Selective synthesis of isoquinolin-3-one derivatives combining Pd-catalysed aromatic alkylation/vinylation with addition reactions: The beneficial effect of water

Article abstract of DOI:10.1002/ejoc.200900255

The three-component, palladium/norbornene-catalysed reaction of 1, haloamides 2 and properly substituted olefins 3 performed in DMF/water at: 80 °C selectively gave 5 and 6 through three- and. four-bond-forming reactions, respec tively. The presence of water was crucial to obtain products in fair to good yields,

Full text of DOI:10.1002/ejoc.200900255

FULL PAPER
DOI: 10.1002/ejoc.200900255
Selective Synthesis of Isoquinolin-3-one Derivatives Combining Pd-Catalysed
Aromatic Alkylation/Vinylation with Addition Reactions: The Beneficial Effect
of Water
Raffaella Ferraccioli*[a] and Alessandra Forni[a]
Keywords: Multicomponent reactions / Palladium / C-H activation / Water effect / Nitrogen heterocycles
The three-component, palladium/norbornene-catalysed re- tively. The presence of water was crucial to obtain products
action of 1, haloamides 2 and properly substituted olefins 3
performed in DMF/water at 80 °C selectively gave 5 and 6
in fair to good yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
through three- and four-bond-forming reactions, respec- Germany, 2009)
Introduction
The rapid creation of molecular complexity in a regio-
and stereodefined manner from simple substrates, combin-
ing economical and environmental aspects, represents a
great challenge in modern organic chemistry.[1] In this field,
multicomponent reactions (MCRs) involving a metal – in
particular palladium-catalysed sequential processes – have
emerged as powerful tools in diversity-oriented synthesis.[2]
They have found multiple applications in the discovery of
new bioactive small molecules. Of special interest are het-
Scheme 1. Proposed synthesis of isoquinolinones 5 and 6 (Z = CO).
erocyclic compounds containing a ring system found in nat-
ural products and drug-like molecules.[3]
As recently reported in the literature, a three-component
reaction combining the Catellani reaction[4] and aza-
Michael addition led to tetrahydroisoquinoline derivatives
5 (Z = CH2, CH-alkyl; R4 = Cbz) in a single synthetic oper-
ation producing three sequential bonds (Scheme 1).[5] The
reaction of o-iodotoluene 1, 2-Br and olefin 3 in the pres-
ence of Pd(OAc)2/2-trifurylphosphane (TFP) and nor-
bornene as catalysts, Cs2CO3 as a base, and in DMF at
80 °C gave 4 as the intermediate, which subsequently under-
went an intramolecular aza-Michael addition under the re-
action conditions.
Considering the great interest in the 1,2,3,4-tetrahydro-
isoquinoline nucleus as the structural motif of many alka-
loids, we further explored the potential of this reaction,
which provides a straightforward entry to the heterocyclic
ring commonly synthesised through Pictet–Spengler-type
cyclisations.[6]
methylbenzyl, allyl] as the starting alkyl halides in the MCR
outlined in Scheme 1. Interestingly, the reaction could selec-
tively lead to structurally diverse isoquinolin-3-ones 5 and
6. Such compounds are attractive synthetic targets both as
precursors and analogues of bioactive compounds.[7]
Results and Discussion
We initially found that the reaction of o-iodotoluene 1,
haloamides 2 and alkenes 3 under the above-mentioned
conditions gave quite a complex mixture, which included no
trace of the expected product. An NMR analysis of the
crude mixture[8] showed that it mainly consisted of byprod-
ucts deriving from undesired transformations of 2, which
was rapidly consumed under the reaction conditions (ca.
20 min at 80 °C by TLC analysis). Control experiments
proved that byproduct formation took place in the presence
of base. Amides bearing a leaving-group (X) in the α posi-
tion can undergo base-promoted self-condensation reac-
tions.[9]
Here, we evaluated the use of readily accessible haloam-
ides 2 [Z = CO; X = Br, Cl; R4 = H, PMB, Ph, (Ϯ)-α-
[a] CNR-ISTM Istituto di Scienze e Tecnologie Molecolari,
Via C. Golgi 19, 20133 Milano, Italy
We then examined the model reaction of 1 (R1 = Me), 2-
Cl (R4 = PMB) and 3 (R5 = CO2Me) using different bases
and solvents (Table 1).[10]
Fax: +39-02-50314141
E-mail: Raffaella.Ferraccioli@istm.cnr.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900255.
Eur. J. Org. Chem. 2009, 3161–3166
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3161

R. Ferraccioli, A. Forni
FULL PAPER
Table 1. Optimisation of reaction conditions.[a]
in both cases (Table 1, Entries 10 and 12). In the last one,
the base-catalysed conversion of 4 was slower (Table 1, En-
try 12).
Comparing data obtained in anhydrous and aqueous
conditions showed that water exerted a beneficial effect on
selectivity when added to polar, coordinating solvents
(Table 1, Entries 1, 11, 6 and 15). On the contrary, the over-
all reaction yields obtained in anhydrous and aqueous THF
remained almost unchanged (Table 1, Entries 9 and 16).
Under the conditions in the final entry of Table 1, we ob-
served that the base-catalysed conversion to 5 remained in-
complete even after prolonged heating.
A few palladium-catalysed transformations (e.g., Heck,
Suzuki, and Buchwald–Hartwig reactions) have been re-
ported to proceed more efficiently in aqueous organic sol-
vents than in anhydrous conditions.[14] As previously re-
ported,[5] our reaction occurred through an ordered se-
quence of steps (Scheme 2, L = TFP): (a) Sequential C–I
and C–H bond activation[4,15] of 1 through the formation
of palladacycle 7, (b) PdII/IV-catalysed aromatic alkylation,
followed by norbornene expulsion leading to PdII complex
8, (c) Vinylation of 8 to give the intermediate 4, thus com-
pleting the catalytic cycle and (d) Intramolecular aza-
Michael addition delivering 5.
While the base-promoted cyclisation of 4 proved to be
slower in aqueous DMF (water = 10%, v/v),[16] we verified
that palladium-catalysed aromatic alkylation/vinylation oc-
curred rapidly under the same conditions. After heating at
80 °C for 10 min, the reaction gave 4 in 49% yield, and we
recovered the unreacted 2-Cl in 37% yield. In addition to a
stabilising effect on the substrate, water could exert a posi-
tive effect on the rate of the catalytic cycle (rate acceleration
of the terminating Heck reaction[14a] or catalyst acti-
vation[14]).
Entry Solvent
Base
Time 5/4[b]
% Isolated
yield
[h]
[c]
1
2
DMF
DMF
Cs2CO3
K2CO3
KHCO3
K2HPO4
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
6
–
–
10
10
18
10
6
100:0
–
0:100
traces/–
–
25
[c]
3
4
DMF
DMF
–
15[d]
5
6
DMF
MeCN
traces
[c]
–
7
8
9
DME
1,4-dioxane
THF
6
100:0
73:27
100:0
100:0
100:0
72:28
100:0
20:80
100:0
24:76
26
44
43
22
10
6
10
11
12
13
14
15
16
DMF/water
DMF/water
DMF/water
DMF/water
DMF/water
MeCN/water Cs2CO3
THF/water Cs2CO3
62[e]
76[f]
45[g]
70[f]
47[f]
32[f]
46[f]
6
12
23
23
22
26
[a] Conditions: 1 (1 equiv., 0.05 ), 2 (2 equiv.), 3 (2 equiv.),
Pd(OAc)2 (10 mol-%), TFP (20 mol-%), norbornene (2.2 equiv.),
base (2 equiv.), 80 °C. [b] 1H NMR analysis of the crude. [c] No
trace of 5 was observed. [d] 3 equiv. of K2HPO4 were used. [e] 5%
water (v/v). [f] 10% water (v/v). [g] 20% water (v/v).
The reaction performed in the presence of K2CO3 or
K2HPO4 gave 25% of 5 and 15% of 4, respectively (Table 1,
Entries 2 and 4). We observed no product or just traces of
it with KHCO3 and K3PO4 (Table 1, Entries 3 and 5). Car-
rying out the reaction in less coordinating solvents such as
DME, THF and 1,4-dioxane with Cs2CO3
[11]
led to 5 in
We used optimised conditions (Table 1, entries 11 and
13) to study the scope of the reaction with respect to
haloamides, o-substituted iodoarenes and olefins. We ob-
tained the best results, in terms of selectivity, by carrying
out the reactions in the presence of Cs2CO3 (Table 2).
The reaction of o-iodotoluene, methyl acrylate and pri-
26–44% yield (Table 1, Entries 7–9). The reaction in MeCN
did not give the expected product (Table 1, Entry 6).
We achieved a significant improvement when we carried
out the reaction in a homogeneous solution of DMF and
10% (v/v) water in the presence of Cs2CO3 or K2CO3. Un-
expectedly, under these conditions, we isolated 5 in 76–70%
yield (Table 1, Entries 11 and 13).[12,13] Also, the overall re- mary or secondary amides 2 (X = Br, Cl) bearing aliphatic
action yield improved with K3PO4 in the presence of water and aromatic substituents, afforded 5 in fair to good yields.
(47%), even if the reaction was less selective, affording a When we used less reactive 2-Cl (Table 2, entries 1–5), we
mixture of 5 and 4 (5/4, 20:80, Table 1, Entry 14).
obtained at least two-fold higher yields than those with the
The amount of water added to DMF appeared to be crit- corresponding 2-Br (Table 2, entries 2–5). We rationalised
ical for the selectivity of the reaction. As reported above, these results in terms of different substrate stability. Under
we obtained the best result using a DMF/water mixture the reaction conditions, 2-Br derivatives could undergo de-
containing 10% (v/v) water. A lower (5%, v/v) and a higher composition faster, a bromine atom being recognised as a
(20%, v/v) water content produced lower yields of product better leaving group than a chlorine. The use of a chiral
Scheme 2. Proposed reaction mechanism.
3162
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3161–3166

Selective Synthesis of Isoquinolin-3-one Derivatives
Table 2. Scope of the reaction leading to 5.[a]
four new bonds and two new rings in a single operation,
giving access to an interesting class of bridged heterocy-
cles.[7c–7d]
Table 3. Scope of the reaction leading to 6 with respect to chlo-
roamides 2.[a]
Entry R4
% Yield of 5 % Yield of 6[c]
dr[b]
[d]
Entry R1
R2
R3
X
R4
H
R5
% Yield
1
2
3
4
PMB
Ph
(Ϯ)-α-methylbenzyl
H
–
55
61
53
traces
65:35
70:30
53:27:12:8
–
[d]
of 5[b]
–
[d]
–
1
2
3
4
Me
Me
Me
Me
H
H
H
H
H
H
H
H
Cl
CO2Me 46
CO2Me 76(35)
CO2Me 52(18)
50
Cl(Br) PMB
Cl(Br) Ph
[a] Conditions: 1 (1 equiv., 0.05 ), 2 (2 equiv.), 3, (2 equiv.),
Pd(OAc)2 (10 mol-%), TFP (20 mol-%), norbornene (2.2 equiv.),
Cs2CO3 (2 equiv.), DMF/water (10% water, v/v), 80 °C, 4 h. [b] H
Cl(Br) (Ϯ)-α-methyl- CO2Me 73(36)[c]
1
benzyl
NMR analysis of the crude. [c] Isolated yields. [d] No evidence of
the formation of 5 (NMR analysis of the crude).
5
6
7
8
9
10
Me
MeO
2,3-benzo
Me
Me
Me
H
H
H
H
H
Me
H
Cl(Br) allyl
CO2Me 32(16)
CO2Me 62
Cl
Cl
Cl
Cl
Cl
PMB
PMB
PMB
PMB
PMB
CO2Me 64[d]
CO2Me 60
H
H
H
The reaction likely proceeded through the same mecha-
nism as that which led to 5. Subsequently, a base-catalysed,
intramolecular addition of the C-4 to C-1 substituent oc-
curred, generating the fourth C–C bond and the second ring
(Scheme 3). Apparently, the COMe group possessed the
requisite properties to favour the cyclisation from the elec-
CN
58
[e]
H
COMe
–
[a] Conditions: 1 (1 equiv., 0.05 ), 2 (2 equiv.), 3, (2 equiv.),
Pd(OAc)2 (10 mol-%), TFP (20 mol-%), norbornene (2.2 equiv.),
Cs2CO3 (2 equiv.), DMF/water (water = 10% v/v), 80 °C, 6 h; PMB
= 4-MeOC6H4CH2. [b] Isolated yields. [c] 12 h; dr = 70:30 (1H
NMR analysis of the crude). [d] 4 equiv. of norbornene were used. tronic and steric point of view.
[e] No trace of 5 was observed in the crude (NMR analysis).
The use of a primary amide appeared to prevent the for-
mation of 6. The reaction with chloroacetamide led to 5
(R4 = H) as the almost exclusive product (Table 3, Entry
4), as the corresponding aza-anion was stable under the re-
action conditions.
We confirmed the structure assigned (by NMR analysis)
to the major diastereomer by the X-ray analysis of 6a (R4
= PMB, Figure 1).
amide containing the (Ϯ)-phenylethylamine unit gave a
mixture (ca. 70:30) of two diastereomers (Table 2, Entry 4).
With R4 = allyl, we obtained 5 in only moderate yield; the
decomposition of 2 was a competing side reaction (Table 2,
Entry 5).
We found a good tolerance towards a variety of electron-
rich iodoarenes (Table 2, entries 2 and 6–8), while we ob-
served low selectivity (less than 20% yield) with iodoarenes
ortho-substituted by electron-withdrawing groups (e.g.,
CF3, Cl).
Surprisingly, we observed a change in product selectivity
upon varying the substituent (R5) of olefin 3. As shown in
Table 2, the use of methyl acrylate or acrylonitrile (Table 2,
Entry 9) as the Heck acceptor gave the corresponding iso-
quinolin-3-one derivative, whereas we observed no trace of
5 using methyl vinyl ketone (Table 2, Entry 10). The reac-
tion of 1, secondary 2-Cl and 3 (R5 = COMe) delivered
diastereomeric mixtures of 1,4-ethanoisoquinolin-3-ones 6
(Scheme 3, Table 3, entries 1–3). This reaction generates
Figure 1. ORTEP plot of 6a (R4 = PMB) with atom-numbering
scheme. Displacement ellipsoids are drawn at the 30% probability.
Conclusions
Structurally different isoquinolinon-3-ones were selec-
tively obtained through the three-component, palladium/
norbornene-catalysed reaction of 1, 2 (Z = CO) and 3.
Interestingly, using haloamides as the starting halides al-
lowed us to incorporate functionality that promoted in situ,
sequential cyclisations, leading to products with increased
molecular complexity. We found an important beneficial ef-
Scheme 3. Synthesis of 1,4-ethanoisoquinolin-3-ones 6.
Eur. J. Org. Chem. 2009, 3161–3166
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3163

R. Ferraccioli, A. Forni
FULL PAPER
25 °C): δ = 2.43 (s, 3 H), 2.70 (dd, J = 14.7, 4.2 Hz, 1 H), 2.90 (dd,
J = 14.7, 8.7 Hz, 1 H), 3.43 (s, 3 H), 3.75 (d, J = 18.9 Hz, 1 H),
3.95 (d, J = 18.9 Hz, 1 H), 5.56 (dd, J = 8.7, 4.2 Hz, 1 H), 7.11–
7.49 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 18.6,
38.3, 39.5, 51.7, 60.1, 125.7, 127.3, 128.2, 129.0, 129.2, 132.5, 132.8,
fect of water as co-solvent, which led to the development
of conditions for successfully performing the reaction.
Experimental Section
133.4, 141.5, 169.1, 170.2 ppm. IR (neat): ν = 2951, 2924, 2852,
˜
1733, 1667, 1599 cm–1. HRMS (ESI): m/z [M + Na]+ calcd. for
General: The palladium-catalysed reactions were performed under
nitrogen using standard Schlenk and vacuum line techniques. 1H
and 13C NMR spectra were recorded at room temperature in
CDCl3 with a 300-AMX spectrometer at 300 and 75 MHz, respec-
tively. Chemical shifts are reported in ppm. High-resolution mass
spectra were obtained with an FT-ICR mass spectrometer. Infrared
spectra were recorded with an FT-IR spectrophotometer. Melting
points are uncorrected.
C19H19NNaO3: 332.12571; found 332.12547.
rac-Methyl [8-Methyl-3-oxo-2-(1-phenylethyl)-1,2,3,4-tetrahydroiso-
quinolin-1-yl]acetate [5, R1 = Me; R2 = R3 = H; R4 = (rac) α-Meth-
ylbenzyl; R5 = CO2Me, major diastereomer]: 41 mg, 73%; pale yel-
1
low, viscous oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.72 (d,
J = 7.5 Hz, 3 H), 1.74 (s, 3 H), 2.71 (dd, J = 15.0, 7.5 Hz, 1 H),
2.87 (d, J = 15.0, 5.1 Hz, 1 H), 3.64 (s, 3 H), 3.64–3.84 (m, 2 H),
4.87 (dd, J = 7.5, 5.1 Hz, 1 H), 6.04 (quartet, J = 7.5 Hz, 1 H),
6.90–7.29 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
16.9, 17.8, 39.0, 41.1, 50.4, 51.7, 51.8, 125.4, 127.3, 127.4, 127.6,
General Procedure for the Synthesis of Tetrahydroisoquinolin-3-ones
(5) and 1,4-Dihydro-1,4-ethanoisoquinolin-3(2H)-ones (6):
A
Schlenk-type flask was charged under nitrogen with Cs2CO3
(108.0 mg, 0.33 mmol), Pd(OAc)2 (3.6 mg, 0.0165 mmol), TFP
(7.7 mg, 0.033 mmol) and norbornene (34.0 mg, 0.36 mmol) in
DMF (1.0 mL). The mixture was stirred at room temp. for 10 min
128.4, 128.5, 132.5, 135.8, 139.7, 170.3, 170.9 ppm. IR (neat): ν =
˜
2950, 1734, 1656, 1538 cm–1. HRMS (ESI): m/z. [M + Na]+ calcd.
for C21H23NNaO3: 360.15701; found 360.15744.
and then treated with
2 (0.33 mmol), 1 (0.165 mmol), 3
Methyl [2-Allyl-8-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl]-
acetate (5, R1 = Me; R2 = R3 = H; R4 = Allyl; R5 = CO2Me):
14 mg, 32%; colourless oil. H NMR (CDCl3, 25 °C): δ = 2.35 (s,
3 H), 2.62 (dd, J = 15.0, 4.2 Hz, 1 H), 2.79 (dd, J = 15.0, 8.7 Hz,
1 H), 3.58–3.8 (m, 3 H overlapped with a singlet at δ = 3.74 ), 3.74
(s, 3 H), 4.79–4.86 (m, 1 H), 5.10–5.18 (m, 3 H), 5.68–5.80 (m, 1
H), 7.04–7.23 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 18.5, 37.9, 39.2, 48.1, 52.1, 54.5, 117.3, 125.6, 127.9, 128.9,
(0.33 mmol), DMF (1.97 mL) and water (0.33 mL). The homogen-
eous solution was heated at 80 °C whilst stirring for the time re-
ported (Table 2 and Table 3) and then cooled to room temp. Satu-
rated aqueous nBu4NCl (40 mL) was added, the mixture was ex-
tracted with AcOEt (2 ϫ 20 mL), the combined organic phases
were dried (Na2SO4), and the solvent was evaporated under vac-
uum. The residue was purified by flash chromatography on silica
1
gel (eluent: hexane/AcOEt). The isolated 6 [31 mg, 55%, R4
=
132.5, 132.6, 132.8, 134.2, 169.6, 171.1 ppm. IR (neat): ν = 2947,
˜
PMB; 29.5 mg, 61%, R4 = Ph; 28 mg, 53%, R4 = (rac)-α-meth-
ylbenzyl] turned out to be mixtures of diastereomers (by NMR
analysis). In the case of R4 = PMB or Ph, the major one (6a) could
be isolated as a diastereomerically pure compound by crystallisa-
tion (AcOEt).
2926, 1735, 1659, 1599 cm–1. HRMS (ESI): m/z [M + Na]+ calcd.
for C16H19NNaO3: 296.12571; found 296.12587.
Methyl [8-Methoxy-2-(4-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydro-
isoquinolin-1-yl]acetate (5, R1 = MeO; R2 = R3 = H; R4 = PMB; R5
1
= CO2Me): 38 mg, 62%; yellow, viscous oil. H NMR (300 MHz,
Methyl (8-Methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate
CDCl3, 25 °C): δ = 2.69 (dd, J = 14.4, 5.6 Hz, 1 H), 2.78 (dd, J =
14.5, 5.6 Hz, 1 H), 3.65 (s, 3 H), 3.67 (d, J = 19.0 Hz, 1 H), 3.76–
3.82 (m, 1 H), 3.77 (s, 3 H), 3.79 (s, 3 H), 4.20 (d, J = 14.7 Hz, 1
H), 5.18 (t, J = 5.6 Hz, 1 H), 5.32 (d, J = 14.7 Hz, 1 H), 6.73–6.85
(m, 4 H), 7.19–7.30 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 37.0, 38.6, 47.8, 51.7, 52.4, 55.2, 55.4, 108.3, 113.9,
119.6, 123.1, 128.8, 129.2, 133.8, 154.4, 158.9, 169.4, 170.9 ppm.
3
(5, R1 = Me; R2 = R = R4 = H; R5 = CO2Me): 18 mg, 46% as a
white solid, m.p. 140–141 °C (AcOEt). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 2.35 (s, 3 H), 2.60–2.73 (m, 2 H), 3.57 (d, J =
19.5 Hz, 1 H), 3.65 (d, J = 19.5 Hz, 1 H), 3.79 (s, 3 H), 5.04 (m, 1
H), 6.06 (br. s, 1 H), 7.05 (d, J = 7.4 Hz, 1 H), 7.12 (d, J = 7.2 Hz,
1 H), 7.23 (t, J = 7.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 18.6, 36.5, 40.3, 50.3, 52.1, 126.2, 128.1, 129.1, 131.9,
IR (neat): ν = 2951, 2838, 1735, 1650, 1600, 1513 cm–1. HRMS
˜
(ESI): m/z [M + Na]+ calcd. for C21H23NNaO5: 392.14684; found
133.2, 171.1, 171.3 ppm. IR (nujol): ν = 3182, 2926, 1731, 1676
˜
cm–1. HRMS (ESI): m/z [M + Na]+ calcd. for C13H15NNaO3:
392.14769.
256.09441; found 256.09472.
Methyl [2-(4-Methoxybenzyl)-3-oxo-1,2,3,4-tetrahydrobenzo[h]iso-
quinolin-1-yl]acetate (5, R1 = R2 = benzo; R3 = H; R4 = PMB; R5
= CO2Me): 41 mg, 64%; colourless, viscous oil. 1H NMR (CDCl3,
25 °C): δ = 2.72 (dd, J = 15.3, 4.6 Hz, 1 H), 2.84 (dd, J = 15.3,
7.3 Hz, 1 H), 3.63 (s, 3 H), 3.72 (s, 3 H), 3.8 (d, J = 19.5 Hz, 1 H),
3.9 (d, J = 19.5 Hz, 1 H), 4.15 (d, J = 14.9 Hz, 1 H), 5.45 (d, J =
14.9 Hz, 1 H), 5.68 (dd, J = 7.3, 4.6 Hz, 1 H), 6.75 (d, J = 8.7 Hz,
2 H), 7.18 (d, J = 8.6 Hz, 2 H), 7.27 (m, 1 H), 7.43–7.51 (m, 2 H),
7.70–7.85 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
37.7, 40.0, 48.1, 52.1, 53.6, 55.2, 114.1, 121.7, 125.6, 125.7, 127.1,
128.3, 128.6, 128.8, 129.0, 129.2, 130.0, 130.2, 132.6 ppm. IR (nu-
Methyl [2-(4-Methoxybenzyl)-8-methyl-3-oxo-1,2,3,4-tetrahydroiso-
quinolin-1-yl]acetate (5, R1 = Me; R2 = R3 = H; R4 = PMB; R5 =
CO2Me): 44 mg, 76%; pale yellow, viscous oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.04 (s, 3 H), 2.52 (dd, J = 15.3,
4.5 Hz, 1 H), 2.73 (dd, J = 15.3, 9.0 Hz, 1 H), 3.59–3.76 (m, 2 H
overlapped with two singlets at δ = 3.68 and 3.74), 3.68 (s, 3 H),
3.74 (s, 3 H), 3.98 (d, J = 12.0 Hz, 1 H), 5.04 (dd, J = 4.5, 9.0 Hz,
1 H), 5.42 (d, J = 12.0 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 2 H), 6.99 (t,
J = 6.9 Hz, 2 H), 7.07–7.15 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 18.3, 38.0, 39.0, 48.0, 52.1, 53.6, 55.2, 114.0,
125.5, 127.8, 128.7, 128.7, 129.3, 132.4, 132.5, 134.3, 159.0, 169.8,
jol): ν = 1732, 1651, 1513 cm–1. HRMS (ESI): m/z [M + Na]+ calcd.
˜
171.2 ppm. IR (neat): ν = 2994, 2952, 2838, 1733, 1658, 1513 cm–1.
˜
for C24H23NNaO4: 412.15193; found 412.15187.
HRMS (ESI): m/z [M + Na]+ calcd. for C21H23NNaO4: 376.15193;
Methyl [2-(4-Methoxybenzyl)-6,8-dimethyl-3-oxo-1,2,3,4-tetrahydro-
isoquinolin-1-yl]acetate (5, R1 = R3 = Me; R2 = H; R4 = PMB; R5 =
found 376.15228.
Methyl (8-Methyl-3-oxo-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1- CO2Me): 36 mg, 60%; colourless, viscous oil. 1H NMR (300 MHz,
yl)acetate (5, R1 = Me; R2 = R3 = H; R4 = Ph; R5 = CO2Me):
CDCl3, 25 °C): δ = 2.01 (s, 3 H), 2.26 (s, 3 H), 2.52 (dd, J = 15.2,
4.3 Hz, 1 H), 2.72 (dd, J = 15.2, 8.6 Hz, 1 H), 3.59 (d, J = 19.2 Hz,
27.5 mg, 54%; yellow, viscous oil. 1H NMR (300 MHz, CDCl3,
3164
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Selective Synthesis of Isoquinolin-3-one Derivatives
1 H), 3.69 (s, 3 H), 3.75 (s, 3 H), 3.69–3.75 (m, 1 H overlapped
with two singlets at δ = 3.69 and 3.75), 3.97 (d, J = 14.8 Hz, 1 H),
4.99 (dd, J = 8.5, 4.3 Hz, 1 H), 5.42 (d, J = 14.8 Hz, 1 H), 6.78 (d,
J = 8.2 Hz, 2 H), 6.80 (s, 1 H), 6.82 (s, 1 H), 7.09 (d, J = 8.2 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 18.2, 20.9, 37.9,
39.1, 47.9, 52.0, 53.5, 55.2, 113.9, 126.1, 128.8, 129.2, 129.5, 131.3,
m/z [M + Na]+ calcd. for C21H23NNaO2: 344.16210; found
344.16257.
8-Methyl-1-(2-oxopropyl)-1,4-dihydroisoquinolin-3(2H)-one (5, R1 =
Me; R2 = R3 = R4 = H; R5 = COMe): 18 mg, 50%; white solid;
1
m.p. 177–178 °C (AcOEt). H NMR (300 MHz, CDCl3, 25 °C): δ
= 2.02 (s, 3 H), 2.10 (s, 3 H), 2.60 (dd, J = 18.6, 2.7 Hz, 1 H), 2.71
(dd, J = 18.6, 10.2 Hz, 1 H), 3.37, (d, J = 18.0 Hz, 1 H), 3.50 (d,
J = 18.0 Hz, 1 H), 4.94 (dt, J = 10.5, 3.3 Hz, 1 H), 6.63 (br. s, 1
H), 6.87 (d, J = 7.5 Hz, 1 H), 6.96 (d, J = 7.2 Hz, 1 H), 7.05 (t, J
= 7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 25 °C): δ = 18.6, 30.1,
36.2, 49.1, 49.2, 126.0, 127.9, 129.1, 131.6, 132.0, 133.0, 171.2,
132.3, 137.5, 158.9, 169.9, 171.2 ppm. IR (nujol): ν = 1733, 1656,
˜
1614 cm–1. HRMS (ESI): m/z [M + Na]+ calcd. for C22H25NNaO4:
390.16758; found 390.16736.
[2-(4-Methoxybenzyl)-8-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-
1-yl]acetonitrile (5, R1 = Me; R2 = R3 = H; R4 = PMB, R5 = CN):
206.2 ppm. IR (nujol): ν = 3323, 3295, 1710, 1677, 1595 cm–1.
1
˜
31 mg, 58%; pale yellow, viscous oil. H NMR (300 MHz, CDCl3,
HRMS (ESI): m/z [M + Na]+ calcd. for C13H15NNaO2: 240.09950;
25 °C): δ = 2.18 (s, 3 H), 2.67–2.69 (m, 2 H), 3.73 (d, J = 19.4 Hz,
1 H), 3.83 (s, 3 H), 3.98 (d, J = 19.4 Hz, 1 H), 4.45 (d, J = 15.0 Hz,
1 H), 4.87 (t, J = 6.0 Hz, 1 H), 5.33 (d, J = 15.0 Hz, 1 H), 6.88 (d,
J = 8.5 Hz, 2 H), 7.10 (d, J = 7.6 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2
H), 7.26 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 18.6, 22.5, 37.6, 48.3, 53.5, 55.2, 114.3, 116.9, 126.1,
128.1, 128.7, 129.2, 129.3, 131.4, 132.6, 132.9, 159.3, 169.4 ppm.
found 240.09969.
General Procedure for the Synthesis of 2: The preparation is modi-
fied from a reported procedure.[17] A solution of amine (8.25 mmol)
and dry Et3N (9.05 mmol) dissolved in dry dichloromethane
(12 mL) was cooled to –5 °C with an ice bath. Chloroacetyl chlo-
ride (or bromoacetyl bromide, 8.25 mmol) dissolved in dichloro-
methane (3 mL) was added dropwise to the stirred solution, and
the temperature was maintained between –2 °C and –5 °C. The re-
action mixture was stirred for 30 min at 0 °C and then allowed to
return to room temperature and stirred for an additional 30 min.
During this time, a precipitate formed in the case of 2 [X = Cl,
Br; R4 = Ph, PMB, (rac)-α-methylbenzyl]. The precipitate was then
filtered and washed with dichloromethane. The filtrate was washed
with HCl (2 , 1ϫ5 mL) and brine (1ϫ15 mL). The organic phase
was separated and dried (Na2SO4), and the solvent was evaporated
under vacuum. The solid residue was crystallised from an appropri-
ate solvent. In the case of 2 (X = Cl; R4 = allyl) an orange oil was
obtained, which was used without further purification. Data for 2-
Cl and 2-Br (R4 = PMB) are not reported in the literature.
IR (neat): ν = 2952, 2932, 2837, 2248, 1731, 1658, 1613 cm–1
.
˜
HRMS (ESI): m/z [M + Na]+ calcd. for C20H20N2NaO2:
343.14170; found 343.14210.
rac-(1R*,4R*,9S*)-1,4-Dihydro-9-hydroxy-2-(4-methoxybenzyl)-
8,9-dimethyl-1,4-ethanoisoquinolin-3(2H)-one (6a, R1 = Me; R2
=
R3 = H; R4 = PMB): Major diastereomer; white solid, m.p. 202–
1
203 °C (AcOEt). H NMR (300 MHz, CDCl3, 25 °C): δ = 1.17 (s,
3 H), 1.55 (dd, J = 13.2, 1.5 Hz, 1 H), 1.96 (s, 3 H), 2.23 (dd, J =
13.2, 3.6 Hz, 1 H), 3.23 (br. s, 1 H), 3.81 (s, 3 H), 3.92 (s, 1 H),
4.44 (d, J = 14.8 Hz, 1 H), 4.64 (dd, J = 3.6, 1.5 Hz, 1 H), 4.80 (d,
J = 14.8 Hz, 1 H), 6.83 (d, J = 8.3 Hz, 2 H), 6.96 (d, J = 7.4 Hz,
1 H), 7.05 (d, J = 8.4 Hz, 2 H), 7.08–7.19 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 17.4, 29.1, 43.2, 47.2, 53.5, 55.3, 62.0,
73.3, 113.9, 123.6, 127.1, 128.2, 128.5, 129.5, 129.9, 136.5, 138.0,
2-Chloro-N-phenylacetamide (2-Cl): 1.24 g, 76%; beige solid; m.p.
123–124 °C (lit.[18] 122–125 °C).
159.0, 173.2 ppm. IR (nujol): ν = 3245, 1644, 1599, 1512 cm–1.
˜
HRMS (ESI): m/z [M + Na]+ calcd. for C21H23NNaO3: 360.15701;
2-Bromo-N-phenylacetamide (2-Br): 1.09 g, 62%; beige solid; m.p.
130–131 °C (isopropyl ether) (lit.[19] 129–131 °C).
found 360.15697.
N-Allyl-2-chloroacetamide (2-Cl): 0.90 g, 82%; yellow-orange oil.
Spectroscopic data are consistent with those reported in the litera-
ture.[20]
rac-(1R*,4R*,9S*)-1,4-Dihydro-9-hydroxy-8,9-dimethyl-2-phenyl-
1,4-ethanoisoquinolin-3(2H)-one (6a, R1 = Me; R2 = R3 = H; R4 =
Ph): Major diastereomer; white solid; m.p. 216–217 °C (AcOEt).
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.18 (s, 3 H), 1.72 (dd, J
= 13.9, 1.0 Hz, 1 H), 2.39 (s, 3 H), 2.49 (dd, J = 13.9, 3.9 Hz, 1
H), 3.96 (s, 1 H), 4.35 (br. s, 1 H), 5.26 (m, 1 H), 7.03–7.22 (m, 4
H), 7.28–7.36 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 18.0, 29.2, 43.6, 58.5, 62.6, 73.0, 124.0, 124.4, 126.2, 127.6,
N-Allyl-2-bromoacetamide (2-Br): 1.0 g, 69%; white solid; m.p. 28–
29 °C (isopropyl ether/hexane) (lit.[17] 27 °C).
rac-2-Bromo-N-(α-methylbenzyl)acetamide (2-Br): 1.7 g, 85%; white
solid; m.p. 90–91 °C (isopropyl ether). Spectroscopic data are con-
sistent with those reported in the literature.[21]
128.8, 129.1, 130.0, 136.4, 137.4, 140.2, 172.4 ppm. IR (nujol): ν =
˜
3304, 1660, 1594 cm–1. HRMS (ESI): m/z [M + Na]+ calcd. for
rac-2-Chloro-N-(α-methylbenzyl)acetamide (2-Cl): 1.47 g, 90%;
white solid; m.p. 76–77 °C (isopropyl ether). Spectroscopic data are
consistent with those reported in the literature.[22]
C19H19NNaO2: 316.13080; found 316.13066.
rac-1,4-Dihydro-9-hydroxy-8,9-dimethyl-2-(1-phenylethyl)-1,4-ethano-
isoquinolin-3(2H)-one [6, R1 = Me; R2 = R3 = H; R4 = (rac)-α-
methylbenzyl]: 1:1 Mixture of the two major diastereomers; white
2-Chloro-N-(4-methoxybenzyl)acetamide (2-Cl): 1.42 g, 81%; light
brown solid; m.p. 104–105 °C (isopropyl ether). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 3.74 (s, 3 H), 4.01 (s, 2 H), 4.35 (d,
J = 5.5 Hz, 2 H), 6.72 (br. s, 1 H), 6.82 (d, J = 8.5 Hz, 2 H), 7.15
(d, J = 8.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
42.5, 43.3, 55.2, 114.2, 129.2, 129.3, 159.2, 165.5 ppm. IR (nujol):
1
solid. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.17 (s, 3 H), 1.54
(s, 6 H), 1.57–1.61 (m, 2 H overlapped with a singlet at δ = 1.63),
1.63 (s, 3 H), 1.64 (d, J = 6.9 Hz, 3 H), 1.74 (d, J = 6.9 Hz, 3 H),
2.18–2.25 (m, 2 H), 2.3–2.8 (br. s, 2 H), 3.85 (s, 1 H), 3.89 (s, 1 H),
4.48–4.50 (m, 1 H), 4.54–4.57 (m, 1 H), 5.73 (quartet, J = 6.9 Hz,
1 H), 5.80 (quartet, J = 6.9 Hz, 1 H), 6.88–6.93 (m, 2 H), 6.99–
7.30 (m, 14 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 16.2,
16.5, 16.8, 29.2, 44.6, 46.1, 49.3, 49.5, 49.6, 49.9, 62.3, 72.1, 73.5,
123.4, 124.5, 126.9, 127.2, 127.3, 127.4, 128.1, 128.3, 128.4, 128.5,
130.0, 130.5, 134.8, 136.2, 137.8, 138.1, 139.0, 139.6, 171.1, 172.0
ν = 3281, 1656, 1617 cm–1. C H ClNO (213.66): calcd. C 56.21,
˜
10 12
2
H 5.66, N 6.56; found C 56.30, H 5.77, N 6.54.
2-Bromo-N-(4-methoxybenzyl)acetamide (2-Br): 1.51 g, 71%; pale
yellow solid; m.p. 120–121 °C (AcOEt). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 3.84 (s, 3 H), 3.94 (s, 2 H), 4.44 (d, J = 5.5 Hz,
2 H), 6.73 (br. s, 1 H); 6.91 (d, J = 8.4 Hz, 2 H), 7.25 (d, J = 8.4 Hz,
ppm. IR (nujol): ν = 3400, 3243, 1650, 1600 cm–1. HRMS (ESI): 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 29.0, 43.6, 55.2,
˜
Eur. J. Org. Chem. 2009, 3161–3166
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3165

R. Ferraccioli, A. Forni
FULL PAPER
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˜
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CCDC-718016 contains the supplementary crystallographic data
for 6a, R4 = PMB. These data can be obtained free of charge from
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Supporting Information (see footnote on the first page of this arti-
1
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[11] The reported solvent/base combination gave the best results in
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Acknowledgments
[12] Although the reactions were performed under aqueous basic
conditions, we had no evidence of methoxycarbonyl group hy-
drolysis.
We thank Consiglio Nazionale delle Ricerche (CNR) for financial
support.
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Received: March 10, 2009
Published Online: May 12, 2009
3166
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Eur. J. Org. Chem. 2009, 3161–3166