Aza-henry reactions of 3,4-dihydroisoquinoline

Article abstract of DOI:10.1002/ejoc.201000955

The aza-Henry reaction of 3,4-dihydroisoquinoline is reported. The reaction is favourable in excess nitromethane under ambient conditions. Isolation of the unstable reaction product is achieved by acylation or alkylation, allowing the synthesis of Reissert-like compounds in good yields from a one-pot, three-component coupling. The rates of reaction for dihydroisoquinoline and the corresponding benzylisoquinolinium ion have been investigated in the presence and absence of base. The reaction with dihydroisoquinoline probably proceeds via an azinic acid tautomer of nitromethane, a reaction pathway unavailable to the isoquinolinium ion. The traditionally problematic reduction of two of the resulting β-nitroamine derivatives was achieved, providing access to a number of new chiral vicinal diamines. 3,4-Dihydroisoquinoline reacts with nitromethane, likely via a cyclic mechanism employing nitromethane's azinic acid tautomer. The product may be alkylated or acylated. Alternatively a Reissert-like one-pot, three-component coupling may be used to generate a range of β-nitroamines which may be reduced to give new isoquinoline-derived chiral, vicinal diamines.

Full text of DOI:10.1002/ejoc.201000955

FULL PAPER
DOI: 10.1002/ejoc.201000955
Aza-Henry Reactions of 3,4-Dihydroisoquinoline
Muneer Ahamed,[a] Thiru Thirukkumaran,[a] Wing Yan Leung,[a] Paul Jensen,[a]
Jade Schroers,[a] and Matthew H. Todd*[a]
Keywords: Nitrogen heterocycles / aza-Henry reaction / nitro-Mannich reaction / Nitroalkanes
The aza-Henry reaction of 3,4-dihydroisoquinoline is re-
ported. The reaction is favourable in excess nitromethane
under ambient conditions. Isolation of the unstable reaction
product is achieved by acylation or alkylation, allowing the
synthesis of Reissert-like compounds in good yields from a
one-pot, three-component coupling. The rates of reaction for
dihydroisoquinoline and the corresponding benzylisoquinol-
inium ion have been investigated in the presence and ab-
sence of base. The reaction with dihydroisoquinoline proba-
bly proceeds via an azinic acid tautomer of nitromethane, a
reaction pathway unavailable to the isoquinolinium ion. The
traditionally problematic reduction of two of the resulting β-
nitroamine derivatives was achieved, providing access to a
number of new chiral vicinal diamines.
the reaction is isolated via alkylation and acylation, and
two of these reaction products are elaborated into the corre-
sponding diamine derivatives.
Introduction
The chemistry of quinoline derivatives remains central to
heterocyclic chemistry, but less is known of the chemistry
of 3,4-dihydroisoquinoline (3,4-DHIQ, 1, see part A of
Scheme 1) than the parent isoquinoline or tetrahydroisoquin-
oline motifs.[1] The aza-Henry (nitro-Mannich) reaction of
3,4-DHIQ with nitromethane to give the corresponding 1-
(nitromethyl)tetrahydroisoquinoline (2) has never been re-
ported and is of interest for four reasons. Firstly, a simple
alkylation-reduction sequence of 2 would rapidly generate
diverse novel chiral vicinal diamines (3), of wide synthetic
and catalytic utility.[2] Secondly, the aza-Henry reaction has
recently been shown to be catalysed asymmetrically by a
wide range of inexpensive ligands, which would permit the
generation of novel enantio-enriched diamines.[3] Thirdly,
the reaction represents a promising new synthetic approach
to the potent anthelmintic praziquantel (PZQ, 4), the drug
of choice for the tropical disease schistosomiasis, and for
which analogues and an inexpensive, enantioselective syn-
thesis are urgently needed.[4,5] Finally, there is a near-ubi-
quitous use in the literature of electron-deficient imines (in-
volving, e.g., N-Boc or N-PMP protection) for the aza-
Henry reaction, an inaccessible strategy for 3,4-DHIQ; thus
the successful demonstration of the aza-Henry reaction
with 3,4-DHIQ would broaden the scope of this important
reaction, potentially leading to future asymmetric examples.
In this report the feasibility and rate of the aza-Henry reac-
tion of 3,4-DHIQ are examined, the unstable product of
Scheme 1. The aza-Henry reaction with 3,4-DHIQ (A) in the syn-
thesis of chiral diamines (3) and praziquantel (4), and (B) the com-
parison with traditional Reissert-type reactions.
The literature contains numerous examples of the reac-
tion of imines with organometallic reagents,[6] or the reac-
tion of alkylated or acylated (Reissert-like) isoquinolines
with (frequently reactive, metallated) nucleophiles (5 to 6,
see Scheme 1, B).[7–9] Recent examples of the reaction of
isoquinolines with non-organometallic species include Shib-
asaki’s catalytic, asymmetric cyanation of isoquinolines,[10]
Jorgensen’s intramolecular organocatalytic annulation reac-
tion of an enamine with an alkyliminium ion in the synthe-
sis of 1,2-dihydroisoquinoline derivatives,[11] and Jacobsen’s
organocatalyzed acyl nitro-Mannich reaction between iso-
quinolines and silyl ketene acetals.[12,13] Reports of similar
[a] School of Chemistry, University of Sydney,
NSW 2006, Australia
Fax: +61-2-9351 3329,
E-mail: matthew.todd@usyd.edu.au
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000955.
View this journal online at
wileyonlinelibrary.com
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Aza-Henry Reactions of 3,4-Dihydroisoquinoline
reactions with dihydroisoquinolines rather than quinolines tion giving 54% product. The rate constant for the decom-
are fewer in number, but, besides the synthesis of Reissert- position under these conditions is approximately 0.04 h–1
type compounds,[14] include intramolecular[15] and intermo- (see Supporting Information).
lecular[16] attack of enolates on alkyldihydroisoquinolinium
salts, enolate addition to a chiral acyldihydroisoquinolin-
ium salt,[17] enantioselective metal-catalyzed addition of
malonates and alkenylzirconocenes to acyldihydroisoquin-
olinium salts,[18] and 1,3-dipolar cycloadditions of the azo-
methine ylides derived from Reissert compounds.[19] It is
typical for the dihydroisoquinoline to be covalently “acti-
vated” by alkylation or acylation (or via formation of the
N-oxide[20]) prior to nucleophilic attack, but in some cases
this is not necessary. It has been shown that “unactivated”
dihydroisoquinolines can react with active methylene com-
pounds (e.g. dimedone)[21] and naphthols,[22,23] to give
stable products and this reaction type will be considered
again below. Despite all the reports of C–C bond formation
with dihydroisoquinolines, and the extensive literature on
Scheme 2. Decomposition, and acylation, of unstable β-nitroamine
2. Reagents and conditions: i) nitromethane, triethylamine; ii) for
the aza-Henry reaction itself,[3,24] the employment of nitro-
alkanes as coupling partners with 3,4-DHIQ and its deriva-
tives is rare. To the best of our knowledge there are only
two examples: the reaction between a nitroalkane and an
alkyldihydroisoquinolinium salt (generated in situ) reported
by Perkin in 1925[25] and Robinson in 1927.[26,27] More re-
cently it has been shown that access to β-nitroamine prod-
ucts similar to those of interest here, but through a different
mechanism, is possible via a cross-dehydrogenative cou-
pling reaction via the formation of an (non-isolated) Reis-
sert-like dihydroisoquinolinium ion derived from an in situ
oxidation.[28]
8a: acetyl chloride, for 8b: chloroacetyl chloride and 2,2,6,6-tet-
ramethylpiperidine; iii) One-pot protocol: nitromethane, acylating
agent (1.1 equiv.), triethylamine (1.1 equiv.), 45 °C, 2 h. Inset: crys-
tal structure for 8b.
Results and Discussion
a) Reaction between 3,4-Dihydroisoquinoline and
Nitromethane
It was not known whether the aza-Henry reaction with
nitromethane could be performed directly on dihydroiso-
quinoline (1). Accordingly, dihydroisoquinoline was mixed
with nitromethane (as solvent) and triethylamine as base
at room temperature for 16 hours (Scheme 2). TLC clearly
indicated a reaction was occurring, but attempts to purify
the reaction mixture by chromatography returned only
starting material. It was assumed the product 2 of the reac-
tion was reverting to starting material via 7; retroaddition
of β-nitroamines is a standard problem encountered during
their purification.[24,29] A simple work-up of this reaction
with no purification removed the excess nitromethane in
Figure 1. Kinetic study on the instability of β-nitroamine 2 and the
corresponding 1H NMR spectra at the following times: (i) 0 min
(top); (ii) 15 min (middle) and (iii) 14 h (bottom). The ratio calcu-
lated is the integral of the signals for the three protons marked blue
in the nitroamine (2) vs. the signals for the protons marked red for
the nitromethane produced by the decomposition reaction (linear
scale of NMR spectra in inset is 0 to 8 ppm).
Attempts to reduce compound 2 in situ to the corre-
sponding amine rapidly, with e.g. samarium iodide,[29] were
unsuccessful. Thus while the aza-Henry reaction could be
observed to occur, synthesis of chiral vicinal diamines by
this route required the isolation of a more stable derivative.
None of these reaction conditions gave any reaction when
isoquinoline was employed in place of dihydroisoquinoline.
1
vacuo and produced a clean H NMR spectrum for this
unstable material (Figure 1). Reversion of 2 to starting ma-
1
terial was monitored by H NMR spectroscopy over time.
A plot of the ratio of the integrals of the signal correspond-
ing to the proton at position 1 (the stereogenic centre) plus
the signal corresponding to the adjacent methylene vs. the
emerging signal corresponding to the methyl group of nitro-
methane indicated compound 2 decomposes rapidly at
room temperature. The asymptote here is approximately
b) Synthesis of Alkylated/Acylated β-Nitroamines by the
aza-Henry Reaction
1) Acylation
Acylation of the unstable β-nitroamine was found to be
1.1, indicating a position of equilibrium for the decomposi- an effective means of isolating a stable product. Thus reac-
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M. H. Todd et al.
FULL PAPER
tion to generate the β-nitroamine, followed by immediate 3) Mechanistic Studies
addition of the relevant acylating agent gave the novel com-
Two aspects of the mechanism of these reactions are of
interest:
1) Which reaction step (alkylation/acylation or attack of
nitromethane) is faster?
pounds 8a and 8b (ca. 50% for two steps). Product 8b could
be easily purified by trituration from ethyl acetate and hex-
ane and its structure was confirmed by X-ray crystallogra-
phy (Scheme 2) – a process that was otherwise complicated
by the presence of a 3:1 mixture of rotamers in the 1H
NMR spectrum. It was found that a simple one-pot reac-
tion was a more convenient experimental procedure for the
preparation of these acylated products. When 3,4-DHIQ
and chloroacetyl chloride were mixed with nitromethane
and triethylamine for two hours at 45 °C, product 8b was
isolated by recrystallisation in a 61% unoptimised yield.
The same one-pot approach was employed in the rapid syn-
thesis of the urea 8c (84% yield) and carbamate 8d (64%)
indicating that a range of acylating agents is compatible
with this reaction. The mechanism of this process, with re-
gards whether attachment of nitromethane or the acyl de-
rivative occurs first, is discussed below.
2) What is the role of the base?
i) Rates of Alkylation/Acylation vs. Attack of
Nitromethane
Initial investigation of the rates of the two processes oc-
curring in these reactions began with the removal of a series
of aliquots over time from the reaction between 3,4-DHIQ
and nitromethane. Alkylation of each aliquot with benzyl
bromide for several minutes was carried out followed by
analysis of the resulting crude samples with 1H NMR spec-
troscopy. Unexpectedly, none of these spectra showed the
presence of any N-alkylated product 9a. Instead another
compound was formed that was not starting material. A
1
downfield peak at δ = 10.6 ppm in the H NMR spectrum
suggested that this species was 10, the N-alkyliminium ion
formed from direct alkylation of the dihydroisoquinoline.
The ionic representation (as opposed to the covalent struc-
ture where the bromide has attacked the acyliminium ion)
The experiments in this paper were conducted with nitromethane
that had not been dried. While the issue of dry vs. wet nitromethane
was not exhaustively studied here, a comparison was performed for
the synthesis of compound 8c. Thus wet nitromethane (used from
the supplier bottle with no anhydrous precautions) was compared
with dry nitromethane (stored over calcium chloride for 16 hours,
followed by filtration through molecular sieves (3 Å). When these
preparations of nitromethane were used for the synthesis of com-
pound 8c, no differences in the yield or speed of the reaction could
be observed.
[30]
is supported by a singlet for the benzylic methylene
group in the NMR spectrum, as opposed to the pro-
nounced AB quartet observed for this methylene in the aza-
Henry reaction product 9a.
Repeated isolation of 10 in these experiments has signifi-
cant implications for the mechanism of the aza-Henry reac-
tion on dihydroisoquinoline. Presumably the alkylation is
fast, and promotes the slower attack of the nitromethane.
To verify this, several NMR experiments were performed
to monitor the reaction between dihydroisoquinoline and
nitromethane/benzyl bromide (Scheme 4). In the first case
the nitromethane was a reagent (1.1 equiv.), and the NMR
spectrum was performed in CDCl3. By monitoring the dis-
appearance of the N=CH starting material proton (δ
=8.3 ppm) and the appearance of the signal for the same
proton at 4.6 ppm for the product, it could be seen that the
reaction was slow: after 66 hours (when monitoring was
stopped) the reaction was only 60% complete. In the second
case mixing 3,4-DHIQ with benzyl bromide under the same
2) Alkylation
Another method of trapping the intermediate species 2
via an alkylation was explored. Such a route, after re-
duction of the nitro moiety, would permit access to a range
of synthetically useful chiral vicinal diamines. Accordingly
3,4-DHIQ was mixed with nitromethane as before, and the
reaction was quenched by the addition of benzyl bromide
(Scheme 3). This one-pot process successfully gave the novel
N-benzyl derivative 9a in 55% isolated yield and the N-allyl
derivative 9b in 63% yield using the same conditions used
for the acylated products. The N-methylated derivative 9c
could not be obtained through a one-pot process and was
only successfully obtained (in 66% yield) by addition of
methyl iodide prior to the addition of nitromethane in a
two-step process.
Scheme 3. Aza-Henry reaction with alkylation. Reagents and con-
ditions: i) as for one-pot procedure, Scheme 2; 9c synthesized by a
two-step process.
Scheme 4. Investigations into the mechanism of the quenched aza-
Henry reaction of dihydroisoquinoline.
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Aza-Henry Reactions of 3,4-Dihydroisoquinoline
conditions and monitoring by NMR spectroscopy indicated
clean production of 10 in 78% yield after 50 min, increasing
to 95% after 220 min.
The implication is that the reaction between dihydroiso-
quinoline and nitroalkanes is slow, but may be promoted by
alkylation or acylation of the ring nitrogen, as in standard
Reissert-like chemistry. The direct reaction between 3,4-
DHIQ and nitromethane occurs rapidly when the nitroal-
kane is in excess (i.e. as the solvent) since quantitative for-
mation of this product was observed by 1H NMR spec-
troscopy (above). This knowledge was applied to the at-
tempted synthesis of the acylated product 8b where the or-
der of reagents was reversed from that used above, i.e. acyl-
ating agent first, followed by nitromethane. This experiment
required performing the acylation of dihydroisoquinoline in
a solvent other than nitromethane (here dichloromethane),
followed by removal of the solvent from the intermediate
and immediate resuspension in nitromethane (with added
base) for the second step. Only a complex mixture was ob-
Scheme 5. Experiments towards understanding the mechanism of
the aza-Henry reaction between 3,4-DHIQ and nitromethane.
1
tained containing no product in the crude H NMR spec-
trum, implying the acyliminium ion intermediate reacted
with other species in the reaction mixture.[31] Thus the one-
pot reactions described above gave good yields of the de-
sired products presumably because the nitromethane was
present in excess and throughout.
amine (11) suggest this mechanism is unrealistic in the pres-
ent case.[32] Simplistically, the excess of nitromethane pro-
motes the bulk reaction by Le Chatelier’s principle, but an
alternative mechanism is needed to explain the data above.
When present in excess, there is presumably a fair quantity
ii) Role of the Base
Base is not necessary for the reaction between 3,4-DHIQ of the methylideneazinic acid tautomer 11 present
and nitromethane: when these reagents were mixed (Scheme 5, c). This species would be able to hydrogen bond
(15 equiv. of CD3NO2 in CDCl3) the NMR spectra of the with the starting material, and form the C–C bond via a
mixture clearly indicated the expected reaction was occur- cyclic mechanism; indeed this mechanism is implied by the
ring, giving the product in 59% yield after three hours and principle of microscopic reversibility if the decomposition
91% yield after 27 hours (Scheme 5, a). On the other hand, mechanism in Scheme 2 is correct. A similar atom-econ-
when 3,4-DHIQ and benzyl bromide were first mixed [to omic mechanism has been suggested by others in related
give the salt (10)] and nitromethane subsequently added cases.[22,23,33] An intermolecular reaction of the azinic acid
without base then no further reaction was observed tautomer in a more usual Reissert fashion must therefore
(Scheme 5, b). It appears base is only necessary for reaction be comparatively slow since the salt 10 is unable to coordi-
between 3,4-DHIQ and nitromethane when the 3,4-DHIQ nate the azinic acid, but the C–C bond forming reaction
is alkylated.
may be accelerated through the addition of a base. Experi-
The mechanism of the aza-Henry reaction traditionally mentally, addition of base to 10 at the same time as the
involves the nucleophilic attack of a nitronate onto an im- nitromethane gave the expected reaction product 9a.
ine. A consideration of the pKa values of nitromethane
In a competition experiment (Scheme 5, d) 3,4-DHIQ
(10.2) and product (ca. 9) and the pKaH value of triethyl- was mixed with 0.5 equiv. of benzyl bromide, generating a
Scheme 6. Potential tautomerism in 10, and crystal structure of the isolated product 9a.
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Scheme 7. Reductions of nitro compounds 8c and 9a, and X-ray crystal structure of 15·OAc.
1:1 mixture of 1 and 10 observed by NMR spectroscopy. remarkably few reliable general procedures in the litera-
This mixture was treated with nitromethane in the absence ture.[35] An interesting report[36] by Anderson describing the
of base. The NMR spectrum showed that the dihydroiso- use of Al/Hg amalgam was investigated but was not suc-
quinoline was being consumed faster than the alkylated cessful with substrates 8a,b and 9a, generating a mixture of
salt, suggesting the reaction mode depicted in Scheme 5 is products.
significant. However, this experiment was also designed to
Raney nickel-catalysed hydrogenation conditions were fi-
test whether the isoquinoline itself could act as a competent nally identified as effective reducing conditions for 8c to
base in an intermolecular aza-Henry reaction with the al- give the novel amine 14 in good yield (Scheme 7). Similar
kylated intermediate 10 (thereby giving consumption of the conditions have since also been used by us for the reduction
salt faster than the 3,4-DHIQ), but the low rate of con- of related nitro compounds derived from N-phenyltetra-
sumption of 10 suggested this mode of reaction was not hydroisoquinolines.[28c] On the other hand, LiAlH4 was
occurring or slow.
found to be effective for the reduction of the N-benzyl de-
Note that in these reactions it is possible that a tautomer rivative 9a, yielding the reduced product 15 in 44% yield.
of the isoquinolinium ion could form (12, Scheme 6), which This diamine has been reported only once in the primary
would lead to product nitroamine 13 upon reaction with research literature, but with minimal characterization.[37]
nitromethane. The identity of the product (which gave a Fortunately, the first X-ray crystal structure of this com-
1
clean H NMR spectrum, indicating a single product was pound could be obtained; the crystal actually contained the
being formed) was established as 9a with X-ray crystal- acetate salt of the expected product, presumably due to ad-
lography suggesting that a tautomerisation, if it occurred, ventitious production of acetic acid during the workup. The
did not interfere with the reaction giving the desired prod- free amine could be reacted further with acetyl chloride to
uct.
functionalise the primary amine (to give 16), suggesting a
synthetic route to a range of new derivatives of these iso-
quinoline-derived chiral vicinal diamines that may now be
explored for their potential as ligands in catalysis.
c) Reductions of β-Nitroamines/Amides to the
Corresponding Amines
Reduction of the nitroalkyl group in a number of prod-
ucts to the corresponding amine with a range of reducing
conditions (including samarium iodide and Pd/C-catalysed
Conclusions
The aza-Henry reaction may be performed directly on
hydrogenation) was unsuccessful, giving either no reaction dihydroisoquinolines to generate the novel β-nitroamine 2.
or mixtures of products. N-Substituted tetrahydroisoquinol- The reaction operates in an excess of nitromethane, without
ines were frequently isolated, presumably arising from in conversion to an “activated” or Reissert compound, pre-
situ reduction of the iminium ion derived from retroad- sumably by an in situ activation of the nitrogen by the
dition of the nitromethane; this product was observed for methylideneazinic acid tautomer. The resultant β-nitro-
example when the combination of triethylamine and formic amine is not thermodynamically stable with respect to start-
acid was employed under hydrogen atmosphere with Pd/C ing materials, but may be alkylated or acylated to give stable
catalyst.[34] Reduction of β-nitroamines is a reaction with compounds. Alkylation of the isoquinoline nitrogen is
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Aza-Henry Reactions of 3,4-Dihydroisoquinoline
to afford a brown oil which was purified by flash column
chromatography (EtOAc) to give 8a as pale yellow crystals (0.061 g,
45%). RF (EtOAc) = 0.54; m.p. 110–112 °C. 1H NMR: Approx.
2.5:1 ratio of rotamers. Major rotamer: δ = 2.20 (s, 3 H, H11), 2.70–
3.15 (m, 2 H, H3), 3.58–3.89 (m, 2 H, H4), 4.61–4.90 (m, 2 H, H9),
6.25 (apparent t, 1 H, J = 5.8 Hz, H1), 7.10–7.30 (m, 4 H, Ar);
minor rotamer: δ = 2.18 (s, 3 H, H11), 2.70–3.15 (m, 3 H, 2 H3 and
1 H4), 4.61–4.90 (m, 3 H, 1 H4 and 2 H9), 5.68 (dd, J = 10.2,
5.2 Hz, 1 H, H1), 7.10–7.30 (m, 4 H, Ar) ppm. 13C NMR Major
rotamer: δ = 22.3, 29.2, 41.9, 51.7, 78.6, 127.6, 127.7, 128.6, 129.4,
132.1, 134.7, 170.7 ppm; minor rotamer: δ = 21.5, 27.8, 35.6, 56.1,
78.8, 127.0, 127.3, 129.0, 130.5, 131.2, 135.7, 170.2 ppm. IR
faster than the C–C bond forming reaction, and standard
Reissert chemistry operates when nitromethane is not in ex-
cess. Effective reducing conditions were found that convert
two of the nitro compounds to the corresponding novel vic-
inal diamine derivatives. Exploration of the catalytic prop-
erties of these new compounds is currently underway.
Experimental Section
General: All reagents and solvents were purchased from Aldrich or
Lancaster, except for 3,4-dihydroisoquinoline which was a gift from
SamiLabs, Bangalore, India. Reagents were used without further
purification. Nitromethane was not dried before use. Flash column
chromatography was performed using Merck Kieselgel 60 silica gel
(SiO2, 0.040–0.063 mm). Thin-layer chromatography (TLC) was
carried out with Merck Kieselgel 60 silica gel precoated aluminum
sheets (0.2 mm). Melting points were measured on Gallenkamp
melting point apparatus. 1H nuclear magnetic resonance spectra
were recorded on a Bruker Avance spectrometer at a frequency of
300.13 MHz (unless otherwise stated) at 300 K. Signals are re-
ported in the order chemical shift (ppm downfield with respect to
internal TMS), multiplicity, integration, coupling constants J (Hz)
and assignments. For AB quartets the separation of the midpoints
of the two doublets is given as ∆ν in Hertz. 13C Nuclear Magnetic
Resonance spectra were recorded on a Bruker Avance 300 spec-
trometer at a frequency of 75.47 MHz (unless otherwise stated) at
300 K. NMR spectra were acquired in CDCl3 unless otherwise
stated. Raw NMR spectroscopic data are available in the Support-
ing Information as jcamp.dx files that may be viewed by processing
programs such as Jspecview. Infra-red spectra were measured on a
Shimadzu Model 8400 FT-IR, and the samples deposited as a thin
film on NaCl plates with dichloromethane. Low-resolution electro-
spray ionization mass spectra were determined on a ThermoQuest
Finnigan LCQ Deca ion trap mass spectrometer. High resolution
mass spectroscopy was performed on a Bruker Fourier Transform
Ion Cyclotron Resonance (FT-ICR) spectrometer in electrospray
mode with a 4.7 T superconducting magnet by Dr. Keith Fisher at
the Australian National University, Canberra, Australia.
(CH Cl ): ν = 1549, 1643 cm–1. MS (ES): m/z (%) = 257.1
˜
2
2
(100) [MNa+], 235.0 (72) [MH+]. HRMS (ESI): calcd. for
C12H14N2NaO3 [MNa+]: 257.090210, found 257.089256;
C12H14N2O3 (234.2512): calcd. C 61.53, H 6.02, N 11.96; found C
61.24, H 6.07, N 11.78.
2-(Chloroacetyl)-1,2,3,4-tetrahydro-1-(nitromethyl)isoquinoline (8b):
To 3,4-dihydroisoquinoline (0.890 g, 6.79 mmol) was added nitro-
methane (90 mL). The solution was allowed to stir for 5 min. Tri-
ethylamine (0.949 g, 1.31 mL, 9.38 mmol, 1.38 equiv.) was added
and stirring was continued overnight before water (50 mL) was
added. The reaction layers were separated and the aqueous layer
was extracted with dichloromethane (3ϫ70 mL). The combined
organic layers were dried with magnesium sulfate and concentrated
under reduced pressure and in vacuo to afford crude β-nitroamine
that was immediately dissolved in dry dichloromethane (40 mL).
2,2,6,6-Tetramethylpiperidine (1.909 g, 13.52 mmol, 1.99 equiv.)
was added followed by chloroacetyl chloride (1.177 g, 10.42 mmol,
1.53 equiv.). The resulting solution was stirred for 2 h, water
(40 mL) was added and the layers were separated. The aqueous
phase was extracted with dichloromethane (3ϫ50 mL). The com-
bined organic layers were dried with magnesium sulfate and con-
centrated under reduced pressure to give a brown oil. This oil was
triturated from ethyl acetate and hexane to afford 8b as pale orange
plates (0.845 g, 46%). RF (3:1 hexane/EtOAc) = 0.13; m.p. 98–
1
103 °C. H NMR (CDCl3): Approx. 3:1 ratio of rotamers: Major
rotamer: δ = 2.92 (dt, J = 16.2, 4.4 Hz, 1 H, H4a), 3.02–3.18 (m, 1
H, H4b), 3.72 (ddd, J = 13.3, 9.7, 4.4 Hz, 1 H, H3a), 3.93 (dt, J =
13.3, 5.0 Hz, 1 H, H3b), 4.17 (ABq, J = 12.4 Hz, 2 H, ∆ν 21.3, H11),
4.67–4.93 (m, 2 H, H9), 6.19 (apparent t, J = 6.3 Hz, 1 H, H1),
7.17–7.30 (m, 4 H, Ar) ppm; minor rotamer: δ = 2.79 (br. d, J =
15.4 Hz, 1 H, H3a), 2.99–3.18 (m, 2 H, H3b and H4a), 4.22 (ABq,
J = 12.4 Hz, 2 H, ∆ν 80.6, H11), 4.67–4.93 (m, 3 H, H4b and H9),
5.75 (dd, J = 9.9 Hz, 1 H and 3.8, H1), 7.17–7.30 (m, 4 H, Ar)
ppm. 13C NMR: Major rotamer: δ = 29.0, 41.5, 41.7, 52.3, 78.4,
127.6, 127.6, 128.8, 129.5, 131.3, 134.5, 166.8 ppm; minor rotamer:
δ = 27.6, 36.6, 41.3, 55.5, 77.8, 127.1, 127.4, 129.1, 130.3, 130.7,
1,2,3,4-Tetrahydro-1-(nitromethyl)isoquinoline (2): To 3,4-dihydro-
isoquinoline (0.890 g, 6.79 mmol) was added nitromethane
(90 mL). The solution was allowed to stir for 5 min. Triethylamine
(0.949 g, 1.30 mL, 9.38 mmol, 1.50 equiv.) was added to the reac-
tion and stirring was continued for 16 h. Water (90 mL) was added,
the reaction layers were separated and the aqueous layer extracted
with dichloromethane (3ϫ70 mL). The combined organic layers
were dried with magnesium sulfate and concentrated under reduced
pressure and in vacuo to afford 2 as a pale yellow solid (1.25 g,
96%). 1H NMR: δ = 2.71 (m, 2 H, H4), 2.94–3.15 (m, 2 H, H3),
4.55–4.59 (m, 2 H, H9), 4.63–4.73 (m, 1 H, H1), 7.11 (m, 4 H, Ar)
ppm. Further characterization was not performed as this com-
pound is unstable with respect to starting materials.
135.1, 166.4 ppm. IR (CH Cl ): ν = 1553, 1659 cm–1. MS (ES): m/z
˜
2
2
(%) = 293.1 (44) [MNa+], 291.1 (100) [MNa+]. HRMS (ESI): calcd.
for C12H13ClN2NaO3 [MNa+]: 291.051240, found 291.050601.
C12H13ClN2O3 (268.6962): calcd. C 53.64, H 4.88, N 10.43; found
C 53.72, H 4.89, N 10.43.
1-[3,4-Dihydro-1-(nitromethyl)isoquinoline-2(1H)-yl]ethanone (8a):
To 3,4-dihydroisoquinoline (0.077 g, 0.58 mmol) was added nitro-
methane (3.9 mL). The solution was allowed to stir for 5 min. Tri-
ethylamine (62 mg, 0.085 mL, 0.61 mmol, 1 equiv.) was added and
stirring was continued for 16 h. Acetyl chloride (0.099 g, 90 µL,
CCDC-634262 contains the supplementary crystallographic data
for this compound. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1.27 mmol, 2 equiv.) was added, and stirring was continued for 2 h One-Pot Procedure: 3,4-Dihydroisoquinoline (1.000 g, 7.624 mmol)
before water (10 mL) was added and the reaction layers were sepa-
rated. The aqueous phase was extracted with diethyl ether
(3ϫ10 mL). The combined organic layers were dried with magne-
sium sulfate and concentrated under reduced pressure and in vacuo
was dissolved in nitromethane (4.5 mL, 84 mmol, 11 equiv.). To this
clear pale yellow solution, chloroacetyl chloride (0.67 mL,
8.39 mmol, 1.1 equiv.) was added followed by triethylamine
(1.2 mL, 0.85 g, 8.4 mmol, 1.1 equiv.). The mixture was stirred at
Eur. J. Org. Chem. 2010, 5980–5988
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5985

M. H. Todd et al.
FULL PAPER
45 °C for 2 h and allowed to cool to room temp. Water (100 mL)
was added and the reaction mixture was extracted with dichloro-
methane (1ϫ50 mL, 2ϫ25 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuo. The crude product
was recrystallised with hexane and ethyl acetate (ca. 1:1) yielding
the isoquinoline derivative as a brown crystalline solid (1.250 g,
61%) spectroscopically identical to the product from the two-step
procedure above.
H1), 4.63 (dd, 1 H, J = 11.1, 9.9 Hz, H9b), 5.02–5.07 (m, 1 H, H13a),
5.09 (br. s, 1 H, H13b), 5.66–5.81(m, 1 H, H12), 6.95–7.30 (m, 4 H,
Ar) ppm. 13C NMR: δ = 23.5, 43.3, 56.9, 58.9, 79.9, 118.2, 126.9,
127.9, 128.1, 129.1, 130.0, 132.5, 135.7, 136.1 ppm. IR (CHCl ): ν
˜
3
= 1558 cm–1. MS (ES): m/z (%) = 345.3 (100) [unidentified peak],
214.3 [M+ – H2O 52], 230.3 (17) [MH+]. HRMS (ESI): calcd. for
C13H16N2O2 [MH+]: 233.12845, found 233.12886.
2-Methyl-1,2,3,4-tetrahydro-1-(nitromethyl)isoquinoline (9c): To 3,4-
dihydroisoquinoline (0.500 g, 3.81 mmol) dissolved in diethyl ether
(3 mL) was added methyl iodide (0.26 mL, 4.18 mmol, 1.1 equiv.).
The resulting solution was stirred for 1 h and concentrated under
reduced pressure. Nitromethane (5 mL) was added and stirring was
continued for 5 min. To the solution was added triethylamine
(0.58 mL, 4.16 mmol, 1.1 equiv.) and stirring was continued for a
further 1 h before water (10 mL) was added and the layers were
separated. The aqueous layer was extracted with dichloromethane
(3ϫ10 mL). The combined organic layers were dried with magne-
sium sulfate and concentrated in vacuo. The product was purified
by flash chromatography (1:2 EtOAc/hexane) to afford 9c as a yel-
1-(Nitromethyl)-N-phenyl-3,4-dihydroisoquinoline-2(1H)-carbox-
amide (8c): By employing the same conditions as the general one-
pot procedure (above), a yellow solid was obtained which was
recrystallized (Et2O) to give 8c as a colourless solid (0.400 g, 84%).
RF (2.3:1 hexane/EtOAc) = 0.45; m.p. 143–144 °C. 1H NMR
(200 MHz): δ = 2.85 (ddd, J = 16.3, 4.4, 4.4, Hz, 1 H, H4a), 3.14
(ddd, J = 16.4, 9.6, 5.1 Hz, 1 H, H4b), 3.46 (ddd, J = 12.4, 9.4,
4.6 Hz, 1 H, H3b), 4.10 (ddd, J = 12.4, 5.1, 4.7 Hz, 1 H, H3a), 4.73
(dd, J = 12.9, 5.1 Hz, 1 H, H9a), 4.93 (dd, J = 12.8, 8.9 Hz, 1 H,
H9b), 5.97 (dd, J = 8.6, 5.1 Hz, 1 H, H1), 7.02–7.43 (m, 9 H, Ar)
ppm. 13C NMR: δ = 28.0, 39.4, 54.6, 79.1, 120.5, 123.7, 127.4,
129.3, 129.8, 131.7, 135.5, 139.0, 155.6 (one Ar and C=O peak
1
low oil (0.52 g, 66%). RF (EtOAc/hexane, 1:2) = 0.54. H NMR: δ
obscured) ppm. IR (CH Cl ): ν = 3333, 1651, 1543 cm–1. MS (ES):
= 2.48 (s, 3 H, CH3), 2.51–2.60 (m, 1 H, H4a), 2.74–2.91 (m, 1 H,
H4b), 3.02–3.08 (m, 2 H, H3), 4.28–4.41 (m, 2 H, H9), 4.53–4.60
(m, 1 H, H1), 6.98–7.10 (m, 4 H, Ar) ppm. 13C NMR: δ = 24.1,
42.6, 46.0, 61.8, 79.9, 126.9, 127.8, 127.9, 129.9, 132.6, 135.5 ppm.
˜
2
2
m/z (%) = 312.1 (100) [MH+]. HRMS (ESI): calcd. for C17H17N3O3
[MH+]: 312.13482, found 312.13406.
2,2,2-Trichloroethyl 1-(Nitromethyl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate (8d): By employing the same conditions as the general
one-pot procedure (above), crude material was obtained and puri-
fied by flash column chromatography (95:5 hexane/EtOAc) to give
8d as a pale yellow oil (0.470 g, 64%). RF (9:1 hexane/EtOAc) =
0.75. 1H NMR: δ = 2.74–2.79 (m, 1 H, H4a), 2.80–2.98 (m, 1 H,
H4b), 3.38–3.52 (m, 1 H, H3a), 4.06–4.13 (m, 1 H, H3b), 4.50–4.90
(m, 4 H, H9,10), 5.83–5.91 (m, 1 H, H1), 7.13–7.18 (m, 4 H, Ar)
ppm. 13C NMR: δ = 28.2, 28.6, 39.4, 39.6, 54.3, 75.7, 77.7, 79.2,
IR (CHCl ): ν = 1540 cm–1. MS (ES): m/z (%) = 146.1 (100) [M+
–
˜
3
CH2NO2], 207.0 (80) [MH+]. HRMS (ESI): calcd. for C11H14N2O2
[MH+]: 207.112811, found 207.113068.
1-(Aminomethyl)-N-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxamide (14): 1-(Nitromethyl)-N-phenyl-3,4-dihydroisoquin-
oline-2(1H)-carboxamide (8c, 0.320 g, 0.100 mmol) was taken in
MeOH (50 mL). Aqueous ammonia (5 mL) was added and the
mixture stirred until the starting material had dissolved. Raney Ni
(1 mL solid in 5–6 mL slurry, ca. 0.6 g of catalyst[38]) was added
and the mixture was degassed with H2 [350 kPa (3.4 atm)ϫ2]. The
reaction mixture was stirred at 1.4 MPa (13.6 atm) at room temp.
for 16 h. Completion of reaction was monitored by TLC and LC-
MS. The solvent was evaporated and the crude material was puri-
fied by flash chromatography to yield amine as colourless needles
(0.240 g, 83%). RF = 0.23 (9:1 DCM/MeOH); m.p. 132–135 °C. 1H
NMR: δ = 2.93–3.26 (m, 4 H, H4,9), 4.14–4.25 (m, 2 H, H3), 5.01–
5.07 (m, 1 H, H1), 6.90–7.05 (t, 1 H, J = 6.7 Hz, H12), 7.05–7.50
(m, 8 H, Ar), 9.39 (br. s, 1 H, NH) ppm. 13C NMR: δ = 29.0, 38.6,
47.7, 60.4, 119.4, 122.4, 126.7, 127.3, 127.4, 129.2, 129.4, 135.2,
127.8, 129.9, 131.4, 134.9, 135.0, 154.3 ppm. IR (CH Cl ): ν =
˜
2
2
1705, 1560 cm–1. MS (ES): m/z (%) = 389.1 (100) [MNa+]. HRMS
(ESI): calcd. for C13H1335Cl3N2NaO4 [MNa+]: 388.98386, found
388.98331.
2-Benzyl-1,2,3,4-tetrahydro-1-(nitromethyl)isoquinoline (9a): By em-
ploying the same conditions as the general one-pot procedure
(above), crude material was obtained that was purified by flash
chromatography to give 9a as yellow crystals (0.400 g, 55%). RF
1
(2.5:1 hexane/EtOAc) = 0.57; m.p. 62–64 °C. H NMR: δ = 2.47–
2.56 (m, 1 H, H3a), 2.87–3.08 (m, 2 H, H3b, H4a), 3.14–3.25 (m, 1
H, H4b), 3.78 (ABq, J = 13.3 Hz, 2 H, ∆ν 23.2, H11), 4.46 (dd, J =
11.3, 4.3 Hz, 1 H, H9a), 4.54 (dd, J = 9.9, 4.3 Hz, 1 H, H9b), 4.72
(dd, J = 11.3, 9.9 Hz, 1 H, H1), 7.05–7.34 (m, 9 H, Ar) ppm. 13C
NMR: δ = 23.3, 42.2, 58.0, 60.1, 79.9, 127.0, 127.8, 128.0, 128.1,
136.0, 140.6, 157.7 ppm. IR (CH Cl ): ν = 3342, 1664, 1547 cm–1.
˜
2
2
MS (ES): m/z (%) = 281. 7 (100) [(MH)+], 562.8 (42) [(M2 H)+].
HRMS (ESI): calcd. for C17H20N3O [MH+]: 282.16009, found
282.16013.
128.8, 129.2, 130.1, 132.6, 135.7, 138.7 ppm. IR (CHCl ): ν = 1553
˜
2
cm–1. MS (ES): m/z (%) = 283.1 (26) [MH+], 222.1 (100) [M+
–
CH2NO2]. HRMS (ESI): calcd. for C17H18N2O2: [MH+]:
283.144650, found 283.144700. C17H18N2O2 (282.3370): calcd. C
72.32, H 6.43, N 9.92; found C 72.58, H 6.73, N 10.00.
(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanaminium Acet-
ate (15·AcOH): To lithium aluminium hydride (0.056 g, 1.52 mmol,
4 equiv.) in tetrahydrofuran (3 mL) cooled to 0 °C, was added drop-
wise 2-benzyl-1,2,3,4-tetrahydro-1-(nitromethyl)isoquinoline (9a,
0.108 g, 0.38 mmol) in tetrahydrofuran (10 mL) under nitrogen.
Stirring was continued at room temp. until completion of the reac-
tion (2 h) as judged by TLC (ninhydrin stain). The reaction mixture
was quenched with ethyl acetate (5 mL) and ice (ca. 1 g). The mix-
ture was filtered through a celite pad with dichloromethane and
the filtrate was concentrated in vacuo. The crude material was puri-
fied with a short plug of silica with a dichloromethane/methanol
solvent system (1:0 rising to 9:1) to afford ninhydrin active frac-
tions, which were concentrated under reduced pressure to afford a
pink oil. This oil was triturated with dichloromethane and hexane
(ca. 1:5) to afford the amine salt as pale yellow prisms (0.052 g,
CCDC-708674 contains the supplementary crystallographic
data for this compound. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2-Allyl-1,2,3,4-tetrahydro-1-(nitromethyl)isoquinoline (9b): By em-
ploying the same conditions as the general one-pot procedure
(above), crude material was obtained that was purified by flash
chromatography (1:3 EtOAc/hexane) to afford the product as a yel-
1
low oil (0.52 g, 65%). RF (1:3 EtOAc/hexane) = 0.48. H NMR: δ
= 2.40–2.52 (m, 1 H), 2.83–3.00 (m, 2 H), 3.08–3.29 (m, 3 H), 4.40
(dd, 1 H, J = 11.1, 4.2 Hz, H9a), 4.48 (dd, 1 H, J = 9.9, 4.2 Hz,
5986
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5980–5988

Aza-Henry Reactions of 3,4-Dihydroisoquinoline
oli, J. Utzinger, Curr. Opin. Infect. Dis. 2008, 21, 659–667; c)
Chemotherapeutic Development Strategies for Schistosomiasis,
C. R. Caffrey, D. L. Williams, M. H. Todd, D. L. Nelson, J.
Keiser, J. Utzinger, in: Antiparasitic and Antibacterial Drug Dis-
covery: From Molecular Targets to Drug Candidates (Ed.: P. M.
Selzer), Wiley-VCH, Weinheim, chapter 16, 2009.
44%). RF (9:1 dichloromethane/methanol) = 0.42; m.p. 117–
119 °C. H NMR (CD3COCD3): δ = 1.85 (s, 3 H, OAc), 2.10–2.31
1
(m, 1 H, H4a), 2.55–2.59 (m, 1 H, H4b), 2.87–3.02 (m, 4 H, H3,9),
3.23–3.30 (m, 2 H), 3.59–3.61 (m, 1 H), 3.72–3.82 (m, 2 H, H10),
6.95 (br. s, 1 H, NH), 7.14–7.44 (m, 9 H, Ar) ppm. 13C NMR
(CD3COCD3): δ = 23.5, 25.1, 44.4, 44.9, 58.8, 61.5, 127.2, 127.6,
128.2, 129.4, 129.5, 130.2, 136.4, 137.1, 141.1, 170.1 (one Ar peak
[5] a) For a description of current efforts in this direction, see the
Synaptic Leap website: http://www.thesynapticleap.org/schisto/
projects; b) P. Roszkowski, J. K. Maurin, Z. Czarnocki, Tetra-
hedron: Asymmetry 2006, 17, 1415–1419.
[6] a) R. Bloch, Chem. Rev. 1998, 98, 1407–1438; b) D. Enders, U.
Reinhold, Tetrahedron: Asymmetry 1997, 8, 1895–1946; c) K.
Yamada, K. Tomioka, Chem. Rev. 2008, 108, 2874–2886; d) D.
Ferraris, Tetrahedron 2007, 63, 9581–9597; e) S. E. Denmark,
O. J.-C. Nicaise, Chem. Commun. 1996, 999–1004; f) G. K.
Friestad, A. K. Mathies, Tetrahedron 2007, 63, 2541–2569.
[7] M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104,
3341–3370.
[8] R. A. Volkmann, Nucleophilic addition to imines and imine de-
rivatives, in: Comprehensive Organic Synthesis, part 1, vol. 1,
Additions to C-X π-bonds (Ed.: S. L. Schreiber), Pergamon, Ox-
ford, 1991, 1, 355–396 (Comprehensive Organic Synthesis, vol.
1).
obscured) ppm. IR (CH Cl ): ν = 3302, 1651 cm–1. MS (ES): m/z
˜
2
2
(%) = 253.3 (100) [(MH)+]. HRMS (ESI): calcd. for C17H21N2
[MH+]: 253.16993, found 253.17018.
CCDC-707603 contains the supplementary crystallographic data
for this compound. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
N-[(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]acetamide
(16): To (2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanamin-
ium acetate (15·AcOH, 0.187 g, 0.592 mmol) in dichloromethane
(10 mL) were added acetyl chloride (46 µL, 0.65 mmol, 1.1 equiv.)
and diisopropylethylamine (150 µL, 0.9 mmol, 1.5 equiv.) and the
reaction mixture was stirred for 16 h after which the reaction was
judged complete by TLC (ninhydrin stain). The reaction mixture
was diluted with water (20 mL) and dichloromethane (20 mL) the
layers were separated and the aqueous phase extracted with further
dichloromethane (20 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The crude amide was washed
with diethyl ether and triturated from dichloromethane and hexane
(1:5) to afford 16 as pale yellow-brown prisms (0.136 g, 77%). RF
[9]
H. Hiemstra, W. N. Speckamp, Additions to N-acyliminium
ions, in: Comprehensive Organic Synthesis, part 1, vol. 2, Ad-
ditions to C–X π-bonds (Ed.: C. H. Heathcock), Pergamon, Ox-
ford, 1991, 2, 1047–1082 (Comprehensive Organic Synthesis,
vol. 2).
K. Funabashi, H. Ratni, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2001, 123, 10784–10785.
K. Frisch, A. Landa, S. Saaby, K. A. Jørgensen, Angew. Chem.
Int. Ed. 2005, 44, 6058–6063.
M. S. Taylor, N. Tokunaga, E. N. Jacobsen, Angew. Chem. Int.
Ed. 2005, 44, 6700–6704.
[10]
[11]
[12]
[13]
[14]
1
(1:1 ethyl acetate/hexane) = 0.58; m.p. 126–128 °C. H NMR: δ =
1.88 (s, 3 H, Me), 2.56–2.62 (m, 1 H, H4), 2.97–3.29 (m, 3 H), 3.67–
3.82 (m, 3 H), 6.10 (br. s, 1 H), 7.15–7.40 (m, 9 H, Ar) ppm. 13C
NMR: δ = 23.7, 24.0, 43.5, 44.1, 57.9, 59.5, 126.8, 127.2, 127.8,
128.6, 128.9, 129.5, 134.8, 135.0, 139.6, 170.2 ppm. IR (CH2Cl2):
M. Ahamed, M. H. Todd, Eur. J. Org. Chem.; DOI: 10.1002/
ejoc.201000877.
a) Y. A. Jackson, E. K. Stephenson, M. P. Cava, Heterocycles
1993, 36, 1047–1050; b) E. Reimann, F. Grasberger, Monatsh.
Chem. 2005, 136, 193–209; c) H. W. Gibson, M. A. G. Berg,
J. C. Dickson, P. R. Lecavalier, H. Wang, J. S. Merola, J. Org.
Chem. 2007, 72, 5759–5770; d) M. S. Sigman, P. Vachal, E. N.
Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279–1281.
O. V. Gulyakevich, I. L. Rubinova, A. A. Govorova, I. P. An-
tonevich, L. P. Solovei, D. B. Rubinov, A. S. Lyakhov, Y. S. Po-
lyakov, A. L. Mikhal’chuk, Mendeleev Commun. 2001, 11, 155–
157.
ν = 1651, 3302 cm–1. MS (ES): m/z (%) = 295.5 (100) [(MH)+].
˜
HRMS (ESI): calcd. for C19H22N2O [MH+]: 295.18049, found
295.18066. C19H22N2O (294.3908): calcd. C 77.52, H 7.53, N 9.52;
found C 77.29, H 7.45, N 9.53.
Supporting Information (see also the footnote on the first page of
[15]
[16]
1
this article): Copies of the H and 13C NMR spectra for all com-
pounds, plus the derivation of the rate equation for the decomposi-
tion shown in Figure 1. JCAMP-DX files for all NMR spectra
which may be opened by any NMR processing program, and the
calculations for the derivation of the rate equation for Figure 1.
Y. Hirai, T. Terada, A. Hagiwara, T. Yamazaki, Chem. Pharm.
Bull. 1988, 36, 1343–1350.
[17]
[18]
K. T. Wanner, I. Praschak, Heterocycles 1989, 29, 29–33.
a) N. Sasamoto, C. Dubs, Y. Hamashima, M. Sodeoka, J. Am.
Chem. Soc. 2006, 128, 14010–14011; b) A. Saito, K. Iimura,
M. Hayashi, Y. Hanzawa, Tetrahedron Lett. 2009, 50, 587–589.
M. Nyerges, A. Dancsó, I. Bitter, G. Blaskó, L. To˝ke, Tetrahe-
dron Lett. 2005, 46, 6927–6930.
a) S. Wang, C. T. Seto, Org. Lett. 2006, 8, 3979–3982; b) Y.
Ukaji, Y. Yoshida, K. Inomata, Tetrahedron: Asymmetry 2000,
11, 733–736; c) B.-X. Zhao, S. Eguchi, Tetrahedron 1997, 53,
9575–9584; d) A. R. Evans, R. Martin, G. A. Taylor, C. H. M.
Yap, J. Chem. Soc. Perkin Trans. 1 1987, 1635–1640.
J. C. Pelletier, M. P. Cava, Synthesis 1987, 474–477.
a) P. D. MacLeod, Z. Li, J. Feng, C.-J. Li, Tetrahedron Lett.
2006, 47, 6791–6794; b) P. D. MacLeod, Z. Li, C.-J. Li, Tetrahe-
dron 2010, 66, 1045–1050.
I. Szatmári, L. Lázár, F. Fülöp, Tetrahedron Lett. 2006, 47,
3881–3883.
H. Adams, J. C. Anderson, S. Peace, A. M. K. Pennell, J. Org.
Chem. 1998, 63, 9932–9934.
R. D. Haworth, W. H. Perkin, J. Chem. Soc. 1925, 127, 1434–
1444.
J. Malan, R. Robinson, J. Chem. Soc. 1927, 2653–2657.
Acknowledgments
[19]
[20]
We thank the University of Sydney, Research Grant Scheme
(LO961 U3298) for funds and John Mackie (Sydney) for help with
the kinetics. We thank the University of Sydney and the School of
Chemistry at the University of Sydney for a studentship (to M. A).
We are grateful to SamiLabs, Bangalore, India for an early gift of
3,4-dihydroisoquinoline.
[21]
[22]
[1] Quinolines and Isoquinolines: Reactions and Synthesis in Het-
erocyclic Chemistry, (Eds.: J. A. Joule, K. Mills), 5th ed., John
Wiley & Sons, New York, 2009, chapter 9.
[2] a) D. Lucet, T. L. Gall, C. Mioskowski, Angew. Chem. Int. Ed.
1998, 37, 2580–2627; b) S. R. S. S. Kotti, C. Timmons, G. Li,
Chem. Biol. Drug Des. 2006, 67, 101–114.
[3] E. Marqués-López, P. Merino, T. Tejero, R. P. Herrera, Eur. J.
Org. Chem. 2009, 2401–2420.
[4] a) A. Fenwick, L. Savioli, D. Engels, R. Bergquist, M. H. Todd,
Trends Parasitol. 2003, 19, 509–515; b) M. J. Doenhoff, D. Ci-
[23]
[24]
[25]
[26]
Eur. J. Org. Chem. 2010, 5980–5988
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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M. H. Todd et al.
FULL PAPER
[27] For the attack of nitromethane on quinoline, see N. J. Leonard,
H. A. DeWalt, G. W. Leubner, J. Am. Chem. Soc. 1951, 73,
3325–3329.
[33]
J. C. Anderson, A. J. Blake, G. P. Howell, C. Wilson, J. Org.
Chem. 2005, 70, 549–555.
J. Yu, J. B. Spencer, Chem. Eur. J. 1999, 5, 2237–2240.
S. L. Ioffe, V. A. Tartakovskii, S. S. Novikov, Russ. Chem. Rev.
1966, 35, 19–32.
[34]
[35]
[28] a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 3672–3673; b)
O. Baslé, C.-J. Li, Green Chem. 2007, 9, 1047–1050; c) A.-S. K.
Tsang, M. H. Todd, Tetrahedron Lett. 2009, 50, 1199–1202.
[29] M. A. Sturgess, D. J. Yarberry, Tetrahedron Lett. 1993, 34,
4743–4746.
[36] J. C. Anderson, H. A. Chapman, Synthesis 2006, 3309–3315.
[37] D. Beaumont, R. D. Waigh, M. Sunbhanich, M. W. Nott, J.
Med. Chem. 1983, 26, 507–515.
[38] A. I. Vogel, Vogel’s Text Book of Practical Organic Chemistry,
5th ed., Longman Group Ltd., London, 1989, p. 450–451.
Received: July 6, 2010
[30] See footnote 13 in ref.[12] for further discussion.
[31] For further discussion of this with regards Reissert chemistry,
see: F. F. Duarte, F. D. Popp, J. Heterocycl. Chem. 1991, 28,
1801–1804.
Published Online: September 20, 2010
[32] This point has been made by Anderson for the closely related
addition of alkyl nitronates to imines, see: ref.[24]
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