Preparation of Substituted Tetrahydroisoquinolines by Pd(II)-Catalyzed NH2-Directed Insertion of Michael Acceptors into C-H Bonds Followed by NH2-Conjugated Addition

Article abstract of DOI:10.1021/acs.organomet.6b00944

3,3-Disubstituted tetrahydroisoquinolines are prepared in one step from Michael acceptors and 2-phenylethylamines under Pd catalysis and Ag₂CO₃ as an oxidant. Presumably, activation of an ortho C-H bond of the aromatic ring with Pd(II) is directed by the primary amine to form a palladacycle. Insertion of the olefin, subsequent conjugated addition of the amine, and reductive elimination of Pd(0) affords the expected products. Silver carbonate is not necessary when 2-phenylethylamines are converted previously to N-benzoyloxy-2-phenylethylamines.

Full text of DOI:10.1021/acs.organomet.6b00944

Article
pubs.acs.org/Organometallics
Preparation of Substituted Tetrahydroisoquinolines by Pd(II)-
Catalyzed NH2‑Directed Insertion of Michael Acceptors into C−H
Bonds Followed by NH2‑Conjugated Addition
Andrea Mancinelli,† Carla Alamillo,† Joan Albert,‡ Xavier Ariza,*,†,§ Haizea Etxabe,† Jaume Farras,†
̀
Jordi Garcia,*,†,§ Jaume Granell,‡ and F. Javier Quijada†
†Departament de Química Inorgan
Universitat de Barcelona, Martí i Franques
‡Departament de Química Inorgan
ica i Organ
i Franques 1-11, 08028 Barcelona, Spain
§CIBER Fisiopatología de la Obesidad y la Nutricion
̀
ica i Organ
1-11, 08028 Barcelona, Spain
ica, Seccio de Química Inorgan
̀
ica, Seccio
́
de Química Organ
̀
ica i Institut de Biomedicina (IBUB), Facultat de Química,
̀
̀
̀
́
̀
ica, Facultat de Quimica, Universitat de Barcelona, Martí
̀
́
(CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain
S
* Supporting Information
ABSTRACT: 3,3-Disubstituted tetrahydroisoquinolines are
prepared in one step from Michael acceptors and 2-
phenylethylamines under Pd catalysis and Ag2CO3 as an
oxidant. Presumably, activation of an ortho C−H bond of the
aromatic ring with Pd(II) is directed by the primary amine to
form a palladacycle. Insertion of the olefin, subsequent
conjugated addition of the amine, and reductive elimination
of Pd(0) affords the expected products. Silver carbonate is not
necessary when 2-phenylethylamines are converted previously
to N-benzoyloxy-2-phenylethylamines.
reported of catalytic processes using primary amines as
directing groups with palladium,3 ruthenium,4 iridium,5 and
rhodium catalysts.6 It should be noted that in some of these
processes, the NH2 fragment participates in a second
subsequent reaction to afford the final organic molecule.
Alternatively, Dong et al. have recently described the use of a
transient imines generated in situ for the palladium-catalyzed
arylation of aliphatic C−H bonds of primary amines.7
It has been recently reported that the ruthenium- and
rhodium-catalyzed ortho-alkenylation of benzylamines affords
the corresponding isoindolines as a consequence of the
reactivity of the five-membered metallacycle formed in the
catalytic process.4b We have also reported that the NH2-
directed Pd(II)-catalytic carbonylation of quaternary aromatic
α-amino esters to yield benzolactams shows a strong bias to six-
membered lactams over the five-membered analogues, which
can be explained by the easy mode in which the six-membered
palladacycle is formed and by its greater reactivity in the
catalytic cycle.3a,8 Taking into account this background and
considering also that Vicente et al. have described the synthesis
of eight-membered palladacycles derived from the insertion of
alkenes into the palladium−carbon bond of six-membered
cyclopalladated primary arylamines,9 we studied the palladium-
catalyzed insertion of olefins into the carbon−hydrogen bond
of some primary amines, selected to obtain six-membered
INTRODUCTION
■
The development of selective methods for the direct
conversion of carbon−hydrogen bonds into carbon-heteroatom
and carbon−carbon bonds remains a critical challenge in
organic chemistry. An interesting approach to address this issue
involves the use of substrates that contain coordinating atoms
(or directing groups) that bind to the metal center in a first
step, and a further rearrangement allows the C−H bond
activation. A variety of palladium, rhodium, ruthenium, iridium,
rhenium, and copper and to a lesser extent manganese, nickel,
iron, and cobalt metal derivatives have been shown to be
effective in this process.1
Palladium complexes are particularly attractive catalysts for
such transformations because ligand-directed C−H functional-
ization at Pd(II) centers can be used to obtain different types of
C−Y bonds (Y being carbon, oxygen, nitrogen, sulfur, or
halogen). Furthermore, Pd(II) can activate C−H bonds, both
at sp2 and sp3 sites, and a wide range of catalytic processes has
been described with different nitrogen-based directing groups.
These include amides, pyridines, triazoles, pyrroles, imines,
oximes, azobenzenes, amines, carboxylic acids, ketones,
aldehydes, esters, and hydroxyl derivatives.2
In contrast, few examples of the use of primary amines as
directing groups have been described in spite of the fact that
this functional group is ubiquitous in organic molecules,
probably because the NH2 group is too reactive toward
different organic functions and also can easily coordinate too
tightly to transition-metal centers. Some examples have been
Received: December 19, 2016
© XXXX American Chemical Society
A
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metallacycles, and the possible subsequent intramolecular
Michael addition to afford tetrahydroisoquinolines (THIQs),
a common and privileged scaffold present in many biologically
active compounds (Scheme 1).10,11
Scheme 4. Synthesis of Amino Esters 9a−b
Scheme 1. Synthesis of THIQs from 2-Phenylethylamines
Reactivity of 2-Phenylethylamines. The preliminary
catalytic studies were focused on the reaction of the primary
amine 4a with methyl acrylate using commercially available
palladium(II) acetate as catalyst and benzoquinone as the
oxidant, in acetic acid at 100 °C. These conditions have shown
to be the best for the carbonylation of primary amines catalyzed
by palladium, and in this case, the choice of benzoquinone as
the oxidant was a key factor for the success of the catalytic
process.3a,8 Furthermore, the use of acetic acid as a solvent
facilitates the cyclopalladation reaction and also the partial
protonation of the amino group slows down the direct
conjugate addition of the amine to methyl acrylate.
RESULTS AND DISCUSSION
■
Synthesis of 2-Phenylethylamines. On the basis of our
experience with NH2-directed carbonylations3a,8 and insertion
of allenes,3b we initially attempted the cyclization of α,α-
disubstituted primary phenylethylamines. Primary amines 4a−c
were obtained by Ritter−Jirgensons reaction12 from alcohols
1a−c in a two-step process. 2-Chloroacetonitrile in acetic acid
using concentrated H2SO4 as catalyst afforded 2-chloroaceta-
mides 2a−c that reacted with thiourea to produce amines 4a−
c. Nitration of amide 2a afforded amide 2d that was converted
into amine 4d by reaction with thiourea (Scheme 2).
Some experiments were performed modifying the benzoqui-
none/amine ratio, the methyl acrylate/amine ratio, and the
reaction time (see Table 1). We found that the insertion of
Scheme 2. Synthesis of Primary Amines 4a−d
Table 1. Reaction of Amine 4a with Methyl Acrylate
t
benzoquinone
(% mol)
methyl acrylate
(% mol)
yield
(%)
ratio
10a:11a
entry (h)
1
2
3
4
3
3
3
6
200
120
120
120
200
120
100
120
41
63
32
35
83:17
86:14
91:9
80:20
Primary amines 5a−c were obtained from 2-phenylacetoni-
triles 3a−c by reaction with Ti(OiPr)4/EtMgBr in Et2O
(Scheme 3).13
Amino esters 9a−b were obtained by formation of Schiff
bases 7a−b followed by alkylation with benzyl bromide and
subsequent acid hydrolysis of the benzylated imines 8a−b
formed (Scheme 4).
methyl acrylate and also the subsequent Michael addition took
place to obtain the expected tetrahydroisoquinoline 10a
regioselectively. Unfortunately, the yields of the processes
were moderate (32−63%) and compound 11a, coming from
the double insertion process, was also obtained in all cases.
Because Ag2CO3 has been shown to be a good oxidant for
the palladium-catalyzed alkenylation of oxalyl-amide-protected
phenylpropylamine derivatives,14 we performed some experi-
ments with this silver(I) oxidant (see Table 2). Good results
were obtained using 10% molar Pd(OAc)2, 1.1 equiv of silver
carbonate and a methyl acrylate/primary amine molar ratio of
2:1, in acetic acid at 100 °C. Under these conditions, the yield
of the process was 95%, and the 10a:11a ratio was 95:5 (Table
2, entry 1).
Scheme 3. Synthesis of Primary Amines 5a−c
The reaction between the primary amine 4a and methyl
acrylate was also performed in the same reaction conditions,
B
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atom. Our findings showing that silver acetate or carbonate
salts should be used instead of the hexafluoroantimonate salt
agree with this proposal because both acetate and carbonate
anions can act as a Brønsted bases as well as bidentate ligands.
When the reaction was performed with the same primary
amine 4a and n-butyl acrylate, in the optimized conditions, the
yield of the process was 93%, and the tetrahydroisoquinoline
10b and double addition product 11b ratio was 98:2. In this
case, the less volatile n-butyl acrylate allowed us to reduce the
amount of acrylate to 1.2 equiv without a decrease in yield
(90%) of 10b. Therefore, we used these conditions as our
standard for a variety of amines and Michael acceptors (Scheme
5).
The reaction between para-substituted phenylethylamines
4b−d and n-butyl acrylate afforded the expected tetrahydroi-
soquinolines 10c−e in 65−85% yield. The reaction works with
either electron-deficient or electron-rich groups attached to the
phenyl group. The more hindered amines 5a−c were still
reactive, and tetrahydroisoquinolines 12a−c were formed.
We next explored the reactivity of different activated
monosubstituted olefins such as 3-buten-2-one, acrylonitrile,
or N-acryloylmorpholine with amines 4a and 5a. Some of these
olefins are volatile and/or are not as good Michael acceptors as
n-butyl acrylate, and as expected, tetrahydroisoquinolines 13a−
b and 14a−c were obtained in lower yields. Amino ester 9a was
also reactive with some of these Michael acceptors, and
tetrahydroisoquinolines 15a−c were obtained as a 1:1 mixture
of diastereoisomers. No double insertion product was detected
in any case, but in the case of N-acryloylmorfoline, the
formation of a 20% of the product of addition of AcOH to N-
acryloylmorpholine was observed.
Table 2. Reaction of Amine 4a with Methyl Acrylate and
Ag2CO3 as Oxidant
t
Pd(OAc)2
(% mol)
methyl acrylate
(% mol)
yield
(%)
ratio
10a:11a
entry (h)
1
2
3
4
5
6
7
3
3
1
3
3
3
6
3
10
10
10
2
200
110
200
200
200
200
200
200
95
37
28
46
65
45
56
81
95:5
92:8
89:11
97:3
97:3
98:2
95:5
95:5
4
5
5
a
8
10
a
2 equiv of silver acetate as the oxidant.
changing the silver carbonate by the corresponding acetate and
hexafluoroantimonate silver salts, in order to evaluate the role
of the silver salt in the process. The results obtained when silver
acetate was used as the oxidant were of the same order
compared to the results obtained with silver carbonate: 81%
yield and a 10a:11a ratio of 95:5 (Table 2, entry 8). In contrast,
the catalytic process did not work when Ag[SbF6] was used as
the oxidant. These results can be explained by a M06 density
functional theory study on the roles of noninnocent additives in
palladium catalyzed C−H bond activation reactions.15 This
work showed that a heterobimetallic Pd(II)-μ-X-Ag(I) species
is the most likely catalyst in a palladium acetate amination
reaction. There is a short contact between silver(I) and
palladium(II) in the transition state, which facilitates the redox
process. Besides this, these authors showed that the proton
abstraction is performed by the anion bonded to the silver
Although the reaction was not diastereoselective, 15a
diastereoisomers could be separated by a flash column
chromatography, using a mixture of ethyl acetate/hexane
(50/50) as the eluent. A NOESY experiment showed that
the hydrogen atom adjacent to the NH fragment presented a
NOE interaction with the protons of the methyl group bonded
Scheme 5. Reaction of Primary Amines 4a−d, 5a−c, and 9a−b with Michael Acceptors
C
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to the chiral carbon atom only in the second eluted
diastereomer, showing that these atoms are in syn disposition
in this diastereoisomer (Chart 1).
Comparison of the results using benzoquinone or silver salts
suggested that the oxidant had a key role in this catalytic
reaction. Therefore, we explored the use of an internal oxidant.
For this purpose, N-benzoyloxy-2-phenylethyl-amines 20a−b
were easily prepared from the corresponding amines 1a and 5a
(Scheme 7).
Chart 1. Syn-15a and anti-15a Diastereomers
Scheme 7. Synthesis of N-Benzoyloxy-2-phenylethyl-amines
20a−b
Amino ester 9b reacted with n-butyl acrylate and acrylonitrile
to afford tetrahydroquinolines 16a−b in 73% and 80% yield,
respectively.
It should be noted that the process does not work with
neither the primary amines 17−18 nor with the amino ester 19
(see Chart 2), showing that the formation of a six-membered
palladacycle and the presence of a quaternary carbon atom in α
position to the amine are key factors for the catalytic process.
We replaced a NH bond of the primary amine with an N-
OR1 bond, OR1 being an oxygen-containing fragment (OBz),
which can act as an internal oxidant. We performed some
experiments of the reaction between n-butyl acrylate and the O-
benzoyl hydroxylamine 20a. We found that effectively the
catalytic process can take place without the addition of any
extraneous oxidant to obtain the same compound of the
corresponding primary amine (10b) under the same conditions
used before: Pd(OAc)2 as a catalyst, acetic acid as a solvent, at
100 °C for 3 h. We also found that the yield of the process and
the ratio between tetrahydroisoquinoline/double addition
product ratio were similar to those obtained in the presence
of Ag2CO3. Slightly better yields were obtained were obtained
when Pd2(dba)3 was used as a catalyst.
Chart 2. Primary Amines 17−19
A plausible mechanism for the alkenylation of primary
amines is shown in Scheme 6. The first step is the
Fortunately, the tetrahydroisoquinolines that were obtained
in lower yields with silver cabonate as an oxidant (i.e., 12a, 13b,
and 14b−c in Scheme 5) gave higher yields when the
corresponding O-benzoylhydroxylamines 20a−b were used
under the new conditions (Scheme 8).
Scheme 6. Plausible Pathway for the ortho-Alkenylation
Scheme 8. Reaction of O-Benzoylhydroxylamines 20a,b with
Michael Acceptors
The formation of a six-membered palladacycle and the
presence of a quaternary carbon atom in α position were also
key factors for the catalytic process, because when the reaction
was performed with compounds 21 and 22 (see Chart 3), no
tetrahydroquinolines were obtained.
The high reactivity of the six-membered metallacycles can
explain why this factor plays a key role in the catalytic process.
cyclometalation of the amine. A computational study has
proposed that this reaction occurs by a highly concerted
process in which the palladium(II) center provides electrophilic
activation of a C−H bond, and an acetato ligand acts as an
intramolecular base for the C−H bond deprotonation.16 In a
second step, the coordination of alkene and subsequent
insertion of this molecule affords the corresponding eight-
membered metallacycles, closely related to those reported in a
stoichiometric reaction by Vicente et al.9 Then β-elimination
and subsequent oxidation of the palladium-hydrido species
formed by silver(I) compounds affords the expected ortho-
alkenylated amines and regenerates the active Pd(II)-acetato
species.
Chart 3. O-Benzoylhydroxylamines 21 and 22
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chloroacetamide as a white solid, which was directly used for the next
steps without further purifications. Thiourea (0.510 g, 6.72 mmol) was
added to a solution of the crude 2-chloroacetamide (5.60 mmol) in a
1:5 mixture of acetic acid and ethanol (60 mL). The reaction was
heated to reflux overnight. Then it was cooled, and the ethanol was
evaporated at reduced pressure. A 2 N aqueous solution of HCl was
added, and the resulting aqueous suspension was washed two times
with CH2Cl2. Solid Na2CO3 was added to the aqueous solution until
pH = 10−11, which was subsequently extracted three times with
CH2Cl2. The collected basic organic phases were dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced pressure to
afford the pure amine.
In a previous work, we have shown that the palladium-catalyzed
carbonylation of amino esters and primary amines shows a
strong bias to the six-membered lactams over five-membered
analogues.8 The fact that full substitution of the carbon in the
α-position of the coordinating atom facilitates the cyclo-
palladation reaction and this can be explained by a decrease in
ΔS‡ requirements.17 This specificity can also be related with the
well-known Thorpe−Ingold effect in organic cyclization
reactions.18
CONCLUSIONS
■
4a. Colorless oil. 0.567 g (3.81 mmol) from 0.750 g (5.00 mmol) of
1
3,3-Disubstituted tetrahydroisoquinolines can be obtained in
one step from Michael acceptors and 1,1-disubstituted-2-
phenylethylamines with catalytic Pd(OAc)2 and Ag2CO3 as
an oxidant. A key point is the use of acetic acid as solvent since
this, presumably, accelerates C−H activation and inhibits
intermolecular conjugate addition of the amine to the Michael
acceptor. The type of silver salt is also important, and bidentate
anions such as carbonate or acetate seem to be necessary. When
2-phenylethylamines are oxidized previously with benzoyl
peroxide to N-benzoyloxy-2-phenylethylamines, the same
reaction can be achieved without using stoichiometric silver
salts. Furthermore, better yields are obtained with Pd(0) for the
less electrophilic Michael acceptors than with Ag2CO3 and
amines. The scope of the reaction is limited to the use of 1,1-
disubstituted-2-phenylethylamines.
1a (76%). H NMR (400 MHz, CDCl3): δ 7.32−7.18 (m, 5H), 2.67
(s, 2H), 1.22 (br s, 2H), 1.12 (s, 6H). 13C NMR (101 MHz, CDCl3):
δ 136.4, 130.4, 127.9, 126.2, 51.1, 44.5, 30.3. HRMS (ESI): m/z calcd
for [M + H]+, 150.1277; found, 150.1280.
4b. Colorless oil. 0.766 g (4.70 mmol) from 0.918 g (5.61 mmol) of
1
2b (84%). H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 8.1 Hz, 2H),
7.07 (d, J = 8.1 Hz, 2H), 2.62 (s, 2H), 2.33 (s, 3H), 1.11 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ 135.7, 135.3, 130.3, 128.7, 50.7, 49.9,
30.3, 21.0. HRMS (ESI): m/z calcd for [M + H]+, 164.1434; found,
164.1428.
4c. Colorless oil. 0.170 g (0.950 mmol) from 0.611 g (3.34 mmol)
of 2c (28%). 1H NMR (400 MHz, CDCl3): δ 7.10 (d, J = 8.6 Hz, 2H),
6.84 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 2.60 (s, 2H), 1.10 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ 158.1, 131.3, 130.4, 113.4, 55.2, 55.2,
50.1 30.1. HRMS (ESI): m/z calcd for [M + H]+, 180.1383; found,
180.1384.
Synthesis of Primary Amine 4d. Compound 1a (0.5 mL, 3.2
mmol) was dissolved in 2-chloroacetonitrile (1.25 mL, 19.5 mmol)
and acetic acid (1.55 mL). The solution was cooled to 0 °C, and
concentrated sulfuric acid (1.55 mL, 29.2 mmol) was added dropwise.
After the addition, the mixture was stirred for 5 h at rt, and then ice
was added carefully. The mixture was extracted three times with
diethyl ether, and the collected organic phases were washed with a
saturated solution of Na2CO3 (twice) and brine. Finally, the organic
phase was dried over anhydrous MgSO4, and the solvent was
evaporated under reduced pressure. The excess of 2-chloroacetonitrile
was removed at vacuum to obtain 2-chloro-N-(2-methyl-1-phenyl-
propan-2-yl)acetamide as a white solid (0.729 g, 3.24 mmol), which
was directly used for the next steps without further purifications. An
acidic mixture of concentrated H2SO4 (5.3 mL, 97 mmol) and
concentrated HNO3 (6.8 mL, 16 mmol) was added to compound 2a
(3.24 mmol) at 0 °C. After the addition, the mixture was stirred for 30
min at room temperature. The solution was diluted with water and
extracted three times with CH2Cl2. The collected organic phases were
washed with a saturated aqueous solution of Na2CO3 and brine.
Finally, the organic phase was dried over anhydrous Na2SO4, and the
solvent was evaporated under reduced pressure. The crude mixture
was purified by flash column chromatography on silica gel (hexane/
ethyl acetate) to afford compound 2d (638 mg, 73%) as an orange
solid. 1H NMR (400 MHz, CDCl3): δ 8.17−8.14 (d, J = 8.7 Hz, 2H),
7.31−7.29 (d, J = 8.7 Hz, 2H), 6.16 (br s, 1H), 3.97 (s, 2H), 3.23 (s,
2H), 1.39 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 165.6, 146.9,
145.4, 131.1, 123.3, 54.5, 44.1, 42.9, 27.1, 27.0. HRMS (ESI): m/z
calcd for [M + H]+, 271.0844; found, 271.0854.
Thiourea (0.213 g, 2.80 mmol) was added to a solution of
compound 2d (0.638 g, 2.36 mmol) in a 1:5 mixture of acetic acid and
ethanol (10 mL). The reaction was heated to reflux overnight. Then it
was cooled, and the ethanol was evaporated at reduced pressure. A 2 N
aqueous solution of HCl was added, and the resulting aqueous mixture
was washed three times with CH2Cl2. Then solid sodium carbonate
was added until reaching pH 10, and the aqueous solution was
extracted three times with CH2Cl2. The organic phase was dried over
anhydrous Na2SO4, filtered, and the solvent was evaporated at reduced
pressure to afford the pure amine 4d as an orange oil (0.389 g, 85%).
1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.6 Hz, 2H), 7.37 (d, J =
8.6 Hz, 2H), 2.77 (s, 2H), 1.25 (br s, 2H), 1.14 (s, 6H). 13C NMR
EXPERIMENTAL SECTION
■
General Considerations. Amino esters 6a−b, 2-phenylacetoni-
triles 3a−c, the amine 17, and the alcohol 1a were obtained from
commercial sources and used as received. The alcohols 1b−c were
prepared by addition of methyl magnesium bromide to the
commercially available ethyl 2-tolylacetate and (4-methoxyphenyl)-
propan-2-one, respectively. Amine 19 was obtained from its
commercially available hydrochloric salt, while O-benzoylhydroxyl-
amines 21 and 22 were prepared respectively from commercial cumyl
amine and phenethylamine following the general procedure for the
oxidation of the amines that is reported in this section. Imines 7a and
8a were prepared according to our previous work.8 Imines 7b and 8b
were obtained by a known procedure.19 Amine 18 was prepared from
2-phenylacetonitrile 3a following a described procedure.20 Benzoyl
peroxide was used as Luperox A75. Solvents were distilled and dried
before use.21 1H (400 MHz) and 13C (101 MHz) nuclear magnetic
resonance (NMR) spectra were registered using a Varian Mercury 400
MHz NMR spectrometer. CDCl3 (99.9%) was used as solvent while
SiMe4 (TMS) was used as reference. The coupling constants (J) are
expressed in Hz, and the chemical shifts are represented in part per
million (ppm). The signals multiplicities are reported with the
following abbreviations: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad). More complicated signals are
described as combination of the indicated abbreviations: e.g dd
(double of doublets), dt (double of triplets), etc. Two-dimensional
experiments (NOESY, HSQC) were performed to confirm the signal
assignments. Mass spectra (HRMS) were recorded in an Agilent LC/
MSD-TOF by CCiTUB at University of Barcelona.
Synthesis of Primary Amines 4a−c from Alcohols. The
corresponding tertiary alcohol (5.61 mmol) was dissolved in 2-
chloroacetonitrile (2.0 mL, 34 mmol) and acetic acid (2.7 mL). The
solution was cooled to 0 °C, and concentrated sulfuric acid (2.7 mL,
50 mmol) was added dropwise. After the addition, the mixture was
stirred for 5 h at rt, and then ice was added carefully. The mixture was
extracted three times with diethyl ether, and the collected organic
phases were washed twice with a saturated solution of Na2CO3 and
brine. Finally, the organic phase was dried over anhydrous MgSO4, and
the solvent was evaporated under reduced pressure. The excess of 2-
chloroacetonitrile was removed under vacuum to obtain the 2-
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(101 MHz, CDCl3): δ 146.3, 131.1, 124.6, 122.6, 49.7, 49.5, 28.2.
HRMS (ESI): m/z calcd for [M + H]+, 195.1128; found, 195.1125.
Synthesis of Primary Amines 5a−c from Nitriles. A 3 M
solution of ethyl magnesium bromide in diethyl ether (14 mL, 41
mmol) was added dropwise to a suspension of the corresponding 2-
arylacetonitrile (10.24 mmol) and titanium(IV) isopropoxide (3.4 mL,
11.3 mmol) in diethyl ether (20 mL) at 0 °C. The reaction was stirred
at rt for 1 h. Then it was cooled again to 0 °C, and a 10% aqueous
solution of NaOH (10 mL) was added. The heterogeneous solution
was stirred at rt for 30 min and filtered through a Celite pad. The
biphasic mixture was extracted twice with diethyl ether. The collected
organic phases were extracted several times with a 2 N aqueous
solution of HCl. The aqueous layer was basified to pH 10−12 with
sodium carbonate and extracted several times with dichloromethane.
The organic solution was finally dried over anhydrous Na2SO4, filtered,
and the solvent was eliminated at reduced pressure to afford the pure
amine.
added. The aqueous phase was extracted three times with CH2Cl2, the
collected organic phases were dried over MgSO4, filtered, and the
solvent was removed under vacuum. The crude yellow oil was purified
by flash column chromatography on silica gel (CH2Cl2/MeOH or
hexane/AcOEt) to give the corresponding tetrahydroisoquinoline.
10a. Yellow oil. 0.111 g (0.475 mmol) from 0.074 g (0.50 mmol) of
compound 4a (95%). 1H NMR (400 MHz, CDCl3): δ 7.17−7.03 (m,
4H), 4.46 (dd, J = 8.9, 3.2 Hz, 1H), 3.67 (s, 3H) 3.02 (dd, J = 16.4, 3.2
Hz, 1H), 2.78 (d, J = 15.9 Hz, 1H), 2.71 (dd, J = 16.4, 8.9 Hz, 1H)
2.51 (d, J = 16.0 Hz, 1H), 1.24 (s, 3H), 1.08 (s, 3H). 13C NMR (101
MHz, CDCl3): δ 172.9, 135.9, 135.1, 129.6, 126.4, 125.9, 124.8, 51.6,
49.7, 49.1, 42.3, 41.1, 31.5, 24.4. HRMS (ESI): m/z calcd for [M +
H]+, 234.1449; found, 234.1483.
11a. Yellow oil. 8 mg (0.03 mmol) from 0.074 g (0.50 mmol) of
compound 4a (5%). 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 15.9
Hz, 1H), 7.43 (dd, J = 6.7, 2.1 Hz, 1H), 7.17−7.03 (m, 2H), 6.32 (d, J
= 15.9 Hz, 1H), 4.48 (dd, J = 8.8, 3.3 Hz, 1H), 3.79 (s, 3H), 3.67 (s,
3H), 2.97 (dd, J = 16.4, 3.3 Hz, 1H), 2.78 (d, J = 15.9 Hz, 1H), 2.66
(dd, J = 16.4, 8.8 Hz, 1H), 2.51 (d, J = 16.0 Hz, 1H), 1.29 (s, 3H), 1.09
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 172.7, 167.4, 142.2, 137.0,
134.7, 133.9, 129.6, 126.4, 124.8, 119.6, 51.6, 49.7, 48.8, 41.9, 39.3,
31.8, 24.5. HRMS ESI: m/z calcd for [M + H]+, 318.1700; found,
318.1702.
5a. Colorless oil. 1.000 g (5.640 mmol) from 1.2 mL (10 mmol) of
1
3a (55%). H NMR (400 MHz, CDCl3): δ 7.31−7.18 (m, 5H), 2.63
(s, 2H), 1.36 (m, 4H), 0.91 (t, J = 7.5 Hz, 6H). 13C NMR (101 MHz,
CDCl3): δ 138.2, 130.6, 127.9, 126.1, 54.1, 45.8, 31.3, 8.1. HRMS
(ESI): m/z calcd for [M + H]+, 178.1590; found, 178.1594.
5b. Colorless oil. 0.559 g (2.70 mmol) from 0.61 mL (4.5 mmol) of
1
3b (60%). H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 8.7 Hz, 2H),
10b. Yellow oil. 0.124 g (0.450 mmol) from 0.074 g (0.50 mmol) of
compound 4a (90%). 1H NMR (400 MHz, CDCl3): δ 7.15−6.98 (m,
4H), 4.41 (dd, J = 8.8, 3.2 Hz, 1H), 4.04 (m, 2H), 2.97 (dd, J = 16.2,
3.3 Hz, 1H), 2.71 (d, J = 15.8 Hz, 1H), 2.65 (dd, J = 16.2, 8.8 Hz, 1H),
2.48 (d, J = 15.8 Hz, 1H), 1.89 (br s, 1H), 1.56−1.48 (m, 2H), 1.34−
1.25 (m, 2H), 1.20 (s, 3H), 1.05 (s, 3H), 0.87 (t, J = 7.3 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ 172.6, 136.3, 135.5, 129.6, 126.3, 125.8,
124.8, 64.4, 49.8, 48.9, 42.4, 41.5, 31.7, 30.6, 24.5, 19.1, 13.7. HRMS
(ESI): m/z calcd for [M + H]+, 276.1958; found, 276.1954.
10c. Yellow oil. 0.123 g (0.425 mmol) from 0.082 g (0.50 mmol) of
compound 4b (85%). 1H NMR (400 MHz, CDCl3): δ 6.95−6.90 (m,
3H), 4.41 (dd, J = 8.9, 3.2 Hz, 1H), 4.11−4.06 (m, 2H), 2.99 (dd, J =
16.2, 3.2 Hz, 1H), 2.73 (d, J = 15.7 Hz, 1H), 2.70 (dd, J = 16.2, 8.9 Hz,
1H), 2.48 (d, J = 15.7 Hz, 1H), 2.30 (s, 3H), 1.63−1.54 (m, 2H),
1.40−1.30 (m, 2H), 1.24 (s, 3H), 1.08 (s, 3H), 0.91 (t, J = 7.4 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 172.6, 135.9, 135.2, 132.2,
129.5, 127.2, 125.4, 64.3, 49.7, 48.9, 42.0, 41.5, 31.6, 30.6, 24.4, 21.2,
19.1, 13.7. HRMS (ESI): m/z calcd for [M + H]+, 290.2115; found,
290.2118.
6.83 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 2.58 (s, 2H), 1.43−1.26 (m,
4H), 0.90 (t, J = 7.5 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 156.1,
131.4, 130.0, 113.4, 55.2, 54.1, 44.7, 31.1, 8.0. HRMS (ESI): m/z calcd
for [M + H]+, 208.1696; found, 208.1695.
5c. Colorless oil. 0.387 g (1.87 mmol) from 0.62 mL (4.50 mmol)
1
of 3c (42%). H NMR (400 MHz, CDCl3): δ 7.23−7.17 (m, 1H),
6.80−6.73 (m, 3H), 3.80 (s, 3H), 2.61 (s, 2H), 1.46−1.30 (m, 4H),
0.91 (t, J = 7.5 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 159.3, 128.9,
123.1, 116.5, 111.3, 55.1, 45.6, 31.1, 8.04. HRMS (ESI): m/z calcd for
[M + H]+, 208.1696; found, 208.1695.
Synthesis of Primary Amines 9a−b from Imines 8a−b.
Amine 9a. A suspension formed by the imine 8a8 (7.90 g, 24.3 mmol),
and a 1 M aqueous solution of HCl (150 mL) was stirred at rt for 1 h,
followed by addition of Et2O. The phases were separated, and the
aqueous layer was washed two times with Et2O. The aqueous phase
was basified to pH 10−11 with Na2CO3 and extracted three times with
Et2O. The ethereal phase was washed with water and brine, dried over
anhydrous MgSO4, and the solvent was evaporated at reduced pressure
1
to give the pure amine 9a (3.500 g, 74%) as a yellow oil. H NMR
10d. Yellow oil. 0.107 g (0.350 mmol) from 0.090 g (0.50 mmol) of
compound 4c (70%). 1H NMR (400 MHz, CDCl3): δ 6.97 (d, J = 8.3
Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 4.41 (dd, J = 8.8, 3.3
Hz, 1H), 4.10−4.07 (m, 2H), 3.77 (s, 3H) 2.99 (dd, J = 16.2, 3.3 Hz,
1H), 2.73 (dd, J = 16.2, 8.8 Hz, 1H), 2.67 (d, J = 15.5 Hz, 1H), 2.47
(d, J = 15.5 Hz, 1H), 1.61−1.53 (m, 2H), 1.37−1.30 (m, 2H), 1.25 (s,
3H), 1.08 (s, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 172.5, 157.7, 137.2, 130.4, 127.4, 112.1, 110.3, 64.4, 55.2,
49.0, 49.0, 41.6, 41.4, 31.6, 30.6, 24.3, 19.1, 13.6. HRMS (ESI): m/z
calcd for [M + H]+, 306.2064; found, 306.2068.
10e. Yellow oil. 0.119 g (0.372 mmol) from 0.110 g (0.566 mmol)
of compound 4d (65%). 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H),
8.01 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.49 (dd, J = 8.4, 3.3
Hz, 1H), 4.11−4.08 (m, 2H), 3.06 (dd, J = 16.3, 3.3 Hz, 1H), 2.84 (d,
J = 16.6 Hz, 1H), 2.80 (dd, J = 16.3, 8.4 Hz, 1H), 2.65 (d, J = 16.6 Hz,
1H), 1.60−1.56 (m, 2H), 1.37−1.32 (m, 2H), 1.28 (s, 3H), 1.09 (s,
3H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 171.7,
143.5, 138.0, 137.5, 130.6, 121.3, 120.2, 64.7, 49.7, 48.9, 42.6, 40.9,
31.4, 30.6, 24.4, 19.1, 13.6. HRMS (ESI): m/z calcd for [M + H]+,
321.1809; found, 321.1820.
(400 MHz, CDCl3): δ 7.31−7.13 (m, 5H), 3.71 (s, 3H), 3.13 (d, J =
13.1 Hz, 1H), 2.81 (d, J = 13.3 Hz, 1H), 1.64 (br s, 2H), 1.40 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 177.4, 136.5, 129.9, 128.3, 126.9,
58.8, 52.0, 46.9, 26.6. HRMS (ESI): m/z calcd for [M + H]+,
194.1176; found, 194.1178.
Amine 9b. Imine 8b19 (1.14 g, 2.70 mmol) was added to a mixture
of a 2 N aqueous solution of HCl (10 mL) and Et2O (50 mL), and the
suspension was stirred overnight at rt. The phases were separated, and
the organic layer was extracted twice with a 2 N aqueous solution of
HCl. The collected aqueous phases were basified to pH 10−11 with
Na2CO3 and extracted several times with CH2Cl2. The collected basic
organic phases were washed with brine, dried on anhydrous MgSO4,
filtered, and the solvent was evaporated to give the pure amine 9b
1
(0.510 g, 70%) as a colorless oil. H NMR (400 MHz, CDCl3): δ
7.31−7.24 (m, 3H), 7.20−7.16 (m, 2H), 4.24 (q, J = 7.1 Hz, 4H, 3.32
(s, 2H), 1.84 (br s, 2H), 1.28 (t, J = 7.1 Hz, 6H). 13C NMR (101
MHz, CDCl3): δ 171.1, 135.1, 130.2, 128.6, 127.4, 66.4, 62.1, 41.8,
14.2. HRMS (ESI): m/z calcd for [M + H]+, 266.1387; found,
266.1393.
General Method for the Reaction of Amines with Michael
Acceptors. The Michael acceptor (0.65 mmol) was added to a
suspension of amine (0.54 mmol), Pd(OAc)2 (12 mg, 0.054 mmol),
and Ag2CO3 (164 mg, 0.595 mmol) in acetic acid (3 mL). The
mixture was stirred at 100 °C for 3 h in a sealed vial. Toluene was
added, and the solution was filtered through a pad of Celite. The
solvents were removed under vacuum. The crude mixture was
dissolved in CH2Cl2, and a saturated aqueous solution of Na2CO3 was
12a. Yellow oil. 0.094 g (0.310 mmol) from 0.088 g (0.50 mmol) of
compound 5a (62%). 1H NMR (400 MHz, CDCl3): δ 7.15−7.06 (m,
4H), 4.35 (dd, J = 9.5, 3.1, 1H), 4.12 (q, J = 7.5 Hz, 2H) 3.05 (dd, J =
16.2, 3.1 Hz, 1H), 2.74 (d, J = 15.8 Hz, 1H), 2.65 (dd, J = 16.2, 9.5 Hz,
1H) 2.54 (d, J = 15.8 Hz, 1H), 1.64−1.27 (m, 8H), 0.93 (t, J = 7.4 Hz,
3H), 0.92 (t, J = 7.5 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 172.7, 136.9, 135.1, 129.8, 126.2, 125.6, 124.6, 64.4,
F
DOI: 10.1021/acs.organomet.6b00944
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
53.3, 48.8, 41.6, 39.2, 32.0, 30.6, 24.5, 19.1, 13.7, 7.5, 7.3. HRMS
(ESI): m/z calcd for [M + H]+, 304.2271; found, 304.2272.
NMR (101 MHz, CDCl3): δ 176.3, 172.4, 135.6, 133.9, 128.9, 126.4,
126.2, 125.4, 64.5, 58.4, 52.0, 50.6, 43.1, 38.6, 30.6, 27.7, 19.1, 13.7.
HRMS (ESI): m/z calcd for [M + H]+: 320.1856, found: 320.1858.
12b. Yellow oil. 0.090 g (0.270 mmol) from 0.104 g (0.502 mmol)
of compound 5b (54%). 1H NMR (400 MHz, CDCl3): δ 6.97 (d, J =
8.3 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.63 (s, 1H), 4.29 (dd, J = 9.4,
3.1 Hz, 1H), 4.12−4.08 (m, 2H), 3.76 (s, 3H) 3.00 (dd, J = 16.2, 3.1
Hz, 1H), 2.73 (dd, J = 16.2, 9.4 Hz, 1H), 2.73 (d, J = 15.5 Hz, 1H),
2.46 (d, J = 15.5 Hz, 1H), 1.64−1.23 (m, 8H), 0.91 (t, J = 7.5 Hz, 3H),
0.89 (t, J = 7.5 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 172.6, 157.6, 137.9, 130.6, 127.2, 112.1, 110.2, 64.4, 55.2,
53.4, 49.0, 41.5, 38.4, 31.9, 30.6, 24.3, 19.1, 13.7, 7.5, 7.3. HRMS
(ESI): m/z calcd for [M + H]+, 334.2377; found, 334.2383.
12c. Yellow oil. 0.172 g (0.516 mmol) from 0.207 g (1.00 mmol) of
compound 5c (52%). 1H NMR (400 MHz, CDCl3): δ 7.01 (d, J = 8.5
Hz, 1H), 6.70 (dd, J = 8.5, 2.7 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 4.29
(dd, J = 9.4, 3.1 Hz, 1H), 4.12−4.08 (m, 2H), 3.76 (s, 3H), 3.00 (dd, J
= 16.2, 3.1 Hz, 1H), 2.70 (d, J = 15.8 Hz, 1H), 2.60 (dd, J = 16.2, 9.4
Hz, 1H), 2.49 (d, J = 15.8 Hz, 1H), 1.64−1.25 (m, 8H), 0.92 (t, J = 7.5
Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 172.7, 157.9, 136.5, 129.0, 125.7, 114.3, 111.8,
64.4, 55.1, 53.3, 48.3, 41.6, 39.6, 31.9, 30.6, 24.4, 19.1, 13.6, 7.5, 7.3.
HRMS (ESI): m/z calcd for [M + H]+, 334.2377; found, 334.2371.
13a. Yellow oil. 0.073 g (0.28 mmol) from 0.089 g (0.50 mmol) of
compound 5a (56%). 1H NMR (400 MHz, CDCl3): δ 7.15−7.07 (m,
4H), 4.37 (dd, J = 9.5, 3.1 Hz, 1H), 3.71 (s, 3H), 3.06 (dd, J = 16.4,
3.1 Hz, 1H), 2.74 (d, J = 15.9 Hz, 1H), 2.65 (dd, J = 16.4, 9.5 Hz, 1H),
2.53 (d, J = 15.9 Hz, 1H), 2.21 (br s, 1H), 1.54−1.30 (m, 4H), 0.91 (t,
J = 7.6 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 173.1, 136.8, 135.1, 129.8, 126.3, 125.7, 124.6, 53.4, 51.6,
48.8, 41.3, 39.2, 31.9, 24.5, 7.6, 7.3. HRMS (ESI): m/z calcd for [M +
H]+, 262.1801; found, 262.1802.
13b. Yellow oil. 0.083 g (0.36 mmol) from 0.150 g (0.847 mmol) of
compound 5a (43%). 1H NMR (400 MHz, CDCl3): δ 7.21−7.09 (m,
4H), 4.32 (dd, J = 7.7, 3.9 Hz, 1H), 2.92 (dd, J = 16.5, 3.9 Hz, 1H),
2.79 (d, J = 15.8 Hz, 1H), 2.70 (dd, J = 16.5, 7.7 Hz, 1H), 2.55 (d, J =
15.8 Hz, 1H), 1.66 (br s, 1H), 1.57−1.44 (m, 2H), 1.44−1.30 (m,
2H), 0.95 (t, J = 7.5 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 135.2, 134.8, 130.0, 127.1, 126.0, 124.7, 118.3, 53.8,
49.3, 38.8, 31.8, 26.6, 25.1, 7.5, 7.5. HRMS (ESI): m/z calcd for [M +
H]+, 229.1697; found, 229.1699.
14a. Yellow oil. 0.055 g (0.26 mmol) from 0.074 g (0.50 mmol) of
compound 4a (51%). 1H NMR (400 MHz, CDCl3): δ 7.17−7.04 (m,
4H), 4.52 (dd, J = 9.0, 3.1 Hz, 1H), 3.12 (dd, J = 17.7, 3.1 Hz, 1H),
2.88 (dd, J = 17.6, 9.0 Hz, 1H), 2.80 (d, J = 15.8 Hz, 1H), 2.51 (d, J =
15.8 Hz, 1H), 2.19 (s, 3H), 2.00 (br s, 1H), 1.24 (s, 3H), 1.11 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 208.6, 136.3, 135.1, 129.7, 126.3,
125.8, 124.6, 50.7, 49.0, 48.9, 42.3, 31.4, 40.7, 24.3. HRMS (ESI): m/z
calcd for [M + H]+, 218.1539; found, 218.1533.
1
Syn-15a: H NMR (400 MHz, CDCl3): δ 7.18−7.09 (m, 4H), 4.51
(dd, J = 9.3, 3.3 Hz, 1H), 4.12 (m, 2H), 3.74 (s, 3H), 3.20 (d, J = 15.7
Hz, 1H), 2.99 (dd, J = 16.5, 3.4 Hz, 1H), 2.80 (d, J = 15.7 Hz, 1H),
2.70 (dd, J = 16.5, 9.2, Hz, 1H), 2.03 (s, 3H), 1.63−1.54 (m, 2H),
1.42−1.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 176.2, 172.3, 135.8, 133.4, 129.6, 126.6, 126.3, 124.9, 64.5,
57.0, 52.3, 49.4, 41.3, 37.8, 30.6, 22.5, 19.1, 13.7. HRMS (ESI): m/z
calcd for [M + H]+, 320.1856; found, 320.1858.
15b. Yellow oil. 0.071 g (0.29 mmol) from 0.097 g (0.50 mmol) of
compound 9a (58%). Anti-15b: 1H NMR (400 MHz, CDCl3): δ
7.20−7.04 (m, 4H), 4.62 (dd, J = 7.0, 4.0 Hz, 1H), 3.55 (s, 3H), 3.22
(d, J = 15.5 Hz, 1H), 2.89 (d, J = 15.5 Hz, 1H), 2.80 (dd, J = 16.4, 4.0
Hz, 1H), 2.65 (dd, J = 16.4, 7.0 Hz, 1H), 1.46 (s, 3H). 13C NMR (101
MHz, CDCl3): δ 176.4, 133.9, 133.6, 129.0, 127.2, 126.7, 125.7, 118.1,
58.7, 52.2, 51.0, 38.5, 28.4, 27.5. HRMS (ESI): m/z calcd for [M +
H]+: 245.1285, found: 245.1283. Syn-15b: 1H NMR (400 MHz,
CDCl3): δ 7.25−7.13 (m, 4H), 4.48 (dd, J = 7.6, 4.3 Hz, 1H), 3.79 (s,
3H), 3.25 (d, J = 15.8 Hz, 1H), 2.90 (dd, J = 16.6, 4.4 Hz, 1H) 2.84 (d,
J = 15.8 Hz, 1H), 2.76 (dd, J = 16.6, 7.5 Hz, 1H), 1.36 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ 175.8, 133.8, 133.4, 129.9, 127.6, 126.7,
125.0, 117.9, 57.0, 52.5, 49.9, 37.6, 26.4, 23.0. HRMS (ESI): m/z calcd
for [M + H]+, 245.1285; found, 245.1283.
15c. Yellow oil. 0.091 g (0.28 mmol) from 0.097 g (0.50 mmol) of
compound 9a (55%). 1H NMR (400 MHz, CDCl3): δ 7.19−7.05 (m,
8H), 4.68 (m, 2H), 3.75 (s, 3H), 3.67−3.58 (m, 12H), 3.60 (s, 3H),
3.47−3.35 (m, 4H), 3.23 (m, 2H), 2.91 (m, 2H), 2.79 (m, 2H), 2.69
(dd, J = 16.1, 9.6 Hz, 1H), 2.60 (dd, J = 16.2, 10.1 Hz, 1H), 1.40 (s,
3H), 1.34 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 176.3, 176.2,
170.1, 169.9, 136.0, 134.2, 133.5, 129.9, 129.0, 126.5, 126.3, 126.1,
126.0, 125.5, 125.0, 66.9, 66.8, 66.5, 66.4, 58.2, 56.8, 52.3, 52.0, 50.8,
49.4, 45.7, 42.5, 41.8, 40.9, 38.8, 37.9, 27.7, 22.4. HRMS (ESI): m/z
calcd for [M + H]+, 333.1809; found, 333.1810.
16a. Yellow oil. 0.103 g (0.263 mmol) from 0.095 g (0.36 mmol) of
compound 9b (73%). 1H NMR (400 MHz, CDCl3): δ 7.20−7.05 (m,
4H), 4.62 (dd, J = 9.6, 3.1 Hz, 1H), 4.30−4.10 (m, 4H), 3.42 (d, J =
15.7 Hz, 1H), 3.22 (d, J = 15.7 Hz, 1H), 2.94 (dd, J = 16.5, 3.4 Hz,
1H), 2.66 (dd, J = 16.5, 9.6, Hz, 1H), 1.68−1.58 (m, 2H), 1.44−1.34
(m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.94 (t, J =
7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 171.9, 170.2, 169.6,
135.8, 132.3, 128.8, 126.6, 126.5, 125.0, 65.9, 64.5, 62.0, 61.6, 50.5,
42.7, 34.2, 30.6, 19.1, 13.9, 13.6. HRMS (ESI): m/z calcd for [M +
H]+, 392.2068; found, 392.2073.
16b. Yellow oil. 0.160 g (0.506 mmol) from 0.167 g (0.63 mmol) of
compound 9b (80%). 1H NMR (400 MHz, CDCl3): δ 7.26−7.08 (m,
4H), 4.69 (m, 1H), 4.30−4.23 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.43
(d, J = 15.7 Hz, 1H), 3.31 (d, J = 15.7 Hz, 1H), 2.79 (dd, J = 16.5, 4.6
Hz, 1H), 2.69 (dd, J = 16.5, 6.8 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.07
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 170.4, 168.9,
133.9, 132.3, 129.2, 127.5, 127.1. 125.5, 117.8, 66.1, 62.3, 61.9, 51.2,
34.2, 28.1, 13.9, 13.9. HRMS (ESI): m/z calcd for [M + H]+,
317.1496; found, 317.1491.
14b. Yellow oil. 0.083 g (0.42 mmol) from 0.149 g (1.00 mmol) of
compound 4a (42%). 1H NMR (400 MHz, CDCl3): δ 7.23−7.05 (m,
4H), 4.40 (dd, J = 7.5, 3.8 Hz, 1H), 2.92 (dd, J = 16.5, 3.8 Hz, 1H),
2.82 (d, J = 15.7 Hz, 1H), 2.72 (dd, J = 16.5, 7.5 Hz, 1H) 2.53 (d, J =
15.8 Hz, 1H), 1.53 (br s, 1H), 1.28 (s, 3H), 1.08 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 135.3, 134.2, 129.9, 127.2, 126.2, 124.8, 118.2,
49.9, 49.4, 42.2, 31.4, 26.5, 24.8. HRMS (ESI): m/z calcd for [M +
H]+, 201.1386; found, 201.1387.
14c. Yellow oil. 0.060 g (0.21 mmol) from 0.075 g (0.50 mmol) of
compound 4a (42%). 1H NMR (400 MHz, CDCl3): δ 7.14−7.02 (m,
4H), 4.56 (dd, J = 9.2, 2.7 Hz, 1H), 3.68−3.39 (m, 8H), 2.93 (dd, J =
16.3, 2.7 Hz, 1H), 2.82 (d, J = 15.8 Hz, 1H), 2.67 (dd, J = 16.2, 9.2 Hz,
1H), 2.47 (d, J = 15.7 Hz, 1H), 2.90 (s, 3H), 2.85 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 170.1, 136.3, 135.2, 129.7, 126.2, 125.7, 124.8,
66.8, 66.4, 49.6, 48.9, 45.7, 42.4, 41.8, 40.5, 31.5, 24.2. HRMS (ESI):
m/z calcd for [M + H]+, 289.1911; found, 289.1915.
Synthesis of Hydroxylamines. A solution of amine (19.4 mmol)
in DMF (15 mL) was added to a suspension of benzoyl peroxide (3.68
g, 11.4 mmol) and K2HPO4 (2.98 g, 17.1 mmol) in DMF (60 mL),
and the mixture was stirred overnight at rt. Water was added, and the
contents were stirred for several minutes until all solids dissolved. The
mixture was extracted with AcOEt and the organic phase was washed
twice with a saturated aqueous solution of NaHCO3. The combined
aqueous fractions were extracted three times with AcOEt. The
combined organic phases were washed with brine. The organic
solution was dried over Na2SO4, filtered, and the solvent was
evaporated to give the crude hydroxylamine that was purified by flash
silica gel chromatography (hexane/ethyl acetate) to obtain the desired
product as a colorless oil.
15a. Yellow oil. 0.124 g (0.388 mmol) from 0.097 g (0.50 mmol) of
compound 9a (78%). Anti-15a: 1H NMR (400 MHz, CDCl3): δ 7.15−
7.04 (m, 4H), 4.59 (dd, J = 9.8, 3.0 Hz, 1H), 4.14 (m, 2H), 3.59 (s,
3H), 3.23 (d, J = 15.5 Hz, 1H), 2.96 (dd, J = 16.4, 3.0 Hz, 1H), 2.81
(d, J = 15.6 Hz, 1H), 2.60 (dd, J = 16.4, 9.8 Hz, 1H), 1.66−1.59 (m,
2H), 1.44 (s, 3H), 1.42−1.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C
20a. Colorless oil. 2.79 g (10.3 mmol) from 3.68 g (11.4 mmol) of
benzoyl peroxide (90%). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J =
7.7 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.35−
G
DOI: 10.1021/acs.organomet.6b00944
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Organometallics
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7.20 (m, 5H), 2.88 (s, 2H), 1.99 (s, 6H). 13C NMR (101 MHz,
CDCl3): δ 166.1, 137.5, 133.3, 130.6, 129.4, 128.6, 128.3, 126.7, 58.7,
45.2, 24.6. HRMS (ESI): m/z calcd for [M + H]+, 270.1489; found,
270.1493.
177−185. (i) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem.
Soc. Rev. 2011, 40, 4740−4761.
(2) For some recent reports on palladium-catalyzed ligand-directed
́
processes: (a) Testa, C.; Gigot, E.; Genc, S.; Decreau, R.; Roger, J.;
20b. Colorless oil. 1.21 g (4.07 mmol) from 1.74 g (5.38 mmol) of
benzoyl peroxide (76%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J =
7.7 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50−7.44 (m, 2H), 7.31−7.21
(m, 5H), 2.87 (s, 2H), 1.60−1.40 (m, 4H), 0.98 (t, J = 7.5, 6H). 13C
NMR (101 MHz, CDCl3): δ 165.8, 136.9, 133.1, 130.4, 129.2, 128.5,
128.2, 126.4, 63.1, 40.3, 25.6, 7.6. HRMS (ESI): m/z calcd for [M +
H]+, 298.1802; found, 298.1806.
General Method for the Reaction of Hydroxylamines with
Michael Acceptors. Butyl acrylate (93 μL, 0.65 mmol) was added to
a suspension of the O-benzoylhydroxylamine (0.54 mmol) and
Pd2(dba)3 (25 mg, 0.027 mmol) in acetic acid (3 mL). The mixture
was stirred at 100 °C for 3 h. Toluene was added, and the solution was
filtered through a pad of Celite. The solvents were removed under
vacuum, the crude mixture was dissolved in CH2Cl2, and a saturated
aqueous solution of Na2CO3 was added. The aqueous phase was
extracted three times with CH2Cl2, the collected organic phases were
dried over MgSO4, filtered, and the solvent was removed under
vacuum.
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The crude yellow oil was purified by flash column chromatography
on silica gel (CH2Cl2/MeOH or hexane/AcOEt) to give the
corresponding tetrahydroisoquinoline.
12a. 0.140 g (0.460 mmol) from 0.160 g (0.540 mmol) of
compound 20b (86%).
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13b. 0.080 g (0.35 mmol) from 0.160 g (0.540 mmol) of
compound 20b (65%).
14b. 0.067 g (0.34 mmol) from 0.165 g (0.610 mmol) of
compound 20a (55%).
14c. 0.129 g (0.448 mmol) from 0.150 g (0.560 mmol) of
compound 20a (80%).
ASSOCIATED CONTENT
* Supporting Information
■
S
(4) (a) Suzuki, C.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2013,
15, 3990−3993. (b) Suzuki, C.; Morimoto, K.; Hirano, K.; Satoh, T.;
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00944.
(5) (a) He, H.; Liu, W.-B.; Dai, L.-X; You, S.-L. J. Am. Chem. Soc.
2009, 131, 8346−8347. (b) Ye, K.-Y.; He, H.; Liu, W.-B.; Dai, L.-X.;
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(6) Jiang, Q.; Duan-Mu, D.; Zhong, W.; Chen, H.; Yan, H. Chem. -
Eur. J. 2013, 19, 1903−1907.
1H and 13C NMR spectra of compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: xariza@ub.edu.
*E-mail: jordigarciagomez@ub.edu.
■
(7) Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.; Dong, G.
Angew. Chem., Int. Ed. 2016, 55, 9084−9087.
(8) Albert, J.; Ariza, X.; Calvet, T.; Font-Bardia, M.; Garcia, J.;
Granell, J.; Lamela, A.; Lop
A.; Santos, D. Organometallics 2013, 32, 649−659.
(9) Garcia-Lopez, J.-A.; Oliva-Madrid, M.-J.; Saura-Llamas, I.;
́
ez, B.; Martinez, M.; Ortega, L.; Rodriguez,
ORCID
Jordi Garcia: 0000-0001-9379-2577
Notes
The authors declare no competing financial interest.
́
Bautista, D.; Vicente, J. Organometallics 2012, 31, 6351−6364.
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Chem. Biol. 2010, 14, 347−361. (b) Scott, J. D.; Williams, R. M. Chem.
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ACKNOWLEDGMENTS
■
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This work was supported by the Generalitat de Catalunya
(2009SGR1037 and 2014SGR107) and the Spanish Ministerio
de Economia y Competitividad (CTQ2009-09692, CTQ2015-
65040-P, SAF2014-52223-C2-1-R, and fellowship to A.M.).
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