7 (CH, d, J = 24 Hz), 116.8 (C), 119.1 (C, d, J = 4 Hz), 125.0
(CH), 133.9 (C, d, J = 8 Hz), 134.0 (CH, d, J = 9 Hz), 148.8 (C), 150.0 (C), 162.3 (CF, d, J = 251 Hz). IR
(neat): υ̃ = 3106, 3014, 2997, 2940, 2915, 2839, 2247, 2211, 1608, 1579, 1516, 1492, 1468, 1457, 1439,
1426, 1411, 1335, 1279, 1251, 1232, 1203, 1151, 1130, 1081, 1023, 969, 939, 929, 883, 849, 819, 798,
764, 731 cm-1. MS (EI): m/z (%) = 295 (100) [M+], 280 (16), 252 (27), 225 (18), 222 (7), 209 (13), 208
(20), 182 (12), 158 (5). HRMS: calcd. (C18H14NO2F) 295.1009; found 295.1008. Anal. Calcd for
C18H14NO2F: C, 73.21; H, 4.78; N, 4.74. Found: C, 73.11; H, 4.82; N, 4.74.
[2-(3,4-Dimethoxyphenylethynyl)-4,5-difluorophenyl]acetonitrile (17): Pd(PPh3)2Cl2 (155 mg, 0.22
mmol, 4 mol%), CuI (84 mg, 0.44 mmol, 8 mol%), PPh3 (115 mg, 0.44 mmol, 8 mol%), i-Pr2NH (5.5
mL) and DMF (5.5 mL) were placed in a round-bottomed flask. After the addition of aryl bromide 13
(1.28 g, 5.52 mmol), the mixture was stirred at 25 °C for 1 h and alkyne 14 (900 mg, 5.55 mmol) was
then added. After the mixture had been stirred at 80 °C for additional 16 h, saturated aqueous NH4Cl
solution was added. The mixture was extracted with MTBE (3 × 50 mL). The combined organic layers
were dried with MgSO4 and concentrated under vacuum. After purification by flash chromatography
(SiO2, PE/EtOAc, 5:1), alkyne 17 (1.36 g, 4.34 mmol, 79%) was isolated as a colorless solid, mp
113-114 °C. 1H NMR (300 MHz, CDCl3): δ = 3.92 (s, 8 H), 6.86 (d, J = 8.5 Hz, 1 H), 7.03 (d, J = 1.9 Hz,
1 H), 7.15 (dd, J = 1.8, 8.2 Hz, 1 H), 7.33 (dd, J = 7.7, 10.5 Hz, 1 H), 7.37 (dd, J = 7.7, 10.6 Hz, 1 H)
13
ppm. C NMR (75 MHz, DEPT, CDCl3): δ = 22.3 (CH2), 55.9 (CH3), 56.0 (CH3), 82.7 (C), 96.6 (C),
111.1 (CH), 113.9 (C), 114.1 (CH), 116.7 (C), 117.6 (CH, d, J = 20 Hz), 119.9 (C, dd, J = 4, 8 Hz), 120.9
(CH, d, J = 19 Hz), 125.2 (CH), 128.6 (C, dd, J = 4, 6 Hz), 149.7 (CF, dd, J = 13, 251 Hz), 148.9 (C),
150.3 (C), 150.1 (CF, dd, J = 13, 254 Hz) ppm. IR (KBr): υ̃ = 3000, 2966, 2939, 2839, 2257, 2214, 1600,
1578, 1517, 1466, 1445, 1424, 1413, 1346, 1320, 1251, 1224, 1173, 1137, 1023, 882, 869, 815, 754 cm-1.
MS (EI): m/z (%) = 313 (100) [M+], 298 (10), 270 (10), 243 (12), 226 (12), 212 (5), 200 (5), 162 (11),
151 (10), 113 (6), 91 (6). HRMS: calcd. (C18H13NO2F2) 313.0914; found 313.0930. Anal. Calcd for
C18H13NO2F2: C, 69.01; H, 4.18; N, 4.47. Found: C, 68.79; H, 4.24; N, 4.41.
2-[2-(3,4-Dimethoxyphenylethynyl)-5-trifluoromethylphenyl]ethylamine (18): A solution of AlCl3
(339 mg, 3.00 mmol) in Et2O (4.5 mL) was rapidly added to a suspension of LiAlH4 (114 mg, 3.00 mmol)

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in Et2O (3.0 mL) and the mixture was stirred at 25 °C for 30 min. Then, a solution of nitrile 15 (1.04 g,
3.00 mmol) in Et2O (6.0 mL) was slowly added. After the mixture had been stirred at 25 °C for additional
2 h, water was added dropwise to decompose the excess of LiAlH4 and aqueous KOH (5.0 mL, c = 5
mol/L) was then added. The colloidal mixture was extracted with Et2O (10 × 30 mL) and the combined
organic layers were dried with MgSO4. After concentration under vacuum and purification by flash
chromatography (SiO2, MTBE/MeOH/NEt3, 9:1:0.01), aminoalkyne 18 (980 mg, 2.81 mmol, 93%) was
1
isolated as a yellow solid, mp 81 °C. H NMR (300 MHz, CDCl3): δ = 2.24 (br s, 2 H), 3.07-3.11 (m, 4
H), 3.90 (s, 3 H), 3.91 (s, 3 H), 6.84 (d, J = 8.3 Hz, 1 H), 7.02 (d, J = 1.7 Hz, 1 H), 7.15 (dd , J = 1.9, 8.3
Hz, 1H), 7.40-7.50 (m, 2 H), 7.60 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 38.3
(CH2), 42.2 (CH2), 55.9 (CH3), 56.0 (CH3), 85.3 (C), 95.6 (C), 111.1 (CH), 114.2 (CH), 114.7 (C), 123.1
(CH, q, J = 4 Hz), 123.9 (CF3, q, J = 272 Hz), 125.1 (CH), 126.0 (CH, q, J = 4 Hz), 127.1 (C), 129.7 (C, q,
J = 33 Hz), 132.5 (CH), 141.8 (C), 148.8 (C), 150.0 (C) ppm. IR (KBr): υ̃ = 3386, 2999, 2946, 2838,
2206, 1615, 1598, 1577, 1518, 1471, 1456, 1441, 1412, 1327, 1256, 1229, 1173, 1125, 1020, 860, 844,
833, 815, 807 cm-1. MS (EI): m/z (%) = 349 (100) [M+], 334 (16), 330 (21), 318 (26), 273 (8), 233 (16),
212 (27), 198 (22), 166 (20), 162 (16), 151 (54), 113 (12), 86 (17). HRMS: calcd. (C19H18NO2F3)
349.1290; found 349.1270. Anal. Calcd for C19H18NO2F3: C, 65.32; H, 5.19; N, 4.01. Found: C, 65.31; H,
5.46; N, 4.28.
2-[2-(3,4-Dimethoxyphenylethynyl)-5-fluorophenyl]ethylamine (19): A solution of AlCl3 (467 mg,
3.50 mmol) in Et2O (4.5 mL) was rapidly added to a suspension of LiAlH4 (133 mg, 3.50 mmol) in Et2O
(3.5 mL) and the mixture was stirred at 25 °C for 30 min. Then, a solution of nitrile 16 (1.03 g, 3.50
mmol) in Et2O (7.0 mL) was slowly added. After the mixture had been stirred at 25 °C for 2 h, water was
added dropwise to decompose the excess of LiAlH4 and aqueous KOH (5.0 mL, c = 5 mol/L) was
subsequently added. The colloidal mixture was extracted with Et2O (10 × 30 mL) and the combined
organic layers were dried with MgSO4. After concentration under vacuum and purification by flash
chromatography (SiO2, MTBE/MeOH/NEt3, 9:1:0.01), aminoalkyne 19 (1.94 g, 3.15 mmol, 90%) was
isolated as a yellow oil. 1H NMR (500 MHz, CDCl3): δ = 1.35 (br s, 2H), 2.99 (t, J = 6.7 Hz, 2 H), 3.07 (t,
J = 6.4 Hz, 2 H), 3.91 (s, 6 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.91 (dt, J = 8.4, 2.5 Hz, 1 H), 6.96 (dd, J = 9.5,
2.4 Hz, 1 H), 7.01 (d, J = 1.5 Hz, 1 H), 7.11 (dd, J = 8.1, 1.6 Hz, 1 H), 7.49 (dd, J = 8.4, 5.9 Hz, 1 H) ppm.
13C NMR (126 MHz, DEPT, CDCl3): δ = 39.0 (CH2), 42.5 (CH2), 55.9 (CH3), 55.9 (CH3), 85.6 (C), 92.7
(C), 111.1 (CH), 113.4 (CH, d, J = 22 Hz), 114.1 (CH), 115.4 (C), 116.2 (CH, d, J = 22 Hz), 119.3 (C, d,
J = 3 Hz), 124.8 (CH), 133.9 (CH, d, J = 9 Hz), 144.3 (C, d, J = 7 Hz), 148.7 (C), 149.6 (C), 162.2 (CF, d,
J = 250 Hz) ppm. IR (neat): υ̃ = 3056, 3933, 2838, 2773, 2364, 1602, 1580, 1516, 1444, 1367, 1328, 1253,
1235, 1131, 1069, 1027, 817, 763, 735, 701 cm-1. MS (EI): m/z (%) = 299 (96) [M+], 298 (47), 283 (11),

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270 (22), 269 (10), 268 (24), 255 (12), 223 (13), 207 (11), 196 (16), 183 (37), 166 (31), 162 (34), 161
(11), 151 (100), 148 (35), 138 (16). HRMS: calcd. (C18H18NO2F) 299.1322; found 299.1322.
2-[2-(3,4-Dimethoxyphenylethynyl)-4,5-difluorophenyl]ethylamine (20): A solution of AlCl3 (467 mg,
3.50 mmol) in Et2O (4.5 mL) was rapidly added to a suspension of LiAlH4 (133 mg, 3.50 mmol) in Et2O
(3.5 mL) and the mixture was stirred at 25 °C for 30 min. Then, a solution of nitrile 17 (1.10 g, 3.50
mmol) in Et2O (7.0 mL) was slowly added. After the mixture had been stirred at 25 °C for 2 h, water was
added dropwise to decompose the excess of LiAlH4 and aqueous KOH (5 mL, c = 5 mol/L) was
subsequently added. The colloidal mixture was extracted with Et2O (10 × 30 mL) and the combined
organic layers were dried with MgSO4. After concentration under vacuum and purification by flash
chromatography (SiO2, MTBE/MeOH/NEt3, 9:1:0.01), aminoalkyne 20 (1.01 g, 3.18 mmol, 91%) was
isolated as a yellow solid, mp 60-61 °C. 1H NMR (300 MHz, CDCl3): δ = 1.37 (br s, 2 H), 2.95 (t, J = 6.4
Hz, 2 H), 3.05 (t, J = 6.1 Hz, 2 H), 3.91 (s, 6 H), 6.84 (d, J = 8,3 Hz, 1 H), 7.00 (d, J = 1.7 Hz, 1 H), 7.05
13
(dd, J = 8.0, 11.0 Hz, 1 H), 7.12 (dd, J = 1.9, 8.3 Hz, 1 H), 7.31 (dd, J = 7.9, 10.7 Hz, 1 H) ppm. C
NMR (75 MHz, DEPT, CDCl3): δ = 38.3 (CH2), 42.5 (CH2), 55.9 (CH3), 56.0 (CH3), 84.6 (C), 93.5 (C),
111.1 (CH), 114.1 (CH), 114.9 (C), 118.0 (CH, d, J = 18 Hz), 119.7 (C, dd, J = 4, 7 Hz), 120.6 (CH, d, J
= 19 Hz), 124.9 (CH), 139.0 (C, dd, J = 4, 5 Hz), 148.4 (CF, dd, J = 13, 247 Hz), 148.8 (C), 149.9 (C),
149.9 (CF, dd, J = 13, 251 Hz) ppm. IR (KBr): υ̃ = 3441, 3040, 3012, 2935, 2834, 2794, 1609, 1591,
1517, 1461, 1417, 1329, 1303, 1259, 1241, 1208, 1155, 1137, 1102, 1029, 861, 807, 766 cm-1. MS (EI):
m/z (%) = 317 (100) [M+], 302 (12), 288 (27), 286 (21), 243 (10), 241 (11), 225 (12), 214 (16), 201 (36),
180 (21), 175 (12), 166 (21), 151 (75), 138 (8), 113 (6). HRMS: calcd. (C18H17NO2F2) 317.1227; found
317.1234. Anal. Calcd for C18H17NO2F2: C, 68.13; H, 5.40; N, 4.41. Found: C, 67.89; H, 5.47; N, 4.36.
1-(3,4-Dimethoxybenzyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (rac-21): In a Schlenk
tube, a mixture of aminoalkyne 18 (175 mg, 0.50 mmol) and Ind2TiMe2 (9 mg, 0.025 mmol, 5 mol%) in
toluene (0.25 mL) was stirred at 105 °C for 16 h. The resulting dark brown solution was cooled to rt and a
mixture of NaBH3CN (63 mg, 1.00 mmol) and ZnCl2 (68 mg, 0.50 mmol) in MeOH (5.0 mL) was added.
After this had been stirred at 25 °C for 24 h, saturated aqueous NH4Cl solution (25 mL) was added and
the mixture was extracted with MTBE (5 × 25 mL). The combined organic layers were dried with MgSO4
and concentrated under vacuum. After purification by flash chromatography (SiO2, MTBE/MeOH/NEt3,
20:1:0.01), 1,2,3,4-tetrahydroisoquinoline rac-21 (169 mg, 0.48 mmol, 96%) was isolated as a yellow
solid, mp 92-94 °C. 1H NMR (300 MHz, CDCl3): δ = 1.13 (br s, 1 H), 2.80-2.96 (m, 4 H), 3.19-3.26 (m, 2
H), 3.84 (s, 3 H), 3.87 (s, 3 H), 4.21 (dd, J = 3.2, 9.5 Hz, 1 H), 6.71 (d, J = 1.7 Hz, 1 H), 6.79 (dd, J = 1.7,
8.1 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 7.33-7.43 (m, 3 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ =

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29.9 (CH2), 40.5 (CH2), 41.8 (CH2), 55.7 (CH3), 55.8 (CH3), 57.1 (CH), 111.2 (CH), 112.1 (CH), 121.3
(CH), 122.2 (CH, q, J = 4 Hz), 124.2 (CF3, q, J = 272 Hz), 126.1 (CH, q, J = 4 Hz), 126.6 (CH), 128.3 (C,
q, J = 32 Hz), 130.7 (C), 136.2 (C), 142.5 (C), 147.7 (C), 148.9 (C) ppm. IR: υ̃ = 3443, 2936, 2835, 1621,
1590, 1516, 1466, 1425, 1338, 1323, 1266, 1237, 1160, 1126, 1077, 1030, 828, 813, 764 cm-1. MS (EI):
m/z (%) = 351 (1) [M+], 350 (3), 349 (4), 334 (4), 332 (11), 214 (6), 201 (94), 200 (100), 198 (23), 185
(22), 173 (7), 151 (35), 131 (11), 113 (7), 107 (7). HRMS: calcd. (C19H20NO2F3) 351.1446; found
351.1401. Anal. Calcd for C19H20NO2F3: C, 64.95; H, 5.74; N, 3.99. Found: C, 64.68; H, 5.80; N, 4.01.
1-(3,4-Dimethoxybenzyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline (rac-22): In a Schlenk tube, a
mixture of aminoalkyne 19 (209 mg, 0.70 mmol) and Ind2TiMe2 (11 mg, 0.04 mmol, 5 mol%) in toluene
(0.10 mL) was stirred at 105 °C for 16 h. The resulting dark brown solution was cooled to rt and a
mixture of NaBH3CN (88 mg, 1.40 mmol) and ZnCl2 (95 mg, 0.70 mmol) in MeOH (5 mL) was added.
After this had been stirred at 25 °C for 24 h, saturated aqueous NH4Cl solution (25 mL) was added and
the mixture was extracted with MTBE (5 × 25 mL). The combined organic layers were dried with MgSO4
and concentrated under vacuum. After purification by flash chromatography (SiO2, MTBE/MeOH/NEt3,
20:1:0.01), 1,2,3,4-tetrahydroisoquinoline rac-22 (198 mg, 0.66 mmol, 94%) was isolated as a yellow oil.
1H NMR (500 MHz, CDCl3): δ = 1.88-1.96 (br s, 1 H), 2.70-2.92 (m, 4 H), 3.16-3.22 (m, 2 H), 3.85 (s, 3
H), 3.87 (s, 3 H), 4.14 (dd, J = 9.6, 3.6 Hz, 1 H), 6.74 (d, J = 1.6 Hz, 1 H), 6.84 (m, 4 H), 7.18 (dd, J = 8.5,
13
5.8 Hz, 1 H) ppm. C NMR (126 MHz, DEPT, CDCl3): δ = 30.5 (CH2), 41.0 (CH2), 42.5 (CH2), 56.3
(CH3), 56.3 (CH3), 111.8 (CH), 112.8 (CH), 113.1 (CH, d, J = 21 Hz), 115.8 (CH, d, J = 20 Hz), 121.8
(CH), 128.1 (CH, d, J = 8 Hz), 131.6 (C), 134.7 (C, d, J = 3 Hz), 138.0 (C, d, J = 7. Hz), 148.2 (C), 149.4
(C), 161.5 (CF, d, J = 244 Hz) ppm. IR (neat): υ̃ = 3000, 2933, 2834, 2360, 2341, 1612, 1589, 1514, 1497,
1463, 1450, 1418, 1330, 1261, 1239, 1027, 935, 914, 857, 810, 763 cm-1. MS (ESI, CH2Cl2): m/z (%) =
302 (30) [M+ + H], 151 (5), 150 (100), 147 (5). HRMS (ESI, CH2Cl2): calcd. (C18H20NO2F + H)
302.1556; found 302.1555.
1-(3,4-Dimethoxybenzyl)-6,7-difluoro-1,2,3,4-tetrahydroisoquinoline (rac-23): In a Schlenk tube, a
mixture of aminoalkyne 20 (159 mg, 0.50 mmol) and Ind2TiMe2 (9 mg, 0.025 mmol, 5 mol%) in toluene
(0.25 mL) was stirred at 105 °C for 16 h. The resulting dark brown solution was cooled to rt and a
mixture of NaBH3CN (63 mg, 1.00 mmol) and ZnCl2 (68 mg, 0.50 mmol) in MeOH (5 mL) was added.
After this had been stirred at 25 °C for 24 h, saturated aqueous NH4Cl solution (25 mL) was added and
the mixture was extracted with MTBE (5 × 25 mL). The combined organic layers were dried with MgSO4
and concentrated under vacuum. After purification by flash chromatography (SiO2, MTBE/MeOH/NEt3,
20:1:0.01), 1,2,3,4-tetrahydroisoquinoline rac-23 (154 mg, 0.48 mmol, 96%) was isolated as a yellow

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solid, mp 60-61 °C. 1H NMR (300 MHz, CDCl3): δ = 1.88 (br s, 1 H), 2.63-2.93 (m, 4 H), 3.10-3.24 (m, 2
H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.08 (dd, J = 3.3, 9.5 Hz, 1 H), 6.74 (d, J = 1.7 Hz, 1 H), 6.78 (dd, J = 1.7,
8.1 Hz, 1 H), 6.84 (d, J = 8.1 Hz, 1 H), 6.89 (dd, J = 8.5, 10.6 Hz, 1 H), 7.03 (dd, J = 8.3, 11.1 Hz, 1 H)
ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 29.3 (CH2), 40.7 (CH2), 41.9 (CH2), 55.8 (CH3), 55.9
(CH3), 56.7 (CH), 111.4 (CH), 112.3 (CH), 114.6 (CH, dd, J = 2, 16 Hz), 117.3 (CH, dd, J = 3, 14 Hz),
121.3 (CH), 130.7 (C), 131.9 (C, dd, J = 4, 5 Hz), 135.0 (C, t, J = 4 Hz), 147.8 (C), 148.3 (CF, dd, J = 12,
248 Hz), 148.5 (CF, dd, J = 12, 248 Hz), 149.0 (C) ppm. IR (KBr): υ̃ = 3007, 2944, 2840, 2211, 1598,
1578, 1517, 1465, 1442, 1407, 1342, 1283, 1266, 1247, 1221, 1189, 1174, 1134, 1023, 882, 863, 808, 765
cm-1. MS (EI): m/z (%) = 319 (2) [M+], 318 (2), 317 (3), 316 (3), 302 (4), 267 (5), 236 (4), 212 (4), 182
(18), 169 (41), 168 (100), 166 (15), 153 (16), 151 (17), 141 (7), 113 (6). HRMS: calcd. (C18H19NO2F2)
319.1384; found 319.1399. Anal. Calcd for C18H19NO2F2: C, 67.70; H, 6.00; N, 4.39. Found: C, 67.48; H,
6.10; N, 4.48.
1-(3,4-Dimethoxybenzyl)-2-methyl-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline
(rac-24):
Aqueous CH2O (0.5 mL, c = 37%, 6.7 mmol) was added to a solution of rac-21 (88 mg, 0.25 mmol) in
MeOH (1.5 mL). After this mixture had been stirred at rt for 3 h, NaBH4 (95 mg, 2.50 mmol) was slowly
added. Subsequently, the reaction mixture was stirred at 25 °C for additional 16 h. Then, saturated
aqueous NH4Cl (15 mL) was added and the mixture was extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were dried with MgSO4 and the solvent was removed under vacuum. After
purification by flash chromatography (SiO2, MTBE/MeOH/NEt3, 95:5:1), rac-24 (62 mg, 0.17 mmol,
1
68%) was isolated as a yellow oil. H NMR (300 MHz, CDCl3): δ = 2.54 (s, 3 H), 2.62-2.95 (m, 4 H),
3.07-3.23 (m, 2 H), 3.72 (s, 3 H), 3.82 (t, J = 6.0 Hz, 1 H), 3.85 (s, 3 H), 6.45 (d, J = 1.8 Hz, 1 H), 6.63
(dd, J = 2.0, 8.7 Hz, 1 H), 6.76 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 1 H),
13
7.32 (br s, 1 H) ppm. C NMR (75 MHz, DEPT, CDCl3): δ = 26.3 (CH2), 40.4 (CH2), 42.8 (CH3), 47.0
(CH2), 55.6 (CH3), 55.8 (CH3), 65.0 (CH), 110.9 (CH), 112.8 (CH), 121.7 (CH), 121.8 (CH, q, J = 4 Hz),
124.2 (CF3, q, J = 272 Hz), 125.5 (CH, q, J = 4 Hz), 128.2 (C, q, J = 32 Hz), 128.5 (CH), 131.5 (C),
135.4 (C), 141.7 (C), 147.4 (C), 148.4 (C) ppm. IR (neat): υ̃ = 2937, 2836, 2787, 1661, 1590, 1516, 1465,
1428, 1324, 1265, 1239, 1159, 1077, 1030, 976, 896, 803, 764, 738 cm-1. MS (EI): m/z (%) = 363 (5) [M+
− 2 H], 348 (4), 346 (4), 215 (46), 214 (100), 212 (22), 199 (16), 195 (7), 151 (15), 144 (4). HRMS: calcd.
(C20H22NO2F3 − 2 H) 363.1446; found 363.1481.
1-(3,4-Dimethoxybenzyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (rac-25): Aqueous CH2O
(0.5 mL, c = 37%, 6.7 mmol) was added to a solution of rac-22 (75 mg, 0.25 mmol) in MeOH (2.0 mL).
After this mixture had been stirred at rt for 3 h, NaBH4 (95 mg, 2.50 mmol) was slowly added.

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Subsequently, the reaction mixture was stirred at 25 °C for additional 16 h. Then, saturated aqueous
NH4Cl (15 mL) was added and the mixture was extracted with CH2Cl2 (5 × 30 mL). The combined
organic layers were dried with MgSO4 and the solvent was removed under vacuum. After purification by
flash chromatography (SiO2, MTBE/MeOH/NEt3, 95:5:1), rac-25 (64 mg, 0.20 mmol, 81%) was isolated
1
as a yellow oil. H NMR (300 MHz, CDCl3): δ = 2.52 (s, 3 H), 2.91-2.56 (m, 4 H), 3.19-3.04 (m, 2 H),
13
3.73-3.76 m (1 H), 3.76 (s, 3 H), 3.85 (s, 3 H), 6.51 (d, J = 1.7 Hz, 1 H), 6.61-6.78 (m, 5 H) ppm. C
NMR (126 MHz, DEPT, CDCl3): δ = 26.4 (CH2), 40.5 (CH2), 42.8 (CH3), 46.7 (CH2), 55.7 (CH3), 55.8
(CH3), 64.6 (CH), 110.9 (CH), 112.2 (CH, d, J = 21 Hz), 112.9 (CH), 114.8 (CH, d, J = 20 Hz), 121.7
(CH), 129.5 (CH, d, J = 8 Hz), 132.0 (C), 133.2 (C), 136.6 (C, d, J = 7 Hz), 147.3 (C), 148.4 (C), 161.0
(CF, d, J = 244 Hz) ppm. IR (neat): υ̃ = 2934, 2834, 2787, 2359, 1613, 1590, 1514, 1496, 1464, 1417,
1374, 1260, 1235, 1155, 1139, 1029, 864, 808, 764 cm-1. MS (ESI, CH2Cl2): m/z (%) = 316 (38) [M+ + H],
164 (100). HRMS (ESI, CH2Cl2): calcd. (C19H22NO2F + H) 316.1713; found 316.1710.
1-(3,4-Dimethoxybenzyl)-6,7-difluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (rac-26): Aqueous
CH2O (0.5 mL, c = 37%, 6.7 mmol) was added to a solution of rac-23 (80 mg, 0.25 mmol) in MeOH (1.5
mL). After this mixture had been stirred at rt for 3 h, NaBH4 (95 mg, 2.5 mmol) was slowly added.
Subsequently, the reaction mixture was stirred at 25 °C for additional 16 h. Then, saturated aqueous
NH4Cl (15 mL) was added and the mixture was extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried with MgSO4 and concentrated under vacuum. After purification by flash
chromatography (SiO2, MTBE/MeOH/NEt3, 95:5:1), rac-26 (70 mg, 0.21 mmol, 84%) was isolated as a
1
yellow oil. H NMR (300 MHz, CDCl3): δ = 2.50 (s, 3 H), 2.53-2.65 (m, 1 H), 2.67-2.86 (m, 3 H),
3.02-3.18 (m, 2 H), 3.69 (t, J = 6.0 Hz, 1 H), 3.79 (s, 3 H), 3.85 (s, 3 H), 6.49 (dd, J = 8.2, 11.2 Hz, 1 H),
6.57 (d, J = 1.9 Hz, 1 H), 6.61 (dd, J = 1.7, 8.1 Hz, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 6.84 (dd, J = 8.1, 10.9
Hz, 1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 25.5 (CH2), 40.3 (CH2), 42.6 (CH3), 46.6 (CH2),
55.8 (CH3), 55.8 (CH3), 64.5 (CH), 111.0 (CH), 112.8 (CH), 116.3 (CH, d, J = 17 Hz), 116.7 (CH, d, J =
16 Hz), 121.7 (CH), 130.9 (C, dd, J = 4, 6 Hz), 131.6 (C), 134.0 (C, t, J = 4 Hz), 147.5 (C), 147.9 (CF, dd,
J = 18, 250 Hz), 148.5 (CF, dd, J = 16, 249 Hz), 148.5 (C) ppm. IR (neat): υ̃ = 2936, 2836, 2798, 1608,
1591, 1516, 1465, 1417, 1375, 1315, 1264, 1238, 1212, 1157, 1140, 1085, 1030, 881, 807, 764 cm-1. MS
(EI): m/z (%) = 333 (5) [M+], 332 (6), 316 (9), 201 (7), 198 (9), 183 (100), 182 (100), 180 (93), 167 (84),
151 (40), 139 (22), 133 (10), 127 (13), 119 (16), 107 (13), 106 (14). HRMS: calcd. (C19H21NO2F2)
333.1540; found 333.1523.
ACKNOWLEDGEMENTS
We thank the Deutscher Akademischer Austauschdienst (DAAD Fellowship for D. M.), the Deutsche

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Forschungsgemeinschaft and the Fonds der Chemischen Industrie for financial support of our research.
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