Ru-catalyzed C[sbnd]H functionalization of phenylglycine derivatives: Synthesis of isoquinoline-1-carboxylates and isoindoline-1-carboxylates

Article abstract of DOI:10.1016/j.molcata.2016.06.026

The reaction of N-unprotected methylesters of phenylglycine derivatives (1a–1f) with electron-rich internal alkynes (2a–2e), catalyzed by [Ru(cymene)Cl₂]₂ (10%), gives the corresponding 3,4-disubstituted isoquinoline-1-carboxylates 3 through C[sbnd]H/N[sbnd]H oxidative coupling. The C[sbnd]H bond activation step is assisted by carboxylates, and N-fluoro-2,4,6-trimethylpyridinium triflate works as the terminal oxidant. The process shows a remarkable tolerance to the presence of diverse electron-releasing and electron-attracting functional groups at the phenyl ring of the amino acid. In addition, the reaction of phenylglycine derivatives (1a–1f) with methyl acrylate (4a) catalyzed by [Ru(cymene)Cl₂]₂ (10%) under the same experimental conditions, gives the corresponding 3,N-disubstituted isoindoline-1-carboxylates 5 through C[sbnd]H/N[sbnd]H coupling. Isoindolines 5 are obtained as a mixture of diastereoisomers, with moderate to high values of diastereomeric excess (up to 80%).

Full text of DOI:10.1016/j.molcata.2016.06.026

Accepted Manuscript
Title: Ru-catalyzed C-H functionalization of phenylglycine
derivatives: synthesis of isoquinoline-1-carboxylates and
isoindoline-1-carboxylates
Author: Sara Ruiz Francisco J. Sayago Carlos Cativiela
Esteban P. Urriolabeitia
PII:
S1381-1169(16)30248-5
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.06.026
MOLCAA 9932
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
23-5-2016
23-6-2016
26-6-2016
Please cite this article as: Sara Ruiz, Francisco J.Sayago, Carlos Cativiela, Esteban
P.Urriolabeitia, Ru-catalyzed C-H functionalization of phenylglycine derivatives:
synthesis of isoquinoline-1-carboxylates and isoindoline-1-carboxylates, Journal of
Molecular Catalysis A: Chemical http://dx.doi.org/10.1016/j.molcata.2016.06.026
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Ru-catalyzed C-H functionalization of phenylglycine derivatives: synthesis of
isoquinoline-1-carboxylates and isoindoline-1-carboxylates
(revised manuscript MOLCAA-D-16-00632)
Sara Ruiz, Francisco J. Sayago, Carlos Cativiela, Esteban P. Urriolabeitia*
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza,
Facultad de Ciencias, Pedro Cerbuna 12, 50009 Zaragoza (Spain)
Corresponding author: Esteban P. Urriolabeitia (esteban@unizar.es). Postal address: ISQCH,
Facultad de Ciencias, Edificio D, planta 4, Pedro Cerbuna 12, 50009 Zaragoza (Spain)
1

Graphical Abstract
2

Highlights
N-unprotected phenylglycine derivatives have been functionalized selectively
Functionalization is catalyzed by Ru(II) complexes through oxidative coupling
Isoquinoline-1-carboxylates are obtained by coupling with internal alkynes
Isoindoline-1-carboxylates are obtained by coupling with methylacrylates
3

Abstract
The reaction of N-unprotected methylesters of phenylglycine derivatives (1a-1f) with electron-rich
internal alkynes (2a-2e), catalyzed by [Ru(cymene)Cl2]2 (10%), gives the corresponding 3,4-
disubstituted isoquinoline-1-carboxylates 3 through C-H/N-H oxidative coupling. The C-H bond
activation step is assisted by carboxylates, and N-fluoro-2,4,6-trimethylpyridinium triflate works as
the terminal oxidant. The process shows a remarkable tolerance to the presence of diverse electron-
releasing and electron-attracting functional groups at the phenyl ring of the amino acid. In addition,
the reaction of phenylglycine derivatives (1a-1f) with methyl acrylate (4a) catalyzed by
[Ru(cymene)Cl2]2 (10%) under the same experimental conditions, gives the corresponding 3,N-
disubstituted isoindoline-1-carboxylates 5 through C-H/N-H coupling. Isoindolines 5 are obtained
as a mixture of diastereoisomers, with moderate to high values of diastereomeric excess (up to
80%).
Keywords
Ru-complexes / Amino acids / C-H activation / Isoquinolines / Isoindolines
4

1. Introduction
Amino acids are a group of molecules with an essential role in the development of life, because
they are the basic structural components of peptides and proteins. The bonding pattern and the
relative arrangement of amino acids change the properties of the peptide or the protein, up to the
point of determining the way in which they are expressed. This close structure-activity relationship
results in that controlled modifications of amino acids could be devised to promote tailored changes.
Therefore the selective synthesis and modification of amino acids is a topic of high interest [1].
C-H functionalizations promoted by metal complexes have emerged as versatile, selective and often
catalytic alternatives to classical and widely employed methods [2], providing in some cases
alternative solutions [3]. Up to now, C(sp2)-H activation of amino acids has focused on
phenylalanine, as summarized in Figure 1 and, to a much lower extent, tryptophane and
heterocyclic derivatives. Thus, Pd-catalyzed halogenations [4a], acetoxylations [4d], aminations
[4a,4b,4d,4f,4h], alkenylations [4a,4i] and carbonylations [4e,4g] have been reported. In addition,
one example of an Ir-catalyzed borylation, followed by Pd-mediated Suzuki coupling to yield
arylated derivatives, has been reported [4c]. Very recently the catalytic functionalization of
phenylglycine has been reported by Yu and coworkers (Figure 1), using Pd catalysts, but only a
limited number of examples was studied [4j,4k].
Figure 1. Functionalization of amino acids and present contribution
5

All the examples reported up to now share some common features. First of all, the reported
processes use expensive Pd- and Ir-salts. It would be highly desirable to develop a catalytic method
using a less expensive metal, such as ruthenium, while retaining the versatility and high activity of
its more expensive counterparts [5]. In addition, with the exception of Pd-catalyzed carbonylations
[4e,4g], the amino acid always has the nitrogen atom protected with a variety of functional groups,
either monodentate or chelate. The presence of the protecting group is required in order for the
reaction to take place. This fact limits the reactivity of the substrate and introduces additional
synthetic steps to protect, and then deprotect, the N atom. In this context, the reactivity of N-
protected phenylglycinates has been studied in our group. These derivatives show a higher
reactivity than the N-unprotected ones, and the C-H bond activation step has a much lower energy
barrier [6]. N-unprotected species are less prone to be activated and, therefore, their
functionalization is still a great challenge.
A close inspection of the literature reveals that Ru-complexes have not so far been used as catalysts
for the C-H functionalization of amino acids, despite their well-known activity in this type of
reactions [7]. For example, we have reported catalytic oxidative couplings between N-unprotected
primary amines and alkynes using Ru(II) complexes to give a wide variety of N-containing
heterocycles [8]. Therefore, it is reasonable to assume that Ru(II) derivatives are very good
candidates to efficiently catalyze the functionalization of amino acids avoiding the mandatory
protection at the N atom. In the present contribution we report the results obtained in the Ru-
catalyzed oxidative coupling of N-unprotected amino acids with alkynes and olefins.
2. Experimental
2.1. General methods
Solvents were used as received from commercial sources. They were not distilled nor subjected to
additional purification. All reactions were carried out without protecting atmosphere. Column liquid
chromatography was performed on aluminum oxide 90 neutral (50−200 μm) or silica gel (70−230
1
13
μm). Melting points were determined on a Gallenkamp apparatus. H and C NMR spectra were
o
recorded in CDCl3 solutions at 25 C on Bruker AV300, ARX300 or AV400 spectrometers ( in
ppm and J in Hz) at a 1H NMR operating frequency of 300.13 or 400.13 MHz, respectively. 1H and
13C NMR spectra were referenced using the solvent signal as an internal standard. The full
assignment of 1H NMR peaks was performed through standard 2D 1H−COSY and selective 1D 1H-
NOESY experiments. Typical mixing times in the case of selective 1D-NOESY experiments were 1
or 2 s, as a function of the irradiated signal. These values of optimized mixing times were set equal
to the longitudinal relaxation time T1, which in turn was determined using the inversion−recovery
1
13
sequence. Once the H NMR signals were fully assigned, the corresponding C NMR peaks were
6

1
1
identified using standard H−13C edited-HSQC and H−13C HMBC 2D-experiments. ESI (ESI+)
mass spectra were recorded using an Esquire 3000 ion-trap mass spectrometer (Bruker Daltonic
GmbH) equipped with a standard ESI/APCI source. Samples were introduced by direct infusion
with a syringe pump. Nitrogen served both as the nebulizer gas and the dry gas. HRMS and ESI
(ESI+) mass spectra were recorded using an MicroToF Q, API-Q-ToF ESI with a mass range from
20 to 3000 m/z and mass resolution 15000 (FWHM). Some products were purified using a
Kugelrohr distillation apparatus model Buchi B-585. The syntheses of the ruthenium catalyst
[[Ru(-Cl)Cl(6-p-cymene)]2 [9a], (3-nitrophenyl)glycine [9b] and methyl arylglycinate
hydrochlorides 1d and 1e [9c], were carried out following published procedures. The spectral data
were compared with the literature data to confirm their structures. Other starting phenylglycines,
alkynes and alkenes were purchased from commercial sources and used as received.
2.2. Synthesis of phenylglycine methyl ester hydrochlorides 1b, 1c, and 1f
2.2.1. Synthesis of methyl (3-nitrophenyl)glycinate hydrochloride (1b)
Thionyl chloride (1.10 mL, 15.08 mmol) was added dropwise to an ice-cooled suspension of (3-
nitrophenyl)glycine (1.39 g, 7.07 mmol) in dry methanol (18 mL). The resulting solution was
stirred at room temperature for 24 h. Then, the solvent was concentrated under vacuum and the
residue was lyophilized to afford a pale orange solid (1.66 g, 6.71 mmol, 95% yield). Mp 178-180
1
ºC; H NMR (D2O, 400 MHz) (, ppm) 8.40-8.33 (m, 2H, C6H4), 7.91-7.86 (m, 1H, C6H4), 7.78-
7.72 (m, 1H, C6H4), 5.49 (s, 1H, CH), 3.83 (s, 3H, CH3); 13C NMR (D2O, 100 MHz) (, ppm) 168.6
(C), 148.2 (C), 134.6 (CH), 132.5 (C), 130.9 (CH), 125.2 (CH), 123.2 (CH), 55.5 (CH3), 54.1 (CH);
HRMS (ESI-TOF) calc. for [C9H11N2O4]+ requires 211.0713, found 211.0705.
2.2.2. Synthesis of methyl (4-chlorophenyl)glycinate hydrochloride (1c)
A solution of 4-chlorobenzaldehyde (4.79 g, 34.08 mmol) in methanol (10 mL) was added dropwise
under vigorous stirring to a solution of KCN (2.48 g, 38.08 mmol) and NH4Cl (2.04 g, 38.08 mmol)
in water (10 mL). The reaction mixture was vigorously stirred at room temperature for 2 h. Then,
water (25 mL) was added and the resulting mixture was extracted with toluene (25 mL). The
aqueous layer was discarded and the toluene phase was extracted with 6N aqueous HCl (3 x 10 mL).
The combined aqueous phase was refluxed for 24 h. After that, the reaction mixture was evaporated
and the resulting residue was suspended in water. The pH was adjusted to 6-7 by means of the
addition of small portions of Na2CO3 to precipitate the amino acid. The (4-chlorophenyl)glycine
was filtered and dried (2.16 g, 11.62 mmol, 34% yield) and used in the next step without further
purification.
7

Thionyl chloride (1.79 mL, 24.59 mmol) was added dropwise to an ice-cooled suspension of (4-
chlorophenyl)glycine (2.16 g, 11.62 mmol) in dry methanol (29 mL). The resulting solution was
stirred at room temperature for 24 h. Then, the solvent was concentrated under vacuum and the
residue was lyophilized to afford a white solid (2.55 g, 10.80 mmol, 93% yield). Mp 196-198 ºC (lit.
1
194-197 ºC [10]); H NMR (D2O, 400 MHz) (, ppm) 7.54-7.50 (m, 2H, C6H4), 7.46-7.41 (m, 2H,
13
C6H4), 5.30 (s, 1H, CH), 3.81 (s, 3H, CH3); C NMR (D2O, 100 MHz) (, ppm) 169.2 (C), 135.9
(C), 129.7 (2 x CH), 129.6 (2 x CH), 129.5 (C), 55.7 (CH3), 53.9 (CH); HRMS (ESI-TOF) calc. for
[C9H11ClNO2]+ requires 200.0473, found 200.0464.
2.2.3. Synthesis of methyl (4-methylphenyl)glycinate hydrochloride (1f)
To a mixture of 4-methylbenzaldehyde (1.18 mL, 10.00 mmol) and benzhydrylamine (2.07 mL,
12.00 mmol) trimethylsilyl cyanide (1.50 mL, 12.00 mmol) was added dropwise. The reaction
mixture was vigorously stirred at room temperature for 30 minutes. Then, the mixture was
evaporated to remove the unreacted trimethylsilyl cyanide and the resulting residue was purified by
column chromatography (eluent: hexane/Et2O 9:1) to afford a colourless oil (2.34 g, 7.48 mmol,
75% yield). Spectroscopic data are in agreement with those described in literature [11].
A solution of the protected aminonitrile (2.34 g, 7.48 mmol) in a 1:1 mixture of concentrated HCl
and trifluoroacetic acid (16 mL) was stirred in a sealed tube at 80 ºC for 18 h. After that, the
reaction mixture was partitioned between water and ether. The organic phase was discarded and the
aqueous phase was washed with ether. Then, the pH was adjusted to 6-7 by means of the addition of
small portions of Na2CO3 to precipitate the amino acid. The (4-methylphenyl)glycine was filtered
and dried (823 mg, 4.98 mmol, 67% yield) and used in the next step without further purification.
-cooled suspension of (4-
methylphenyl)glycine (823 g, 4.98 mmol) in dry methanol (13 mL). The resulting solution was
stirred at room temperature for 24 h. Then, the solvent was concentrated under vacuum and the
residue was lyophilized to afford a white solid (1.05 g, 4.88 mmol, 98% yield). Mp 190-192 ºC (lit.
192-193 ºC [12]); 1H NMR (MeOD, 400 MHz) (, ppm) 7.37-7.28 (m, 4H, C6H4), 5.14 (s, 1H, CH),
13
3.80 (s, 3H, CH3), 2.37 (s, 3H, CH3); C NMR (MeOD, 100 MHz) (, ppm) 170.2 (C), 141.7 (C),
131.2 (2 x CH), 130.3 (C), 129.1 (2 x CH), 57.3 (CH3), 53.9 (CH), 21.2 (CH3); HRMS (ESI-TOF)
calc. for [C10H14NO2]+ requires 180.1019, found 180.1016.
2.3. General synthesis of methyl isoquinoline-1-carboxylate derivatives 3 (3aa-3ae and 3ba-3fa)
The corresponding phenylglycine methyl ester hydrochloride (1.5 mmol) was first dissolved in a
saturated solution of KHCO3 in water (2 mL) and stirred until bubbling ceased. Then, the solution
8

was extracted with CH2Cl2 (3  10 mL), the organic layer was separated and dried over MgSO4 and
then evaporated to dryness, in order to afford the pure phenylglycine methyl ester derivative 1a-f.
The phenylglycine methyl ester derivative (1 mmol) and the alkyne 2a-e (2 mmol) were added to a
suspension of [Ru(p-cymene)Cl2]2 (61.2 mg, 0.1 mmol), NaOAc (164.1 g, 2.0 mmol), K[PF6] (18.7
mg, 0.1 mmol) and N-fluoro-2,4,6-trimethylpyridium triflate (289.3 mg, 1 mmol) in HFIP
(hexafluoroisopropanol, 3 mL) into a Young’s flask. The solution was stirred and heated at 60 °C
for 24 h. After the reaction time was completed, the solvent was removed to dryness. The resulting
solid residue was dissolved in CH2Cl2, filtered over neutral alumina and eluted first with 100 mL of
CH2Cl2 affording a yellow solution. Evaporation of the yellow solution to dryness gave the
corresponding products 3, although impure. Pure compounds 3 were obatined by further
purification by column chromatography on silica gel eluting with mixtures of hexane/diethylether,
and/or by Kugelrohr distillation, as specified on each particular case.
In the case of compound 3ab further elution with 50 mL of CH2Cl2/MeOH 95:5 afforded a brown
solution. The brown solution contained very small amounts of organometallic product 3ab.OM,
which was purified by further column chromatography using ethyl acetate/hexane (90:10 to 50:50)
and crystallized as reported in Section 2.8. The small amount of crystalline 3ab.OM obtained in
different batches precluded its full spectroscopic characterization.
2.4. Characterization of products type 3
2.4.1. Methyl 3,4-diethylisoquinoline-1-carboxylate (3aa): dark yellow oil (177 mg, 73%). Purified
0
1
by Kugelrohr distillation at 80 C for 90 minutes. H NMR (CDCl3, 300 MHz) (, ppm) 8.52 (dd,
3
4
4
1H, C6H4, JHH = 8.5, JHH = 1.4 Hz), 7.94 (dd, 1H, C6H4, 3JHH = 8.7, JHH = 1.0 Hz), 7.59 (m, 1H,
C6H4), 7.47 (m, 1H, C6H4), 3.98 (s, 3 H, CH3), 2.99 (m, 4H, CH2CH3), 1.27 (t, 3H, CH2CH3, 3JHH
=
3
13
7.6 Hz), 1.21 (t, 3H, CH2CH3, JHH = 7.6 Hz); C NMR (CDCl3, 75 MHz) (, ppm) 167.0 (C),
153.1 (C), 146.9 (C) 135.8 (C), 133.1 (C), 130.1 (CH), 126.8 (CH), 126.7 (CH), 125.1 (C), 123.1
(CH), 52.9 (CH3), 28.4 (CH2), 21.1 (CH2), 14.7 (CH3), 15.0 (CH3); HRMS (ESI-TOF) calc. for
[C15H17NNaO2]+ requires 266.1151, found 266.1178.
2.4.2. Methyl 3,4-diphenylisoquinoline-1-carboxylate (3ab): pale yellow solid (136 mg, 40%).
1
Purified by column chromatography, elution with hexane/diethyl ether (90/10 to 50/50). H NMR
(CDCl3, 300 MHz) (, ppm) 8.63 (m, 1H, C6H4), 7.58 (m, 3H, C6H4), 7.28 (m, 5H, Ph), 7.13 (m, 5H,
Ph), 4.02 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz) (, ppm) 166.7 (C), 149.6 (C), 148.5 (C), 140.0
(C), 137.0 (C), 136.8 (C), 133.9 (C), 131.0 (CH), 130.6 (CH), 130.4 (CH), 128.4 (CH), 128.0 (CH),
127.7 (CH), 127.7 (CH), 127.4 (CH), 126.2 (CH), 126.1 (CH), 125.2 (C), 53.0 (CH3); HRMS (ESI-
TOF) calc. for [C23H17NNaO2]+ requires 362.1151, found 362.1164.
9

2.4.3. Methyl 3-methyl-4-propylisoquinoline-1-carboxylate (3ac1) and methyl 4-methyl-3-
propylisoquinoline-1-carboxylate (3ac2): compounds 3ac1 and 3ac2 were separated and purified by
column chromatography, elution with hexane/diethyl ether (90/10 to 50/50). 3ac1 eluted first.
3ac1: orange solid (41 mg, 17%). Traces of subproducts were removed by Kugelrohr distillation at
80 0C for 90 minutes. 1H NMR (CDCl3, 300 MHz) (, ppm) 8.62 (d, 1H, C6H4, 3JHH = 8.6 Hz), 7.96
(dd, 1H, C6H4, 3JHH = 8.7, 4JHH = 1.1 Hz), 7.64 (ddd, 1H, C6H4, 3JHH = 8.5, 3JHH = 6.8, 4JHH =1.3 Hz),
3
3
4
7.51 (ddd, 1H, C6H4, JHH = 8.5, JHH = 6.8, JHH = 1.2 Hz), 4.01 (s, 3H, O-CH3), 2.99 (m, 2H,
3
CH2CH2CH3), 2.71 (s, 3H, CH3), 1.60 (m, 2H, CH2CH2CH3), 1.02 (t, 3H, CH2CH2CH3, JHH = 7.4
13
Hz); C NMR (CDCl3, 75 MHz) (, ppm) 166.6 (C), 148.2 (C), 146.0 (C), 136.1 (C), 133.0 (C),
130.2 (CH), 127.0 (CH), 126.7 (CH), 125.3 (C), 53.0 (CH3), 123.1 (CH), 30.5 (CH2), 23.2 (CH2),
22.4 (CH3), 14.5 (CH3). HRMS (ESI-TOF) calc. for [C15H17NNaO2]+ requires 266.1151, found
266.1154. 3ac2: yellow solid (61 mg, 25%). Traces of subproducts were removed by Kugelrohr
distillation at 80 0C for 90 minutes. 1H NMR (CDCl3, 300 MHz) (, ppm) 8.55 (ddd, 1H, C6H4, 3JHH
4
5
3
4
5
= 8.6, JHH = 1.3, JHH = 0.7 Hz), 7.96 (ddd, 1H, C6H4, JHH = 8.6, JHH = 1.4, JHH = 0.7 Hz), 7.63
3
3
4
(ddd, 1H, C6H4, JHH = 7.6, JHH = 6.7, JHH = 1.8 Hz), 7.51 (m, 1H, C6H4), 4.00 (s, 3H, O-CH3),
3
2.97 (m, 2H, CH2CH2CH3), 2.60 (s, 3H, CH3), 1.70 (m, 2H, CH2CH2CH3), 0.95 (t, 3H, JHH = 7.3
Hz, CH2CH2CH3); 13C NMR (CDCl3, 75 MHz) (, ppm) 165.9 (C), 151.3 (C), 145.5 (C), 135.6 (C),
129.0 (CH), 126.5 (C), 125.9 (CH), 125.5 (CH), 123.7 (C), 122.3 (CH), 51.91 (CH3), 36.9 (CH2),
22.2 (CH2), 13.2 (CH3), 13.1 (CH3). HRMS (ESI-TOF) calc. for [C15H17NNaO2]+ requires 266.1151,
found 266.1162.
2.4.4. Methyl 3-methyl-4-phenylisoquinoline-1-carboxylate (3ad1) and methyl 4-methyl-3-
phenylisoquinoline-1-carboxylate (3ad2): compounds 3ad1 and 3ad2 were obtained as a mixture in
1:4 molar ratio. Compound 3ad1 could not be obtained in pure form (it was always contaminated
with 3ad2), while 3ad2 was obtained in pure form by column chromatography by elution with
hexane/diethyl ether (90/10 to 50/50). Traces of subproducts were removed by Kugelrohr
0
1
distillation at 80 C for 90 minutes. Compound 3ad2: dark yellow oil (141 mg, 51%). H NMR
(CDCl3, 300 MHz) (, ppm) 8.64 (ddd, 1H, C6H4, 3JHH = 8.5, 4JHH = 1.4, 5JHH = 0.7 Hz), 8.03 (ddd,
1H, C6H4, 3JHH = 8.6, 4JHH = 1.3, 5JHH = 0.7 Hz), 7.70 (ddd, 1H, C6H4, 3JHH = 8.4, 3JHH = 6.8, 4JHH
=
1.4 Hz), 7.59 (ddd, 1H, C6H4, 3JHH = 8.2, 3JHH = 6.8, 4JHH = 1.2 Hz), 7.51 (m, 2H, Ph), 7.37 (m, 3H,
Ph), 3.97 (s, 3H, O-CH3), 2.61 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz) (, ppm) 166.8 (C), 150.9
(C), 146.8 (C), 140.5 (C), 137.1 (C), 130.5 (CH), 130.1 (CH), 128.2 (CH), 128.1 (C), 127.9 (CH),
127.8 (CH), 127.0 (CH) 125.1 (C), 124.0 (CH), 52.9 (CH3), 16.1 (CH3). HRMS (ESI-TOF) calc. for
[C18H15NNaO2]+ requires 300.0995, found 300.1005.
10

2.4.5. Methyl 4-(tert-butyl)-3-methylisoquinoline-1-carboxylate (3ae1), methyl 3-(tert-butyl)-4-
methylisoquinoline-1-carboxylate (3ae2) and methyl 1-amino-2-(tert-butyl)-3-methyl-1H-indene-1-
carboxylate (3ae3): compounds 3ae1, 3ae2 and 3ae3 were separated and purified by column
chromatography. Elution with hexane/diethyl ether (90/10 to 50/50) gave pure 3ae1 as the product
which eluted first, then 3ae3 and finally 3ae2.
3ae1: yellow solid (39 mg, 15%). 1H NMR (CDCl3, 300 MHz) (, ppm) 8.51 (dd, 1H, C6H4, 3JHH
8.3, 4JHH = 1.1 Hz), 8.32 (dd, 1H, C6H4, 3JHH = 8.8, 4JHH = 1.2 Hz), 7.52 (ddd, 1H, C6H4, 3JHH = 8.8,
=
4
3
3
4
3JHH = 6.7, JHH = 1.1 Hz), 7.43 (ddd, 1H, C6H4, JHH = 8.3, JHH = 6.7, JHH = 1.2 Hz), 4.00 (s, 3H,
13
OCH3), 2.81 (s, 3H, CH3), 1.64 (s, 9H, C(CH3)3); C NMR (CDCl3, 75 MHz) (, ppm) 166.6 (C),
147.5 (C), 145.5 (C), 140.0 (C), 136.9 (C), 127.8 (CH), 126.3 (CH), 126.1 (CH), 125.9 (CH), 125.6
(C), 53.0 (CH3), 37.1 (C), 33.3 (CH3), 28.9 (CH3). HRMS (ESI-TOF) calc. for [C16H19NNaO2]+
requires 280.1308, found 280.1297. 3ae2: yellow solid (64 mg, 25%). 1H NMR (CDCl3, 300 MHz)
(, ppm) 8.56 (ddd, 1H, C6H4, 3JHH = 8.5, 4JHH = 1.3, 5JHH = 0.7 Hz), 8.01 (ddd, 1H, C6H4, 3JHH = 8.7,
4JHH = 1.2 Hz, 5JHH = 0.7 Hz), 7.62 (ddd, 1H, C6H4, 3JHH = 8.7, 3JHH = 6.8, 4JHH = 1.3 Hz), 7.51 (ddd,
1H, C6H4, 3JHH = 8.6, 3JHH=6.8, 4JHH = 1.2 Hz), 3.99 (s, 3H, O-CH3), 2.78 (s, 3H, CH3), 1.50 (s, 9H,
13
C(CH3)3); C NMR (CDCl3, 75 MHz) (, ppm) 167.3 (C), 157.6 (C), 144.5 (C), 137.9 (C), 129.6
(CH), 127.9 (C), 126.9 (CH), 126.2 (CH), 124.5 (C), 123.2 (CH), 52.6 (CH3), 38.8 (C), 30.8 (CH3),
16.6 (CH3). HRMS (ESI-TOF) calc. for [C16H19NNaO2]+ requires 280.1308, found 280.1285. 3ae3:
yellow oil (104 mg, 40%). 1H NMR (CDCl3, 300 MHz) (, ppm) 7.18 (m, 1H, C6H4), 7.07 (m, 3H,
13
C6H4), 3.52 (s, 3H, OCH3), 2.14 (s, 3H, CH3), 2.02 (sbroad, 2H, NH2), 1.28 (s, 9H, C(CH3)3); C
NMR (CDCl3, 75 MHz) (, ppm) 175.4 (C), 151.6 (C), 147.3 (C), 145.7 (C), 135.2 (C), 128.4 (CH),
125.7 (CH), 119.8 (CH), 118.5 (CH), 72.6 (C), 52.4 (CH3), 34.2 (C), 30.2 (CH3), 13.1 (CH3).
HRMS (ESI-TOF) calc. for [C16H22NO2]+ requires 260.1645, found 260.1645.
2.4.6. Methyl 3,4-diethyl-7-nitroisoquinoline-1-carboxylate (3ba): white solid (118 mg, 41%).
0
Purified by Kugelrohr distillation at 80 C for 90 minutes, and then column chromatography:
1
elution with hexane/diethyl ether (90/10 to 50/50). H NMR (CDCl3, 300 MHz) (, ppm) 9.61 (d,
1H, C6H3, 4JHH = 2.4 Hz), 8.38 (dd, 1H, C6H3, 3JHH = 9.4, 4JHH = 2.4 Hz), 8.11 (d, 1H, C6H3, 3JHH
=
3
3
9.4 Hz), 4.06 (s, 3H, CH3), 3.11 (q, 2H, CH2CH3, JHH = 7.6 Hz), 3.04 (q, 2H, CH2CH3, JHH = 7.6
3
3
13
Hz), 1.32 (t, 3H, CH2CH3, JHH = 7.5 Hz), 1.27 (t, 3H, CH2CH3, JHH = 7.6 Hz); C NMR (CDCl3,
75 MHz) (, ppm) 165.9 (C), 157.1 (C), 148.1 (C), 145.9 (C), 138.1 (C), 133.7 (C), 125.3 (CH),
124.0 (C), 124.0 (CH), 123.3 (CH), 53.4 (CH3), 28.6 (CH2), 21.4 (CH2), 15.0 (CH3), 14.4 (CH3).
HRMS (ESI-TOF) calc. for [C15H16N2NaO4]+ requires 311.1002, found 311.0998.
11

2.4.7. Methyl 6-chloro-3,4-diethylisoquinoline-1-carboxylate (3ca): yellow oil (164 mg, 60%).
1
Purified by column chromatography: elution with hexane/diethyl ether (90/10 to 50/50). H NMR
(CDCl3, 300 MHz) (, ppm) 8.54 (dd, 1H, C6H3, 3JHH = 9.2, 5JHH = 0.6 Hz), 7.88 (dd, 1H, C6H3, 4JHH
5
3
4
= 2.1, JHH = 0.6 Hz), 7.39 (dd, 1H, C6H3, JHH = 9.2, JHH = 2.1 Hz), 3.98 (s, 3H, OCH3), 2.96 (m,
3
3
13
4H, CH2), 1.26 (t, 3H, JHH = 7.6 Hz), 1.20 (t, 3H, JHH = 7.6 Hz); C NMR (CDCl3, 75 MHz) (,
ppm) 166.6 (C), 154.3 (C), 146.5 (C), 136.8 (C), 136.6 (C), 132.4 (C), 128.6 (CH), 127.8 (CH),
123.4 (C), 122.2 (CH), 53.0 (CH3), 28.5 (CH2), 21.2 (CH2), 14.9 (CH3), 14.6 (CH3). HRMS (ESI-
TOF) calc. for [C15H16ClNNaO2]+ requires 300.0764, found 300.0762.
2.4.8. Methyl 7-bromo-3,4-diethylisoquinoline-1-carboxylate (3da1) and methyl 5-bromo-3,4-
diethylisoquinoline-1-carboxylate (3da2): not separated. Obtained as a colorless oil (106 mg, 33%
mixture: 25 and 8%). Purified by column chromatography: elution with hexane/diethyl ether (90/10
to 50/50). HRMS (ESI-TOF) calc. for [C15H16BrNNaO2]+ requires 344.0257, found 344.0266. 3da1
4
5
(major isomer): 1H NMR (CDCl3, 300 MHz) (, ppm) 8.82 (dd, 1H, C6H3, JHH = 2.0, JHH = 0.5
5
Hz), 7.83 (dd, 1H, C6H3, 3JHH = 9.2, JHH = 0.5 Hz), 7.69 (dd, 1H, C6H3, 3JHH = 9.2, 4JHH = 2.0 Hz),
4.00 (s, 3H, OCH3), 3.0 (m, 4H, CH2), 1.26 (m, 6H, CH2CH3); 13C NMR (CDCl3, 75 MHz) (,
ppm) 166.4 (C), 153.6 (C), 145.3 (C), 134.4 (C), 133.6 (CH), 133.6 (C), 129.0 (CH), 126.3 (C),
125.0 (CH), 121.4 (C), 53.1 (CH3), 28.4 (CH2), 21.2 (CH2), 15.0 (CH3), 14.6 (CH3). 3da2 (minor
isomer): 1H NMR (CDCl3, 300 MHz) (, ppm) 8.34 (dd, 1H, C6H3, 3JHH = 8.5, 4JHH = 1.3 Hz), 7.98
(dd, 1H, C6H3, 3JHH = 7.5, 4JHH = 1.3 Hz), 7.25 (dd, 1H, C6H3, 3JHH = 8.5, 3JHH = 7.5 Hz), 4.00 (s, 3H,
3
OCH3), 3.51 (q, CH2, 2H, JHH = 7.4 Hz), 3.0 (m, 2H, CH2), 1.26 (m, 6H, CH2CH3); 13C NMR
(CDCl3, 75 MHz) 167.1 (C), 156.2 (C), 148.7 (C), 138.5 (CH), 134.4 (C), 133.0 (C), 126.9 (CH),
126.8 (C), 117.9 (C), 53.1 (CH3), 29.1 (CH2), 22.1 (CH2), 16.8 (CH3), 14.7 (CH3).
2.4.9. Methyl 3,4-diethyl-6-methoxyisoquinoline-1-carboxylate (3ea): yellow solid (197 mg, 72%).
1
Purified by column chromatography: elution with hexane/diethyl ether (90/10 to 50/50). H NMR
(CDCl3, 400 MHz) (, ppm) 8.56 (m, 1H, C6H3), 7.20 (m, 2H, C6H3), 4.06 (s, 3H, C(=O)OCH3),
3.95 (s, 3H, OCH3), 3.05 (m, 4H, CH2CH3), 1.35 (t, 3H, CH2CH3, 3JHH = 7.6 Hz), 1.30 (t, 3H,
13
CH2CH3, 3JHH = 7.6 Hz); C NMR (CDCl3, 100 MHz) (, ppm) 167.1 (C), 160.6 (C), 153.5 (C),
146.2 (C) 137.9 (C), 131.9 (C), 128.6 (CH), 121.0 (C), 119.5 (CH), 101.2 (CH), 55.3 (CH3), 52.8
(CH3), 28.6 (CH2), 21.3 (CH2), 14.8 (CH3), 14.4 (CH3). HRMS (ESI-TOF) calc. for
[C16H19NNaO3]+ requires 296.1257, found 296.1253.
2.4.10. Methyl 3,4-diethyl-6-methylisoquinoline-1-carboxylate (3fa): yellow oil (193 mg, 75%).
Purified by column chromatography: elution with hexane/diethyl ether (90/10 to 50/50).1H NMR
12

3
(CDCl3, 300 MHz) (, ppm) 8.44 (d, 1H, C6H3, JHH = 8.8 Hz), 7.69 (s, 1H, C6H3), 7.31 (dd, 1H,
C6H3, 3JHH = 8.8, 4JHH = 1.6 Hz), 3.98 (d, 3H, CH3, 4JHH = 1.2 Hz), 2.99 (m, 4H, CH2CH3), 2.47 (s,
13
3H, OCH3), 1.25 (m, 6H, CH2CH3); C NMR (CDCl3, 75 MHz) (, ppm) 167.1 (C), 153.1 (C),
146.5 (C), 140.3 (C), 136.1 (C), 132.6 (C), 129.1 (CH), 126.5 (CH), 123.6 (C), 122.0 (CH), 52.9
(CH3), 28.5 (CH2), 22.4 (CH3), 21.1 (CH2), 15.0 (CH3), 14.8 (CH3). HRMS (ESI-TOF) calc. for
C16H19NNaO2 requires 280.1308, found 280.1298.
2.5. General synthesis of methyl isoindoline-1-carboxylate derivatives 5 (5aa-5fa)
The corresponding phenylglycine methyl ester hydrochloride (1.5 mmol) was first dissolved in a
saturated solution of KHCO3 in water (10 mL) and stirred until bubbling ceased. Then, the solution
was extracted with CH2Cl2 (3  10 mL), the organic layer was separated and dried over MgSO4 and
then evaporated to dryness, in order to afford the pure phenylglycine methyl ester derivative.
The phenylglycine methyl ester derivative 1a-f (1 mmol) and alkene 4a (2 mmol) were added to a
suspension of [Ru(p-cymene)Cl2]2 (61.2 mg, 0.1 mmol), NaOAc (164.1 g, 2.0 mmol), K[PF6] (18.7
mg, 0.1 mmol) and N-fluoro-2,4,6-trimethylpyridium triflate (289.3 mg, 1 mmol) in
hexafluoroisopropanol (3 mL) into a Young’s flask. The solution was stirred and heated at 60 °C
for 24 h. After the reaction time was completed, the solvent was removed to dryness. After the
reaction time was completed, the solvent was removed to dryness. The resulting solid residue was
dissolved in CH2Cl2, filtered over neutral alumina and eluted with 100 mL of CH2Cl2, affording a
yellow solution. The yellow solution contained the corresponding product 5 contaminated with
other reaction side products. It was evaporated to dryness and the residue was further purified by
column chromatography on silica gel eluting with mixtures of hexane/diethylether, and/or by
Kugelrohr distillation, as specified on each particular case.
2.6. Characterization of products type 5
2.6.1. Methyl 3-(2-methoxy-2-oxoethyl)-2-(3-methoxy-3-oxopropyl)isoindoline-1-carboxylate (5aa):
orange oil (44 mg, 13%). 5aa was obtained as a mixture of diastereoisomers in 1:0.4 molar ratio. It
was purified by column chromatography: elution with hexane/diethyl ether (90/10 to 50/50). HRMS
(ESI-TOF) calc. for [C17H21NNaO6]+ requires 358.1261, found 358.1270. Major diastereoisomer:
1H NMR (CDCl3, 300 MHz) (, ppm) 7.15 (m, 4H, C6H4), 4.65 (s, 1H, CH), 4.57 (t, 1H, CH, 3JHH
6.2 Hz), 3.67 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 3.24 (m, 1H, N-CH2CH2),
=
2
3
3.11 (m, 1H, N-CH2CH2), 2.85 (dd, 1H, CH-CH2, JHH = 15.9, JHH = 5.8 Hz), 2.65 (dd, 1H, CH-
2
3
13
CH2, JHH = 15.9, JHH = 5.8 Hz), 2.46 (m, 2H, N-CH2CH2); C NMR (CDCl3, 75 MHz) (, ppm)
173.0 (C), 172.6 (C), 172.4 (C), 142.1 (C), 136.9 (C), 128.4 (CH), 127.7 (CH), 122.7 (CH), 122.5
(CH), 71.3 (CH), 65.9 (CH), 52.3 (CH3), 51.6 (CH3), 51.6 (CH3), 49.5 (CH2), 41.9 (CH2), 33.45
13

(CH2). Minor diastereoisomer: 1H NMR (CDCl3, 300 MHz) (, ppm) 7.15 (m, 4H, C6H4), 4.92 (d,
1H, CH, 4JHH = 2.6 Hz,), 4.79 (m, 1H, CH), 3.64 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.60 (s, 3H,
2
OCH3), 3.24 (m, 1H, N-CH2CH2), 3.11 (m, 1H, N-CH2CH2), 2.85 (dd, 1H, CH-CH2, JHH = 15.9,
2
3
13
3JHH = 5.8 Hz), 2.65 (dd, 1H, CH-CH2, JHH = 15.9, JHH = 5.8 Hz), 2.46 (m, 2H, N-CH2CH2); C
NMR (CDCl3, 75 MHz) (, ppm) 172.2 (C), 127.5 (CH), 122.7 (CH), 122.4 (CH), 67.9 (CH), 63.7
(CH), 51.9 (CH3), 51.7 (CH3), 51.7 (CH3), 43.1 (CH2), 39.1 (CH2), 34.12 (CH2). Some C were not
observed for the minor isomer due to partial overlap with signals of the major isomer.
2.6.2.
Methyl
3-(2-methoxy-2-oxoethyl)-2-(3-methoxy-3-oxopropyl)-6-nitroisoindoline-1-
carboxylate (5ba): yellow oil (103 mg, 27%). 5ba was obtained as a mixture of diastereoisomers in
1:0.3 molar ratio. The major diastereoisomer could be separated and purified by column
1
chromatography: elution with hexane/diethyl ether (90/10 to 50/50). Major diastereoisomer: H
NMR (CDCl3, 300 MHz) (, ppm) 8.21 (m, 2H, C6H3), 7.41 (m, 1H, C6H3), 4.90 (s, 1H, CH), 4.79
3
(t, 1H, CH, JHH = 6.2 Hz), 3.83 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.43 (dt,
2
3
2
3
1H, NCH2CH2, JHH = 14.4, JHH = 7.4 Hz), 3.28 (dt, 1H, NCH2CH2, JHH = 13.4, JHH = 6.5 Hz),
3.05 (dd, 1H, CHCH2, 2JHH = 16.3, 3JHH = 5.0 Hz), 2.80 (dd, 1H, CHCH2, 2JHH = 16.3, 3JHH = 7.1 Hz),
2.62 (t, 2H, NCH2CH2, 3JHH = 6.9 Hz); 13C NMR (CDCl3, 75 MHz) 172.3 (C), 171.7 (C), 171.3 (C),
148.8 (CH), 148.2 (CH), 138.4 (CH), 124.2 (CH), 123.6 (CH), 118.6 (CH), 70.4 (CH), 65.7 (CH),
52.8 (CH3), 51.9 (CH3), 51.8 (CH3), 49.2 (CH2), 40.7 (CH2), 33.1 (CH2). HRMS (ESI-TOF) calc.
for [C17H20N2NaO8]+ requires 403.1112, found 403.1118.
2.6.3.
Methyl
5-chloro-3-(2-methoxy-2-oxoethyl)-2-(3-methoxy-3-oxopropyl)isoindoline-1-
carboxylate (5ca): yellow oil (137 mg, 37%). 5ca was obtained as a mixture of diastereoisomers in
1:0.2 molar ratio. They were separated and purified by column chromatography: elution with
1
hexane/diethyl ether (90/10 to 50/50). The minor isomer eluted first. Major diastereoisomer: H
NMR (CDCl3, 300 MHz) (, ppm) 7.16 (m, 2H, C6H3), 7.11 (m, 1H, C6H3), 4.60 (d, 1H, CH, 4JHH
1.3 Hz), 4.53 (dd, 1H, CH, 3JHH = 6.7, 3JHH = 5.8 Hz), 3.67 (s, 6H, OCH3), 3.60 (s, 3H, OCH3), 3.25
=
2
3
(m, 2H, NCH2CH2), 3.08 (dt, 2H, NCH2CH2, JHH = 13.4, JHH = 6.6 Hz), 2.84 (dd, 1H, CHCH2,
3
2
3
2JHH = 16.1, JHH = 5.5 Hz), 2.63 (dd, 1 H, CHCH2, JHH = 16.1, JHH = 6.9 Hz), 2.45 (t, 2H,
3
13
NCH2CH2, JHH = 7.1 Hz); C NMR (CDCl3, 75 MHz) (, ppm) 172.5 (C), 172.5 (C), 172.1 (C),
144.1 (C), 135.4 (C), 134.3 (C), 128.0 (CH), 124.0 (CH), 123.0 (CH), 70.7 (CH), 65.5 (CH), 52.4
(CH3), 51.7 (CH3), 51.6 (CH3), 49.4 (CH2), 41.6 (CH2), 33.4 (CH2). HRMS (ESI-TOF) calc. for
[C17H20ClNNaO6]+ requires 392.0871, found 392.0872. Minor diastereoisomer: 1H NMR (CDCl3,
300 MHz) (, ppm) 7.15 (m, 2H, C6H3), 7.13 (m, 1H, C6H3), 4.91 (d, 1H, CH, 4JHH = 2.5 Hz), 4.78
(dt, 1H, CH, 3JHH = 6.3, 4JHH = 2.8 Hz), 3.66 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.61 (s, 3H, OCH3),
3.18 (m, 2H, NCH2CH2), 2.84 (dd, 1H, CHCH2, 2JHH = 16.1, 3JHH = 3.9 Hz), 2.53 (m, 3H, CH2); 13C
14

NMR (CDCl3, 75 MHz) (, ppm) 172.3 (C), 171.9 (C), 171.8 (C), 144.6 (C), 135.5 (C), 134.3 (C),
127.9 (CH), 123.6 (CH), 123.2 (CH), 67.2 (CH), 63.6 (CH), 52.0 (CH3), 51.8 (CH3), 51.7 (CH3),
43.0 (CH2), 38.6 (CH2), 33.8 (CH2). HRMS (ESI-TOF) calc. for [C17H20ClNNaO6]+ requires
392.0871, found 392.0859.
2.6.4.
Methyl
4-bromo-3-(2-methoxy-2-oxoethyl)-2-(3-methoxy-3-oxopropyl)isoindoline-1-
and methyl 6-bromo-3-(2-methoxy-2-oxoethyl)-2-(3-methoxy-3-
carboxylate
(5da1)
oxopropyl)isoindoline-1-carboxylate (5da2): yellow oil (156 mg, 38%). 5da was obtained as the
mixture of the two possible regioisomers (5da1:5da2 = 0.4:1 molar ratio), which were not
separated. The mixture was purified by column chromatography: elution with hexane/diethyl ether
(90/10 to 50/50). HRMS (ESI-TOF) calc. for [C17H20BrNNaO6]+ requires 436.0366, found
436.0347. 5da1 (minor isomer): 1H NMR (CDCl3, 300 MHz) (, ppm) 7.37 (m, 1H, C6H3), 7.23 (m,
1H, C6H3), 7.08 (m, 1H, C6H3), 4.69 (s, 1H, CH), 4.66 (s, 1H, CH), 3.67 (s, 3H, OCH3), 3.67 (s, 3H,
OCH3), 3.58 (s, 3H, OCH3), 3.25 (m, 1H, NCH2CH2), 3.11 (m, 1H, NCH2CH2), 3.04 (m, 1H,
2
3
13
CHCH2), 2.76 (dd, 1H, CHCH2, JHH = 16.0, JHH = 8.9 Hz), 2.45 (m, 2H, NCH2CH2); C NMR
(CDCl3, 75 MHz) (, ppm) 172.6 (C), 172.6 (C), 172.3 (C), 141.8 (C), 139.7 (C), 132.1 (CH), 129.6
(CH), 122.4 (CH), 117.5 (C), 72.2 (CH), 68.1 (CH), 52.4 (CH3), 51.7 (CH3), 51.6 (CH3), 51.4 (CH2),
1
40.4 (CH2), 33.9 (CH2). 5da2 (major isomer): H NMR (CDCl3, 300 MHz) (, ppm) 7.38 (m, 1H,
C6H3), 7.34 (m, 1H, C6H3), 7.00 (d, 1H, C6H3, 3JHH = 8.1 Hz), 4.64 (t, 1H, CH, 4JHH = 1.2 Hz), 4.51
(m, 1H, CH), 3.69 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 3.25 (dt, 1H, NCH2CH2,
3
2JHH = 13.6, JHH = 7.5 Hz), 3.10 (m, 1H, NCH2CH2), 2.85 (dd, 1H, CHCH2, 2JHH = 16.0, 3JHH = 5.5
Hz), 2.62 (dd, 1H, CHCH2, 2JHH = 16.0, 3JHH = 7.0 Hz), 2.45 (m, 2H, NCH2CH2); 13C NMR (CDCl3,
75 MHz) (, ppm) 172.5 (C), 172.3 (C), 172.1 (C), 141.1 (C), 139.1 (C), 131.5 (CH), 126.0 (CH),
124.2 (CH), 121.5 (C), 70.7 (CH), 65.5 (CH), 52.5 (CH3), 51.7 (CH3), 51.7 (CH3), 49.3 (CH2), 41.5
(CH2), 33.4 (CH2).
2.6.5.
Methyl
5-methoxy-3-(2-methoxy-2-oxoethyl)-2-(3-methoxy-3-oxopropyl)isoindoline-1-
carboxylate (5ea): yellow oil (161 mg, 44 %). 5ea was obtained as a mixture of diastereoisomers in
1:0.2 molar ratio. The major diastereoisomer could be separated and purified by column
1
chromatography: elution with hexane/diethyl ether (90/10 to 50/50). Major diastereoisomer: H
NMR (CDCl3, 300 MHz) (, ppm) 7.12 (d, 1H, C6H3, 3JHH = 8.4 Hz), 6.73 (dd, 1H, C6H3, 3JHH = 8.6,
4JHH = 2.4 Hz), 6.64 (d, 1H, C6H3, 4JHH = 2.3 Hz), 4.57 (s, 1H, CH), 4.52 (t, 1H, CH, 3JHH = 6.3 Hz),
3.71 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 3.25 (dt, 1H,
2
3
2
3
NCH2CH2, JHH = 13.5, JHH = 7.6 Hz), 3.07 (dt, 1H, NCH2CH2, JHH = 13.4, JHH = 6.7 Hz), 2.84
2
3
2
3
(dd, 1H, CH-CH2, JHH = 15.9, JHH = 5.8 Hz), 2.64 (dd, 1H, CHCH2, JHH = 15.9, JHH = 6.8 Hz),
15

2.44 (t, 2H, NCH2CH2, 3JHH = 7.2 Hz); 13C NMR (CDCl3, 75 MHz) (, ppm) 173.3 (C), 172.6 (C),
172.5 (C), 160.17 (C), 143.7 (C), 129.0 (C), 123.5 (CH), 113.9 (CH), 107.7 (CH), 70.7 (CH), 65.9
(CH), 55.5 (CH3), 52.2 (CH3), 51.7 (CH3), 51.6 (CH3), 49.6 (CH2), 41.9 (CH2), 33.4 (CH2). HRMS
(ESI-TOF) calc. for [C18H23NNaO7]+ requires 388.1367, found 388.1371
2.6.6.
Methyl
3-(2-methoxy-2-oxoethyl)-2-(3-methoxy-3-oxopropyl)-5-methylisoindoline-1-
carboxylate (5fa): yellow oil (231 mg, 66%). 5fa was obtained as a mixture of diastereoisomers in
1:0.1 molar ratio. The major diastereoisomer could be separated and purified by column
1
chromatography: elution with hexane/diethyl ether (90/10 to 50/50). Major diastereoisomer: H
NMR (CDCl3, 300 MHz) (, ppm) 7.10 (d, 1H, C6H3, 3JHH = 7.8 Hz), 6.99 (dd, 1H, C6H3, 3JHH = 7.8,
3
4JHH= 0.6 Hz), 6.90 (s, 1H, C6H3), 4.59 (s, 1H, CH), 4.52 (t, 1H, CH, JHH = 6.2 Hz), 3.67 (s, 3H,
OCH3), 3.65 (s, 3H, OCH3), 3.59 (s, 3H, OCH3), 3.25 (dt, 1H, NCH2CH2, 2JHH = 13.5, 3JHH=7.6 Hz),
2
3
2
3
3.07 (dt, 1H, NCH2CH2, JHH = 13.4, JHH=6.7 Hz), 2.83 (dd, CHCH2, JHH = 15.9, JHH=5.8 Hz),
3
2.64 (dd, CHCH2,2JHH = 15.9,3JHH= 6.6 Hz), 2.44 (t, 2H, NCH2CH2, JHH = 7.2 Hz), 2.26 (s, 3H,
13
CH3); C NMR (CDCl3, 75 MHz) (, ppm) 173.1 (C), 172.6 (C), 172.5 (C), 142.3 (C), 138.3 (C),
134.1 (C), 128.6 (CH), 123.0 (CH), 122.4 (CH), 70.9 (CH), 65.8 (CH), 52.2 (CH3), 51.6 (CH3),
51.6 (CH3), 49.6 (CH2), 41.9 (CH2), 33.4 (CH2), 21.4 (CH3). HRMS (ESI-TOF) calc. for
C18H23NNaO6 requires 372.1418, found 372.1422.
1
2.7. Methyl 3-((2-methoxy-2-oxo-1-phenylethyl)amino)propanoate (6): H NMR (CDCl3, 300 MHz)
(, ppm) 7.24 (m, 5H, C6H5), 4.31 (s, 1H, CH), 3.60 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 2.75 (m,
2H, NCH2CH2), 2.45 (t, 2H, CH2, NCH2CH2, 3JHH = 6.5 Hz); 13C NMR (CDCl3, 75 MHz) (, ppm)
172.9 (C), 172.8 (C), 137.5 (C), 128.8 (CH), 128.3 (CH), 127.5 (CH), 65.4 (CH), 52.3 (CH3), 51.7
(CH3), 42.7 (CH2), 34.4 (CH2); HRMS (ESI-TOF) calc. for [C13H18NO4]+ requires 252.1230, found
252.1221.
2.8. X-Ray crystallography. Crystal structure determination of 3ab.OM
Crystals of compound 3ab.OM of adequate quality for X-ray measurements were grown from
diffusion of a CH2Cl2 solution of the crude compound in n-hexane at 8 ºC. A single crystal was
mounted at the end of a quartz fiber in a random orientation, covered with perfluorinated oil and
placed under a cold stream of N2 gas. The X-ray data collection was performed on an Oxford
Diffraction Xcalibur2 diffractometer using graphite-monocromated Mo-K radiation (
0.71073
Å). A hemisphere of data was collected based on -scan or -scan runs. The diffraction frames
were integrated using the program CrysAlis RED [13] and the integrated intensities were corrected
for absorption with SADABS [14]. The structures were solved and developed by Patterson and
16

Fourier methods [15]. All non-hydrogen atoms were refined with anisotropic displacement
parameters. The hydrogen atoms were placed at idealized positions and treated as riding atoms.
Each H atom was assigned an isotropic displacement parameter equal to 1.2 times the equivalent
2
isotropic displacement parameter of its parent atom. The structures were refined to Fo and all
reflections were used in the least-squares calculations [16]. Crystallographic data (including
structure factors) for the structure of 3ab.OM had been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC 1474382. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
17

3. Results and Discussion
3.1. Ru-catalyzed synthesis of isoquinoline-1-carboxylates.
The coupling between methyl phenylglycinate (1a) and 3-hexyne (2a), catalyzed by the Ru(II)
dimer [Ru(-Cl)Cl(6-p-cymene)]2, [Ru], to give methyl 3,4-diethylisoquinoline-1-carboxylate
(3aa) was used as model reaction for the optimization process. The starting point was the conditions
previously reported by us for the Ru-catalyzed synthesis of isoquinolines from primary amines:
molar ratio 1a/2a = 1/2, [Ru] (10%), KPF6 (10%), Cu(OAc)2 (1 equiv.), MeOH, 100 ºC, 24 h [8].
Under these conditions the isoquinoline is not formed (Table 1, entry 1). Instead, a very complex
mixture of decomposition products is obtained. The same result is observed when tert-amyl alcohol
(tAmOH) is used as solvent (entry 2). The reaction is cleaner in HFIP (hexafluoroisopropanol),
affording a low 10% yield of isolated 3aa (entry 3). This solvent has provided very good results in
the coupling of alkynes with other substrates, as we have recently shown [17]. Other solvents were
unable to provide higher yields.
Table 1. Optimization of the reaction conditions for the catalytic synthesis of 3aa.(a)
Entry
1
Solvent
MeOH
tAmOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
Oxidant
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
[F+]
Temperature
time
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
Additives
KPF6
Yield (%)
100
100
100
100
80
-
-
2
KPF6
3
KPF6
10
10
32
36
27
-
4
KPF6/NaOAc
KPF6/NaOAc
KPF6
5
[F+]
6
2 Ag(OAc)
2 AgPF6
Ag2CO3
PhI(OAc)2
Oxone
80
7
80
NaOAc
8
80
KPF6/NaOAc
KPF6/NaOAc
KPF6/NaOAc
KPF6
9
80
-
10
11
12
13
14
15
80
6
2 Ag(OAc)
2 Ag(OAc)
[F+]
100
120
60
48
10
73
28.5
-
KPF6
KPF6/NaOAc
KPF6/NaOAc
KPF6/NaOAc
[F+]
[F+]
40
20
(a) phenylglycine methyl ester derivative 1a (1 mmol), alkyne 2a (2 mmol), [Ru] (10% mol) in all
cases; HFIP = hexafluoroisopropanol; [F+] = 2,4,6-trimethylpyridinium triflate
Next we focused our attention in the correct choice of the oxidant. Our previous experience with
amino acids showed that the N-fluoro-2,4,6-trimethylpyridinium triflate salt ([F+]) is very efficient
in oxidative couplings with this type of substrates [4i]. This oxidant, however, requires a source of
18

acetates in order to accomplish the C-H bond activation step [7b,18]. Using [F+] in combination
with NaOAc, a similar low 10% yield is obtained (entry 4). Interestingly, a slight decrease in the
reaction temperature to 80 ºC promotes a significant increase of the yield, up to 32% (entry 5),
showing that decomposition pathways are probably competing with the annulation process. Other
oxidants were tested. Silver salts AgOAc and AgPF6 in combination with NaOAc (entries 6 and 7)
give 3aa in isolated yields comparable to those obtained with the fluoropyridinium salt. However,
Ag2CO3 (entry 8) and other classical oxidants such as PhI(OAc)2 (entry 9) or oxone (entry 10) were
ineffective.
Therefore, both AgOAc and [F+] (in combination with NaOAc), show the same efficiency but still
need additional improvement. The isolated yield of 3aa increases up to 48% (entry 11) when
o
AgOAc is used as oxidant by increasing the temperature to 100 C. Further increasing, however,
does not have a positive effect (entry 12). In clear contrast, the effect of temperature in the reaction
with [F+] is the opposite. Expectedly, by decreasing the temperature to 60 ºC the yield increases (up
to 73%, entry 13), probably because the competing decomposition pathways are minimized. Longer
reaction times (48 h) afford virtually the same yield. However, a further decrease of the reaction
temperature gave poorer conversions and, consequently, lower isolated yields (entries 14 and 15).
At 40 ºC the isolated yield is only around 28%, while at room temperature the reaction does not
take place and starting 1a is recovered.
Once the optimal reaction conditions for the oxidative coupling of methyl phenylglycinate (1a) and
3-hexyne (2a) to give the isoquinoline-1-carboxylate (3aa) have been determined, the scope of the
reaction has been examined. As for the alkynes, the reaction works with electron-rich alkynes and
aromatic alkynes. The results are summarized in Figure 2. Diphenylacetylene (2b) reacts with 1a to
give 3,4,-diphenylisoquinolinone-1-carboxylate (3ab) in a modest 40% yield, and a similar yield of
3(4)-methyl-4(3)-propylisoquinoline-1-carboxylate (3ac) was obtained from the coupling of 2-
hexyne (2c) with 1a (42%). Gratifyingly, better yields were obtained for coupling involving 1-
phenylpropyne (2d), giving the corresponding isoquinoline 3ad in 64% yield. In the same way, 1a
reacted with 4,4-dimethyl-2-pentyne (2e), giving three different coupling products 3ae in a global
80% yied. Only the monoinsertion of alkynes in type 3 products has been observed in all studied
cases. This selectivity is worthy of note because in analogous reactions with benzylamines a double
alkyne insertion took place, affording 8-vinyl-isoquinolines [8]. Regarding asymmetric alkynes, the
regioselectivity of the insertion depends on the alkyne. Approximately equimolar amounts of the
two regioisomers are obtained when 2-hexyne is employed (3ac). On the other hand, a remarkable
selectivity was observed in the case of 1-phenylpropyne (3ad), the most abundant isomer being that
with the phenyl ring close to the N atom, probably due to steric factors and in keeping with previous
observations in closely related systems [8a].
19

The reaction of 1a with 4,4-dimethyl-2-pentyne (2e) deserves some additional comments. The
crude reaction mixture contains three different species (Figure 2), which are easily separated by
column chromatography. Two of them are the expected regioisomers of methyl (tert-butyl)-
methylisoquinoline-1-carboxylate (3ae1 and 3ae2), obtained in 15% and 25% yield, respectively,
while NMR characterization of the third compound revealed that it is methyl 1-amino-2-(tert-
butyl)-3-methyl-1H-indene-1-carboxylate (3ae3), obtained in 40% isolated yield. Therefore the
combined yield of this reaction is about 80%.
Figure 2. Scope of the oxidative coupling to give isoquinoline-1-carboxylates 3
20

The regiochemistry of 3ae1 and 3ae2 has been determined by selective 1D-NOESY measurements
t
(see Supporting Information) and shows that the most abundant isomer is that with the Bu group
adjacent to the nitrogen atom. This is consistent with previous results obtained in our group, since
this orientation is the same than that observed in related Ru-catalyzed synthesis of N-heterocycles
[8], and in reported stoichiometric Pd insertions [19a]. However, the regiochemistry here observed
is the opposite to that determined in Ru-mediated stoichiometric synthesis of isoquinolinium salts
[19b]. The subtle differences in the Ru-complexes [(6-benzene)Ru vs (6-cymene)Ru], as well as
in the substrates (N,N-dimethylbenzylamines vs phenylglycine), could account for the different
reactivity, as it has been shown that the regioselectivity in the insertion of this alkyne is largely
dependent on steric factors.
The formation of different compounds 3ae1-3ae3 involves two different reaction mechanisms
which share the initial steps of the catalytic cycle: the Ru-promoted and acetate-assisted ortho-CH
bond activation of the methyl phenylglycinate [18] and the migratory insertion of the internal
alkyne into the Ru-C bond (Figure 3). This results in the formation of a cycloruthenated
intermediate. From this species the reductive elimination can take place according to our previous
mechanistic determinations [8]. The C-N coupling involves the decoordination of the N atom and
subsequent nucleophilic attack to the metallated vinylic carbon, giving a dihydroisoquinolonium
salt and a Ru(0) fragment which is then oxidized to Ru(II) by the pyridinium salt. Next, the
dihydroisoquinolonium salt further evolves by deprotonation to give a dehydroisoquinoline, which
aromatizes by dehydrogenation affording the isoquinolines 3ae1 and 3ae2. On the other hand, the
formation of 3ae3 strongly suggests an alternative reaction pathway, also depicted in Figure 3. This
alternative mechanism involves the deprotonation of the C of the orthoruthenated phenylglycine
and further attack of the carbanion to a vinylic carbon giving the indene unit. The formation of the
carbanion is explained by the presence of an excess of base (acetate) and by the acidic nature of the
H on the alpha carbon. After the C-C coupling the corresponding Ru(0) species is similarly
oxidized to Ru(II) by the pyridinium salt. Although the formation of the indene derivative is
observed in the largest extent in this case (3ae3), the presence of analogous indene side-products in
other cases cannot be totally discarded.
21

Figure 3. Proposed mechanistic pathways to explain the formation of isoquinoline and indene
derivatives
As for the scope of phenylglycines, the reaction works for substrates which contain both electron-
attracting and electron-releasing substituents. Good yields are obtained when methoxy and methyl
substituents are present in para position of the starting materials (3ea 72% and 3fa 75%
respectively). Slightly lower isolated yields are obtained when the chloride group is in para position
(3ca, 60%). In this case the likely product of dechlorination (3aa) was not observed, showing that
the reaction has a notable tolerance for different functional groups. Moreover, the presence of the
chlorine atom allows further orthogonal reactivity, for instance through Heck or Suzuki processes.
On the other hand, only moderate yields were achieved when bromide or the strong electron-
attracting nitro group are in meta positions (3da 33% and 3ba 41%). Interestingly, the reaction of
the nitro derivative is regioselective, and only the less hindered product 3ba with the nitro group at
7-position is obtained, while in the case of the phenylglycinate containing a bromine atom, the two
possible regioisomers (incorporating bromine in 5- and in 7-positions), were obtained. As expected,
the less hindered 7-Br isomer was formed in higher amount (3.1/1 molar ratio).
3.2. Ru-catalyzed synthesis of isoindoline-1-carboxylates (5aa-5fa).
Prompted by the remarkable results obtained in the synthesis of isoquinoline-1-carboxylates 3 by
oxidative coupling, we have attempted the analogous insertion reactions using alkenes. The most
important results obtained in this reaction are presented in Figure 4.
22

Figure 4. Scope of the oxidative coupling to give isoindoline-1-carboxylates 5
Using the same reaction conditions than those described for the synthesis of isoquinolines 3,
phenylglycines 1a-1f react with methyl acrylate 4a (1:2 molar ratio) to give the corresponding
isoquinoline-1-carboxylates 5aa-5fa in yields up to 66% (Figure 4). Since some of the yields are
quite low, a further optimization of the reaction parameters was attempted, but the effort proved
ineffective. Nevertheless, in all the studies cases the reaction takes place with full conversion of the
starting amino ester 1, and NMR yields calculated from the reaction crude are higher than the
isolated yields reported in Figure 4. The difficulties which arose during the purification step (by
column chromatography) and the formation of side-products (as detailed below) account for this
disagreement.
The scope of the studied phenylglycines is depicted in Figure 4. Substituents of electron-
withdrawing and electron-donating nature are tolerated, although better yields are obtained for
methyl (5fa) and methoxy (5ea) groups (66% and 44% yield, respectively) than for chloride (5ca),
bromide (5da) or nitro (5ba) moieties (37%, 38% and 27%). Regarding the alkenes, the scope is
limited to acrylates. Alkenes bearing other strong electron-attracting functional groups
(phosphonate, sulfonate, sulfone) or relatively more electron-rich alkenes (for instance, styrene) did
not show significant reactivity.
23

In all the cases the reaction takes place with the incorporation of two equivalents of alkene 4a. One
of the alkenes is consumed by reaction with the amino group through a classical hydroamination or
aza-Michael addition process. This step occurs without the metal mediation, as has been confirmed
by the direct treatment of 1a with 4a, affording the expected N-protected phenylglycine 6 (Figure 5).
Surprisingly, the reaction of 6 with acrylate 4a under the optimized catalytic conditions does not
afford the isoquinoline-1-carboxylate product 5aa. This fact suggests that N-protected
phenylglycine 6 is not an intermediate in the synthesis of 5aa, and that hydroamination takes place
in a late stage of the reaction.
Figure 5. Some control experiments in the synthesis of isoquinoline-1-carboxylates 5
According to these observations, we propose that the first equivalent of alkene reacts with
phenylglycine 1a to give the corresponding Heck intermediate A, shown in Figure 6. This reaction
takes place presumably through the cycloruthenation of 1a by C-H activation, followed by
migratory insertion of the alkene and -elimination from the corresponding alkyl derivative to yield
A. After that, A may undergo two different pathways, none of which can be ruled out with the
present data: either the intramolecular aza-Michael addition affording isoindoline B, followed by
intermolecular amination to afford 5aa or, alternatively, the intermolecular aza-Michael coupling to
form intermediate C which finally yields 5aa by an intramolecular hydroamination process.
24

Figure 6. Proposed pathways for the oxidative synthesis of isoindoline-1-carboxylates 5
Isoindolines 5 have two stereogenic centers and are obtained as mixtures of diastereoisomers, as it
is clear from their 1H NMR spectra. The values of diastereomeric excess are in the range of 50-80%,
proving that the reaction occurs with a notable degree of diastereoselectivity. In order to get more
information about the relative configurations of the new stereogenic centers, selective NOE
experiments have been carried out in the major diastereoisomer of 5ca (see Supporting Information).
The perturbation of the signal at 4.60 ppm (C1-H) produces NOE enhancements in the ester groups
at 3.60 and 3.67 ppm, meaning that the substituents in C1 (CO2Me) and in C3 (CH2CO2Me) are in
mutual trans positions. Therefore, the relative configurations in the major diastereoisomer are
(1S,3R/1R,3S). This result is agrees with previous observations in very closely related systems, and
probably accounts for a minimization of the steric interactions between the different substituents
[4i].
3.3. Characterization of the crude reaction products
The two preceding sections show that Ru(II) complexes are efficient catalysts for the site-selective
transformation of N-unprotected amino acids, such as phenylglycine, through C-H bond activation
reactions. The successful synthesis of isoquinoline-1-carboxylates 3 and isoindoline-1-carboxylates
5 provides the proof-of-concept that opens the door for future and diverse modifications using Ru-
catalysts. However, the yields obtained in some cases are low, even under optimized reaction
conditions, indicating the existence of additional processes competing against the target reaction.
The analysis of crude mixtures, prior to purification, provides important clues on the nature of these
side-reactions. Our analysis show, in many cases, the presence of variable amounts of
25

organometallic species of Ru(II) coordinated to the 6-cymene ligand, in addition to the expected
organic derivatives.
We were able to isolate one of these organometallic derivatives from the reaction of phenylglycine
1a with diphenylacetylene 2b. After isoquinoline 3ab has been separated and purified by column
chromatography, further elution with a mixture CH2Cl2/MeOH (see Experimental) allows to isolate
a brown fraction. Deep red crystals of 3ab.OM were obtained from crystallization of the brown
fraction in CH2Cl2/hexane, and were of enough quality for the determination of the crystal structure
by X-ray diffraction methods. The drawing of the organometallic complex 3ab.OM is shown in
Figure 8, with selected bond distances and angles.
Figure 8. Drawing of organometallic compound 3ab.OM. Selected bond distances [Å] and angles
[º]: C2-Ru1 2.239(3), C3-Ru1 2.202(3), C4-Ru1 2.230(3), C5-Ru1 2.302(3), C6-Ru1 2.209(3),
C7-Ru1 2.159(3), C40-Ru1 2.085(3), N1-Ru1 2.084(2), O1-Ru1 2.067(2), O1-Ru1-N1 76.68(7),
O1-Ru1-C40 90.15(9), N1-Ru1-C40 78.20(9).
The structure shows that the Ru(II) center is located in a three-legged piano-stool environment
(basically a distorted octahedral environment) in which one Ru-C bond, one Ru-N bond and one
Ru-O bond make up the three legs and the 6-cymene ligand the seat of the stool. The cymene
ligand shows the expected 6-bonding mode and the internal bond distances and angles are similar
to those found in closely related examples [8b,20]. However, the C,N,O-tridentate ligand that
occupies the other three coordination sites is remarkable. It is likely that this ligand has been formed
in several consecutive steps. The first one may consist in the cycloruthenation of phenylglycine 1a
26

by ortho-C-H bond activation, migratory insertion of diphenylacetylene and reductive elimination
of 3,4-diphenyl-isoquinoline-1-carboxylate fragment (3ab). This isoquinoline is then able to
undergo a second C-H activation at the ortho position of the 3-phenyl ring and a subsequent
migratory insertion of a second equivalent of diphenylacetylene, forming a vinyl seven-membered
ring. Demethylation of the ester function by saponification can take place at any stage of this
sequence; the reactions are performed in the presence of base (NaOAc) in a protic and acidic
solvent (HFIP), and the presence of water in the solvent cannot be excluded.
Although we have not isolated any final products arising from a double alkyne insertion, complex
3ab.OM proves that they are actually formed. This fact could explain the low yields observed in
some of the examples, because reagents (alkyne) are being consumed by forming these side-
products, the target product (3ab) is being removed from the reaction medium and Ru is being
sequestered in the form of stable complexes, thus decreasing the effective concentration of the
catalyst. Further work with the aim of decreasing the extent of this type of side-reactions is
currently being developed in our laboratory.
4. Conclusions
The C-H functionalization of N-unprotected amino acids, such as methyl phenylglycinate, is
achievable using ruthenium complexes as catalysts. Two different processes have been optimized.
The Ru-catalyzed oxidative coupling of methyl arylglycinates 1 with internal alkynes 2 affords the
corresponding substituted isoquinoline-1-carboxylates 3, for a wide scope of alkynes and aryl-
substituted methyl arylglycinates. The selective incorporation of only one unit of alkyne takes place
even though, in the case of asymmetric alkynes, the regioselectivity of the insertion is modest. On
the other hand the Ru-catalyzed oxidative coupling of methyl arylglycinates 1 with electron-poor
alkenes 4 gives rise to the substituted isoindoline-1-carboxylates 5, for different aryl-substituted
methyl arylglycinates.
Acknowledgments
Funding by the Ministerio de Economia y Competitividad (MINECO) (Spain, Project CTQ2013-
40855-R) and Gobierno de Aragón-Fondo Social Europeo (Spain, groups E40 and E97) is
gratefully acknowledged. S. R. thanks Gobierno de Aragón for a PhD grant. Authors would also
like to acknowledge the use of Servicio General de Apoyo a la Investigación-SAI, Universidad de
Zaragoza.
27

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