Synthesis of Polysubstituted Isoquinolines and Related Fused Pyridines from Alkenyl Boronic Esters via a Copper-Catalyzed Azidation/Aza-Wittig Condensation Sequence

Article abstract of DOI:10.1021/acs.joc.7b02831

An efficient and straightforward synthesis of isoquinolines is reported from internal alkenyl boronic esters, easily prepared from the corresponding 1,2-bis(boronates), via a sequential copper-catalyzed azidation/aza-Wittig condensation. This synthetic method has been used to synthesize quinisocaine, a topical anesthetic used for the treatment of pain and pruritus, and further extended to thieno[2,3-c]pyridines by using 2-thiophenecarboxaldehyde as coupling partner in the first step.

Full text of DOI:10.1021/acs.joc.7b02831

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Article
Synthesis of Polysubstituted Isoquinolines and Related
Fused Pyridines from Alkenyl Boronic Esters via a Copper-
Catalyzed Azidation/Aza-Wittig Condensation Sequence
Vankudoth Jayaram, Tailor Sridhar, Gangavaram V. M. Sharma, Fabienne Berrée, and Bertrand Carboni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02831 • Publication Date (Web): 18 Dec 2017
Downloaded from http://pubs.acs.org on December 18, 2017
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Synthesis of Polysubstituted Isoquinolines and Related Fused Pyridines
from Alkenyl Boronic Esters via a Copper-Catalyzed Azidation/Aza-Wittig
Condensation Sequence
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Vankudoth Jayaram,a Tailor Sridhar,a Gangavaram V. M. Sharma,a* Fabienne Berrée,b and
Bertrand Carboni b*
a
Organic and Biomolecular Chemistry Division, CSIRꢀIndian Institute of Chemical
Technology, Tarnaka, Hyderabadꢀ500 007, India.
b
Université de Rennes 1, Institut des Sciences Chimiques de Rennes, UMR CNRS 6226
Campus de Beaulieu, 35042, Rennes Cedex, France
esmvee@iict.res.in (G.V.M.S.).
bertrand.carboni@univꢀrennes1.fr (B.C.).
Abstract:
An efficient and straightforward synthesis of isoquinolines is reported from internal alkenyl
boronic esters, easily prepared from the corresponding 1,2ꢀbis(boronates), via a sequential
copperꢀcatalyzed azidation / azaꢀWittig condensation. This synthetic method has been used to
synthesize quinisocaine, a topical anesthetic used for the treatment of pain and pruritus, and
further extended to thieno[2,3ꢀc]pyridines by using 2ꢀthiophenecarboxaldehyde as coupling
partner in the first step.
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INTRODUCTION
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The isoquinoline core, and the related heterocycleꢀfused pyridine motifs, can be found
in many natural products.1 These structural frameworks also constitute the common
substructures of a large variety of biologically active substances and organic materials.2,3 Due
to such diverse properties, rapid and efficient routes to access isoquinolines are still attracting
considerable attention from organic chemists over the past few years and a number of
different synthetic strategies were devised for these nitrogen heterocycles. If the Bischlerꢀ
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Napieralski and PomerantzꢀFritsch reactions are classically used, alternative protocols,
often possessing milder reaction conditions, wider substrate scope, and better functional
compatibilities, are now available.6 During the past decade, transitionꢀmetalꢀcatalyzed
annulation reactions have proven to be valuable key process for the synthesis of
isoquinolines.7 With respect to processes that do not use metal catalysts, intramolecular azaꢀ
Wittig reaction,8 which occurs under mild and neutral conditions, has been also exploited to
access isoquinolines and isoquinolones.9 To the best of our knowledge, this approach was
hitherto restricted to esterꢀsubstituted substrates resulting from the condensation reaction of
an aldehyde with ethyl or methyl azidoacetate.
Organoboranes have recently emerged as valuable precursors of azido compounds via
their copper(II)ꢀcatalyzed reaction with sodium or trimethylsilyl azide 10 that greatly increases
the range of available vinyl azides. In this context, and on the basis of our previous works on
alkenyl 1,2ꢀbis(boronic esters),11 herein we report a practical access to isoquinolines from
these easily available starting material, based on a three steps sequence: regioselective
SuzukiꢀMiyaura coupling with a 2ꢀformyl aryl bromide / azidation / azaꢀWittig condensation
(Scheme 1).
Scheme 1. Synthesis of isoquinolines 4 from alkenyl 1,2ꢀbis(boronic esters) 1
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RESULTS AND DISCUSSION
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(E)ꢀAlkenyl 1,2ꢀbis(boronates) 1a-e were first prepared in good yields from the
corresponding 1ꢀalkynes and bis(pinacolato)diboron in the presence of
tetrakis(triphenylphosphine)platinum as catalyst, according to reported procedures.12 These
compounds were then regioselectively converted to the internal boronic esters via Suzuki–
Miyaura crossꢀcouplings with 2ꢀformyl aromatic halides in the presence of Pd(dppf)Cl2 and
K3PO4 in THF/H2O at reflux as previously reported.11 Yields are good to moderate with the
formation of a single (E)ꢀstereoisomer 2, as ascertained by NMR spectroscopy (Scheme 2).
Replacement of the aldehyde group by an ester, ketone or amide motif has no significant
influence on the course of the coupling reaction.
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Scheme 2. Suzuki–Miyaura crossꢀcouplings with 1,2ꢀbis(boronates) 1 a,b
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Ar
BPin
R1
ArBr, PdCl2(dppf)
PinB
PinB
R1
2a-v
K3PO4, THF/H2O
reflux, 1 h
R
R
1a R = n-Bu, R1 = H
1d R = C3H6OTBS, R1 = H
1e R = R1 = C3H7
1b R = CH2Ph, R1 = H
1c R = CH2ꢀcHex, R1 = H
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Me
OMe
CHO
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OMe
PinB
PinB
nBu
PinB
OMe
PinB
nBu
PinB
nBu
nBu
nBu
CHO
(75%)
CHO
CHO
CHO
(51%)
2b (58%)
2c (56%)
(52%)
2e
2d
2a
O
OMe
CHO
O
OMe
PinB
OTBS
PinB
PinB
nBu
Pi
nB
cHex
cHex
nBu
CHO
CHO
CHO
2g
2h
2i
(58%)
(52%)
O
(62%)
OMe
(52%)
CHO
2f
OTBS
O
OMe
PinB
PinB
PinB
PinB
PinB
cHex
Ph
cHex
cHex
CHO
Ph
CHO
F
CHO
OMe
CHO
(62%)
(52%)
2j(54%)
2k (57%)
2l
2m
2n (58%)
OMe
OTBS
OMe
PinB
PinB
PinB
PinB
TBSO
TBSO
Ph
nBu
2r (32%)
3
3
CHO
CHO
CHO
CHO
(64%)
2o
2p (58%)
2q (56%)
PinB
PinB
nBu
PinB
nBu
PinB
C3H7
nBu
C3H7 CHO
O
2t (52%)
OMe
O
NH2
O
2u (56%)
Me
2s (55%)
2v (62%)
a General conditions: 1 (0.5 mmol), [1, 1'ꢀbis (diphenyl phosphino)ferrocene] dichloropalladium(II) ( 0.01 mmol), potassium
phosphate tribasic monohydrate (1.5 mmol) and arylbromide (0.5 mmol), THF (5 mL)/water (0.1 mL), reflux, 1 h. b Yields of
isolated products.
We then studied the copperꢀcatalyzed transformation of compounds 2 to the
corresponding azides in methanol that took place at room temperature after 6 h, to give the
azide in good yields (72 to 92%). The reaction was compatible with the presence of various
functionalities, including carbonyl groups, alkyl and silyl ethers, fluorine, ester and amide
(Scheme 3).
Scheme 3. Copperꢀcatalyzed conversion of boronates 2 into azides 3.a,b
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We further investigated the substrate scope of the intramolecular azaꢀWittig reaction
of azidoaldehydes 3aꢀ3v in the presence of triethylphosphite. The desired quinolines 4a-4u
o
were isolated in yields ranging from 82% to 93% after 2 hours at 35 C in THF (Scheme 4).
This cyclization was not restricted to aldehyde derivatives and good yields were also
observed with a ketone and an ester group. While, it failed with the amide 3v.
Scheme 4. Synthesis of isoquinolines 4 from azides 3.a,b
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R2
R4
R1
R3
R2
R3
P(OEt)3, 4 Å MS
THF, rt to 35oC, 2h
N
N3
R
O
R
R1
4
R
4a-u
3a-3v
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OMe
nBu
OMe
OMe
N
N
N
N
N
nBu
Me
nBu
nBu
nBu
(93%)
N
(85%)
(83%)
4d
4a
4b
4c (85%)
4e (84%)
OTBS
OMe
OMe
N
N
N
cHex
cHex
nBu
O
nBu
O
4f(90%)
4g(82%)
4h (91%)
4i (89%)
OTBS
OMe
OMe
N
N
N
N
N
cHex
cHex
cHex
O
O
Ph
4m
Ph
4n
(90%)
(87%)
(89%)
4j (92%)
4k(88%)
4l
OMe
OMe
OTBS
F
N
3
N
N
N
TBSO
Ph
TBSO
OMe
nBu
3
(86%)
4o
4p(85%)
OMe
N
3 4q (92%)
4r (91%)
Me
NH2
N
N
N
C3H7
nBu
C3H7
nBu
nBu
4s (91%)
4t (87%)
4u (88%)
4v (0%)
o
a General conditions: 3 (0.5 mmol) THF (3 mL), 4 A molecular sieves and triethylphosphite (0.5 mmol), THF (4 mL), rt, 30min.;
triethoxyphosphite (1 mmol), 35 °C, 1.5 h. b Yields of isolated products.
Like isoquinolines, thieno[2,3ꢀc]pyridines, which belong to the related fused pyridine
family, are an important class of biologically active molecules.13,14 Our above described
approach was transposed to this class of heterocycles, to provide the starting Suzuki partner
as a thiophene derivative. We thus succeeded to synthesize compounds 6aꢀ6d according to a
three steps sequence in good overall yields from 3ꢀbromothiopheneꢀ2ꢀcarboxaldehyde and 3ꢀ
bromobenzothiopheneꢀ2ꢀcarboxaldehyde selected as model heteroaromatic halides (Table 1).
Table 1. Synthesis of thieno[2,3ꢀc]pyridines 8 from bisboronates 1.a
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Finally, the utility of this sequence was demonstrated by the synthesis of quinisocaine,
(dimethisoquin), a topical anesthetic used for the treatment of pain and pruritus.15 The
boronate 10 was first synthesized from 1a and 2ꢀ(dimethylamino) ethyl 2ꢀbromobenzoate 9 in
a 62% yield. In presence of sodium azide and copper sulfate, it was readily converted to the
corresponding azide 11, which after an intramolecular azaꢀWittig condensation, gave
quinisocaine 12 in 81% yield (Scheme 5).
Scheme 5. Synthesis of Quinisocaine.
In conclusion, an efficient and widely applicable synthesis of isoquinolines from easily
accessible or commercially available reactants was developed. The key features of this
method are a regioselective Suzuki coupling at the terminal CꢀB bond of a (E)ꢀ1ꢀalkeneꢀ1,2ꢀ
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diboronic ester, the copperꢀcatalyzed azidation and intramolecular AzaꢀWittig reactions. This
approach has been successfully extended to thieno[2,3ꢀc]pyridines and exemplified by the
synthesis of quinisocaine, a topical anesthetic.
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EXPERIMENTAL SECTION
General Information and Materials. All commercially available chemicals were used
without further purification. Tetrahydrofuran (THF) and diethylether were used as received.
Analytical thin layer chromatography was performed on Silica Gel 60 F254 plates. The
compounds were characterized by H, 13C NMR and 11B NMR. Spectra were recorded in
1
CDCl3 (internal standard: 7.26 ppm for 1H; 77.00 ppm for 13C). 11B NMR chemical shifts are
related to external BF3·OEt2 (0.0 ppm). Highꢀresolution mass spectra (HMRS) were recorded
on a microꢀTOFꢀQ II mass analyzer or QꢀTOF 2 using positive ion electrospray. Compounds
1 were synthesized according to literature procedures.12
General Procedure for the Suzuki–Miyaura Cross-Couplings with 1, 2-Bis(boronates)
(1a-1e). Synthesis of compounds 2a-2v and 6a-6d. A solution of bispinacolate ester 1 (0.89
mmol) in THF (8.9 mL) and water (0.18 mL) was degassed under argon atmosphere before
the addition of [1, 1’ꢀbis (diphenyl phosphino)ferrocene] dichloropalladium(II) (13.5 mg,
0.018 mmol), potassium phosphate tribasic monohydrate (616 mg, 2.66 mmol) and
arylbromide (0.89 mmol). The reaction mixture was heated at reflux for 1 h, cooled to room
temperature, diluted with water and extracted with Et2O (2 x 25 mL). The combined organic
extracts were dried (MgSO4) and evaporated under vacuum. The residue was purified by
column chromatography (230ꢀ400 mesh Silica gel, EtOAc in Hexane) to give the
corresponding Suzuki products 2 or 6.
The characterisation of compounds 2a, 2b, 2d, 2e, 2l, 2n and 2o was already reported in our
previous paper.11
(E)-4-Methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-
1
enyl)benzaldehyde (2c). 164 mg (56%). Colorless oil, Rf = 0.10 (EtOAc/Hexane 10:90). H
NMR (500 MHz, CDCl3): δ 10.22 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.30 (s, 1H), 7.16 (d, J =
7.9 Hz, 1H), 7.11 (s, 1H), 2.37ꢀ2.34 (m, 5H), 1.58ꢀ1.45 (m, 2H), 1.39 (td, J = 14.6, 7.2 Hz,
2H), 1.12 (s, 12H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 192.0, 143.7,
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142.9, 136.5, 131.5, 130.8, 128.5, 128.1, 83.4, 37.2, 31.8, 24.5, 22.4, 21.7, 14.0 (the carbon α
to boron was not found). HRMS (ESI+): m/z (M+H)+ calculated for C20H30O3B 329.2288,
found 329.2289.
(E)-5-(tert-Butyldimethylsilyloxy)-4-methoxy-2-(2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)hex-1-enyl)benzaldehyde (2f). 245 mg (58%). Colorless oil, Rf = 0.10
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(EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 10.07 (s, 1H), 7.36 (s, 1H), 7.17 (s,
1H), 6.74 (s, 1H), 3.87 (s, 3H), 2.41ꢀ2.28 (m, 2H), 1.50 (ddd, J = 14.6, 9.4, 4.0 Hz, 2H), 1.44ꢀ
13
1.35 (m, 2H), 1.09 (s, 12H), 0.99 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H), 0.15 (s, 6H). C NMR
(126 MHz, CDCl3): δ 190.9, 155.2, 144.3, 141.8 (br), 139.2, 135.9, 127.6, 118.9, 112.8, 83.4,
55.5, 37.1, 31.9, 25.7, 24.6, 22.4, 18.5, 14.0, ꢀ4. HRMS (ESI+): m/z (M+H)+ calculated for
C26H44O5BSi 475.3051, found 475.3041.
(E)-4-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-enyl)benzo[d][1,3]dioxole-
1
5-carbaldehyde (2g). 166 mg (52%). Colourless oil, Rf = 0.50 (EtOAc/Hexane 20:80). H
NMR (500 MHz, CDCl3): δ 10.26 (s, 1H), 7.19 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.74 (dd, J
= 8.0, 0.6 Hz, 1H), 6.12 (s, 2H), 2.38ꢀ2.28 (m, 2H), 1.52ꢀ1.45 (m, 2H), 1.42ꢀ1.33 (m, 2H),
1.15 (s, 12H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 189.5, 148.5, 147.7,
136.3, 135.6, 123.0, 117.5, 112.2, 102.5, 83.4, 37.0, 31.8, 24.7, 24.6, 22.4, 14.0 (the carbon α
to boron was not found). HRMS (ESI+): m/z (M+H)+ calculated for C20H28O5B 359.2030,
found.359.2030.
(E)-2-(3-Cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-
enyl)benzaldehyde (2h). 175 mg (62%). Colourless oil, Rf = 0.10 (EtOAc/Hexane 10:90). 1H
NMR (400 MHz, CDCl3): δ 10.29 (d, J = 0.5 Hz, 1H), 7.86 (dd, J = 7.7, 1.2 Hz, 1H), 7.46
(td, J = 7.5, 1.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.26 (s, 1H), 2.27
(dd, J = 7.1, 1.0 Hz, 2H), 1.82ꢀ1.65 (m, 5H), 1.46 (dtd, J = 10.9, 7.2, 3.6 Hz, 1H), 1.28ꢀ1.18
13
(m, 3H), 1.09 (s, 12H), 0.96ꢀ.93 (m, 2H). C NMR (126 MHz, CDCl3): δ 192.4, 143.0,
137.4, 133.7, 133.0, 130.4, 127.9, 127.2, 83.4, 45.6, 38.0, 33.3, 26.5, 26.4, 24.5 (the carbon α
to boron was not found). HRMS (ESI+): m/z (M+Na)+ calculated for C22H31O3BNa 377.2264,
found 377.2267.
(E)-2-(3-Cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enyl)-5-
methoxybenzaldehyde (2i). 159 mg (52%). Colourless oil, Rf = 0.30 (EtOAc/Hexane 10:90).
1H NMR (500 MHz, CDCl3): δ 10.26 (s, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.22 (d, J = 8.5 Hz,
1H), 7.18 (s, 1H), 7.04 (dd, J = 8.5, 2.8 Hz, 1H), 3.85 (s, 3H), 2.25 (dd, J = 7.1, 1.0 Hz, 2H),
1.78ꢀ1.70 (m, 5H), 1.53ꢀ1.38 (m, 1H), 1.29ꢀ1.17 (m, 3H), 1.11 (s, 12H), 1.01ꢀ0.87 (m, 2H).
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13C NMR (126 MHz, CDCl3): δ 192.0, 158.8, 140.1, 139.8 (br), 136.8, 136.3, 134.5, 131.7,
120.8, 109.7, 83.4, 55.5, 45.7, 38.0, 33.3, 26.5, 26.4, 24.5. HRMS (ESI+): m/z (M+Na)+
calculated for C23H33BO4Na 407.2369, found 407.2343.
(E)-1-(3-Cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enyl)-2-
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naphthaldehyde (2j). 174 mg (54%). Colorless oil, Rf = 0.20 (EtOAc/Hexane 10:90). H
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NMR (400 MHz, CDCl3): δ 10.45 (d, J = 0.8 Hz, 1H), 8.12 (dd, J = 8.3, 0.7 Hz, 1H), 7.96 (d,
J = 8.6 Hz, 1H), 7.87ꢀ7.75 (m, 2H), 7.56 (ddd, J = 8.3, 6.9, 1.3 Hz, 2H), 7.34 (s, 1H), 2.46
(dd, J = 22.9, 6.7 Hz, 2H), 1.91ꢀ1.65 (m, 5H), 1.58ꢀ1.50 (m, 1H), 1.33ꢀ1.17 (m, 3H), 1.05 (d,
J = 10.6 Hz, 2H), 0.86 (s, 6H), 0.78 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 193.0, 144.3,
135.7, 134.5, 132.5, 131.5, 128.4, 128.1, 127.3, 126.9, 126.4, 121.9, 83.2, 45.5, 38.1, 33.5,
26.5, 26.4, 24.2 (the carbon α to boron was not found). HRMS (ESI+): m/z (M+Na)+
calculated for C26H33O3BNa 427.2420, found 427.2424.
(E)-4-(3-Cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-
enyl)benzo[d][1,3]dioxole-5-carbaldehyde (2k). 181 mg (57%). Yellow solid (m.p = 81ꢀ85
oC), Rf = 0.50 (EtOAc/Hexane 20:80). 1H NMR (400 MHz, CDCl3): δ 10.26 (s, 1H), 7.14 (s,
1H), 6.88 (d, J = 7.9 Hz, 1H), 6.74 (dd, J = 8.0, 0.8 Hz, 1H), 6.12 (s, 2H), 2.22 (dd, J = 7.1,
0.9 Hz, 2H), 1.81ꢀ1.65 (m, 5H), 1.44 (ddd, J = 11.0, 7.4, 3.6 Hz, 1H), 1.25ꢀ1.15 (m, 3H), 1.14
13
(s, 12H), 0.99ꢀ0.85 (m, 2H). C NMR (101 MHz, CDCl3): δ 189.6, 148.3, 147.7, 137.3,
135.6, 123.1, 117.5, 112.2, 102.5, 83.4, 45.5, 37.9, 33.3, 26.5, 26.4, 24.6 (the carbon α to
boron was not found). HRMS (ESI+): m/z (M+Na)+ calculated for C23H31O5BNa 421.2162,
found 421.2162.
(E)-2-(3-Phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-
enyl)benzaldehyde (2m). 151 mg (52%). Colourless oil, Rf = 0.10 (EtOAc/Hexane 10:90). 1H
NMR (400 MHz, CDCl3): δ 10.27 (s, 1H), 7.85 (dd, J = 7.7, 1.4 Hz, 1H), 7.51ꢀ7.43 (m, 1H),
7.40ꢀ7.34 (m, 2H), 7.33ꢀ7.28 (m, 5H), 7.23ꢀ7.14 (m, 1H), 3.70 (d, J = 1.4 Hz, 2H), 0.96 (s,
12H). 13C NMR (101 MHz, CDCl3): δ 192.2, 142.4, 139.9, 137.9, 133.7, 133.0, 130.42,
129.2, 128.6, 128.3, 127.4, 126.1, 83.5, 43.4, 24.4 (the carbon α to boron was not found).
HRMS (ESI+): m/z (M+H)+ calculated for C22H26O3B 349.1975, found 349.1970.
(E)-2-(5-(tert-Butyldimethylsilyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)pent-1-enyl)benzaldehyde (2p). 154 mg (58%). Colorless oil, Rf = 0.10 (EtOAc/Hexane
10:90). 1H NMR (400 MHz, CDCl3): δ 10.27 (s, 1H), 7.86 (dd, J = 7.7, 1.0 Hz, 1H), 7.47 (td,
J = 7.5, 1.2 Hz, 1H), 7.40ꢀ7.27 (m, 3H), 3.68 (t, J = 6.5 Hz, 2H), 2.48ꢀ2.32 (m, 2H), 1.82ꢀ
13
1.64 (m, 2H), 1.09 (s, 12H), 0.99ꢀ0.85 (m, 12H), 0.07 (s, 6H). C NMR (101 MHz, CDCl3):
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δ 192.2, 142.9, 136.8, 133.7, 133.0, 130.3, 128.0, 127.2, 83.5, 62.7, 33.8, 32.8, 26.0, 24.5,
18.3, ꢀ5.1 (the carbon α to boron was not found). HRMS (ESI+): m/z (M+NH4)+ calculated
for C24H43NO4BSi 448.3054, found 448.3055.
(E)-5-(tert-Butyldimethylsilyloxy)-2-(5-(tert-butyldimethylsilyloxy)-2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)pent-1-enyl)-4-methoxybenzaldehyde (2q). 219 mg
(56%). Colorless oil, Rf = 0.30 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 10.06
(s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.74 (s, 1H), 3.87 (s, 3H), 3.68 (t, J = 6.5 Hz, 2H), 2.39
(dd, J = 8.0, 6.6 Hz, 2H), 1.79ꢀ1.70 (m, 2H), 1.08 (s, 12H), 0.99 (s, 9H), 0.91 (s, 9H), 0.15 (s,
6H), 0.07 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 190.8, 155.2, 144.3, 139.1, 136.4, 127.6,
118.9, 112.8, 83.4, 62.8, 55.5, 33.6, 32.9, 26.0, 25.7, 24.6, 18.5, 18.3, ꢀ4.6, ꢀ5.1 (the carbon α
to boron was not found). HRMS (ESI+): m/z (M+Na)+ calculated for C31H55O6BNaSi2
613.3528, found 613.3538.
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(E)-5-Fluoro-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-
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enyl)benzaldehyde (2r). 95 mg (32%). Colourless oil, Rf = 0.10 (EtOAc/Hexane 5:95). H
NMR (400 MHz, CDCl3): δ 10.22 (d, J = 3.0 Hz, 1H), 7.54 (dd, J = 9.0, 2.8 Hz, 1H), 7.29ꢀ
7.24 (m, 1H), 7.17 (dt, J = 8.3, 2.8 Hz, 2H), 2.36 (td, J = 7.7, 1.3 Hz, 2H), 1.55ꢀ1.44 (m, 2H),
1.41ꢀ1.34 (m, 2H), 1.09 (s, 12H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ
191.0, 161.9 (d, J = 248 Hz), 139.3 (d, J = 2.6 Hz), 135.4 (d, J = 6 Hz), 135.2, 132.3 (d, J = 7
Hz), 120.1 (d, J = 22 Hz), 113.4 (d, J = 22 Hz), 83.5, 37.1, 31.8, 24.5, 22.4, 14.0 (the carbon
α to boron was not found). HRMS (ESI+): m/z (M+Na)+ calculated for C19H26O3BFNa
355.1857, found 355.1856.
(E)-2-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)oct-4-en-4-yl)benzaldehyde (2s). 155
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mg (55%). Yellow solid (m.p = 52ꢀ55 C), Rf = 0.10 (EtOAc/Hexane 5:95). H NMR (400
MHz, CDCl3): δ 10.15 (d, J = 0.6 Hz, 1H), 7.89 (dd, J = 7.8, 1.1 Hz, 1H), 7.47 (td, J = 7.5,
1.4 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.18 (dd, J = 7.6, 0.7 Hz, 1H), 2.52ꢀ2.26 (m, 4H), 1.52ꢀ
1.44 (m, 2H), 1.38ꢀ1.24 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H), 0.93ꢀ0.84 (m, 15H). 13C NMR (101
MHz, CDCl3): δ 192.9, 149.2, 146.4, 134.3, 132.9, 130.2, 126.7, 126.3, 82.9, 37.3, 33.0, 24.3,
23.2, 20.7, 14.6, 14.3 (the carbon α to boron was not found). HRMS (ESI+): m/z (M+H)+
calculated for C21H32O3B 343.2444, found 343.2444.
(E)-Methyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-enyl)benzoate (2t).
160 mg (52%). Colorless oil, Rf = 0.20 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3):
δ 7.92 (dd, J = 7.8, 1.1 Hz, 1H), 7.41 (s, 1H), 7.39ꢀ7.34 (m, 1H), 7.31 (ddd, J = 6.4, 3.5, 1.2
Hz, 1H), 7.28ꢀ7.25 (m, 1H), 3.86 (s, 3H), 2.33 (ddd, J = 7.7, 1.2, 1.2 Hz, 2H), 1.56ꢀ1.44 (m,
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2H), 1.42ꢀ1.36 (m, 2H), 1.14 (s, 12H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3):
δ 167.7, 141.4, 140.4, 131.3, 130.8, 130.2, 128.4, 126.7, 83.2, 51.8, 37.1, 31.9, 24.6, 22.4,
14.0 (the carbon α to boron was not found). HRMS (ESI+): m/z (M+Na)+ calculated for
C20H29O4BNa 367.2057, found 367.2068.
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(E)-1-(2-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-enyl)phenyl)ethanone
(2u). 164 mg (56%). Colorless oil, Rf = 0.30 (EtOAc/Hexane 10:90). 1H NMR (500 MHz,
CDCl3): δ 7.65 (dd, J = 8.0, 1.3 Hz, 1H), 7.37ꢀ7.32 (m, 1H), 7.31ꢀ7.26 (m, 2H), 7.23 (s, 1H),
2.55 (s, 3H), 2.37ꢀ2.25 (m, 2H), 1.53ꢀ1.45 (m, 2H), 1.43ꢀ1.35 (m, 2H), 1.13 (s, 12H), 0.93 (t,
J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3): 13C NMR (126 MHz, CDCl3): δ 201.5, 140.4,
139.6, 137.6, 130.9, 130.9, 128.6, 126.9, 83.2, 37.1, 31.9, 30.1, 24.6, 22.5, 14.1 (the carbon α
to boron was not found). HRMS (ESI+): m/z (M+Na)+ calculated for C20H29O3BNa 351.2107,
found 351.2112.
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(E)-2-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-enyl)benzamide (2v). 183
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mg (62%). Colorless oil, Rf = 0.40 (MeOH/CHCl3 10:90). H NMR (500 MHz, CDCl3): δ
7.67 (d, J = 6.9 Hz, 1H), 7.31 (t, J = 6.6 Hz, 2H), 7.20 (d, J = 6.8 Hz, 1H), 7.11 (s, 1H), 6.45
(br, 1H), 5.72 (br, 1H), 2.32 (t, J = 7.3 Hz, 2H), 1.50ꢀ1.44 (m, 2H), 1.39ꢀ1.33 (m, 2H), 1.10
(s, 12H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 171.2, 138.9, 137.7, 133.8,
130.1, 130.0, 128.1, 127.3, 83.6, 36.6, 31.6, 29.7, 24.5, 22.4, 13.9 (the carbon α to boron was
not found). HRMS (ESI+): m/z (M+Na)+ calculated for C19H28O3NBNa 352.2060, found
352.2086.
(E)-3-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-enyl)thiophene-2-
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carbaldehyde (6a). 168 mg (59%). Colorless oil, Rf = 0.20 (EtOAc/Hexane 10:90). H NMR
(500 MHz, CDCl3): δ 9.95 (d, J = 1.2 Hz, 1H), 7.56 (dd, J = 5.0, 1.1 Hz, 1H), 7.19ꢀ7.11 (m,
1H), 7.06 (s, 1H), 2.36 (td, J = 7.7, 1.3 Hz, 2H), 1.52ꢀ1.46 (m, 2H), 1.41ꢀ1.35 (m, 2H), 1.18
(s, 12H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 183.4, 149.0, 138.8, 132.9,
130.6, 130.1, 83.8, 37.6, 31.7, 24.7, 22.4, 13.9 (the carbon α to boron was not found). HRMS
(ESI+): m/z (M+Na)+ calculated for C17H25O3BNaS 343.1515, found 343.1513.
(E)-3-(3-Cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-
o
enyl)thiophene-2-carbaldehyde (6b). 184 mg (64%). Yellow solid (m.p = 55ꢀ58 C), Rf =
0.20 (EtOAc/Hexane 10:90). 1H NMR (500 MHz, CDCl3): δ 9.96 (d, J = 1.0 Hz, 1H), 7.56
(dd, J = 5.0, 0.6 Hz, 1H), 7.15 (d, J = 5.0 Hz, 1H), 7.01 (s, 1H), 2.25 (d, J = 7.1 Hz, 2H),
1.80ꢀ1.57 (m, 5H), 1.52ꢀ1.38 (m, 1H), 1.31ꢀ1.11 (m, 3H), 1.08 (s, 12H), 0.99ꢀ0.84 (m, 2H).
13C NMR (126 MHz, CDCl3): δ 183.5, 148.9, 138.8, 132.9, 131.6, 130.2, 83.7, 46.0, 37.9,
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33.3, 26.5, 26.3, 24.6 (the carbon α to boron was not found). HRMS (ESI+): m/z (M+Na)+
calculated for C20H29O3BNaS 383.1828, found 383.1831.
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(E)-3-(3-Phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enyl)thiophene-2-
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carbaldehyde (6c). 167 mg (58%).White solid (m.p = 95ꢀ98 C), Rf = 0.30 (EtOAc/Hexane
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10:90). H NMR (400 MHz, CDCl3): δ 9.95 (d, J = 1.1 Hz, 1H), 7.57 (dd, J = 5.0, 0.9 Hz,
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1H), 7.32ꢀ7.21 (m, 5H), 7.19 (d, J = 5.3 Hz, 1H), 7.11 (s, 1H), 3.69 (d, J = 1.1 Hz, 2H), 1.04
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(s, 12H). C NMR (126 MHz, CDCl3): δ 183.2, 148.3, 139.4, 139.1, 133.0, 131.9, 130.1,
129.2, 128.4, 126.3, 83.8, 43.8, 24.5 (the carbon α to boron was not found). HRMS (ESI+):
m/z (M+) calculated for C20H23O3BS 354.1461, found 354.1460.
(E)-3-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-enyl)benzo[b]thiophene-2-
carbaldehyde (6d). 172 mg (52%). Colourless oil, Rf = 0.10 (EtOAc/Hexane 10:90). 1H NMR
(500 MHz, CDCl3): δ 10.08 (s, 1H), 7.89ꢀ7.78 (m, 2H), 7.52ꢀ7.45 (m, 1H), 7.40 (ddd, J = 8.1,
7.1, 1.1 Hz, 1H), 7.06 (s, 1H), 2.47 (td, J = 7.6, 1.3 Hz, 2H), 1.62ꢀ1.52 (m, 2H), 1.44ꢀ1.43 (m,
2H), 1.00 (s, 12H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 185.9, 145.5,
141.3, 139.7, 139.1, 129.9, 127.9, 124.9, 124.7, 123.0, 83.6, 37.2, 31.8, 24.4, 22.4, 14.0 (the
carbon α to boron was not found). HRMS (ESI+): m/z (M+H)+ calculated for C21H28O3BS
371.1852, found 371.1851.
General Procedure for the Synthesis of vinyl Azides from Boronates 2 or 6a. Synthesis of
compounds 3a-3u and 7a-7d. To a stirred solution of boronic ester 2 or 6 (0.477 mmol) in
MeOH (2 mL), sodium azide (0.572 mmol) and copper sulfate (0.298 mmol) were added at
room temperature and stirred for 6 h. The reaction mixture was diluted with water and
extracted with CH2Cl2 (2 x 5 mL). The combined organic extracts were dried (MgSO4) and
evaporated under vacuum. The resulting residue was purified by column chromatography
(230ꢀ400 mesh Silica gel, EtOAc in Hexane) to give vinyl azide 3 or 7 in 69ꢀ92% yield.
(Z)-2-(2-Azidohex-1-enyl)benzaldehyde (3a). 99 mg (91%). Colorless oil, Rf= 0.10
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(EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 10.15 (s, 1H), 7.83 (dd, J = 7.7, 1.3
Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.54 (td, J = 7.6, 1.4 Hz, 1H), 7.37 (td, J = 7.7, 0.9 Hz,
1H), 6.30 (s, 1H), 2.49 (dd, J = 11.5, 3.8 Hz, 2H), 1.70ꢀ1.63 (m, 2H), 1.51ꢀ148 (m, 2H), 1.00
(t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 192.4, 139.3, 137.7, 133.3, 133.0, 130.6,
130.4, 127.1, 111.1, 33.4, 30.0, 22.1, 13.8. IR (neat): 3056, 2957, 2930, 2865, 2110, 1695,
1630, 1591. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C13H16ON 202.1232, found
202.1231.
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(Z)-2-(2-Azidohex-1-enyl)-5-methoxybenzaldehyde (3b). 85 mg (75%). Colorless oil, Rf=
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0.10 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 10.13 (s, 1H), 7.53ꢀ7.46 (m,
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1H), 7.35 (d, J = 2.9 Hz, 1H), 7.14ꢀ7.08 (m, 1H), 6.15 (s, 1H), 3.86 (s, 3H), 2.50ꢀ2.45 (m,
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2H), 1.67ꢀ1.64 (m, 2H), 1.53ꢀ1.44 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). C NMR (126 MHz,
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CDCl3): δ 191.9, 158.6, 138.6, 134.0, 131.7, 130.9, 120.7, 112.4, 110.4, 55.5, 33.3, 30.0,
22.1, 13.8. IR (neat): 2956, 2864, 2108, 1717, 1595, 1494. HRMS (ESI+): m/z (MꢀN2+H)+
calculated for C14H18NO2 232.1338, found 232.1345.
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(Z)-2-(2-Azidohex-1-enyl)-5-methylbenzaldehyde (3c). 87 mg (78%). Colorless oil, Rf=
0.10 (EtOAc/Hexane 5:95). 1H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 7.73 (d, J = 7.9 Hz,
1H), 7.42 (s, 1H), 7.18 (d, J= 7.9 Hz, 1H), 6.27 (s, 1H), 2.53ꢀ2.45 (m, 2H), 2.42 (s, 3H), 1.72ꢀ
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1.62 (m, 2H), 1.51ꢀ1.47 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). C NMR (126 MHz, CDCl3): δ
192.1, 144.2, 139.0, 137.6, 130.9, 130.90, 130.8, 128.0, 111.2, 33.4, 30.0, 22.1, 21.9, 13.8. IR
(neat): 2958, 2929, 2865, 2113, 1692, 1634, 1601, 1563. HRMS (ESI+): m/z (MꢀN2+H)+
calculated for C14H18ON 216.1382, found 216.1396.
(Z)-1-(2-Azidohex-1-enyl)naphthalene (3d). 87 mg (76%). Colorless oil, Rf= 0.10
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(EtOAc/Hexane 5:95). H NMR (300 MHz, CDCl3): δ 10.31 (s, 1H), 8.07 (d, J = 8.2 Hz,
1H), 7.99 (d, J = 8.6 Hz, 1H), 7.86 (t, J = 9.3 Hz, 2H), 7.63 (dd, J = 10.2, 6.2 Hz, 1H), 7.59
(dd, J = 10.0, 6.3 Hz, 1H), 6.22 (s, 1H), 2.69ꢀ2.58 (m, 2H), 1.88ꢀ1.69 (m, 2H), 1.61ꢀ1.56 (m,
2H), 1.06 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 192.6, 142.5, 139.0, 136.0,
131.6, 131.0, 128.7, 128.6, 128.1, 126.8, 126.0, 122.4, 33.1, 30.1, 22.3, 13.8. IR (neat) :
2956, 2928, 2865, 2107, 1710, 1625, 1591. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for
C17H18NO 252.1388, found 252.1391.
(Z)-2-(2-Azidohex-1-enyl)-4,5-dimethoxybenzaldehyde (3e). 107 mg (92%). Colorless oil,
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Rf= 0.30 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 10.07 (s, 1H), 7.36 (s, 1H),
7.06 (s, 1H), 6.18 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 2.54ꢀ2.43 (m, 2H), 1.72ꢀ1.62 (m, 2H),
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1.54ꢀ1.43 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3): δ 190.3, 153.3,
148.2, 139.1, 133.2, 126.5, 112.0, 110.18, 110.1, 56.1, 56.0, 33.4, 30.0, 22.1, 13.8. IR (neat):
3316, 2956, 2864, 2113, 1716, 1680, 1630, 1597. HRMS (ESI+): m/z (MꢀN2+H)+ calculated
for C15H20NO3 262.1443, found 262.1446.
(Z)-2-(2-Azidohex-1-enyl)-5-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde
(3f).
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105 mg (85%). Colorless oil, Rf= 0.10 (EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3):
δ 9.99 (s, 1H), 7.29 (s, 1H), 7.14 (s, 1H), 6.29 (s, 1H), 3.90 (s, 1H), 2.54ꢀ2.41 (m, 2H), 1.68ꢀ
1.64 (m, 2H), 1.51ꢀ1.47 (m, 2H), 1.03ꢀ0.95 (m, 12H), 0.19ꢀ0.14 (m, 6H). 13C NMR (101
MHz, CDCl3): δ 190.7, 155.3, 144.1, 138.3, 133.1, 126.7, 121.7, 112.71, 110.7, 55.6, 55.5,
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33.6, 30.1, 25.6, 22.1, 18.4, 13.8, ꢀ4.5. IR (neat):3303, 2956, 2931, 2858, 2112, 1682, 1601.
HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C20H32O3NSi 362.2152, found 362.2171.
(Z)-4-(2-Azidohex-1-enyl)benzo[d][1,3]dioxole-5-carbaldehyde (3g). 86 mg (75%).
Colorless oil, Rf= 0.20 (EtOAc/Hexane 10:90). 1H NMR (500 MHz, CDCl3): δ 10.19 (s, 1H),
7.08 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 6.11 (s, 2H), 2.49ꢀ2.41 (m,
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2H), 1.69ꢀ1.59 (m, 2H), 1.52ꢀ1.41 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). C NMR (126 MHz,
CDCl3): δ 188.9, 149.9, 147.3, 138.1, 130.0, 123.4, 116.9, 111.2, 102.5, 33.3, 29.7, 22.1,
14.0, 13.8. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C14H16NO3 246.1130, found
246.1132.
(Z)-2-(2-Azido-3-cyclohexylprop-1-enyl)benzaldehyde (3h). 97 mg (85%). Colorless oil,
Rf= 0.10 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 10.16 (s, 1H), 7.83 (dd, J =
7.7, 1.3 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.54 (td, J = 7.6, 1.4 Hz, 1H), 7.37 (td, J = 7.7, 1.1
Hz, 1H), 6.25 (s, 1H), 2.37 (d, J = 7.2 Hz, 2H), 1.89 (d, J = 1.8 Hz, 1H), 1.87 (d, J = 1.8 Hz,
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1H), 1.82ꢀ1.73 (m, 3H), 1.61ꢀ1.57 (m, 1H), 1.34ꢀ1.18 (m, 3H), 1.05ꢀ1.02 (m, 2H). C NMR
(101 MHz, CDCl3): δ 192.4, 137.9, 137.6, 133.3, 132.9, 130.5, 130.4, 127.1, 112.4, 41.8,
36.5, 33.0, 26.3, 26.1. IR (neat) : 2924, 2850, 2112, 1696, 1630, 1594. HRMS (ESI+): m/z
(MꢀN2+H)+ calculated for C16H20ON 242.1545, found 242.1554.
(Z)-2-(2-Azido-3-cyclohexylprop-1-enyl)-5-methoxybenzaldehyde (3i). 92 mg (79%).
Colorless oil, Rf= 0.10 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 10.14 (s, 1H),
7.51 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 2.9 Hz, 1H), 7.18ꢀ7.02 (m, 1H), 6.10 (s, 1H), 3.86 (s,
3H), 2.35 (d, J = 7.2 Hz, 2H), 1.92ꢀ1.65 (m, 5H), 1.60ꢀ1.58 (m, 1H), 1.38ꢀ1.14 (m, 3H), 1.04ꢀ
1.01 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 191.8, 158.6, 137.1, 134.0, 131.7, 130.9, 120.7,
112.3, 111.8, 55.5, 41.6, 36.5, 33.0, 26.3, 26.1. IR (neat): 2924, 2849, 2113, 1690, 1635,
1599. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C17H22O2N 272.1651, found 272.1662.
(Z)-1-(2-Azido-3-cyclohexylprop-1-enyl)-2-naphthaldehyde (3j). 96 mg (81%). Colorless
oil, Rf= 0.10 (EtOAc/Hexane 5:95). 1H NMR (400 MHz, CDCl3): δ 10.32 (d, J = 0.8 Hz, 1H),
8.08 (dd, J = 8.3, 0.7 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.89ꢀ7.81 (m, 2H), 7.65ꢀ7.54 (m,
2H), 6.19 (s, 1H), 2.52 (d, J = 7.1 Hz, 2H), 2.03ꢀ1.92 (m, 2H), 1.87ꢀ1.78 (m, 2H), 1.78ꢀ1.66
(m, 2H), 1.40ꢀ1.24 (m, 3H), 1.20ꢀ1.08 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 192.6, 141.1,
139.0, 136.0, 131.7, 131.0, 128.7, 128.63, 128.2, 126.8, 125.9, 122.4, 109.2, 41.6, 36.4, 33.2,
26.2, 26.1. IR (neat) : 2924, 2850, 2114, 1684, 1642, 1591. HRMS (ESI+): m/z (Mꢀ
N2+H)+calculated for C20H22ON 292.1701, found 292.1712.
(Z)-4-(2-Azido-3-cyclohexylprop-1-enyl)benzo[d][1,3]dioxole-5-carbaldehyde (3k). 99
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mg (84%). Colorless oil, Rf= 0.10 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ
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10.20 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.13 (s, 1H), 6.11 (s, 2H),
2.33 (d, J = 7.2 Hz, 2H), 1.86 (d, J = 13.2 Hz, 2H), 1.81ꢀ1.68 (m, 3H), 1.63ꢀ1.58 (m, 1H),
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1.35ꢀ1.26 (m, 3H), 1.09ꢀ0.96 (m, 2H). C NMR (101 MHz, CDCl3): δ 188.9, 149.8, 147.3,
136.7, 130.0, 123.5, 116.9, 112.7, 112.6, 102.5, 41.7, 36.5, 32.9, 26.3, 26.1. IR (neat): 2923,
2853, 2115, 1688, 1630. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C17H20O3N 286.1443,
found 286.1454.
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(Z)-2-(2-Azido-3-cyclohexylprop-1-enyl)-5-(tert-butyldimethylsilyloxy)-4-
methoxybenzaldehyde (3l). 103 mg (82%). Colorless oil, Rf= 0.10 (EtOAc/Hexane 10:90).
1H NMR (500 MHz, CDCl3) δ 10.00 (s, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 6.25 (s, 1H), 3.90 (s,
3H), 2.35 (d, J = 7.1 Hz, 2H), 1.87 (d, J = 12.0, Hz, 2H), 1.77 (d, J = 12.9 Hz, 2H), 1.64ꢀ1.50
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(m, 2H), 1.37ꢀ1.21 (m, 3H), 1.11ꢀ0.90 (m, 11H), 0.17 (s, 6H). C NMR (100 MHz, CDCl3):
δ 190.6, 155.4, 144.0, 136.7, 133.1, 126.6, 121.5, 112.6, 112.0, 55.5, 41.9, 36.4, 32.9, 26.1,
26.2, 25.6, 18.5, ꢀ4.6. IR (neat) : 2928, 2854, 2116, 1685, 1629, 1595. HRMS (ESI+): m/z
(MꢀN2+H)+ calculated for C23H36O3NSi 402.2465, found 402.2482.
(Z)-2-(2-Azido-3-phenylprop-1-enyl)benzaldehyde(3m). 88 mg (78%). Colorless oil, Rf=
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0.10 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3) δ 10.14 (s, 1H), 7.83 (d, J = 7.5
Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.39ꢀ7.37 (m, 5H), 7.32ꢀ7.29 (m,
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1H), 6.36 (s, 1H), 3.84 (s, 2H). C NMR (126 MHz, CDCl3): δ 192.4, 137.8, 137.2, 136.0,
133.3, 130.9, 130.5, 130.4, 128.9, 128.9, 113.3, 40.5. IR (neat): 2924, 2851, 2111, 1693,
1630, 1595. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C16H14ON 236.1075, found
236.1086.
(Z)-2-(2-Azido-3-phenylprop-1-enyl)-5-methoxybenzaldehyde (3n). 84 mg (72%).
Colorless oil, Rf= 0.30 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 10.12 (s, 1H),
7.56 (d, J = 8.6 Hz, 1H), 7.40ꢀ7.34 (m, 5H), 7.31 (d, J = 4.3 Hz, 1H), 7.11 (dd, J = 8.6, 2.9
Hz, 1H), 6.21 (s, 1H), 3.86 (s, 3H), 3.83 (s, 2H). 13C NMR (101 MHz, CDCl3): δ 191.8,
158.8, 137.0, 136.1, 134.1, 131.8, 130.4, 128.9, 128.8, 127.3, 120.6, 112.8, 112.6, 55.5, 40.3.
IR (neat) : 2924, 2851, 2109, 1689, 1631, 1598. HRMS (ESI+): m/z (MꢀN2+H)+ calculated
for C17H16O2N 266.1181, found 266.1192.
(Z)-2-(2-Azido-3-phenylprop-1-enyl)-4,5-dimethoxybenzaldehyde (3o). 108 mg (91%).
Colorless oil, Rf= 0.40 (EtOAc/Hexane 20:80). 1H NMR (500 MHz, CDCl3): δ 10.06 (s, 1H),
7.42ꢀ7.35 (m, 5H), 7.34ꢀ7.31 (m, 1H), 7.11 (s, 1H), 6.22 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H),
3.83 (s, 2H). 13C NMR (126 MHz, CDCl3): δ 190.2, 153.3, 148.3, 137.6, 135.9, 132.8, 129.0,
128.9, 127.4, 126.6, 112.2, 112.0, 110.4, 56.2, 56.0, 40.4. IR (neat): 2926, 2851, 2118, 2086,
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1677, 1632, 1594. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C18H18O3N 296.1287, found
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296.1297.
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(Z)-2-(2-Azido-5-(tert-butyldimethylsilyloxy)pent-1-enyl)benzaldehyde (3p). 97 mg (80%).
Colorless oil, Rf= 0.10 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H),
7.78 (dd, J = 7.7, 1.1 Hz, 1H), 7.61ꢀ7.55 (m, 1H), 7.48 (dt, J = 13.4, 2.9 Hz, 1H), 7.32 (t, J =
7.2 Hz, 1H), 6.25 (s, 1H), 3.70 (t, J = 6.0 Hz, 2H), 2.70ꢀ2.32 (m, 2H), 1.92ꢀ1.71 (m, 2H), 0.86
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(s, 9H), 0.03 (s, 6H). C NMR (101 MHz, CDCl3): δ 192.3, 139.1, 137.6, 133.3, 133.0,
130.5, 130.3, 127.1, 111.1, 61.6, 31.0, 30.1, 26.0 25.9, ꢀ5.3. HRMS (ESI+): m/z (MꢀN2+H)+
calculated for C18H28NO2Si 318.1889, found 318.1890.
(Z)-2-(2-Azido-5-(tert-butyldimethylsilyloxy)pent-1-enyl)-5-(tert-butyldimethylsilyloxy)-
4-methoxybenzaldehyde (3q). 108 mg (84%). Colorless oil, Rf= 0.15 (EtOAc/Hexane 10:90).
1H NMR (400 MHz, CDCl3): δ 9.99 (s, 1H), 7.29 (s, 1H), 7.13 (s, 1H), 6.30 (s, 1H), 3.89 (s,
3H), 3.75 (t, J = 6.0 Hz, 2H), 2.62ꢀ2.50 (m, 2H),1.91ꢀ1.84 (m, 2H), 1.00 (s, 9H), 0.92 (s, 9H),
0.17 (s, 6H), 0.08 (s, 6H).13C NMR (101 MHz, CDCl3): δ 190.7, 155.3, 144.1, 138.1, 133.0,
126.7, 121.6, 112.6, 110.8, 61.7, 55.6, 31.0, 30.2, 25.9, 25.6, 18.4, 18.3, ꢀ4.5, ꢀ5.2. IR (neat):
2954, 2930, 2857, 2112, 1688, 1599. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for
C25H44O4NSi2 478.2809, found 478.2837.
(Z)-2-(2-Azidohex-1-enyl)-5-fluorobenzaldehyde (3r). 96 mg (86%). Colorless oil, Rf=
1
0.10 (EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 10.11 (d, J = 2.3 Hz, 1H), 7.57
(dd, J = 8.6, 5.3 Hz, 1H), 7.52 (dd, J = 8.8, 2.9 Hz, 1H), 7.28ꢀ7.19 (m, 1H), 6.14 (s, 1H),
2.54ꢀ2.41 (m, 2H), 1.68ꢀ1.64 (m, 2H), 1.51ꢀ1.46 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 190.8, 162.7, 139.8, 134.6 (d, J = 5.7 Hz), 134.0 (d, J = 3.0 Hz), 132.4
(d, J = 7.0 Hz), 120.6 (d, J = 21. Hz), 115.61 (d, J = 22. Hz), 109.7, 33.3, 29.9, 22.1, 13.8. IR
(neat): 2958, 2930, 2862, 2112, 1694, 1638, 1592. HRMS (ESI+): m/z (MꢀN2+H)+ calculated
for C13H15ONF 220.1138, found 220.1147.
(Z)-2-(5-Azidooct-4-en-4-yl)benzaldehyde (3s). 99 mg (84%). Colorless oil, Rf= 0.10
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(EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 10.03 (s, 1H), 7.94 (d, J = 7.7 Hz,
1H), 7.58 (dd, J = 10.8, 4.2 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 2.60ꢀ
2.45 (m, 2H), 2.43ꢀ2.29 (m, 2H), 1.72ꢀ1.62 (m, 2H), 1.32ꢀ1.27 (m, 2H), 1.08 (t, J = 7.4 Hz,
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3H), 0.88 (t, J = 7.3 Hz, 3H). C NMR (126 MHz, CDCl3): δ 192.5, 159.2, 156.6, 133.6,
129.3, 127.4, 123.3, 122.1, 121.9, 36.5, 30.4, 21.8, 21.6, 14.1, 13.7. HRMS (ESI+): m/z (Mꢀ
N2+H)+ calculated for C15H20ON 230.1545, found 230.1550.
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(Z)-Methyl 2-(2-azidohex-1-enyl)benzoate (3t). 89 mg (79%). Colorless oil, Rf= 0.10
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5
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(EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 7.89 (dd, J = 7.9, 1.3 Hz, 1H), 7.73
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(d, J = 7.9 Hz, 1H), 7.47 (td, J = 7.6, 1.3 Hz, 1H), 7.29ꢀ7.22 (m, 1H), 6.33 (s, 1H), 3.87 (s,
3H), 2.50ꢀ2.42 (m, 2H), 1.65 (ddd, J = 12.6, 8.5, 6.3 Hz, 2H), 1.48 (dd, J = 14.9, 7.4 Hz, 2H),
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0.99 (t, J = 7.3 Hz, 3H). C NMR (126 MHz, CDCl3): δ 167.8, 136.4, 136.3, 131.5, 130.7,
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130.3, 128.7, 126.5, 114.0, 51.9, 33.5, 30.0, 22.0, 13.8. IR (neat): 2956, 2868, 2109, 1721,
1638, 1598, 1568. HRMS (ESI+): m/z (MꢀN2+H)+calculated for C14H18NO2 232.1338, found
232.1345
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(Z)-1-(2-(2-Azidohex-1-enyl)phenyl)ethanone(3u). 93 mg (84%). Colorless oil, Rf= 0.10
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(EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 7.79ꢀ7.54 (m, 2H), 7.44 (td, J = 7.8,
1.2 Hz, 1H),7.28 (t, J = 7.6 Hz, 1H), 6.12 (s, 1H), 2.56 (s, 3H), 2.43 (dd, J = 9.9, 5.4 Hz, 2H),
1.71ꢀ1.55 (m, 2H), 1.52ꢀ1.42 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3):
δ 201.8, 137.5, 136.6, 134.4, 131.0, 130.8, 128.7, 126.6, 114.0, 33.4, 29.9, 29.6, 22.1, 13.8.
IR (neat): 2958, 2930, 2867, 2110, 1683, 1638, 1595, 1565. HRMS (ESI+): m/z (MꢀN2+H)+
calculated for C14H18ON 216.1382, found 216.1396.
(Z)-2-(2-Azidohex-1-enyl)benzamide (3v). 96 mg (86%). Colorless oil, Rf= 0.30
(EtOAc/Hexane 30:70). 1H NMR (500 MHz, CDCl3):δ 7.79 (d, J = 7.9 Hz, 1H), 7.55 (dd, J =
7.7, 1.3 Hz, 1H), 7.41 (td, J = 7.7, 1.3 Hz, 1H), 7.26ꢀ7.22 (m, 1H), 6.04 (s, 1H), 5.79 (br, 2H),
2.49ꢀ2.41 (m, 2H), 1.65ꢀ1.60 (m, 2H), 1.46ꢀ1.43 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 171.1, 137.6, 133.2, 133.0, 130.1, 130.1, 127.5, 126.8, 112.4, 33.6,
30.0, 22.1, 13.8. IR (neat): 2956, 2864, 2108, 1717, 1595, 1494. IR (neat) : 3365, 3178, 2926,
2857, 2105, 1644, 1453. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C13H17N2O 217.1341,
found 217.1328.
(Z)-3-(2-Azidohex-1-enyl)thiophene-2-carbaldehyde (7a). 97 mg (88%). Colorless oil, Rf=
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0.10 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 10.03 (s, 1H), 7.76 (d, J = 5.2
Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H), 6.30 (s, 1H), 2.55ꢀ2.43 (m, 2H), 1.65 (dt, J = 12.7, 7.5 Hz,
2H), 1.52ꢀ1.43 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 182.1,
143.4, 140.1, 137.3, 133.7, 130.2, 106.4, 33.8, 30.1, 22.1, 13.8. IR (neat): 2958, 2930, 2867,
2112, 1655, 1627, 1522. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C11H14NOS 208.0796,
found 208.0807.
(Z)-3-(2-Azido-3-cyclohexylprop-1-enyl) thiophene-2-carbaldehyde (7b). 105 mg (92%).
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Colorless oil, Rf= 0.10 (EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 10.03 (d, J =
0.8 Hz, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H), 6.24 (s, 1H), 2.37 (d, J = 7.2
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Hz, 2H), 1.91ꢀ1.71 (m, 5H), 1.62ꢀ1.59 (m, 1H), 1.37ꢀ1.14 (m, 3H), 1.03ꢀ1.00 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 182.1, 143.4, 138.7, 137.3, 133.7, 130.1, 107.7, 42.0, 36.7, 32.9,
26.2, 26.1. HRMS (ESI+): m/z (MꢀN2+H)+ calculated for C14H18NOS 248.1109, found
248.1130.
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(Z)-3-(2-Azido-3-phenylprop-1-enyl) thiophene-2-carbaldehyde (7c). 99 mg (87%).
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Colorless oil, Rf= 0.20 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 9.97 (d, J =
0.6 Hz, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.64 (d, J = 5.1 Hz, 1H), 7.44ꢀ7.28 (m, 5H), 6.31 (s,
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1H), 3.85 (s, 2H). C NMR (101 MHz, CDCl3): δ 182.1, 143.0, 138.4, 137.7, 135.6, 133.8,
130.1, 129.0, 128.8, 127.5, 108.2, 40.7. IR (neat): 3448, 3086, 2923, 2127, 1651, 1622.
HRMS (ESI+): m/z (M+Na)+ calculated for C14H11ON3SNa 292.0520, found 292.0532.
(Z)-3-(2-
A
zidohex-1-enyl)benzo[b]thiophene-2-carbaldehyde (7d). 97 mg (75%).
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Colourless oil, Rf= 0.10 (EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 10.15 (s,
1H), 7.88ꢀ7.84 (m, 1H), 7.80ꢀ7.77 (m, 1H), 7.52ꢀ7.47 (m, 1H), 7.42 (ddd, J = 8.1, 7.1, 1.1 Hz,
1H), 5.96 (t, J = 0.8 Hz, 1H), 2.64ꢀ2.54 (m, 2H), 1.80ꢀ1.67 (m, 2H), 1.60ꢀ1.48 (m, 2H), 1.04
(t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 184.5, 142.2, 140.6, 139.0, 137.7, 136.5,
127.1, 123.8, 123.4, 122.2, 104.1, 32.2, 28.9, 21.1, 12.8. HRMS(ESI+): m/z (MꢀN2+H)+
calculated for C15H16ONS 258.0953, found 258.0973.
General Procedure for the Cyclisation of Vinyl Azides 3 and 7. Synthesis of
compounds 4a-4u and 8a-8d. A solution of triethylphosphite (58 mg, 0.349 mmol) in THF (3
mL) was added to a stirred solution of azide 3 or 7 (0.349 mmol) in THF (2 mL) with 4 Å
molecular sieves at room temperature. Nitrogen evolved immediately. After 30 min, an
additional triethylphosphite (116 mg, 0.698 mmol) was added and the mixture was heated at
o
35 C for 1.5 h. The solvent was removed under reduced pressure to give a residue, which
was purified by column chromatography (230ꢀ400 mesh Silica gel, EtOAc in Hexane) to
afford the isoquinoline 4 or thienopyridine 8.
3-Butylisoquinoline (4a).16 60 mg (93%). Colorless oil, Rf = 0.40 (EtOAc/Hexane 10:90).
1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 7.93 (dd, J = 8.2, 0.7 Hz, 1H), 7.75 (d, J = 7.8
Hz, 1H), 7.64 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.52 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.47 (s,
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1H), 2.97ꢀ2.92 (m, 2H), 1.86ꢀ1.74 (m, 2H), 1.49ꢀ1.38 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). C
NMR (126 MHz, CDCl3): δ 155.8, 152.0, 136.5, 130.2, 127.5, 127.0, 126.2, 126.1, 117.9,
37.8, 32.1, 22.5, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for C13H16N 186.1283, found
186.1288.
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3-Butyl-7-methoxyisoquinoline (4b). 56 mg (85%). Colorless oil, Rf = 0.70
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(EtOAc/Hexane 20:80). H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 7.65 (d, J = 9.0 Hz,
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1H), 7.40 (s, 1H), 7.32ꢀ7.27 (m, 1H), 7.18 (d, J = 2.5 Hz, 1H), 3.93 (s, 3H), 2.94ꢀ2.87 (m,
2H), 1.84ꢀ1.69 (m, 2H), 1.50ꢀ1.36 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz,
CDCl3): δ 157.7, 154.0, 150.5, 132.2, 128.0, 127.6, 123.4, 117.8, 104.5, 55.4, 37.6, 32.2,
22.5, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for C14H18NO 216.1388, found 216.1389.
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3-Butyl-7-methylisoquinoline (4c). 57 mg (85%). Yellow solid (m.p = 50ꢀ55 C), Rf =
0.40 (EtOAc/Hexane 10:90). 1H NMR (500 MHz, CDCl3): δ 9.13 (s, 1H), 7.82 (d, J = 8.3 Hz,
1H), 7.51 (s, 1H), 7.37 (s, 1H), 7.35 (dd, J = 8.3, 1.4 Hz, 1H), 2.95ꢀ2.88 (m, 2H), 2.53 (s,
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1H), 1.85ꢀ1.72 (m, 2H), 1.47ꢀ1.36 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). C NMR (126 MHz,
CDCl3): δ 155.8, 151.6, 140.5, 136.9, 128.6, 127.3, 125.5, 125.0, 117.4, 37.8, 32.1, 22.5,
22.1, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for C14H18N 200.1439, found 200.1447.
2-Butylbenzo[f]isoquinoline (4d). 56 mg (83%). Colorless oil, Rf = 0.40 (EtOAc/Hexane
10:90). 1H NMR (500 MHz, CDCl3): δ 9.17 (s, 1H), 8.68 (ddd, J = 7.0, 3.3, 3.2 Hz, 1H), 8.26
(s, 1H), 7.91 (dt, J = 5.7, 3.1 Hz, 1H), 7.77 (s, 2H), 7.74ꢀ7.64 (m, 2H), 3.11ꢀ2.99 (m, 2H),
1.94ꢀ1.81 (m, 2H), 1.54ꢀ1.42 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3):
δ 158.1, 151.2, 135.4, 133.6, 128.7, 128.5, 128.4, 127.3, 126.9, 125.0, 124.7, 123.1, 114.1,
38.4, 32.5, 22.6, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for C17H18N 236.1439, found
236.1441.
3-Butyl-6,7-dimethoxyisoquinoline (4e).16 57 mg (84%). Yellow solid (m.p = 160ꢀ162
oC), Rf = 0.50 (EtOAc/Hexane 40:60). H NMR (400 MHz, CDCl3): δ 9.29 (s, 1H), 7.68 (s,
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1H), 7.51 (s, 1H), 7.19 (s, 1H), 4.13 (s, 3H), 4.10 (s, 3H), 3.22 (dd, J = 7.6, 7.6 Hz, 2H), 1.98ꢀ
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1.85 (m, 2H), 1.51ꢀ1.41 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). C NMR (126 MHz, CDCl3): δ
157.8, 152.4, 145.9, 142.0, 137.4, 122.6, 120.6, 106.6, 104.4, 56.8 (2C), 32.4, 31.4, 22.0,
13.7. HRMS (ESI+): m/z (M+H)+ calculated for C15H20O2N 246.1490, found 246.1504.
3-Butyl-6-(tertbutyldimethylsilyloxy)-7-methoxyisoquinoline (4f). 64 mg (90%). Yellow
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solid (m.p = 116ꢀ119 C), Rf = 0.50 (EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ
8.93 (s, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 6.97 (s, 1H), 3.94 (s, 1H), 2.94ꢀ2.81 (m, 2H), 1.83ꢀ
1.68 (m, 2H), 1.48ꢀ1.34 (m, 2H), 1.03 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H), 0.20 (s, 6H). 13C
NMR (126 MHz, CDCl3): δ 155.2, 154.3, 149.5, 145.8, 133.9, 123.0, 116.9, 115.4, 104.3,
55.4, 37.6, 32.3, 25.7, 22.5, 18.5, 14.0, ꢀ4.6. HRMS (ESI+): m/z (M+H)+ calculated for
C20H32O2NSi 346.2202, found 346.2200.
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8-Butyl-[1,3]dioxolo[4,5-f]isoquinoline (4g). 56 mg (82%). Colorless oil, Rf = 0.50
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(EtOAc/Hexane 20:80). H NMR (500 MHz, CDCl3): δ 9.25 (s, 1H), 7.39 (s, 1H), 7.35ꢀ7.31
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(m, 2H), 6.21 (s, 2H), 3.10ꢀ2.72 (m, 2H), 1.87ꢀ1.71 (m, 2H), 1.47ꢀ1.35 (m, 2H), 0.96 (t, J =
7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 153.6, 145.2, 143.8, 132.4, 119.5, 117.9, 114.8,
113.8, 102.2, 37.7, 32.1, 22.5, 14.0. HRMS (ESI m/z (M+H)+ calculated for C14H16O2N
230,1181, found 230.1192.
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3-(Cyclohexylmethyl)isoquinoline (4h). 61 mg (91%). Yellow solid (m.p = 45ꢀ48 C), Rf
= 0.40 (EtOAc/Hexane 10:90) .1H NMR (500 MHz, CDCl3): δ 9.15 (s, 1H), 7.86 (d, J = 8.2
Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.62ꢀ7.54 (m, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.36 (s, 1H),
2.74 (d, J = 7.1 Hz, 2H), 1.89ꢀ1.73 (m, 1H), 1.66ꢀ1.57 (m, 5H), 1.28ꢀ1.05 (m, 4H), 1.03ꢀ0.89
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(m, 2H). C NMR (126 MHz, CDCl3): δ 154.5, 152.0, 136.3, 130.2, 127.5, 127.0, 126.3,
126.0, 119.0, 46.0, 38.5, 33.2, 26.6, 26.3. HRMS (ESI+): m/z (M+H)+ calculated for C16H20N
226.1596, found 226.1595.
3-(Cyclohexylmethyl)-7-methoxyisoquinoline (4i). 61 mg (89%). Colorless oil, Rf = 0.35
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(EtOAc/Hexane 20:80). H NMR (500 MHz, CDCl3): δ 9.11 (s, 1H), 7.65 (d, J = 9.0 Hz,
1H), 7.36 (s, 1H), 7.31 (dd, J = 8.9, 2.5 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H), 2.77
(d, J = 7.1 Hz, 2H), 1.87ꢀ1.82 (m, 1H), 1.73ꢀ1.63 (m, 5H), 1.29ꢀ1.14 (m, 3H), 1.07ꢀ0.96 (m,
2H). 13C NMR (126 MHz, CDCl3): δ 157.7, 152.6, 150.5, 132.0, 128.0, 127.6, 123.5, 118.9,
104.5, 55.4, 45.8, 38.6, 33.2, 26.6, 26.3. HRMS (ESI+): m/z (M+H)+ calculated for C17H22ON
256.1701, found 256.1704.
2-(Cyclohexylmethyl)benzo[f]isoquinoline (4j). 64 mg (92%). Colorless oil, Rf = 0.40
(EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 8.73ꢀ8.62 (m, 1H), 8.22
(s, 1H), 7.99ꢀ7.86 (m, 1H), 7.78 (s, 2H), 7.74ꢀ7.65 (m, 2H), 2.92 (d, J = 7.2 Hz, 2H), 1.97ꢀ
1.87 (m, 1H), 1.80ꢀ1.63 (m, 5H), 1.35ꢀ1.18 (m, 3H), 1.14ꢀ1.02 (m, 2H). 13C NMR (126 MHz,
CDCl3): δ 156.9, 151.2, 135.2, 133.6, 128.7, 128.5, 128.4, 127.3, 126.9, 125.0, 124.7, 123.2,
115.1, 46.6, 38.9, 33.3, 26.6, 26.3. HRMS (ESI+): m/z (M+H)+ calculated for C20H22N
276.1752, found 276.1752.
8-(Cyclohexylmethyl)-[1,3]dioxolo[4,5-f]isoquinoline (4k). 60.5 mg (88%). Colorless oil,
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Rf = 0.40 (EtOAc/Hexane 20:80). H NMR (500 MHz, CDCl3): δ 9.25 (s, 1H), 7.34 (s, 1H),
7.34ꢀ7.28 (m, 2H), 6.20 (s, 2H), 2.75 (d, J = 7.1 Hz, 2H), 1.91ꢀ1.80 (m, 1H), 1.75ꢀ1.64 (m,
5H), 1.22ꢀ1.15 (m, 3H), 1.05ꢀ0.98 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 152.2, 145.1,
143.8, 141.6, 132.2, 119.6, 119.0, 114.8, 113.8, 102.3, 46.0, 38.4, 33.2, 26.6, 26.3. HRMS
(ESI+): m/z (M+H)+ calculated for C17H20ON2 270.1494, found 270.1492.
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6-(tertButyldimethylsilyloxy)-3-(cyclohexylmethyl)-7-methoxyisoquinoline (4l). 65 mg
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(90%). Colorless oil, Rf = 0.50 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3) δ 8.94
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(s, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.97 (s, 1H), 3.94 (s, 3H), 2.73 (d, J = 7.1 Hz, 2H), 1.90ꢀ
1.77 (m, 1H), 1.71ꢀ1.63 (m, 5H), 1.28ꢀ1.14 (m, 3H), 1.07ꢀ0.96 (m, 2H), 1.04 (s, 9H), 0.20 (s,
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6H). C NMR (75 MHz, CDCl3): δ 155.2, 153.0, 149.6, 145.8, 133.6, 123.05, 117.8, 115.4,
104.3, 55.4, 46.0, 38.5, 33.3, 26.6, 26.3, 25.7, 18.5, ꢀ4.6. HRMS (ESI+): m/z (M+H)+
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calculated for C23H36O2NSi 386.2515, found 386.2536.
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3-Benzylisoquinoline (4m).17 59 mg (89%). White solid (m.p = 56ꢀ58 C), Rf = 0.30
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(EtOAc/Hexane 20:80). H NMR (400 MHz, CDCl3): δ 9.22 (s, 1H), 7.93 (d, J = 8.1 Hz,
1H), 7.71 (d, J = 8.2 Hz, 1H), 7.63 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.53 (ddd, J = 8.0, 6.9, 1.1
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Hz, 1H), 7.42 (s, 1H), 7.36ꢀ7.29 (m, 4H), 7.27ꢀ7.19 (m, 1H), 4.32 (s, 2H). C NMR (101
MHz, CDCl3): δ 154.4, 152.3, 139.8, 136.5, 130.4, 129.2, 128.6, 127.5, 127.1, 126.6, 126.3,
126.2, 118.7, 44.3. HRMS (ESI+): m/z (M+H)+ calculated for C16H14N 220.1126, found
220.1133.
3-Benzyl-7-methoxyisoquinoline (4n). 59 mg (87%). White solid (m.p = 78ꢀ80 oC), Rf = 0.70
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(EtOAc/Hexane 40:60). H NMR (500 MHz, CDCl3): δ 9.12 (s, 1H), 7.62 (d, J = 9.0 Hz,
1H), 7.36 (s, 1H), 7.33ꢀ7.28 (m, 4H), 7.28 (dd, J = 5.0, 1.6 Hz, 1H), 7.22 (dt, J = 8.8, 4.5 Hz,
1H), 7.19 (d, J = 2.5 Hz, 1H), 4.29 (s, 2H), 3.93 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
158.0, 152.5, 150.8, 140.0, 132.2, 129.2, 128.5, 128.2, 127.83, 126.3, 123.6, 118.6, 104.6,
55.4, 44.1. HRMS (ESI+): m/z (M+H)+ calculated for C17H16NO 250.1232, found 250.1248.
3-Benzyl-6,7-dimethoxyisoquinoline (4o).18 59 mg (86%). Yellow solid (m.p = 182ꢀ185 oC),
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Rf = 0.50 (EtOAc/Hexane 50:50). H NMR (400 MHz, CDCl3): δ 9.36 (br, 1H), 7.57 (br,
1H), 7.47 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.1 Hz, 1H),
7.10 (s, 1H), 4.62 (s, 2H), 4.09 (s, 3H), 4.07 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 157.9,
152.5, 145.0, 141.7, 137.4, 135.9, 129.6, 129.21, 127.5, 122.7, 121.1, 106.7, 104.6, 56.91,
56.8, 38.5. HRMS (ESI+): m/z (M+H)+ calculated for C18H18O2N 280.1337, found 280.1347.
3-(3-(tertButyldimethylsilyloxy)propyl)isoquinoline (4p). 59 mg (85%). Colorless oil, Rf
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= 0.50 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 9.15 (s, 1H), 7.88 (d, J = 8.1
Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.63ꢀ7.56 (m, 1H), 7.51ꢀ7.45 (m, 1H), 7.44 (s, 1H), 3.65 (t,
J = 6.3 Hz, 2H), 2.99ꢀ2.92 (m, 2H), 2.01ꢀ1.97 (m, 4H), 0.86 (s, 9H), 0.00 (s, 6H). 13C NMR
(126 MHz, CDCl3): δ 155.2, 152.0, 136.5, 130.2, 127.5, 127.1, 126.3, 126.1, 118.1, 62.5,
34.4, 32.8, 26.1, 18.3, ꢀ5.2. HRMS (ESI+): m/z (M+H)+ calculated for C18H28ONSi 302.1940,
found 302.1943.
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6-(tertButyldimethylsilyloxy)-3-(3-(tert-butyldimethylsilyloxy)propyl)-7-
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methoxyisoquinoline (4q). 67 mg (92%). Colorless oil, Rf = 0.60 (EtOAc/Hexane 20:80). H
NMR (300 MHz, CDCl3): δ 8.93 (s, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 6.97 (s, 1H), 3.95 (s, 3H),
3.70 (t, J = 6.3 Hz, 2H), 3.04ꢀ2.82 (m, 2H), 2.10ꢀ1.94 (m, 2H), 1.04 (s, 9H), 0.91 (s, 9H),
0.20 (s, 6H), 0.06 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 155.2, 153.8, 149.6, 145.8, 133.8,
123.1, 117.0, 115.4, 104.3, 62.7, 55.4, 34.3, 33.0, 26.0, 25.7, 18.5, 18.3, ꢀ4.6, ꢀ5.2. HRMS
(ESI+): m/z (M+H)+ calculated for C25H44O3NSi2 462.2860, found 462.2875.
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3-Butyl-7-fluoroisoquinoline (4r). 60 mg (91%). Colorless oil, Rf = 0.10 (EtOAc/Hexane
10:90). 1H NMR (400 MHz, CDCl3): δ 9.16 (s, 1H), 7.76 (dd, J = 9.0, 5.2 Hz, 1H), 7.53 (dt, J
= 14.9, 7.4 Hz, 1H), 7.47 (s, 1H), 7.43 (td, J = 8.8, 2.6 Hz, 1H), 3.00ꢀ2.87 (m, 2H), 1.88ꢀ1.71
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(m, 2H), 1.49ꢀ1.33 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). C NMR (126 MHz, CDCl3): δ 159.8
(d, J = 248 Hz), 155.5 (d, J = 1.6 Hz), 151.2 (d, J = 5.3 Hz), 133.5, 128.7 (d, J = 8.3 Hz),
127.4 (d, J = 8.0 Hz), 120.9 (d, J = 25.6 Hz), 117.7, 110.4 (d, J = 20.5 Hz), 37.7, 32.1, 22.5,
14.0. HRMS (ESI+): m/z (M+H)+ calculated for C13H15FN 204.1188, found 204.1191.
3,4-Dipropylisoquinoline (4s).19 60 mg (91%). Colorless oil, Rf = 0.40 (EtOAc/Hexane
10:90). 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.97 (dd, J = 8.6, 0.7 Hz, 1H), 7.91 (d, J
= 8.1 Hz, 1H), 7.70ꢀ7.63 (m, 1H), 7.51 (ddd, J = 8.0, 5.1, 1.0 Hz, 1H), 3.05ꢀ2.99 (m, 2H),
2.99ꢀ2.92 (m, 2H), 1.86ꢀ1.78 (m, 2H), 1.73ꢀ1.65 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H), 1.05 (t, J =
7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 152.9, 150.1, 135.3, 129.9, 128.1, 128.0, 127.2,
125.6, 123.0, 37.3, 29.9, 224.1, 23.6, 14.6, 14.3. HRMS (ESI+): m/z (M+H)+ calculated for
C15H20N 214.1596, found 214.1601.
3-Butyl-1-methoxyisoquinoline (4t). 58 mg (87%). Colorless oil, Rf = 0.10
(EtOAc/Hexane 5:95). 1H NMR (400 MHz, CDCl3): δ 8.21ꢀ8.13 (m, 1H), 7.64 (d, J = 8.1 Hz,
1H), 7.58 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.43 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.00 (s, 1H),
4.11 (s, 3H), 2.82ꢀ2.73 (m, 2H), 1.83ꢀ1.71 (m, 2H), 1.46ꢀ1.36 (m, 2H), 0.96 (t, J = 7.4 Hz,
3H). 13C NMR (126 MHz, CDCl3): δ 160.2, 153.0, 138.6, 130.1, 125.6, 125.4, 124.0, 118.1,
111.7, 53.4, 37.6, 31.4, 22.4, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for C14H18ON
216.1388, found 216.1398.
3-Butyl-1-methylisoquinoline (4u).20 58 mg (88%). Colorless oil, Rf = 0.10
1
(EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 8.07 (dd, J = 8.4, 0.9 Hz, 1H), 7.73
(d, J = 8.2 Hz, 1H), 7.62 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.51 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H),
7.32 (s, 1H), 2.95 (s, 3H), 2.92ꢀ2.86 (m, 2H), 1.82ꢀ1.74 (m, 2H), 1.48ꢀ1.39 (m, 2H), 0.96 (t, J
13
= 7.4 Hz, 3H). C NMR (126 MHz, CDCl3): δ 158.0, 154.5, 136.6, 129.8, 126.8, 126.0,
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125.8, 125.5, 116.5, 37.9, 32.1, 22.6, 22.3, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for
C14H18N 200.1439, found 200.1445.
6
7
8
6-Butylthieno [3,4-c] pyridine (8a). 56 mg (86%). Colorless oil, Rf = 0.40 (EtOAc/Hexane
1
10:90). H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.55 (s, 1H),
9
7.30 (d, J = 5.3 Hz, 1H), 2.94ꢀ2.87 (m, 2H), 1.77 (tt, J = 7.7, 6.8 Hz, 2H), 1.47ꢀ1.35 (m, 2H),
0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 156.0, 145.7, 143.9, 133.8, 132.0,
122.7, 116.2, 37.7, 32.5, 22.5, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for C11H14NS
192.0847, found 192.0856.
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6-(Cyclohexylmethyl)thieno[3,4-c]pyridine (8b). 63 mg (94%). Colorless oil, Rf = 0.40
1
(EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.66 (d, J = 5.4 Hz,
1H), 7.50 (d, J = 0.7 Hz, 1H), 7.29 (dd, J = 5.4, 0.7 Hz, 1H), 2.77 (d, J = 7.1 Hz, 2H), 1.85ꢀ
1.76 (m, 1H), 1.70ꢀ1.62 (m, 5H), 1.28ꢀ1.13 (m, 3H), 1.09ꢀ0.95 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 154.7, 145.4, 143.9, 133.8, 131.9, 122.7, 117.1, 46.0, 38.8, 33.2, 26.5, 26.3. HRMS
(ESI+): m/z (M+H)+ calculated for C14H18NS 232.1160, found 232.1163.
6-Benzylthieno[3,4-c]pyridine (8c). 59 mg (88%). Colorless oil, Rf = 0.30 (EtOAc/Hexane
1
20:80). H NMR (500 MHz, CDCl3): δ 9.09 (s, 1H), 7.66 (d, J = 5.3 Hz, 1H), 7.49 (s, 1H),
7.31ꢀ7.29 (m, 4H), 7.25 (d, J = 2.8 Hz, 1H), 7.24ꢀ7.19 (m, 1H), 4.28 (s, 2H). 13C NMR (101
MHz, CDCl3): δ 154.7, 145.8, 144.1, 139.9, 134.2, 132.2, 129.1, 128.6, 126.3, 122.8, 116.8,
44.2. HRMS (ESI+): m/z (M+H)+ calculated for C14H12NS 226.0690, found 226.0686.
3-Butylbenzo[4,5]thieno[2,3-c]pyridine (8d). 53 mg (78%), colourless oil, Rf = 0.20
(EtOAc/Hexane 10:90). 1H NMR (500 MHz, CDCl3) δ 9.05 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H),
7.89 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.63ꢀ7.53 (m, 1H), 7.50 (t, J = 7.4 Hz, 1H), 3.07ꢀ2.86
(m, 2H), 1.92ꢀ1.73 (m, 2H), 1.52ꢀ1.39 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 157.1, 143.9, 142.5, 141.4, 133.8 , 133.2, 128.9, 124.7, 123.3, 122.8, 114.4, 38.0,
32.5, 22.5, 14.0
242.1015.
.
HRMS (ESI+): m/z (M+H)+ calculated for C15H16NS 242,1004, found
Synthesis of Quinisocaine 12: Compounds 10, 11 and 12 were prepared according to the
above procedures (for compound 11: the reaction was performed at 40 °C for 18h).
(E)-2-(Dimethylamino)ethyl2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-
enyl)benzoate (10). From 0.89 mmol of 9,21 221 mg (62%). Colorless oil, Rf = 0.50
(MeOH/CHCl3 10:90). 1H NMR (500 MHz, CDCl3): δ 7.92 (dd, J = 7.8, 0.9 Hz, 1H), 7.44 (s,
1H), 7.39ꢀ7.34 (m, 1H), 7.32 (dd, J = 9.6, 2.7 Hz, 1H), 7.29ꢀ7.25 (m, 1H), 4.38 (t, J = 6.0 Hz,
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2H), 2.71 (dd, J = 11.1, 5.1 Hz, 2H), 2.35ꢀ2.29 (m, 8H), 1.53ꢀ1.46 (m, 2H), 1.43ꢀ1.35 (m,
2H), 1.14 (s, 12H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 166.0, 140.4,
139.4, 130.3, 129.8, 129.2, 128.6, 127.4, 125.7, 82.1, 61.6, 56.7, 44.7, 36.2, 30.9, 23.6, 21.5,
13.0 (the carbon α to boron was not found). HRMS (ESI+): m/z (M+H)+ calculated for
C23H37O4BN 402.2816, found 402.2827.
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(E) and (Z) 2-(Dimethylamino)ethyl 2-(2-azidohex-1-enyl)benzoate (11). From 0.5 mmol
1
of 10, 81 mg (52%). Colorless oil, Rf = 0.45 (MeOH/CHCl3 10:90) H NMR (500 MHz,
CDCl3): δ 7.89 (dd, J = 7.8, 0.9 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.54ꢀ7.41 (m, 1H), 7.26ꢀ
7.22 (m, 1H), 6.34 (s, 1H), 4.41 (t, J = 5.8 Hz, 2H), 2.75 (t, J = 4.9 Hz, 2H), 2.56ꢀ2.40 (m,
2H), 2.37 (s, 6H), 1.73ꢀ1.58 (m, 2H), 1.53ꢀ1.40 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR
(126 MHz, CDCl3): δ 167.2, 136.5, 136.3, 131.5, 130.7, 130.3, 128.7, 126.5, 114.0, 62.5,
57.6, 45.6, 33.5, 30.0, 22.1, 13.8. HRMS (ESI+): m/z (M+H)+ calculated for C17H25O2N4
317.1977, found 317.1991.
Quinisocaine 12. From 0.16 mmol of 11, 34 mg (81%). Colorless oil, Rf = 0.16
1
(MeOH/CHCl3 10:90). H NMR (500 MHz, CDCl3): δ 8.19 (d, J = 8.3 Hz, 1H), 7.63 (d, J =
8.1 Hz, 1H), 7.58 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.42 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.00 (s,
1H), 4.67 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.80ꢀ2.70 (m, 2H), 2.42 (s, 6H), 1.77ꢀ
13
1.74 (m, 2H), 1.46ꢀ1.33 (m, 2H), 0.95 (, J = 7.4 Hz t, 3H). C NMR (100 MHz, CDCl3): δ
159.5, 152.9, 138.6, 130.1, 125.5, 125.3, 124.0, 118.0, 111.8, 63.7, 58.0, 45.8, 37.5, 31.4,
22.3, 14.0. HRMS (ESI+): m/z (M+H)+ calculated for C17H25ON2 273.1966, found 273.1965.
1
Supporting Information. H and 13C spectra of compounds 1d, 2c, 2f-k, 2m, 2p-2v, 3aꢀ3v,
4aꢀ4u, 6a-6d, 7a-7d, 8a-8d, 10, 11 and quinisocaine 12. This material is available free of
charge via the Internet at http://pubs.acs.org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research has been performed as part of the IndoꢀFrench ״Joint Laboratory for
Sustainable Chemistry at Interfaces", FB and BC thank CNRS and the University of Rennes 1
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for support of this research. V.J. and G.V.M.S thank UGC and CSIR, New Delhi for research
fellowship.
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31
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33
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42
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44
45
46
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51
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29
ACS Paragon Plus Environment