Synthesis of 3-benzylisoquinolines by domino imination/cycloisomerisation of 2-propargylbenzaldehydes

Article abstract of DOI:10.1039/c4ob01583e

An easy entry to uncommon 2-propargylbenzaldehydes was developed. 2-Propargylbenzaldehydes demonstrated to be suitable building blocks for the synthesis of 3-benzyl isoquinolines by microwave promoted domino imination/cycloisomerisation in the presence of

Full text of DOI:10.1039/c4ob01583e

Organic &
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Synthesis of 3-benzylisoquinolines by domino
imination/cycloisomerisation of 2-propargyl-
benzaldehydes†
Cite this: Org. Biomol. Chem., 2014,
12, 8019
Monica Dell’Acqua,*a Valentina Pirovano,a Giorgio Confalonieri,a Antonio Arcadi,b
Elisabetta Rossia and Giorgio Abbiati*a
An easy entry to uncommon 2-propargylbenzaldehydes was developed. 2-Propargylbenzaldehydes
demonstrated to be suitable building blocks for the synthesis of 3-benzyl isoquinolines by microwave pro-
moted domino imination/cycloisomerisation in the presence of ammonium acetate. A small library of
3-benzyl isoquinolines was obtained in good yields under mild reaction conditions. Two alternative plaus-
ible reaction mechanisms are proposed.
Received 25th July 2014,
Accepted 2nd September 2014
DOI: 10.1039/c4ob01583e
www.rsc.org/obc
in two valuable Pd-catalysed multicomponent processes invol-
ving a one-pot coupling/addition/cyclisation sequence starting
Introduction
During the past twenty years, many researchers have been fas- from simple building blocks, i.e., ortho-bromoarylaldehydes,
cinated by the development of new domino1 strategies for the terminal alkynes and a nucleophile, methanol6 or ammonia,7
synthesis of heterocyclic compounds,2 a field of research in respectively.
constant evolution. A domino reaction is a process involving
In order to extend the scope of our research, we have
two or more bond-forming transformations taking place under recently explored the reactivity of 2-alkynylacetophenones
the same reaction conditions without adding additional (keto-homologues of the 2-alkynylbenzaldehydes) and their
reagents and catalysts. The subsequent reactions are a conse- pyridine analogues. We have found that the imination/annula-
quence of the functionalities formed in the previous steps. tion reactions of these less reactive substrates with ammonia
The possibility of building up simple and complex hetero- needed a promoter, and silver triflate proved to be the pre-
cycles starting from easily achievable building blocks by a ferred catalyst for these transformations, yielding the expected
single sequential transformation is something deeply fascinat- N-cyclisation products in addition to variable amounts of the
ing for all synthetic chemists.
isomeric carboannulation products.8
For many years, we have been interested in the development
After having obtained these interesting results, we were
of new sequential synthetic strategies for the construction of intrigued by the idea of preparing some 2-propargylbenzalde-
oxygen- or nitrogen-containing heterocycles starting from hydes and to test their reactivity in the domino transform-
alkyne derivatives bearing a proximate carbonyl group. In par- ations described above. While the coupling of an alkynyl group
ticular, we have employed the addition/cycloisomerisation in the ortho position of an ortho-haloarylaldehyde is a simple
reactions of 2-alkynylbenzaldehydes (and their related hetero- and well-known Pd-catalysed procedure, the introduction of a
aromatic systems) in the presence of simple oxygen or nitrogen propargyl group in the same position is much more challen-
nucleophiles as useful tools to synthesise some interesting ging, and only a few examples are reported in the literature.9
compounds such as isoquinolines,3 dihydroisobenzofurans,4 The most acknowledged approach was described by Eberbach
and isochromenes.5
and co-workers9a,b in 2000. The method includes five synthetic
Moreover, the domino approaches to dihydroisobenzo- steps starting from the 2-bromobenzaldehyde. The first step of
furans and isoquinolines have also been successfully transformed the approach involves the protection of the carbonyl group as
a cyclic acetal, followed by a coupling reaction between the
lithiated acetal derivative and the 3-bromo-1-(trimethylsilyl)-
1-propyne. The triple bond is then deprotected by fluoride pro-
moted desilylation, and functionalized by a Sonogashira coup-
ling or by a base promoted nucleophilic substitution with
aDipartimento di Scienze Farmaceutiche – Sezione di Chimica Generale e Organica
“A. Marchesini”, Università degli Studi di Milano, via G. Venezian, 21 – 20133 Milano,
Italy. E-mail: monica.dellacqua@unimi.it, giorgio.abbiati@unimi.it
bDipartimento di Scienze Fisiche e Chimiche, Via Vetoio – 67010 L’Aquila, Italy
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
methyl bromide. Finally, the acid promoted deprotection of
the aldehyde gives the desired product. This is a useful and
c4ob01583e
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elegant method, and yet it presents some drawbacks: (1) the
lithiation reaction is often a troublesome step requiring strictly
controlled conditions; (2) the 3-bromo-1-(trimethylsilyl)-
1-propyne is a rather expensive starting material; (3) the desilyl-
ation of the TMS-protected propargyl intermediate can experi-
ence scarce reproducibility (when fluoride promoted) or can
give the isomeric allene (when base promoted).
Owing to the lack of general methods for the preparation
of 2-propargyl arylaldehydes, the reactivity of these superior
homologues of 2-alkynyl benzaldehydes has been less
explored. For example, Eberbach and his co-workers have
employed the 2-propargylbenzaldehydes as key-intermediates
in the synthetic route to 2-propargylaryl nitrones, thus leading
the way to the synthesis of the 1,2-dihydro[c]benzazepin-
3-ones.9a,b On the other hand, Yamamoto’s research group has
documented the synthesis of important frameworks starting
from these substrates. In 2010, they discovered an efficient
metallic catalyst-free benzannulation with dialkylamines
giving rise to various 2-dialkylaminonaphthalenes,10 and two
years later they developed a smart synthetic approach to 2,3-
dihydro-1H-inden-1-one derivatives through
a Ni-catalysed
Fig. 1 Some examples of biologically active isoquinolines.
intramolecular hydroacylation of 2-propargylbenzaldehydes.11
The 1-oxo-5-ynes are a class of related propargyl-based sub-
strates, bearing a mandatory oxy group in the propargylic
position. Liu and co-workers have described a highly stereo-
selective Au-catalysed synthesis of 9-oxabicyclo[3.3.1]nona-4,7-
dienes from diverse 1-oxo-4-oxy-5-ynes.12 In 2013, a namesake
of Liu (and his co-workers) proposed a new synthetic route to
indeno[1,2-b]quinolones by reactions of 2-propargylbenzalde-
hydes with N-aryl amines based on an intramolecular aza-
Diels–Alder (Povarov) reaction.13
compounds, such as the PPAR-γ activity modulators16 pro-
posed for the treatment of conditions such as type II diabetes
and obesity, and the protein kinase inhibitors17 proposed for
treating cancer, diabetes and Alzheimer’s disease (Fig. 1).
Results and discussion
In this work, we describe a general and effective approach With Eberbach’s seminal work in mind, we developed an
to 2-propargylbenzaldehydes and their participation in micro- alternative strategy, in order to simplify the preparation of the
wave promoted domino addition/cycloisomerisation reactions propargylic scaffolds. The peculiar feature of our approach is
in the presence of ammonia for the synthesis of 3-benzyliso- the preliminary preparation of properly substituted propargyl
quinolines (Scheme 1).
bromides 2: this implies avoiding the use of expensive (3-bromo-
The isoquinoline nucleus is the core of various biologically prop-1-yn-1-yl)trimethylsilane and the subsequent desilylation
active compounds, such as the alkaloid papaverine and the step. Compounds 2a–h were prepared in two steps: first of
anaesthetic quinisocaine (Fig. 1). Saturated, functionalized all, the cheap and easily available propargyl alcohol was func-
and polycyclic isoquinolines show different important tionalized by reaction with various aryl iodides under standard
pharmacological properties;14 moreover, some simple 3-benzyl Sonogashira cross-coupling conditions18 to give the substi-
isoquinolines are also significantly active, and may be useful tuted propargyl alcohols 1a–h, used in some cases for the sub-
as lead compounds for developing potential chemotherapeutic sequent step without the need of
a chromatographic
agents. For example, some 1- and 3-benzylisoquinolines (e.g., purification. The compounds 1a–h were then reacted with
6,7-dimethoxy-3-veratryl-isoquinoline) and the corresponding bromine and triphenylphosphine19 to give the desired substi-
quaternary salts have been tested for antimicrobial, antimalar- tuted propargyl bromides 2a–h (Table 1).
ial, cytotoxic, and anti-HIV activities.15 On top of this, the
The Sonogashira coupling did not seem to be strongly influ-
3-benzylisoquinoline structure is the skeleton of some patented enced by the nature of substituents on the phenyl ring; in fact,
the yields of the reactions were in general very good for both
electron-rich and electron-poor aryl iodides (entries 1–7). The
presence of a group in the ortho-position of the aryl moiety
was well tolerated too (entries 6–8). Conversely, in the bro-
mination step, the presence of stronger EWGs on the aryl
moiety gave low yields (entries 4 and 5).
We then optimised the coupling step between the 2-bromo-
benzaldehyde partner and the substituted propargyl bromides
Scheme 1 Synthesis
benzylisoquinolines.
of
2-propargylbenzaldehydes
and
3-
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Table 1 Preparation of propargyl bromides
Entry
1, 2
R
t (h) step 1
1 Yielda (%)
t (h) step 2
2 Yielda (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
4-Cl
1.0
1.5
2.0
3.0
2.0
3.0
3.0
2.0
99b
99b
99b
77c
99b
87c
99c
95c
2.0
2.0
2.0
2.0
2.5
2.5
2.5
2.0
81d
90d
99d
57c
59d
68c
81d
85c
4-CH3
4-SO2CH3
3-CF3
2-C2H5
2-CH3, 3-Cl
2-(i-Pr)
g
h
a Yields refer to pure isolated products. b Yields after simple work-up. c Yields after column chromatography. d Yields after filtration on a short
silica pad.
Scheme 2 Optimised sequence for the synthesis of 2-propargylbenzaldehydes 4.
through a Grignard reaction: this allowed us to skip the annoy- bromide was found to be critical,20 and the best results were
ing lithiation step described in the Eberbach approach. We obtained using 1 M solution of the aryl bromide in tetrahydro-
protected the 2-bromobenzaldehyde and the 5-fluoro-2-bromo- furan, while using a more diluted solution resulted in worse
benzaldehyde as cyclic acetals by treating them with ethylene reproducibility and longer reaction times. The majority of the
glycol and p-toluenesulfonic acid in toluene at reflux. Then, a yields of the reactions ranged from fair to very good with all
stirred solution of properly protected benzaldehyde in anhy- aryl propargyl bromides, while worse results were obtained in
drous tetrahydrofuran and magnesium turnings was heated at the presence of a methylsulfonyl group on arylalkyne terminus
80 °C under a protective nitrogen atmosphere. Once the mag- (entry 4), or of a fluorine atom on the benzaldehyde moiety
nesium was almost completely dissolved, we slowly added the (entry 9). In addition, the presence of a bulky group in the
suitable substituted propargyl bromides 2a–h, and the reaction ortho position of the aryl iodide resulted in reduced yields
mixture was heated at 80 °C to give the 2-propargylbenzalde- (entry 8).
hyde acetals 3a–i. These intermediates were then hydrolysed to
We also explored the Grignard coupling step under micro-
give the corresponding 2-propargylbenzaldehydes 4a–i by treat- wave heating.21 Arylmagnesium species can be efficiently
ment with p-toluenesulfonic acid in a mixture of water and generated from magnesium turnings and aryl bromides (or
acetone at reflux (Scheme 2).
chlorides) under dielectric heating.20 The reactions performed
The key step of this procedure is the Grignard coupling under dielectric heating were faster and the yields of 3 were
reaction between 2-bromobenzaldehyde acetals and substi- comparable to those observed under traditional heating
tuted propargyl bromides 2 (Table 2). The concentration of aryl (see footnote entries 1–3 and 5). In the end, however, as the
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We then ran the reaction under the conditions previously
adopted for the addition/cycloisomerisation reactions of
2-alkynylbenzaldehydes (i.e., 20 equiv. of NH3).3 This uncata-
lysed reaction at 100 °C under microwave heating gave the
corresponding isoquinoline 5b in low yield (entry 1). A tenta-
tive approach to promote the formation of the imine inter-
mediate by the use of molecular sieves did not result in any
improvement (entry 2). Based on our previous experience with
2-alkynylacetophenones,8 we planned to catalyse the reaction
with AgOTf (10 mol%) both under dielectric and conventional
heating conditions (entries 3–5). Under conventional heating
the reaction yield raised to 51% in 6 h at 60 °C (entry 4), while
under microwave heating at 100 °C the reaction gave almost
the same yield in only 10 minutes (entry 5). Aiming to improve
the yield, we tried some other metal catalysts potentially able
to promote the reaction. Following the procedure previously
optimised in our laboratory for the imination/annulation of
2-acetyl and 2-benzoyl N-propargylindoles22 and 2-acetyl-N-pro-
pargylpyrroles,3 we tried to catalyse the reaction with 0.5 equiv.
of titanium tetrachloride, but these conditions gave poor
yields (entry 6), while in the presence of a catalytic amount of
TiCl2(indenyl)2 the desired product was obtained in 47% yield
(entry 7). Using InCl3 as the catalyst gave comparable yield to
the best results obtained in this screening (cf. entries 8, 4 and
5). We also tested some gold-based catalysts, well renowned as
an alkynophilic Lewis acid, but the results were still unsatisfac-
tory (entries 9–11).23
Table 2 Grignard coupling reactions and deprotection of an aldehyde
group
t (h)
step 1 (%)
3 Yielda t (h)
4 Yieldf
Entry 3, 4 R1 R2
step 2 (%)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
F
H
4-Cl
4-CH3
4-SO2CH3
3-CF3
2-C2H5
2-CH3, 3-Cl 4.0
2-(i-Pr)
4-Cl
3.0
3.0
3.0
4.0
4.0
4.0
61b
81c
68d
32
2.0
2.0
2.0
2.0
2.0
2.0
3.0
2.5
3.0
85
94
96
82
78
89
89
82
78
76e
79
77
38
54
3.0
5.5
a Yields refer to pure isolated products after flash column
chromatography on a short silica gel column. b Under μW approach:
reaction time, 50 min; yield, 70%. c Under μW approach: reaction time,
50 min; yield, 65%. d Under μW approach: reaction time, 50 min;
yield, 64%. e Under μW approach: reaction time, 50 min; yield, 56%.
f Yields refer to the pure isolated product after flash column
chromatography.
Table 3 Screening of reaction conditions with methanolic ammonia
Entry Catalyst (mol%)
Energy – T (°C) t (min) 5b Yield (%)
The homogeneous – but not completely satisfactory –
results obtained under metal catalysis suggested that the
tricky point of the approach was not the activation of the triple
bond but, more probably, the nature of the nitrogen partner:
this prompted us to try different ammonia sources.
1
2
3
4
5
6
7
8
—
μW – 100
μW – 100
μW – 100
Oil bath – 60
μW – 100
μW – 100
10
20
10
360
10
10
10
20
40
50
10
36a
14a
41b
51b
48a
34a
47a
49a
36a
46a
42b
4 Å mol. sieves
AgOTf (10)
AgOTf (10)
AgOTf (10)
TiCl4 (50)
TiCl2(Indenyl)2 (5) μW – 100
InCl3 (10)
NaAuCl4 (5)
AuCl3 (5)
Au(PPh3)NTf2 (3)
In the existing literature, several ammonium salts are listed
as alternative ammonia sources (e.g., (NH4)2CO3, NH4HCO3,
HCO2NH4), and NH4OAc proved to be the most effective
among them.24 Ammonium acetate is the salt of a weak acid
(acetic acid) and a weak base (ammonia), and therefore it is
easily decomposed by heat to AcOH and NH3. On top of this,
ammonium acetate is a practical choice because it is an in-
expensive and easy-to-handle solid. It has been employed only
two times in the isoquinoline synthesis, that is in the cyclisa-
tion of 2-(1,1-difluoroalkenyl)-benzaldehyde25 and, more
recently, in a Pd-catalysed multicomponent approach starting
from 2-bromobenzaldehydes and terminal alkynes.26 However,
the reactivity of the 2-propargylbenzaldehydes with
ammonium acetate is unprecedented.
μW – 100
μW – 80
μW – 100
μW – 100
9
10
11
a Yields calculated via 1H NMR using dimethyl terephthalate (DMT) as
an internal standard. b Yields refer to pure isolated products.
microwave approach presented some reproducibility problems
we decided to choose conventional heating as the standard
procedure, because this enabled an easier control of the reac-
tion progress. The dioxolane intermediates 3 were not so
stable, in particular at room temperature and in the presence
of a slightly acidic solvent (i.e., deuterochloroform); therefore,
after a quick 1H NMR and MS characterization, they were
directly hydrolysed into the corresponding aldehydes 4 with
yields ranging from good to excellent.
For this reason, we screened the optimal reaction con-
ditions for the synthesis of 3-benzylisoquinolines with
ammonium acetate as the ammonia source, and the results
are shown in Table 4.
Having optimized an effective entry to 2-propargylbenzalde-
hydes 4, we then explored the reactivity of these starting
materials to synthesise 3-benzylisoquinolines. At first, we
screened the optimal reaction conditions on the 2-propargyl-
benzaldehyde 4b as a model substrate in the presence of
methanolic ammonia3 (Table 3).
It has been reported that a large excess of NH4OAc is
necessary for an effective ammonia generation,27 so the first
experiment was performed with 20 equiv. of NH4OAc in
ethanol at 120 °C under microwave irradiation. After
30 minutes, the reaction gave the desired product 5b in a
promising 68% yield (entry 1). Then, we tried the reaction in
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Table 4 Screening of reaction conditions with ammonium acetate
Table 5 Scope and limitation of the approach
Entry
4, 5
R1
Ar
5 Yielda (%)
Entry
NH4OAc
Solvent
T (°C)
5b Yield (%)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
F
Ph-
4-Cl-Ph-
78
93
74
67
81
71
83
76
71
1
2
3
4
5
6
7
20 equiv.
20 equiv.
10 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
EtOH
DMSO
DMSO
DMSO
120
120
120
80
80
80
68a
83a
79a
99a
—
4-CH3-Ph-
4-SO2CH3-Ph-
3-CF3-Ph-
2-C2H5-Ph-
(2-CH3, 3-Cl)-Ph-
2-(i-Pr)-Ph-
4-Cl-Ph-
H2O
H2O–EtOH (3 : 1)
H2O–DMSO (3 : 1)
—
—
80
a Yields calculated via 1H NMR using dimethyl terephthalate (DMT) as
an internal standard.
a Yields refer to pure isolated products.
DMSO27b and we were pleased to observe a good rise in yield
(entry 2). The reduction of the amount of ammonium acetate
to 10 equiv. gave only a modest reduction of the reaction yield
(entry 3). Conversely, an excellent rise in yields was observed
when we lowered the temperature (entry 4). Aiming to make
the approach more environmentally-friendly, we tried to use
water as the solvent (entry 5), but all our attempts were unsuc-
cessful, also in the presence of EtOH or DMSO as co-solvents
(entries 6 and 7).
Working under the best available conditions, we investi-
gated the scope and the limitation of the approach. The
results are shown in Table 5.
This microwave-enhanced protocol proved to be a general
route for the synthesis of an array of isoquinolines in very
good yields (entries 1–9). Both electron-donating and electron-
withdrawing substituents were allowed on the phenyl group at
alkynyl terminus (entries 1–5). The presence of a bulky substi-
tuent in the ortho position of the arylalkyne moiety did not
seem to affect the reaction course (entries 6–8). Moreover, the
presence of a fluorine group on the benzaldehyde moiety was
also well tolerated (entry 9). All the reactions were clean and
complete within 30 minutes, and the final products were easily
and quickly purified by flash column chromatography. All the
products have been fully characterized by 1H NMR and 13C
NMR spectroscopy, as well as by MS spectrometry.
In accordance with our previous findings,28 we proposed a
tentative reaction mechanism in which two different pathways
are feasible (Scheme 3). The first step, the in situ formation of
an imine intermediate (I) by reaction of 2-propargylbenzalde-
hydes 4 with the ammonia obtained by thermal cleavage of
ammonium acetate, is common to both paths. To explain the
cycloisomerisation step there are two conceivable pathways: (a)
the triple bond undergoes a 6-exo-dig cyclisation directly by the
imine, and the subsequent isomerisation leads to the for-
mation of the final product 5; (b) the reaction conditions (heat
and ammonia) promote the isomerisation of the triple bond to
Scheme 3 Proposed reaction mechanism.
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allene,29 thus allowing the intramolecular attack of the nucleo- spectra were recorded with a Perkin Elmer FT-IR 16 PC spectro-
phile on the central carbon of the allene framework30 with meter, using discs of NaCl for liquid samples and KBr tablets
direct formation of the isoquinoline 5. On top of this, the for solid samples. The absorbance is reported in wavenumbers
regiospecificity observed is probably due to the resonance (cm−1) with values between 4000 and 400 cm−1. Low resolution
stabilization of the six-membered cyclisation product with MS spectra were recorded with a Fisons MD 800 spectrometer
respect to the alterative seven-membered one. As proof of that, with an electron impact source and a Thermo-Finnigan LCQ-
the 7-endo-dig cyclisation mode is quite uncommon in the advantage AP electrospray/ion trap equipped instrument,
literature (c).31
using a syringe pump device to directly inject sample solu-
tions. The values are reported as the mass–charge ratio and
the relative intensities of the most significant peaks are shown
in brackets. High resolution MS spectra were recorded with
an instrument equipped with an electrospray source and an
Conclusions
We have developed a new, easy and effective access to neg- ICR-FTMS analyser. The melting points of the solid products
lected 2-propargylbenzaldehydes. These building blocks were measured with a Stuart Scientific SMP3 apparatus and
proved to be suitable substrates for domino addition/cyclo- are uncorrected. Microwave promoted reactions were per-
isomerisation reactions in the presence of a nitrogen nucleo- formed with a single-mode Personal Chemistry microwave
phile. The synthesis of the 3-benzylisoquinoline nucleus was synthesizer “Emrys Creator,” using sealed glass vessels. The
achieved in an easy way and in very good yields by a microwave temperature was detected with an infrared sensor.
enhanced methodology. Ammonium acetate proved to be the
General procedure for the synthesis of aryl propargyl alcohols
(1a–h)
most effective nitrogen source for this purpose. This approach
represents a useful, simple and unprecedented alternative
access to the 3-benzylisoquinoline skeleton, which is an Under a nitrogen atmosphere, to a solution of the appropriate
important framework in a number of different molecules of aryl iodide (6.00 mmol) in DEA (18 mL), propargyl alcohol
biological interest.
(403.8 mg, 0.419 mL, 7.20 mmol) and trans-dichlorobis(triphe-
nylphosphine)palladium(II) (84.3 mg, 0.120 mmol) were
added. The reaction was stirred at room temperature for
15 min, and then CuI (12.0 mg, 0.063 mmol) was added. The
reaction mixture was stirred at 50 °C until no starting product
was detectable by TLC analysis (eluent: hexane–ethyl acetate =
Experimental
General experimental details
All the reactions that involve the use of reagents sensitive to 95 : 5). After cooling to room temperature, the mixture was con-
oxygen or hydrolysis were carried out under an inert atmos- centrated under reduced pressure, poured in a HCl 0.1 N aq.
phere. The glassware was previously dried in an oven at 110 °C solution (60 mL) and extracted with diethyl ether (3 × 40 mL).
and set with cycles of vacuum and nitrogen. Also syringes, The organic layers were dried over Na2SO4 and the solvent was
used to transfer reagents and solvents, were previously set removed under reduced pressure. Unless otherwise stated, the
under a nitrogen atmosphere. Some solvents, used for reac- compounds were used without the need for chromatographic
tions sensitive to oxygen and hydrolysis, were distilled and purification.
stored under a protected atmosphere of nitrogen, according to
3-Phenylprop-2-yn-1-ol (1a). Reaction time: 1 h. Yield:
1
the following standard operations: dichloromethane: distilled 785 mg (99%). Brown oil. H NMR (CDCl3, 200 MHz): δ = 2.95
on CaCl2 and placed on 4 Å sieves into a recycling appliance. (bs, 1H, OH), 4.50 (s, 2H, CH2), 7.29–7.33 (m, 3H, HAr),
Anhydrous THF, DMSO and ethanol are commercially avail- 7.43–7.45 (m, 2H, HAr). These data are in good agreement with
able. The chromatographic column separations were con- literature values.32
ducted by the flash technique, using silica gel Davisil LC 60 Å
3-(4-Chlorophenyl)prop-2-yn-1-ol (1b). Reaction time: 1.5 h.
(230–400 mesh). For thin-layer chromatography (TLC), silica Yield: 989 mg (99%). Brown solid. Mp 74–77 °C (lit. 76–78 °C).
gel 60 F254 FLUKA thin-layer plates were employed and the 1H NMR (CDCl3, 200 MHz): δ = 2.20 (bs, 1H, OH), 4.49 (s, 2H,
detection was performed by irradiation with UV light (λ = CH2), 7.28 (d, J = 8.5 Hz, 2H, HAr), 7.36 (d, J = 8.5 Hz, 2H, HAr).
254 nm and/or 366 nm). 1H NMR analyses were performed These data are in good agreement with literature values.33
with a Varian-Gemini 200 at 200 MHz at room temperature.
3-(p-Tolyl)prop-2-yn-1-ol (1c). Reaction time: 2 h. Yield:
The coupling constants (J) are expressed in hertz (Hz) and the 868 mg (99%). Yellow wax. 1H NMR (200 MHz, CDCl3): δ = 2.50
chemical shifts (δ) in ppm. The multiplicity of the proton (bs, 1H, OH), 2.34 (s, 3H, CH3), 4.48 (s, 2H, CH2), 7.10 (d, J =
spectra was described by the following abbreviations: 8.1 Hz, 2H, HAr), 7.33 (d, J = 8.1 Hz, 2H, HAr). These data are in
s (singlet), d (doublet), t (triplet), q (quartet), dt (double triplet), good agreement with literature values.34
dd (double doublet), ddd (double double doublet), m (multi-
3-(4-(Methylsulfonyl)phenyl)prop-2-yn-1-ol
(1d). Reaction
plet). 13C NMR analyses were performed with the same instru- time: 3 h. Eluent for chromatography: hexane–EtOAc (5 : 5).
ments at 50.3 MHz; an APT sequence was used to distinguish Yield: 971 mg (77%). Light brown solid. Mp 81–82 °C. 1H NMR
the methine and methyl carbon signals from those arising (200 MHz, CDCl3): δ = 2.41 (bs, 1H, OH), 3.04 (s, 3H, CH3),
from methylene and quaternary carbon atoms. Infrared 4.49 (s, 2H, CH2), 7.53 (d, J = 8.1 Hz, 2H, HAr), 7.85 (d, J =
8024 | Org. Biomol. Chem., 2014, 12, 8019–8030
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8.1 Hz, 2H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 44.6 (CH3), no starting product was detectable by TLC analysis (eluent:
51.5 (CH2), 83.9 (Csp), 91.9 (Csp), 127.5 (CHAr), 128.8 (Cq), 132.6 hexane–ethyl acetate = 9 : 1). Hexane (130 mL) was added to
(CHAr), 140.0 (Cq). ESI-MS m/z (%): 211.2 (45) [M + H]+, 233.1 precipitate the phosphine oxide and the white suspension was
(60) [M + Na]+, 242 (100) [M + CH3OH + H]+. HRMS ESI [M + passed through a short silica pad (3 cm diameter × 2 cm
H]+ calcd for C10H11O3S 211.0423, found 211.424.
height) and washed with hexane. The crude product was freed
3-(3-(Trifluoromethyl)phenyl)prop-2-yn-1-ol (1e). Reaction from solvents under reduced pressure. Unless otherwise
time: 2 h. Yield: 1.19 g (99%). Light yellow oil. 1H NMR stated, the compounds were used without the need of chroma-
(CDCl3, 200 MHz): δ = 2.03 (s, 1H, OH), 4.51 (s, 2H, CH2), tographic purification.
7.39–7.46 (m, 1H, HAr), 7.52–7.59 (m, 2H, HAr), 7.68 (s, 1H,
(3-Bromoprop-1-yn-1-yl)benzene (2a). Reaction time: 2 h.
HAr). 13C NMR (50.3 MHz, CDCl3): δ = 51.7 (CH2), 84.4 (Csp), Yield: 1.97 g (81%). Light yellow oil. 1H NMR (200 MHz,
1
89.1 (Csp), 123.8 (Cq), 123.9 (q, JC–F = 272.0 Hz, CF3), 125.2 (q, CDCl3): δ = 4.17 (s, 2H, CH2), 7.31–7.36 (m, 3H, HAr), 7.43–7.48
3
3JC–F = 3.8 Hz, CHAr), 128.7 (q, JC–F = 3.8 Hz, CHAr), 129.0 (m, 2H, HAr). These data are in good agreement with literature
2
(CHAr), 131.2 (q, JC–F = 33.0 Hz, Cq), 134.9 (CHAr). ESI-MS m/z values.35
(%): 223.1 (100) [M + Na]+. HRMS ESI [M + H]+ calcd for
C10H8F3O 201.0522, found 201.0520.
1-(3-Bromoprop-1-yn-1-yl)-4-chlorobenzene
(2b). Reaction
time: 2 h. Yield: 2.58 g (90%). Colourless oil. 1H NMR
3-(2-Ethylphenyl)prop-2-yn-1-ol (1f). Reaction time:
3
h. (200 MHz, CDCl3): δ = 4.14 (s, 2H, CH2), 7.29 (d, J = 8.6 Hz, 2H,
Eluent for chromatography: hexane–EtOAc (9 : 1). Yield: HAr), 7.37 (d, J = 8.6 Hz, 2H, HAr). These data are in good agree-
836 mg (87%). Light yellow oil. 1H NMR (200 MHz, CDCl3): δ = ment with literature values.36
1.24 (t, J = 7.5 Hz, 3H, CH3), 1.81 (bs, 1H, OH), 2.80 (q, J = 7.5
1-(3-Bromoprop-1-yn-1-yl)-4-methylbenzene (2c). Reaction
Hz, 2H, CH2), 4.54 (s, 2H, CH2), 7.09–7.31 (m, 3H, HAr), 7.41 time: 2 h. Yield: 2.59 g (99%). Light yellow oil. 1H NMR
(d, J = 7.5 Hz, 1H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 15.0 (200 MHz, CDCl3): δ = 2.35 (s, 3H, CH3), 4.17 (s, 2H, CH2), 7.12
(CH3), 27.8 (CH2), 52.0 (CH2), 84.6 (Csp), 90.8 (Csp), 121.8 (Cq), (d, J = 7.8 Hz, 2H, HAr) 7.34 (d, J = 7.8 Hz, 2H, HAr). These data
125.8 (CHAr), 128.1 (CHAr), 128.9 (CHAr), 132.6 (CHAr), 146.5 are in good agreement with literature values.37
(Cq). ESI-MS m/z (%): 301 (52) [dimer − H2 − H2O + H]+, 303
(32) [dimer − H2O + H]+, 339 (100) [dimer + H2O + H]+. HRMS Reaction time: 2 h. Eluent for chromatography: hexane–EtOAc
ESI [M + H]+ calcd for C11H13O 161.0961, found 161.0959. (6 : 4). Yield: 1.94 g (57%). Brown solid. Mp: 98–102 °C. 1H
3-(3-Chloro-2-methylphenyl)prop-2-yn-1-ol (1g). Reaction NMR (200 MHz, CDCl3): δ = 3.05 (s, 3H, CH3), 4.15 (s, 2H,
1-(3-Bromoprop-1-yn-1-yl)-4-methylsulfonylbenzene
(2d).
time: 3 h. Eluent for chromatography: hexane–EtOAc (9 : 1). CH2), 7.60 (d, J = 8.6 Hz, 2H, HAr), 7.88 (d, J = 8.6 Hz, 2H, HAr).
1
Yield: 1.07 g (99%). Light brown solid. Mp: 54–59 °C. H NMR 13C NMR (50.3 MHz, CDCl3): δ = 14.4 (CH2), 44.6 (CH3), 84.8
(200 MHz, CDCl3): δ = 1.71 (bs, 1H, OH), 2.50 (s, 3H, CH3), (Csp), 88.4 (Csp), 127.6 (CHAr), 128.2 (Cq), 132.8 (CHAr), 140.6
4.54 (s, 2H, CH2), 7.06 (t, J = 7.9 Hz, 1H, HAr), 7.32 (d, J = 7.9 (Cq). ESI-MS m/z (%): 217.3 (100) [M − Br + Na]+, 273.2/275.1
Hz, 2H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 18.5 (CH3), 51.8 (18) [M + H]+, 295.0/297.1 (31) [M + Na]+. HRMS ESI [M + H]+
(CH2), 84.2 (Csp), 91.9 (Csp), 124.5 (Cq), 126.7 (CHAr), 129.7 calcd for C10H10BrO2S 272.9579, found 272.9581.
(CHAr), 130.9 (CHAr), 134.9 (Cq), 138.3 (Cq). ESI-MS m/z (%):
1-(3-Bromoprop-1-yn-1-yl)-3-(trifluoromethyl)benzene (2e).
145.1 (50) [M − Cl]+, 164.8 (100) [M − H2O + H]+, 180.9 (75) Reaction time: 2.5 h. Yield: 1.94 g (59%). Dark yellow oil. 1H
[M + H]+. HRMS ESI [M + H]+ calcd for C10H10ClO 181.0415, NMR (200 MHz, CDCl3): δ = 4.15 (s, 2H, CH2), 7.39–7.50 (m,
found 181.0413.
3-(2-Isopropylphenyl)prop-2-yn-1-ol (1h). Reaction time: (50.3 MHz, CDCl3): δ = 14.6 (CH2), 85.2 (Csp), 86.0 (Csp), 123.4
1H, HAr), 7.54–7.65 (m, 2H, HAr), 7.70 (s, 1H, HAr). 13C NMR
1
3
2 h. Eluent for chromatography: hexane–EtOAc (9 : 1). Yield: (Cq), 123.8 (q, JC–F = 272.8 Hz, CF3), 125.6 (q, JC–F = 3.8 Hz,
1
3
994 mg (95%). Brown oil. H NMR (200 MHz, CDCl3): δ = 1.25 CHAr), 128.9 (q, JC–F = 3.8 Hz, CHAr), 129.1 (CHAr), 131.3 (q,
(d, J = 7.0 Hz, 6H, CH3), 3.44 (sept, J = 7.0 Hz, 1H, CH), 4.54 (s, 2JC–F = 33.0 Hz, Cq), 135.1 (CHAr). ESI-MS m/z (%): 206.4 (100)
2H, CH2), 7.08–7.17 (m, 1H, HAr), 7.26–7.30 (m, 2H, HAr), 7.41 [M − Br + Na]+. HRMS ESI [M + H]+ calcd for C10H7BrF3
(d, J = 7.3 Hz, 1H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 23.4 262.9678, found 262.9681.
(CH3), 31.7 (CH), 51.9 (CH2), 84.6 (Csp), 91.1 (Csp), 121.5 (Cq),
1-(3-Bromoprop-1-yn-1-yl)-2-ethylbenzene
(2f). Reaction
125.2 (CHAr), 125.7 (CHAr), 129.1 (CHAr), 132.8 (CHAr), 150.8 time: 2.5 h. Eluent for chromatography: hexane–EtOAc (9 : 1).
(Cq). ESI-MS m/z (%): 174.2 (10) [M]+, 234.4 (100) [M + AcOH]+. Yield: 1.90 g (68%). Light yellow oil. 1H NMR (200 MHz,
HRMS ESI [M + H]+ calcd for C12H15O 175.1117, found CDCl3): δ = 1.25 (t, J = 7.6 Hz, 3H, CH3), 2.80 (q, J = 7.6 Hz, 2H,
175.1119.
CH2), 4.21 (s, 2H, CH2), 7.07–7.34 (m, 3H, HAr), 7.41 (dd, J =
7.4, 1.1 Hz, 1H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 15.1
(CH3), 15.7 (CH2), 27.8 (CH2), 86.0 (Csp), 87.7 (Csp), 121.5 (Cq),
125.8 (CHAr), 128.2 (CHAr), 129.3 (CHAr), 132.7 (CHAr), 147.0
General procedure for the synthesis of aryl propargyl bromides
(2a–h)
Triphenylphosphine (3.93 g, 15.0 mmol) was dissolved in (Cq). ESI-MS m/z (%): 143.1 (75) [M − Br]+, 447 (100) [dimer +
dichloromethane (40 mL). Bromine (2.40 g, 15.0 mmol) was H]+. HRMS ESI [M + H]+ calcd for C11H12Br 223.0117, found
then added dropwise at 0 °C and stirred for 30 min. The appro- 223.0120.
priate functionalized propargyl alcohols 1a–h (12.5 mmol)
1-(3-Bromoprop-1-yn-1-yl)-3-chloro-2-methylbenzene
(2g).
were added at 0 °C and the reaction mixture was stirred until Reaction time: 2.5 h. Yield: 2.47 g (81%). Yellow solid. Mp:
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60–65 °C. 1H NMR (200 MHz, CDCl3): δ = 2.50 (s, 3H, CH3), added to Mg turnings. The mixture was stirred for 1 h at 80 °C
4.19 (s, 2H, CH2), 7.07 (t, J = 7.6 Hz, 1H, HAr), 7.32 (d, J = under a nitrogen atmosphere until the Mg was almost comple-
7.6 Hz, 2H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 15.1 (CH2), tely dissolved. Then the propargyl bromides (2a–h) (2.0 mmol)
18.4 (CH3), 85.3 (Csp), 88.7 (Csp), 124.1 (Cq), 126.7 (CHAr), 130.0 were added and the reaction was stirred at 80 °C until no start-
(CHAr), 130.9 (CHAr), 135.0 (Cq), 138.7 (Cq). ESI-MS m/z (%): ing product was detectable by TLC analysis. After cooling to rt,
649.5 (100) [trimer − Br + H]+. HRMS ESI [M + H]+ calcd for the reaction mixture was poured in a saturated ammonium
C10H9BrCl 242.9571, found 242.9576.
chloride solution (30 mL) and extracted with diethyl ether (3 ×
1-(3-Bromoprop-1-yn-1-yl)-2-isopropylbenzene (2h). Reaction 20 mL). The organic layers were washed with brine (40 mL)
time: 2 h. Eluent for chromatography: hexane–EtOAc (9 : 1). and dried over Na2SO4. The solvent was evaporated under
Yield: 2.52 g (85%). Light brown oil. 1H NMR (200 MHz, reduced pressure and the crude was quickly purified by flash
CDCl3): δ = 1.26 (d, J = 7.0 Hz, 6H, CH3), 3.41 (sept, J = 7.0 Hz, chromatography on a short silica gel column. The dioxolane
1H, CH), 4.21 (s, 2H, CH2), 7.09–7.17 (m, 1H, HAr), 7.26–7.32 intermediates were not very stable (in particular at rt or in
(m, 2H, HAr), 7.40 (d, J = 7.3 Hz, 1H, HAr).13C NMR (50.3 MHz, a slightly acidic solvent such as deuterochloroform), so after
CDCl3): δ = 15.8 (CH2), 23.3 (CH3), 31.8 (CH), 86.0 (Csp), 87.9 1H NMR and MS characterization they were immediately con-
(Csp), 121.1 (Cq), 125.2 (CHAr), 125.7 (CHAr), 129.4 (CHAr), 132.8 verted into the corresponding aldehydes.
(CHAr), 151.3 (Cq). ESI-MS m/z (%): 157.4 (100) [M − Br]+.
HRMS ESI [M + H]+ calcd for C12H14Br 237.0273, found Reaction time: 3 h. Eluent for chromatography: hexane–EtOAc
2-(2-(3-Phenylprop-2-yn-1-yl)phenyl)-1,3-dioxolane
(3a).
237.0277.
(99 : 1). Yield: 0.32 g (61%). Light brown oil. 1H NMR
(200 MHz, CDCl3): δ = 4.01 (s, 2H, CH2), 4.04–4.10 (m, 2H,
O-CH2), 4.11–4.17 (m, 2H, O-CH2), 6.07 (s, 1H, CH), 7.22–7.50
(m, 7H, HAr), 7.53–7.71 (m, 2H, HAr). These data are in good
General procedure for the synthesis of 2-(2-bromophenyl)-1,3-
dioxolanes
Ethylene glycol (1.80 g, 1.62 mL, 29.0 mmol) and p-toluene- agreement with literature values.9a
sulfonic acid·H2O (50 mg, 0.26 mmol) were added to a solution
2-(2-(3-(4-Chlorophenyl)prop-2-yn-1-yl)phenyl)-1,3-dioxolane
of 2-bromobenzaldehyde or 2-bromo-5-fluorobenzaldehyde (3b). Reaction time: 3 h. Eluent for chromatography: hexane–
(14.5 mmol) in toluene (40 mL). The mixture was heated at EtOAc (99 : 1). Yield: 0.48 g (81%). Light yellow oil. 1H NMR
reflux in a Dean–Stark apparatus for 3 hours. After cooling to (200 MHz, CDCl3): δ = 3.99 (s, 2H, CH2), 4.05–4.09 (m, 2H,
room temperature, the mixture was washed with a satd aq. O-CH2), 4.12–4.16 (m, 2H, O-CH2), 6.05 (s, 1H, CH), 7.24–7.38
NaHCO3 solution (40 mL) and with brine (40 mL). The organic (m, 6H, HAr), 7.61 (m, 2H, HAr). ESI-MS m/z (%): 299.2 (100)
phase was dried over Na2SO4 and the solvent was removed at [M + H]+.
reduced pressure. The residue was purified by flash column
chromatography, affording the desired dioxolane derivatives.
2-(2-Bromophenyl)-1,3-dioxolane. Eluent for chromato- (99 : 1). Yield: 0.39
2-(2-(3-(p-Tolyl)prop-2-yn-1-yl)phenyl)-1,3-dioxolane
Reaction time: 3 h. Eluent for chromatography: hexane–EtOAc
(68%). Dark yellow oil. 1H NMR
(3c).
g
graphy: hexane–EtOAc (95 : 5). Yield: 3.02 g (91%). Colourless (200 MHz, CDCl3): δ = 2.34 (s, 3H, CH3), 3.99 (s, 2H, CH2),
1
oil. H NMR (200 MHz, CDCl3): δ = 4.05–4.10 (m, 2H, O-CH2), 4.04–4.10 (m, 2H, O-CH2), 4.17–4.10 (m, 2H, O-CH2), 6.07 (s,
4.13–4.18 (m, 2H, O-CH2), 6.10 (s, 1H, CH), 7.20 (dt, J = 7.3, 1H, CH), 7.06–7.15 (m, 2H, HAr), 7.27–7.43 (m, 4H, HAr),
1.8 Hz, 1H, HAr), 7.34 (dt, J = 7.5, 1.4 Hz, 1H, HAr), 7.58 (dt, J = 7.52–7.69 (m, 2H, HAr). ESI-MS m/z (%): 279.3 (100) [M + H]+.
7.5, 1.6 Hz, 2H, HAr). These data are in good agreement with These data are in good agreement with literature values.9a
literature values.38
2-(2-(3-(4-(Methylsulfonyl)phenyl)prop-2-yn-1-yl)phenyl)-1,3-
2-(2-Bromo-5-fluorophenyl)-1,3-dioxolane. Eluent for chrom- dioxolane (3d). Reaction time: 4 h. Eluent for chromatography:
1
atography: hexane–EtOAc (9 : 1). Yield: 2.83 g (79%). Colourless hexane–EtOAc (7 : 3). Yield: 0.22 g (32%). Light brown oil. H
1
oil. H NMR (200 MHz, CDCl3): δ = 4.03–4.10 (m, 2H, O-CH2), NMR (200 MHz, CDCl3): δ = 3.04 (s, 3H, CH3), 4.03 (s, 2H,
4.13–4.20 (m, 2H, O-CH2), 6.04 (s, 1H, CH), 6.95 (tdd, J = 8.5, CH2), 4.04–4.11 (m, 2H, O-CH2), 4.11–4.18 (m, 2H, O-CH2),
3.1, 0.6 Hz, 1H, HAr), 7.33 (dd, J = 3.1, 9.3 Hz, 1H, HAr) 7.52 6.04 (s, 1H, CH), 7.28–7.48 (m, 3H, HAr), 7.53–7.65 (m, 3H,
(dd, J = 5.1, 8.7 Hz, 1H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = HAr), 7.87 (d, J = 8.5 Hz, 2H, HAr). ESI-MS m/z (%): 343.5 (100)
4
2
65.8 (CH2), 102.2 (d, JC–F = 1.1 Hz, CH), 115.3 (d, JC–F
=
=
=
[M + H]+.
2-(2-(3-(3-(Trifluoromethyl)phenyl)prop-2-yn-1-yl)phenyl)-1,3-
dioxolane (3e). Reaction time: 4 h. Eluent for chromatography:
24.4 Hz, CHAr), 117.0 (d, JC–F = 3.0 Hz, Cq), 117.9 (d,2 JC–F
4
3
3
22.9 Hz, CHAr), 134.5 (d, JC–F = 7.6 Hz, CHAr), 139.2 (d, JC–F
1
1
6.9 Hz, Cq), 162.2 (d, JC–F = 247 Hz, C–F). ESI-MS m/z (%): hexane–EtOAc (99 : 1). Yield: 0.51 g (76%). Yellow oil. H NMR
247.2/245.2 (100) [M]+. HRMS ESI [M
C9H9BrFO2 246.9764, found 246.9761.
+
H]+ calcd for (200 MHz, CDCl3): δ = 4.01 (s, 2H, CH2), 4.05–4.11 (m, 2H,
O-CH2), 4.12–4.18 (m, 2H, O-CH2), 6.06 (s, 1H, CH), 7.29–7.63
(m, 7H, HAr), 7.70 (s, 1H, HAr). ESI-MS m/z (%): 333.2 (100)
General procedure for the Grignard coupling reaction (3a–i)
[M + H]+.
Mg turnings were activated by trituration in a mortar. Mg turn-
2-(2-(3-(2-Ethylphenyl)prop-2-yn-1-yl)phenyl)-1,3-dioxolane
ings (53 mg, 2.2 mmol) were charged in a reaction flask under (3f). Reaction time: 4 h. Eluent for chromatography: hexane–
a nitrogen atmosphere. An appropriate amount of 1,3-dioxo- EtOAc (99 : 1). Yield: 0.46 g (79%). Yellow oil. 1H NMR
lane derivative (2.0 mmol) was dissolved in THF (2 mL) and (200 MHz, CDCl3): δ = 1.25 (t, J = 7.6 Hz, 3H, CH3), 2.83 (q, J =
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7.6 Hz, 2H, CH2), 4.05 (s, 2H, CH2), 4.06–4.10 (m, 2H, O-CH2), 1H, CHO). 13C NMR (50.3 MHz, CDCl3): δ = 23.8 (CH2), 83.0
4.11–4.18 (m, 2H, O-CH2), 6.07 (s, 1H, CH), 7.07–7.24 (m, 3H, (Csp), 88.0 (Csp), 122.2 (Cq), 127.7 (CHAr), 128.8 (CHAr), 130.2
HAr), 7.27–7.47 (m, 3H, HAr), 7.58 (dd, J = 1.8, 7.3 Hz, 1H, HAr), (CHAr), 133.1 (CHAr), 133.5 (Cq), 134.0 (CHAr), 134.2 (Cq), 134.3
7.63–7.72 (m, 1H, HAr). ESI-MS m/z (%): 293.2 (100) [M + H]+, (CHAr), 138.6 (Cq), 192.9 (CHO). ESI-MS m/z (%): 255.0 (100)
263 (20) [M − CH2CH3]+.
2-(2-(3-(3-Chloro-2-methylphenyl)prop-2-yn-1-yl)phenyl)-1,3- found 255.0572.
dioxolane (3g). Reaction time: 4 h. Eluent for chromatography: 2-(3-(p-Tolyl)prop-2-yn-1-yl)benzaldehyde
[M + H]+. HRMS ESI [M + H]+ calcd for C16H12ClO2 255.0571,
(4c). Reaction
1
hexane–EtOAc (99 : 1). Yield: 0.48 g (77%). Yellow oil. H NMR time: 2 h. Eluent for chromatography: hexane–EtOAc (99 : 1).
1
(200 MHz, CDCl3): δ = 2.51 (s, 3H, CH3), 4.05 (s, 2H, CH2), Yield: 337 mg (96%). Orange oil. H NMR (200 MHz, CDCl3):
4.06–4.11 (m, 2H, O-CH2), 4.12–4.17 (m, 2H, O-CH2), 6.06 (s, δ = 2.34 (s, 3H, CH3), 4.29 (s, 2H, CH2), 7.11 (d, J = 7.9 Hz, 2H,
1H, CH), 7.04 (t, J = 7.8 Hz, 1H, HAr), 7.28–7.44 (m, 4H, HAr), HAr), 7.34 (d, J = 8.0 Hz, 2H, HAr), 7.47 (m, 1H, HAr), 7.61 (dt,
7.58 (dd, J = 1.9, 7.3 Hz, 1H, HAr), 7.63 (dd, J = 1.0, 7.2 Hz, 1H, J = 1.5, 7.5 Hz, 1H, HAr), 7.82 (dt, J = 7.7, 1.4 Hz, 2H, HAr),
HAr). ESI-MS m/z (%): 313.1 (100) [M + H]+.
2-(2-(3-(2-Isopropylphenyl)prop-2-yn-1-yl)phenyl)-1,3-dioxolane literature values.9a
10.28 (s, 1H, CHO). These data are in good agreement with
(3h). Reaction time: 3 h. Eluent for chromatography: hexane–
2-(3-(4-(Methylsulfonyl)phenyl)prop-2-yn-1-yl)benzaldehyde
EtOAc (99 : 1). Yield: 0.23 g (38%). Brown oil. 1H NMR (4d). Reaction time: 2 h. Eluent for chromatography: hexane–
(200 MHz, CDCl3): δ = 1.25 (d, J = 7.0 Hz, 6H, CH3), 3.48 (sept, EtOAc (8 : 2). Yield: 367 mg (82%). Yellow oil. 1H NMR
J = 7.0 Hz, 1H, CH), 4.05 (s, 2H, CH2), 4.02–4.11 (m, 2H, (200 MHz, CDCl3): δ = 3.03 (s, 3H, CH3), 4.37 (s, 2H, CH2), 7.49
O-CH2), 4.12–4.17 (m, 2H, O-CH2), 6.07 (s, 1H, CH), 7.07–7.16 (dt, J = 1.0, 7.3 Hz, 1H, HAr), 7.59 (d, J = 8.4 Hz, 2H, HAr),
(m, 1H, HAr), 7.24–7.29 (m, 2H, HAr), 7.32–7.41 (m, 2H, HAr), 7.57–7.67 (m, 1H, HAr), 7.72 (d, J = 7.4 Hz, 1H, HAr), 7.80–7.84
7.42–7.51 (m, 1H, HAr), 7.58 (dd, J = 1.8, 7.4 Hz, 1H, HAr), 7.67 (m, 1H, HAr), 7.86 (d, J = 8.5 Hz, 2H, HAr), 10.22 (s, 1H, CHO).
(d, J = 7.1 Hz, 1H, HAr). ESI-MS m/z (%): 307.2 (100) [M + H]+.
13C NMR (50.3 MHz, CDCl3): δ = 23.8 (CH2), 44.7 (CH3), 82.4
2-(2-(3-(4-Chlorophenyl)prop-2-yn-1-yl)-5-fluorophenyl)-1,3- (Csp), 91.7 (Csp), 127.5 (CHAr), 127.9 (CHAr), 129.6 (Cq), 130.2
dioxolane (3i). Reaction time: 5.5 h. Eluent for chromato- (CHAr), 132.6 (CHAr), 133.5 (Cq), 134.3 (CHAr), 134.4 (CHAr),
graphy: hexane–EtOAc (99 : 1). Yield: 0.34 g (54%). Light yellow 137.9 (Cq), 139.7 (Cq). ESI-MS m/z (%): 619.0 (100) [dimer +
oil. 1H NMR (200 MHz, CDCl3): δ = 3.92 (s, 2H, CH2), 4.00–4.09 Na]+, 321.3 (40) [M + Na]+. HRMS ESI [M + H]+ calcd for
(m, 2H, O-CH2), 4.10–4.21 (m, 2H, O-CH2), 6.03 (s, 1H, CH), C17H15O3S 299.0736, found 299.0732.
6.99–7.18 (m, 2H, HAr), 7.21–7.42 (m, 4H, HAr), 7.54 (dd, J =
5.5, 8.5 Hz, 1H, HAr). ESI-MS m/z (%): 317.4 (100) [M + H]+.
2-(3-(3-(Trifluoromethyl)phenyl)prop-2-yn-1-yl)benzaldehyde
(4e). Reaction time: 2 h. Eluent for chromatography: hexane–
EtOAc (99 : 1). Yield: 337 mg (78%). Pale yellow solid. Mp:
42–46 °C. 1H NMR (200 MHz, CDCl3): δ = 4.32 (s, 2H, CH2),
General procedure for the cleavage of 1,3-dioxolanes
p-Toluenesulfonic acid·H2O (14 mg, 0.075 mmol) was added to 7.34–7.97 (m, 8H, HAr), 10.25 (s, 1H, CHO). 13C NMR
a solution of the an appropriate amount of 1,3-dioxolanes 3a-i (50.3 MHz, CDCl3): δ = 23.4 (CH2), 82.6 (Csp), 88.8 (Csp), 123.9
1
(1.5 mmol) in a mixture of acetone–water = 1.2 : 1 (10 mL). The (q, JC–F = 272.0 Hz, CF3), 124.1 (Cq), 124.6 (CHAr), 124.7 (q,
mixture was refluxed until completion of the reaction (2–3 h), 3JC–F = 3.8 Hz, CHAr), 128.6 (q, JC–F = 3.8, CHAr), 129.0 (CHAr),
3
2
detectable by TLC analysis (eluent: hexane–ethyl acetate 9 : 1). 130.2 (CHAr), 131.1 (q, JC–F = 32.0 Hz, Cq), 133.5 (Cq), 134.3
After cooling to rt, satd aqueous NaHCO3 (40 mL) was added (CHAr), 135.0 (CHAr), 138.3 (Cq), 193.1 (CHO). ESI-MS m/z (%):
and the solution was extracted with diethyl ether (20 × 3). The 289.4 (100) [M + H]+. HRMS ESI [M + H]+ calcd for C17H12F3O
combined organic phases were washed with brine (30 mL), 289.0835, found 289.0834.
dried over Na2SO4 and the solvent was removed at reduced
pressure. The residue was purified by flash chromatography, tion time: 2 h. Eluent for chromatography: hexane–EtOAc
affording the desired 2-propargylbenzaldehydes 4a–i.
(99 : 1). Yield: 331 mg (89%). Yellow oil. 1H NMR (200 MHz,
2-(3-(2-Ethylphenyl)prop-2-yn-1-yl)benzaldehyde (4f). Reac-
2-(3-Phenylprop-2-yn-1-yl)benzaldehyde (4a). Reaction time: CDCl3): δ = 1.23 (t, J = 7.6 Hz, 3H, CH3), 2.80 (q, J = 7.5 Hz, 2H,
2 h. Eluent for chromatography: hexane–EtOAc (99 : 1). Yield: CH2), 4.35 (s, 2H, CH2), 7.04–7.30 (m, 3H, HAr), 7.38–7.53 (m,
1
280 mg (85%). Yellow oil. H NMR (200 MHz, CDCl3): δ = 4.30 2H, HAr), 7.61 (dt, J = 1.6, 7.5 Hz, 1H, HAr), 7.83 (dt, J = 7.2, 1.5
(s, 2H, CH2), 7.27–7.34 (m, 3H, HAr), 7.38–7.53 (m, 3H, HAr), Hz, 2H, HAr), 10.28 (s, 1H, CHO). 13C NMR (50.3 MHz, CDCl3):
7.54–7.67 (m, 1H, HAr), 7.74–7.90 (m, 2H, HAr), 10.28 (s, 1H, δ = 15.1 (CH3), 23.9 (CH2), 28.0 (CH2), 82.9 (Csp), 90.3 (Csp),
CHO). These data are in good agreement with literature 122.8 (Cq), 125.8 (CHAr), 127.5 (CHAr), 128.1 (CHAr), 128.4
values.9a
2-(3-(4-Chlorophenyl)prop-2-yn-1-yl)benzaldehyde
(CHAr), 130.2 (CHAr), 132.5 (CHAr), 133.5 (Cq), 133.7 (CHAr),
(4b). 134.2 (CHAr), 139.2 (Cq), 146.4 (Cq), 192.9 (CHO). ESI-MS m/z
Reaction time: 2 h. Eluent for chromatography: hexane–EtOAc (%): 263.3 (100) [M + CH3]+, 249.2 (30) [M + H]+. HRMS ESI
(99 : 1). Yield: 359 mg (94%). Light yellow solid. Mp: 64–68 °C. [M + H]+ calcd for C18H17O 249.1274, found 249.1277.
1H NMR (200 MHz, CDCl3): δ = 4.29 (s, 2H, CH2), 7.27 (d, J =
2-(3-(3-Chloro-2-methylphenyl)prop-2-yn-1-yl)benzaldehyde
8.7 Hz, 2H, HAr), 7.37 (d, J = 8.6 Hz, 2H, HAr), 7.48 (dt, J = 7.4, (4g). Reaction time: 3 h. Eluent for chromatography: hexane–
1.3 Hz, 1H, HAr), 7.61 (dt, J = 1.5, 7.5 Hz, 1H, HAr), 7.76 (d, J = EtOAc (99 : 1). Yield: 358 mg (89%). Pale yellow solid. Mp:
7.6 Hz, 1H, HAr), 7.84 (dd, J = 1.4, 7.5 Hz, 1H, HAr), 10.26 (s, 90–94 °C. 1H NMR (200 MHz, CDCl3): δ = 2.50 (s, 3H, CH3),
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4.35 (s, 2H, CH2), 7.05 (t, J = 7.8 Hz, 1H, HAr), 7.31 (m, 2H, 1H, HAr), 7.72 (d, J = 7.7 Hz, 1H, HAr), 7.93 (d, J = 7.3 Hz, 1H,
HAr), 7.49 (dt, J = 1.2, 7.4 Hz, 1H, HAr), 7.62 (dt, J = 1.6, 7.5 Hz, HAr), 9.22 (s, 1H, HAr). 13C NMR (CDCl3, 50.3 MHz): δ = 44.6
1H, HAr), 7.78 (d, J = 7.6 Hz, 1H, HAr), 7.85 (dd, J = 1.6, 7.4 Hz, (CH2), 118.9 (CHAr), 126.5 (CHAr), 126.6 (CHAr), 126.8 (CHAr),
1H, HAr), 10.26 (s, 1H, CHO). 13C NMR (50.3 MHz, CDCl3): δ = 127.4 (Cq), 127.7 (CHAr), 128.8 (CHAr), 129.5 (CHAr), 130.5
18.5 (CH3), 23.9 (CH2), 82.9 (Csp), 91.5 (Csp), 125.4 (Cq), 126.6 (CHAr), 136.8 (Cq), 140.1 (Cq), 152.6 (CHAr), 154.7 (Cq). ESI-MS
(CHAr), 127.6 (CHAr), 129.2 (CHAr), 130.1 (CHAr), 130.1 (CHAr), m/z (%): 220.3 (100) [M + H]+. HRMS ESI [M + H]+ calcd for
130.8 (CHAr), 133.5 (Cq), 134.1 (CHAr), 134.3 (CHAr), 134.9 (Cq), C16H14N 220.1121, found 220.1123.
138.2 (Cq), 138.8 (Cq), 193.0 (CHO). ESI-MS m/z (%): 269.3
3-(4-Chlorobenzyl)isoquinoline (5b). Eluent for chromato-
(100) [M + H]+. HRMS ESI [M + H]+ calcd for C17H14ClO graphy: hexane–EtOAc (95 : 5). Yield: 71 mg (93%). Light brown
269.0728, found 269.0725.
solid. Mp: 78–80 °C. 1H NMR (200 MHz, CDCl3): δ = 4.27 (s,
2-(3-(2-Isopropylphenyl)prop-2-yn-1-yl)benzaldehyde
(4h). 2H, CH2), 7.16–7.34 (m, 4H, HAr), 7.42 (s, 1H, HAr), 7.48–7.63
Reaction time: 2.5 h. Eluent for chromatography: hexane– (m, 1H, HAr), 7.67 (dd, J = 1.3, 6.6 Hz, 1H, HAr), 7.73 (d, J =
1
EtOAc (99 : 1). Yield: 322 mg (82%). Light yellow oil. H NMR 8.1 Hz, 1H, HAr), 7.94 (d, J = 8.0 Hz, 1H, HAr), 9.21 (s, 1H, HAr).
(200 MHz, CDCl3): δ = 1.24 (d, J = 7.0 Hz, 6H, CH3), 3.45 (sept, 13C NMR (50.3 MHz, CDCl3): δ = 43.6 (CH2), 119.1 (CHAr),
J = 7.0 Hz, 1H, CH), 4.35 (s, 2H, CH2), 7.08–7.16 (m, 1H, HAr), 126.49 (CHAr), 127.1 (CHAr), 127.4 (Cq), 127.8 (CHAr), 128.9
7.24–7.28 (m, 2H, HAr), 7.41–7.45 (m, 2H, HAr), 7.49 (dd, J = (CHAr), 130.8 (CHAr), 130.9 (CHAr), 132.5 (Cq), 136.8 (Cq), 138.4
1.1, 7.3 Hz, 1H, HAr), 7.61 (dt, J = 1.5, 7.3 Hz, 1H, HAr), 7.83 (dt, (Cq), 152.4 (CHAr), 153.8 (Cq). ESI-MS m/z (%): 254.3 (100)
J = 1.5, 7.3 Hz, 1H, HAr), 10.29 (s, 1H, CHO). 13C NMR [M + H]+. HRMS ESI [M + H]+ calcd for C16H13ClN 254.0731,
(50.3 MHz, CDCl3): δ = 23.3 (CH3), 24.0 (CH2), 31.7 (CH), 83.0 found 254.0730.
(Csp), 90.5 (Csp), 122.5 (Cq), 125.1 (CHAr), 125.7 (CHAr), 127.5
3-(4-Methylbenzyl)isoquinoline (5c). Eluent for chromato-
(CHAr), 128.6 (CHAr), 130.2 (CHAr), 132.7 (CHAr), 133.6 (Cq), graphy: hexane–EtOAc (95 : 5). Yield: 55 mg (74%). Brown
133.7 (CHAr), 134.2 (CHAr), 139.2 (Cq), 150.6 (Cq), 192.9 (CHO). solid. Mp: 55–59 °C. 1H NMR (200 MHz, CDCl3): δ = 2.33 (s,
ESI-MS m/z (%): 285.2 (100) [M + Na]+, 263.3 (10) [M + H]+. 3H, CH3), 4.28 (s, 2H, CH2), 7.13 (d, J = 8.1 Hz, 2H, HAr), 7.22
HRMS ESI [M + H]+ calcd for C19H19O 263.1430, found (d, J = 8.1 Hz, 2H, HAr), 7.42 (s, 1H, HAr), 7.47–7.57 (m, 1H,
263.1428.
HAr), 7.58–7.68 (m, 1H, HAr), 7.71 (d, J = 7.6 Hz, 1H, HAr), 7.93
2-(3-(4-Chlorophenyl)prop-2-yn-1-yl)-5-fluorobenzaldehyde (d, J = 7.5 Hz, 1H, HAr), 9.21 (s, 1H, HAr). 13C NMR (50.3 MHz,
(4i). Reaction time: 3 h. Eluent for chromatography: hexane– CDCl3): δ = 21.3 (CH3), 44.0 (CH2), 118.9 (CHAr), 126.5 (CHAr),
EtOAc (99 : 1). Yield: 317 mg (78%). White solid. Mp: 65 °C. 1H 126.8 (CHAr), 127.3 (Cq), 127.8 (CHAr), 129.3 (CHAr), 129.5
NMR (200 MHz, CDCl3): δ = 4.21 (s, 2H, CH2), 7.22–7.39 (m, (CHAr), 130.6 (CHAr), 136.1 (Cq), 136.9 (Cq), 152.3 (CHAr), 154.8
5H, HAr), 7.54 (dd, J = 2.8, 8.5 Hz, 1H, HAr), 7.70 (dd, J = 5.1, (Cq). ESI-MS m/z (%): 234.3 (100) [M + H]+. HRMS ESI [M + H]+
8.5 Hz, 1H, HAr), 10.25 (d, JH–F = 1.2 Hz 1H, CHO). 13C NMR calcd for C17H16N 234.1277, found 224.1275.
(50.3 MHz, CDCl3): δ = 23.0 (CH2), 83.1 (Csp), 87.7 (Csp), 119.1
3-(4-(Methylsulfonyl)benzyl)isoquinoline (5d). Eluent for
2
2
(d, JC–F = 22.1 Hz, CHAr), 121.2 (d, JC–F = 21.0 Hz, CHAr), chromatography: hexane–EtOAc (6 : 4). Yield: 64 mg (67%).
3
121.9 (Cq), 128.8 (CHAr), 132.2 (d, JC–F = 7.2 Hz, CHAr), 133.1 Light brown oil. 1H NMR (200 MHz, CDCl3): δ = 3.01 (s, 3H,
(CHAr), 134.4 (Cq), 134.5 (d, 4JC–F = 3.4 Hz, Cq). 135.0 (d, 3JC–F
=
=
CH3), 4.37 (s, 2H, CH2), 7.50 (m, 3H, HAr), 7.54–7.79 (m, 3H,
HAr), 7.86 (d, J = 8.1 Hz, 2H, HAr), 7.94 (m, 1H, HAr), 9.20 (s,
1
4
5.7 Hz, Cq), 162.1 (d, JC–F = 248 Hz, C–F), 191.1 (d, JC–F
1.5 Hz, CHO). ESI-MS m/z (%): 532.2 (100) [dimer + Na − Cl]+. 1H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 44.3 (CH2), 44.8
HRMS ESI [M + H]+ calcd for C16H11ClFO 273.0477, found (CH3), 119.4 (CHAr), 126.5 (CHAr), 127.3 (CHAr), 127.6 (Cq),
273.0479.
127.8 (CHAr), 127.9 (CHAr), 130.3 (CHAr), 130.9 (CHAr), 136.71
(Cq), 138.8 (Cq), 146.7 (Cq), 152.8 (Cq), 152.9 (CHAr). ESI-MS
m/z (%): 298.3 (100) [M + H]+. HRMS ESI [M + H]+ calcd for
C17H16NO2S 298.0896, found 298.0898.
General procedure for the synthesis of 3-benzylisoquinolines
(5a–i)
A
stirred solution of the 2-propargylbenzaldehydes 4a–i
3-(3-(Trifluoromethyl)benzyl)isoquinoline (5e). Eluent for
(0.318 mmol) in dry DMSO (2 mL) and ammonia acetate chromatography: hexane–EtOAc (95 : 5). Yield: 74 mg (81%).
(489 mg, 6.36 mmol) was heated at 80 °C in a sealed vial for Brown solid. Mp: 60–65 °C. 1H NMR (200 MHz, CDCl3): δ =
30 min in a single-mode microwave synthesizer. The mixture 4.36 (s, 2H, CH2), 7.36–7.61 (m, 5H, HAr), 7.61–7.72 (m, 2H,
was poured into water (40 mL), extracted with EtOAc (3 × HAr), 7.75 (m, 1H, HAr), 7.95 (m, 1H, HAr), 9.24 (s, 1H, HAr).
20 mL), and the organic layers were dried over Na2SO4. The 13C NMR (50.3 MHz, CDCl3): δ = 44.2 (CH2), 119.2 (CHAr),
1
3
solvent was removed at reduced pressure and the resulting 124.6 (q, JC–F = 272.0 Hz, CF3), 123.5 (q, JC–F = 3.8 Hz, CHAr),
3
crude was purified by flash column chromatography, affording 126.1 (q, JC–F = 3.8 Hz, CHAr), 126.5 (CHAr), 127.1 (CHAr),
the desired isoquinolines 5a–i.
127.5 (Cq), 127.8 (CHAr), 129.2 (CHAr), 130.8 (CHAr), 132.8
3-Benzylisoquinoline (5a). Eluent for chromatography: (CHAr), 136.8 (Cq), 140.9 (Cq), 152.7 (CHAr), 153.4 (Cq) (one Cq
hexane–EtOAc (95 : 5). Yield: 55 mg (78%). Red solid. Mp: obscured). ESI-MS m/z (%): 288.4 (100) [M + H]+. HRMS ESI
60–61 °C. 1H NMR (CDCl3, 200 MHz): δ = 4.33 (s, 2H, CH2), [M + H]+ calcd for C17H13F3N 288.0995, found 288.0992.
7.21–7.29 (m, 1H, HAr), 7.32–7.34 (m, 4H, HAr), 7.43 (s, 1H,
3-(2-Ethylbenzyl)isoquinoline (5f). Eluent for chromato-
HAr), 7.53 (dt, J = 6.6, 1.5 Hz, 1H, HAr), 7.63 (dt, J = 6.6, 1.5 Hz, graphy: hexane–EtOAc (98 : 2). Yield: 56 mg (71%). Brown oil.
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1H NMR (200 MHz, CDCl3): δ = 1.17 (t, J = 7.5 Hz, 3H, CH3), MIUR (Ministero dell’Istruzione, dell’Università
2.68 (q, J = 7.5 Hz, 2H, CH2), 4.39 (s, 2H, CH2), 7.16–7.31 (m, Ricerca) for financial support.
5H, HAr), 7.48–7.57 (m, 1H, HAr), 7.51–7.61 (m, 1H, HAr),
e
della
7.63–7.66 (m, 1H, HAr), 7.94 (dd, J = 7.9, 0.6 Hz, 1H, HAr), 9.23
(s, 1H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 15.2 (CH3), 26.1
(CH2), 41.6, (CH2), 118.5 (CHAr), 126.3 (CHAr), 126.5 (CHAr),
Notes and references
126.8 (CHAr), 127.2 (CHAr), 127.7 (Cq), 128.8 (CHAr), 130.5
(CHAr), 130.9 (CHAr), 136.7 (Cq), 137.2 (Cq), 143.0 (Cq), 152.4
(CHAr), 154.9 (Cq). ESI-MS m/z (%): 248.3 (100) [M + H]+, 270.1
(22) [M + Na]+. HRMS ESI [M + H]+ calcd for C18H18N 248.1434,
found 248.1434.
3-(3-Chloro-2-methylbenzyl)isoquinoline (5g). Eluent for
chromatography: hexane–EtOAc (95 : 5). Yield: 71 mg (83%).
Brown solid. Mp: 58–60 °C. 1H NMR (200 MHz, CDCl3): δ =
2.33 (s, 3H, CH3), 4.37 (s, 2H, CH2), 7.12–7.15 (m, 2H, HAr),
7.21 (s, 1H, HAr), 7.26–7.34 (m, 1H, HAr), 7.50–7.70 (m, 3H,
HAr), 7.89–8.00 (dd, J = 1.1, 8.4 Hz, 1H, HAr), 9.23 (s, 1H, HAr).
13C NMR (50.3 MHz, CDCl3): δ = 16.6 (CH3), 43.0 (CH2), 118.5
(CHAr), 126.5 (CHAr), 126.9 (CHAr), 127.4 (Cq), 127.7 (CHAr),
128.1 (CHAr), 129.2 (CHAr), 130.6 (CHAr), 135.3 (Cq), 135.5 (Cq),
136.7 (Cq), 140.0 (Cq), 152.5 (CHAr), 153.7 (Cq). ESI-MS m/z (%):
268.3 (100) [M + H]+. HRMS ESI [M + H]+ calcd for C17H15ClN
268.0888, found 268.0888.
1 For reviews on domino reactions, see: (a) D. Enders,
C. Grondal and M. R. M. Hüttl, Angew. Chem., Int. Ed.,
2007, 46, 1570; (b) Domino Reactions in Organic Synthesis,
ed. L. F. Tietze, G. Brasche and K. Gericke, Wiley-WCH,
Weinheim, 2006; (c) H.-C. Guo and J.-A. Ma, Angew. Chem.,
Int. Ed., 2006, 45, 354; (d) L. F. Tietze, Chem. Rev., 1996, 96,
115; (e) L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed.
Engl., 1993, 32, 131.
2 For reviews on domino approaches to heterocycles,
see: (a) A. Padwa and S. K. Bur, Tetrahedron, 2007, 63,
5341; (b) L. F. Tietze and N. Rackelmann, Pure Appl. Chem.,
2004, 76, 1967; (c) A. Padwa, Pure Appl. Chem., 2003,
75, 47.
3 M. Dell’Acqua, D. Facoetti, G. Abbiati, E. Rossi, M. Alfonsi
and A. Arcadi, Eur. J. Org. Chem., 2009, 2852.
4 M. Dell’Acqua, D. Facoetti, G. Abbiati and E. Rossi, Syn-
thesis, 2010, 2367.
3-(2-Isopropylbenzyl)isoquinoline (5h). Eluent for chrom-
atography: hexane–EtOAc (95 : 5). Yield: 63 mg (76%). Light
brown solid. Mp: 62–64 °C. 1H NMR (200 MHz, CDCl3): δ =
1.16 (d, J = 7.0 Hz, 6H, CH3), 3.22 (sept, J = 7.0 Hz, 1H, CH),
4.43 (s, 2H, CH2), 7.19–7.40 (m, 5H, HAr), 7.47–7.55 (m, 1H,
HAr), 7.60–7.66 (m, 2H, HAr), 7.94 (m, 1H, HAr), 9.24 (s, 1H,
HAr). 13C NMR (50.3 MHz, CDCl3): δ = 24.0 (CH3), 29.4 (CH),
41.8 (CH2), 118.5 (CHAr), 125.9 (CHAr), 126.1 (CHAr), 126.5
(CHAr), 126.7 (CHAr), 127.3 (Cq), 127.5 (CHAr), 127.7 (CHAr),
130.5 (CHAr), 131.1 (CHAr), 136.4 (Cq), 136.7 (Cq), 147.8 (Cq),
152.3 (CHAr), 155.2 (Cq). ESI-MS m/z (%): 262.3 (100) [M + H]+.
HRMS ESI [M + H]+ calcd for C19H20N 262.1590, found
262.1593.
5 M. Dell’Acqua, B. Castano, C. Cecchini, T. Pedrazzini,
V. Pirovano, E. Rossi, A. Caselli and G. Abbiati, J. Org.
Chem., 2014, 79, 3494.
6 M. Dell’Acqua, D. Facoetti, G. Abbiati and E. Rossi, Tetrahe-
dron, 2011, 67, 1552.
7 M. Dell’Acqua, G. Abbiati and E. Rossi, Synlett, 2010, 2672.
8 M. Dell’Acqua, G. Abbiati, A. Arcadi and E. Rossi, Org.
Biomol. Chem., 2011, 9, 7836.
9 (a) K. Knobloch, M. Keller and W. Eberbach, Eur. J. Org.
Chem., 2001, 3313; (b) K. Knobloch and W. Eberbach, Org.
Lett., 2000, 2, 1117; (c) S. Chang, M. Lee, D. J. Jung,
E. J. Yoo, S. H. Cho and S. K. Han, J. Am. Chem. Soc., 2006,
128, 12366.
3-(4-Chlorobenzyl)-7-fluoroisoquinoline (5i). Eluent for 10 T. Jin, F. Yang and Y. Yamamoto, Org. Lett., 2010, 12, 388.
chromatography: hexane–EtOAc (95 : 5). Yield: 62 mg (71%). 11 F. Yang, T. Jin and Y. Yamamoto, Tetrahedron, 2012, 68, 5223.
1
Brown oil. H NMR (200 MHz, CDCl3): δ = 4.27 (s, 2H, CH2), 12 T.-M. Teng, A. Das, D. B. Huple and R.-S. Liu, J. Am. Chem.
7.18–7.33 (m, 4H, HAr), 7.37–7.49 (m, 2H, HAr), 7.54 (dd, J =
Soc., 2010, 132, 12565.
2.4, 8.7 Hz, 1H, HAr), 7.73 (dd, J = 5.2, 9.0 Hz, 1H, HAr), 9.17 (s, 13 M. Chen, N. Sun and Y. Liu, Org. Lett., 2013, 15, 5574.
1H, HAr). 13C NMR (50.3 MHz, CDCl3): δ = 43.3 (CH2), 110.9 (d, 14 The Chemistry of Heterocyclic Compounds: Isoquinolines, ed.
2
2JC–F = 20.6 Hz, CHAr), 119.1 (CHAr), 121.8 (d, JC–F = 25.5 Hz,
G. M. Coppola and H. F. Schuster, John Wiley & Sons,
New York, 1981, Part 3, vol. 38.
CHAr), 127.9 (d, 3JC–F = 8.4 Hz, Cq), 129.0 (CHAr), 129.2 (d, 3JC–F
= 8.4 Hz, CHAr), 130.8 (CHAr), 132.6 (Cq), 134.0 (Cq), 138.1 (Cq), 15 K. Iwasa, M. Moriyasu, Y. Tachibana, H.-S. Kim, Y. Wataya,
151.3 (d,4JC–F = 5.7 Hz, CHAr), 153.2 (d,4JC–F = 2.7 Hz, CHAr),
W. Wiegrebe, K. F. Bastow, L. M. Cosentino, M. Kozuka and
K.-H. Lee, Bioorg. Med. Chem., 2001, 9, 2871.
1
161.0 (d, JC–F = 249 Hz, C–F). ESI-MS m/z (%): 272.3 (100)
[M + H]+. HRMS ESI [M + H]+ calcd for C16H12ClFN 272.0637, 16 F. De la Brouse-Elwood, J.-L. Chen, T. D. Cushing,
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