Exploring Partners for the Domino α-Arylation/Michael Addition Reaction Leading to Tetrahydroisoquinolines

Article abstract of DOI:10.1002/ejoc.201601300

Sulfonates, sulfonamides, and phosphonates have proven useful nucleophiles for palladium-catalyzed intramolecular α-arylation reactions leading to tetrahydroisoquinolines. Although the sulfonate α-arylation reaction can be successfully combined in a domino process with a broad range of Michael acceptors, only vinyl sulfones can be used in Michael additions when starting from sulfonamides. No domino process was developed with the phosphonate derivative. DFT calculations were carried out to gain more insights into the experimental differences observed in the reactions involving these substrates.

Full text of DOI:10.1002/ejoc.201601300

A Journal of
Accepted Article
Title: Exploring new partners for the domino alfa-arylation/Michael addition reaction
leading to tetrahydroisoquinolines
´
´
´
Authors: Daniel Sole; Ferran Perez-Janer; Yago Garc´ıa-Rodeja; Israel Fernandez
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European Journal of Organic Chemistry
10.1002/ejoc.201601300
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Exploring New Partners for the Domino -Arylation/Michael
Addition Reaction Leading to Tetrahydroisoquinolines
Daniel Solé,*[a] Ferran Pérez-Janer,[a] Yago García-Rodeja,[b] and Israel Fernández*[b]
Abstract: Sulfonates, sulfonamides and phosphonates are useful
nucleophiles for palladium-catalyzed intramolecular -arylation
leading to tetrahydroisoquinolines. While the sulfonate -arylation
can be successfully combined in a domino process with a broad
range of Michael acceptors, only vinyl sulfones can be used in
Michael additions when starting from sulfonamides. No domino
process was developed with the phosphonate derivative. Density
functional theory (DFT) calculations were carried out to gain more
insight into the experimental differences observed in the reactions
involving these substrates.
heterocycles, we were interested in exploring the feasibility of
other electron-withdrawing groups in the domino -
arylation/Michael addition strategy.
In this paper, we expand our previous studies towards the
use of sulfonates, sulfonamides[6] and phosphonates[7] as
nucleophiles in the -arylation[8] step of the domino process
leading to tetrahydroisoquinolines[9] (Scheme 1). The combined
experimental and computational study of these reactions
establishes the scope and limitations of these electron-
withdrawing groups as alternatives to sulfones.
Introduction
In the continuous search for more environmentally friendly
reaction processes, domino reactions have emerged as a
powerful tool for synthetic organic chemists.[1] Ideally,
a
multicomponent domino process would simply involve the mixing
of all the reagents, which would then participate
chemoselectively in a particular sequence of events leading to
the final product without requiring any additional modification of
the reaction conditions.[2] The advantages of domino strategies
Scheme 1. Domino -arylation/Michael addition process.
include lower costs,
purification, and often higher overall reaction yields.
a more expeditious procedure, less
Results and Discussion
In the last years, different domino processes combining
palladium-catalyzed transformations with Michael addition
reactions have been developed for the synthesis of a variety of
aza-heterocycles.[3] In this context, we have recently reported
In our previous work on the -arylation/Michael addition
domino process, we realized that the Pd-catalyzed reaction
constituted the most challenging step of the entire
transformation. Thus, we first examined the -arylation of
sulfonate 1a, sulfonamides 1b and 1d, and phosphonate 1c
(Table 1).
Treatment of 1a with Pd2(dba)3/xantphos as the catalyst
and K3PO4 as the base in THF, an effective combination for the
intramolecular -arylation of -amino sulfones,[4] afforded
tetrahydroisoquinoline 2a in a modest 27% yield (entry 1). While
exchanging the solvent for toluene increased the yield up to 45%
(entry 2), changing the base to Cs2CO3 resulted in the complete
decomposition of the material. In this context, it should be noted
that 2a was rather unstable and partially decomposed during the
chromatographic purification, as evidenced by the isolation of
significant amounts of phenol.
The reaction of sulfonamide 1b using the couple
Pd2(dba)3/xantphos and K3PO4 in THF led to the desired
tetrahydoisoquinoline 2b in 46% yield (entry 3). Interestingly,
performing the -arylation of 1b using Cs2CO3 as the base
afforded 2b in 75% yield (entry 4). Treatment of phosphonate 1c
under the same reaction conditions gave 2c in 61% yield (entry
5). The use of PPh3 as the ligand instead of xantphos afforded a
similar result (entry 6), while PCy3 increased the yield
considerably up to 80% (entry 7). The use of K3PO4 as the base,
efficient
syntheses
of
highly
functionalized
tetrahydroisoquinolines[4] and indoles[5] by domino aza-
Michael/Pd-catalyzed -arylation/Michael addition processes
based on the use of sulfones both as electrophiles and
nucleophiles. To further generalize the application of these
synthetic methodologies and access diversely functionalized
[a]
D. Solé, F. Pérez-Janer
Laboratori de Química Orgànica, Facultat de Farmàcia,
Universitat de Barcelona
Av. Joan XXIII 27-31, 08028 Barcelona, Spain
E-mail: dsole@ub.edu
http://www.ub.edu/farmaco/ca/quimica/llistat_recerca
Y. García-Rodeja, I. Fernández
[b]
Departamento de Química Orgánica I, Facultad de Ciencias
Químicas,
Universidad Complutense de Madrid
Ciudad Universitaria, 28040 Madrid, Spain
E-mail: israel@quim.ucm.es
http://www.ucm.es/info/biorgmet/espanol/isra.html
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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maintaining the same combination of Pd source and ligand,
resulted in a slower reaction (entry 8).
(entry 1). A similar reaction was observed when using methyl
vinyl sulfone as the Michael acceptor, which afforded 3ab in
70% yield (entry 2). The -arylation/conjugated addition tandem
process was also possible when using methyl acrylate, phenyl
ethenesulfonate and N,N-dibenzylethenesulfonamide, which
allowed us to prepare 3ac, 3ad, and 3ae, respectively, in
moderate yields (entries 3-5). It should be noted that, except
when using N,N-dibenzylethenesulfonamide as the Michael
acceptor, the domino reactions from 1a proceeded with higher
yields than the -arylation, confirming that the observed lower
yield of the latter is partially due to the degradation of the
arylated sulfonate 2a under the reaction conditions.
Table 1. Pd-catalyzed -arylation of 1a-c.[a]
Table 2. Tandem -arylation/Michael addition reactions.[a]
Entry
1
[Pd]/ligand
(mol%)
Base
Solvent
THF
Products
(yield)[b]
1
2
3
4
5
1a
1a
1b
1b
1c
Pd2(dba)3 (7.5)
xantphos (15)
K3PO4
K3PO4
K3PO4
Cs2CO3
Cs2CO3
2a (27%)[c]
2a (45%)[c],[d]
2b (46%)[e]
2b (75%)
Pd(PPh3)4 (10)
xantphos (10)
toluene
THF
Entry
Z
Y
[Pd]/ligand
Base
Products
(yield)[b]
Pd2(dba)3 (7.5)
xantphos (15)
1
2
3
4
5
6
7
SO3Ph
SO3Ph
SO3Ph
SO3Ph
SO3Ph
SO2NBn2
SO2NBn2
SO2Ph
SO2Me
CO2Me
SO3Ph
SO2NBn2
SO2Ph
SO2Me
Pd2(dba)3
xantphos
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
Cs2CO3
3aa
(68%)
Pd2(dba)3 (7.5)
xantphos (15)
THF
2c (61%)[e]
Pd2(dba)3
xantphos
3ab
Pd2(dba)3 (7.5)
xantphos (15)
THF
(70%)[c]
6
7
1c
1c
Pd(PPh3)4 (10)
Cs2CO3
Cs2CO3
THF
THF
2c (59%)[e]
2c (80%)
Pd2(dba)3
xantphos
3ac
(43%)[c]
Pd2(dba)3 (7.5)
PCy3 (15)
Pd2(dba)3
xantphos
3ad
(50%)
8
1c
Pd2(dba)3 (7.5)
PCy3 (15)
K3PO4
THF
1c:2c
(1:2.5)[f]
Pd2(dba)3
xantphos
3ae
(25%)
[a] Reaction conditions: [Pd]/ligand (see table), base (3 equiv.) in the indicated
solvent at 120ºC for 72 h in a sealed tube. [b] Yield refers to products isolated
by chromatography. [c] Significant amounts of phenol were observed in the
reaction mixture. [d] A similar result was obtained when using Pd(PPh3)4 (15)
and xantphos (15) as the catalyst; however, the higher amount of PPh3 ligand
hindered the isolation and purification of 2a. [e] Significant amounts of the
corresponding hydrodehalogenation product were observed in the reaction
mixture. [f] 1H NMR ratio, yields were not quantified.
Pd(PPh3)4
Pd(PPh3)4
3ba
(74%)
3bb
(67%)[c]
[a] Reaction conditions: [Pd] (10%), ligand (10%), base (3 equiv.), and Michael
acceptor (1.5 equiv.) in THF at 120ºC in a sealed tube for 72 h. [b] Yield refers
to products isolated by chromatography. [c] Michael acceptor (3 equiv.).
Finally, sulfonamide 1d, which has an acidic H atom at the
nitrogen, failed to undergo a similar -arylation, and was
recovered unaltered under all explored reaction conditions.
The results in Table 1 show that sulfonates, sulfonamides
as well as phosphonates can undergo -arylation and,
consequently, they are all potential candidates for the proposed
domino cascades. We therefore decided to explore the -
arylation/Michael addition domino process using these
substrates with a variety of Michael acceptors (Table 2).
In the tandem reactions, sulfonamide 1b afforded parallel
results to sulfonate 1a with phenyl vinyl sulfone and methyl vinyl
sulfone (entries 6-7), but no product was formed when using
methyl
acrylate,
phenyl
ethenesulfonate
and
N,N-
dibenzylethenesulfonamide as the Michael acceptor, and only
the -arylation product 2b was isolated. Similarly, phosphonate
1c also failed to undergo the -arylation/conjugated addition
tandem process with any of the Michael acceptors explored
herein. Once again, the corresponding -arylation compound 2c
was the only product isolated in the reaction mixtures.
Gratifyingly, treatment of sulfonate 1a with a catalytic
amount of Pd(PPh3)4/xantphos and K3PO4 in the presence of
phenyl vinyl sulfone in THF afforded sulfonate 3aa in 68% yield
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European Journal of Organic Chemistry
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It is noteworthy that in all domino reactions with 1a and 1b,
the-arylation took place without any interference from the
competing Heck reaction, which agrees with the unfeasibility
previously observed for this particular pathway when using
sulfones in the domino process.[5]
According to our previous study involving 2-iodoanilines
and sulfones,[5] two alternative reaction pathways for the above
palladium-catalyzed -arylation reactions leading to the
observed tetrahydroisoquinolines 2 can be envisaged: the direct
base-mediated -arylation reaction and a concerted metalation-
deprotonation (CMD) C–H activation process. The competition
between the two pathways in the reactions involving the new
nucleophiles was explored computationally by means of density
functional theory calculations.[10] To this end, we computed the
corresponding reaction profiles starting from INT0, the
intermediate formed after a model benzylamine derivative (in
which the benzyl group attached to the nitrogen atom was
replaced by a methyl group) underwent oxidative addition to the
model Pd(PMe3)2 catalyst, in the presence of carbonate as the
base.
Figure 1. Computed reaction profiles for the palladium catalyzed α-arylation reaction of INT0A. Relative free energies (ΔG, at 298 K) and bond distances are
given in kcal/mol and angstroms, respectively. All data were computed at the PCM(tetrahydrofuran)-B3LYP-D3/def2-TZVP//PCM(tetrahydrofuran)-B3LYP-
D3/def2-SVP level.
Figure 1 shows the reaction profiles for the process
involving INT0A (Z = SO3Ph). The base-mediated -arylation
pathway (in blue) begins with the base-mediated deprotonation
of the acidic hydrogen atom at the carbon atom linked to the
sulfonate group, therefore leading to the carbanionic
intermediate INT1A in a strongly exergonic process (ΔGR = –
28.1 kcal/mol). This species would then evolve to complex
take place to produce the tetrahydroisoquinoline 2MA. This
exergonic step (ΔGR = –13.8 kcal/mol) proceeds via TS1A, a
transition state associated with the direct formation of the new
C−C bond, with a relatively high activation barrier of 28.2
kcal/mol. A similar activation barrier of 28.6 kcal/mol was
computed for the strongly related direct -arylation reaction
involving 2-iodoaniline derivatives with Z = SO2Me,[5] thus
indicating that neither the substrate nor the Z group has a
significant influence on this reaction step. Alternatively, INT2A
can be transformed into the coordinatively unsaturated complex
INT3A by releasing the iodide ligand in an endergonic process
(ΔGR = 6.5 kcal/mol). This species would be then converted into
INT2A by the slightly endergonic (ΔGR
= 5.6 kcal/mol)
coordination of the carbanion to the transition metal and
concomitant release of a phosphine ligand. This step typically
proceeds with the initial endergonic release of the phosphine
ligand to produce a coordination vacant which is then saturated
by the carbanionic ligand. The latter intramolecular coordination
is typically associated with a low barrier (< 10 kcal/mol)[11] and
therefore, it does not constitute the rate-limiting step of the
transformation. The reductive elimination reaction would then
the final reaction product 2MA in
a
highly exergonic
transformation (ΔGR = –20.3 kcal/mol) through TS3A with a
much lower activation barrier of 14.2 kcal/mol.
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European Journal of Organic Chemistry
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The alternative reaction pathway involving the C–H
activation begins with the also highly exergonic (ΔGR = –30.4
kcal/mol) replacement of the iodide and phosphine ligand in
These calculations indicate that the -arylation of sulfonate
1a in the presence of Cs2CO3 could proceed through the two
competing mechanisms sharing the common intermediate
INT3A, from which the reductive elimination affords the
tetrahydroisoquinoline. As no -arylation product was isolated in
the reactions of 1a when using Cs2CO3 as the base, we can
conclude that the failure of the transformation has to be due to
the instability of the arylated sulfone under the reaction
conditions. In contrast, the -arylation of 1a did take place when
using K3PO4 as the base, and in this case, the reaction should
follow the base-mediated pathway through INT1A.
Similar conclusions (i.e. preference of the C–H activation)
can be drawn for the analogous system with the phosphonate
substituent (Z = PO(OMe)2 in the calculations, see Figure S1 in
the Supporting Information). In this particular transformation,
although the CMD step proceeds with a higher activation barrier
of 16.5 kcal/mol, this pathway is still preferred over the direct -
arylation reaction. Indeed, the corresponding transition state for
the latter process (TS1C) lies 17.8 kcal/mol above that
associated with the CMD reaction (TS2C, see Figure S1).
Thus, starting from phosphonate 1c and using Cs2CO3, the
-arylated product 2c could be formed by both competing
mechanisms, while in the presence of K3PO4, only the base-
mediated -arylation pathway would be operative.
–2
INT0A by the bidendate CO3 ligand, thus forming the anionic
complex INT4A. A concerted metalation deprotonation (CMD)
C–H activation reaction assisted by the carbonate ligand then
occurs to produce INT5A in a slightly endergonic transformation
(ΔGR = 2.6 kcal/mol). Strikingly, this reaction step proceeds with
an activation barrier of only 9.6 kcal/mol (via TS2A), which is
much lower than that computed not only for the direct -arylation
via TS1A (see above) but also for the analogous process
involving 2-iodoaniline derivatives with Z = SO2Me (∆G = 26.1
–
kcal/mol).[5] Subsequent release of the HCO3 ligand would
produce INT3A which, as mentioned above, readily evolves to
the final reaction product via TS3A. Although, based on the
computed relative activation barriers, our calculations suggest
that the CMD pathway is strongly favored for the benzylamine
derivative
with
Z
=
SO3Ph,
the
alternative
INT1AINT2AINT5A or INT1AINT2AINT3A pathways
cannot be completely discarded.
We also explored the analogous C–H activation/reductive
elimination sequence from INT6A, the intermediate formed upon
coordination of the benzylic nitrogen atom to the transition metal
in INT4A. However, the CMD reaction pathway from INT6A can
be considered as non-competitive in view of the much higher
activation barrier (∆G = 28.2 kcal/mol) and endergonicity (ΔGR =
14.3 kcal/mol, from INT6A) computed for the corresponding
CMD reaction via TS4A (see Figure 1).
The scenario involving the sulfonamide group (Z
=
SO2NMe2 in the calculations) is slightly different to that found for
Z = SO3Ph or PO(OMe)2 (see Figure 2).
Figure 2. Computed reaction profiles for the palladium catalyzed α-arylation reaction of INT0A. Relative free energies (ΔG, at 298 K) and bond distances are
given in kcal/mol and angstroms, respectively. All data were computed at the PCM(tetrahydrofuran)-B3LYP-D3/def2-TZVP//PCM(tetrahydrofuran)-B3LYP-
D3/def2-SVP level.
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European Journal of Organic Chemistry
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Indeed, in this case, the corresponding CMD reaction step Conclusions
proceeds with a much higher activation barrier (∆G = 35.5
kcal/mol, via TS2B), which makes this process unlikely. This is
in part due to the higher C–H bond strength in INT4B than in
INT4A, as confirmed by the corresponding computed Wiberg
bond indices (0.89 and 0.86 for INT4B and INT4A, respectively)
and more likely due to higher pKa of the R–CH2–SO2NMe2
species as compared to R–CH2–SO3Ph.[12] Therefore, the
preferred -arylation pathway when Z = SO2NMe2 seems to be
INT0B  INT1B  INT2B  INT3B  TS3B  2MB. In this
particular case, it can also be suggested that the nitrogen atom
of the sulfonamide can coordinate the transition metal in the
coordinatively unsaturated complex INT3B. However, although
such coordination is strongly exergonic (ΔGR = –11.3 kcal/mol),
the corresponding reductive elimination reaction via TS3B’
proceeds with a much higher activation barrier (∆G = 28.7
In summary, this joint experimental-computational comparative
study has established the feasibility of using different
nucleophiles and Michael acceptors in the domino -
arylation/Michael
addition
process
leading
to
tetrahydroisoquinolines. Our calculations indicate that two
competing mechanisms, namely the direct base-mediated -
arylation reaction and a concerted metalation-deprotonation
(CMD) C–H activation process, can be operative in the -
arylation step of sulfonates and phosphonates when using
Cs2CO3 as the base. In contrast, in the sulfonamide reaction, the
base-mediated process seems to be preferred over the
concerted metalation-deprotonation pathway. Our study also
indicates that the success of the two-step domino process is
strongly related to the electrophilicity of the Michael acceptor.
Main Text Paragraph.
kcal/mol) than the analogous process involving TS3B (∆G
=
15.9 kcal/mol).
Finally, we investigated the reasons for the observed lower
yields in the domino reactions involving methyl acrylate (43%) or
N,N-dibenzylethenesulfonamide (25%) with respect to vinyl
sulfones (ca. 70%) as Michael acceptors (see Table 2). As
shown in Figure 3, the computed activation barriers involving Y =
CO2Me (∆G = 19.7 kcal/mol) or Y = SO2NMe2 (∆G = 21.6
kcal/mol) are clearly higher than that computed for the Michael
addition reaction involving the vinyl sulfone (Y = SO2Ph, ∆G =
15.8 kcal/mol). This can be ascribed to the relative
electrophilicity of the Michael acceptor, which can be roughly
estimated by the relative energy of the corresponding LUMO: –
1.64 eV (Y = SO2Ph) > –1.49 eV (Y = CO2Me) > –1.11 eV (Y =
SO2NMe2). Therefore, the experimentally observed reactivity
trend is very likely related to the relative electrophililicity of the
Michael acceptor used in the -arylation/Michael addition
domino process.
Experimental Section
General Remarks: All commercially available reagents were used
without further purification. All nonaqueous reactions were carried out
under an argon atmosphere. TLC was carried out on SiO2 (silica gel 60
F254, Merck), and the spots were located with UV light, 1% iodoplatinate
reagent or 1% aqueous KMnO4. Flash chromatography was carried out
on SiO2 (silica gel 60, SDS, 230-400 mesh ASTM). Drying of organic
extracts during workup of reactions was performed over anhydrous
Na2SO4. Solvents were evaporated with a rotatory evaporator. 1H- and
13C-NMR spectra were recorded using Me4Si as the internal standard,
with a Varian Mercury 400 instrument. Chemical shifts are reported in
ppm downfield (δ) from Me4Si for 1H- and 13C- NMR. HRMS were
obtained using a LC/MSD TOF mass spectrometer.
Typical Method for the Pd(0)-Catalyzed -Arylation Reaction (Table
1, Entry 4). A mixture of sulfonamide 1b (75 mg, 0.123 mmol), Pd2(dba)3
(8 mg, 0.009 mmol), xantphos (11 mg, 0.018 mmol), and Cs2CO3 (120
mg, 0.37 mmol) in THF (8 mL) was stirred at 120 ºC in a sealed tube for
72 h. The reaction mixture was partitioned between saturated NaHCO3
aqueous solution and Et2O. The organic extracts were dried and
concentrated. The residue was purified by chromatography (CH2Cl2) to
give sulfonamide 2b (45 mg, 75%).
Phenyl 2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-sulfonate (2a).
Chromatography (SiO2, from hexanes to CH2Cl2). Orange oil. 1H NMR
(CDCl3, 400 MHz) δ 3.03 (dd, J = 13.0 and 4.2 Hz, 1H), 3.50 (d, J = 15.2
Hz, 1H), 3.71 (d, J = 12.8 Hz, 1H), 3.73 (ddd, J = 13.0, 4.2 and 1.0 Hz,
1H), 3.79 (d, J = 12.8 Hz, 1H), 3.94 (d, J = 15.2 Hz, 1H), 4.72 (t, J = 4.2
Hz, 1H), 6.99-7.02 (m, 2H), 7.09 (d, J = 7.4 Hz, 1H), 7.19-7.34 (m, 8H),
7.40 (d, 2H), 7.65 (d, J = 7.4 Hz, 1H), 13C NMR (CDCl3, 100.6 MHz) δ
51.4 (CH2), 55.2 (CH2), 62.3 (CH), 62.3 (CH2), 122.2 (2 CH), 125.4 (C),
126.8 (CH), 126.9 (CH), 127.3 (CH), 127.5 (CH), 128.5 (2 CH), 129.0
(CH), 129.2 (2 CH), 129.7 (2 CH), 130.5 (CH), 137.1 (C), 137.4 (C),
149.3 (C). HRMS (ESI-TOF) calcd. for C22H22NO3S: 380.1315 [M+H]+;
found: 380.1324.
Figure 3. Computed reaction profiles for the Michael addition reaction
involving 2MA and the different Michael acceptors. Relative free energies (ΔG,
at 298 K) are given in kcal/mol. All data were computed at the
PCM(tetrahydrofuran)-B3LYP-D3/def2-TZVP//PCM(tetrahydrofuran)-B3LYP-
D3/def2-SVP level.
N,N,2-Tribenzyl-1,2,3,4-tetrahydroisoquinoline-4-sulfonamide (2b).
Chromatography (SiO2, from CH2Cl2 to CH2Cl2-MeOH 1%). Brown oil. 1H
NMR (CDCl3, 400 MHz) δ 2.78 (dd, J = 12.8 and 4.4 Hz, 1H), 3.37 (d, J =
15.2 Hz, 1H), 3.57 (d, J = 12.8Hz, 1H), 3.69 (dd, J = 12.8 and 2.4 Hz, 1H),
3.78 (d, J = 12.8 Hz, 1H), 3.90 (d, J = 15.2 Hz, 1H), 4.12 (s, 4H), 4.50 (dd,
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European Journal of Organic Chemistry
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J = 4.4 and 2.4 Hz, 1H), 6.95-6.99 (m, 4H), 7.06-7.31 (m, 14H), 7.71 (d, J
= 7.6 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 52.1 (CH2), 52.3 (CH2),
55.2 (CH2), 63.0 (CH2), 64.9 (CH), 126.6 (C), 126.7 (CH), 127.1 (CH),
127.4 (CH), 127.6 (CH), 128.2 (CH), 128.5 (CH), 128.6 (CH), 128.8 (CH),
129.7 (CH), 130.8 (CH), 136.4 (C), 136.6 (C), 136.7 (C). HRMS (ESI-
TOF) calcd. for C30H31N2O2S: 483.2101 [M+H]+; found: 483.2103.
J = 11.2, 8.0 and 5.2 Hz, 1H), 2.69 (ddd, J = 11.2, 8.0 and 5.2 Hz, 1H),
2.84 (ddd, J = 16.2, 11.2 and 5.2 Hz, 1H), 3.18 (dd, J = 12.4 and 1.6 Hz,
1H), 3.38 (d, J = 12.4 Hz, 1H), 3.58 (d, J = 14.8 Hz, 1H), 3.63 (s, 3H),
3.69 (d, J = 13.2 Hz, 1H), 3.70 (d, J = 14.8 Hz, 0031H), 3.74 (d, J = 13.2
Hz, 1H), 6.84 (m, 2H), 7.08 (dd, J = 7.6 and 1.2 Hz, 1H), 7.16-7.38 (m,
10H), 7.77 (dd, J = 7.6 and 1.2 Hz, 1H). 13C NMR (CDCl3, 100.5 MHz) δ
29.7 (CH2), 32.5 (CH2), 51.9 (CH3), 56.3 (CH2), 57.0 (CH2), 62.6 (CH2),
69.2 (C), 122.1 (2 CH), 126.8 (CH), 127.2 (CH), 127.3 (CH), 127.7 (CH),
128.4 (CH), 128.6 (2 CH), 128.7 (CH), 129.1 (C), 129.2 (2 CH), 129.6 (2
CH), 137.2 (C), 137.3 (C), 149.3 (C). 173.0 (C). HRMS (ESI-TOF) cald
for C26H28NO5S: 466.1683 [M + H]+; found: 466.1683.
Diethyl 2-benzyl-1,2,3,4-tetrahydroisoquinolin-4-ylphosphonate (2c).
Chromatography (SiO2, from CH2Cl2 to CH2Cl2/MeOH 4%). Yellow oil. 1H
NMR (CDCl3, 400 MHz) δ 1.16 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H),
2.86 (ddd, J = 25.2, 11.6 and 4.8 Hz, 1H), 3.29 (td, J = 11.6 and 4.8 Hz,
1H), 3.42-3.51 (m, 2H), 3.64 (d, J = 13.2 Hz, 1H), 3.73 (dd, J = 15.2 and
1.6 Hz, 1H), 3.76 (d, J = 13.2 Hz, 1H), 3.84-4.09 (m, 4H), 6.98 (m, 1H),
7.11-7.19 (m, 2H), 7.24-7.41 (m, 5H), 7.54 (m, 1H). 13C NMR (CDCl3,
100.5 MHz) δ 16.4 (d, JC-P = 6.1 Hz, CH3), 16.5 (d, JC-P = 4.5 Hz, CH3),
Phenyl
2-benzyl-4-[2-(phenoxysulfonyl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-4-sulfonate (3ad). Yellow foam. 1H NMR
(CDCl3, 400 MHz) δ 2.93 (td, J = 12.4 and 3.2 Hz, 1H), 2.99 (td, J = 12.4
and 3.2 Hz, 1H), 3.11 (td, J = 12.4 and 3.2 Hz, 1H), 3.27 (s, 2H), 3.56 (d,
J = 15.2 Hz, 1H), 3.63 (d, J = 12.8 Hz, 1H), 3.72 (td, J = 12.4 and 3.2 Hz,
1H), 3.78 (d, J = 12.8 Hz, 1H), 3.82 (d, J = 15.2 Hz, 1H), 6.87 (m, 2H),
7.13 (dd, J = 7.6 and 0.8 Hz, 1H), 7.17-7.38 (m, 15H), 7.82 (dd, J = 8.0
and 1.2 Hz, 1H). 13C NMR (CDCl3, 100.5 MHz) δ 32.3 (CH2), 46.7 (CH2),
56.6 (CH2), 56.8 (CH2), 62.6 (CH2), 68.0 (C), 122.0 (2 CH), 122.1 (2 CH),
127.1 (CH), 127.4 (CH), 127.6 (CH), 127.7 (CH), 128.0 (CH), 128.1 (CH),
128.3 (C), 128.9 (2 CH), 129.2 (CH), 129.3 (2 CH), 129.8 (2 CH), 130.1
(2 CH), 136.7 (C), 137.1 (C), 149.0 (C), 149.1 (C). HRMS (ESI-TOF) cald
for C30H30NO6S2: 564.1509 [M + H]+; found: 564.1518.
38.9 (d, JC-P = 137.9 Hz, CH), 51.6 (d, JC-P = 4.6 Hz, CH2), 55.7 (d, JC-P
=
1.5 Hz, CH2), 62.1 (d, JC-P = 6.1 Hz, CH2), 62.2 (d, JC-P = 6.9 Hz, CH2),
62.8 (CH2), 126.3 (d, JC-P = 3.0 Hz, CH), 126.7 (d, JC-P = 3.0 Hz, CH2),
126.9 (d, JC-P = 2.3 Hz, CH2), 127.3 (s, CH), 128.3 (s, 2 CH), 129.4 (s, 2
CH), 129.6 (s, C), 129.7 (d, JC-P = 4.6 Hz, CH), 135.5 (d, JC-P = 6.9 Hz, C),
138.0 (s, C). HRMS (ESI-TOF) calcd. for C20H27NO3P: 360.1723 [M+H]+;
found: 360.1724.
Typical Method for the Domino Reactions (Table 2, Entry 1). A
mixture of sulfonate 1a (75 mg, 0.148 mmol), Pd(PPh3)4 (17 mg, 0.015
mmol), xantphos (8.5 mg, 0.015 mmol), phenyl vinyl sulfone (37 mg, 0.22
mmol), and K3PO4 (94 mg, 0.44 mmol) in THF (8 mL) was stirred at 120
ºC in a sealed tube for 72 h. The reaction mixture was poured into water
and extracted with Et2O. The organic extracts were washed with brine,
dried, and concentrated. The residue was purified by flash
chromatography (SiO2, from CH2Cl2 to CH2Cl2-MeOH 1%) to give
sulfonate 3aa (55 mg, 68%).
Phenyl
2-benzyl-4-[2-(N,N-dibenzylaminosulfonyl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-4-sulfonate (3ae). Yellow oil. 1H NMR (CDCl3,
400 MHz) δ 2.68-2.79 (m, 2H), 2.88-2.99 (m, 1H), 3.07 (dd, J = 12.4 and
1.2 Hz, 1H), 3.26 (d, J = 12.4 Hz, 1H), 3.20-3.33 (m, 1H), 3.54 (d, J =
14.8 Hz, 1H), 3.61 (d, J = 13.2 Hz, 1H), 3.69 (d, J = 14.8 Hz, 1H), 3.71 (d,
J = 13.2 Hz, 1H), 4.22 (d, J = 15.2 Hz, 2H), 4.30 (d, J = 15.2 Hz, 2H),
6.85 (m, 2H), 7.09 (dd, J = 7.6 and 1.2 Hz, 1H), 7.17-7.35 (m, 20H), 7.71
(dd, J = 8.0 and 0.8 Hz, 1H). 13C NMR (CDCl3, 100.5 MHz) δ 31.7 (CH2),
49.7 (CH2), 50.3 (2 CH2), 56.5 (CH2), 57.0 (CH2), 62.6 (CH2), 68.4 (C),
122.0 (2 CH), 127.0 (CH), 127.4 (CH), 127.5 (CH), 127.8 (CH), 128.1 (2
CH), 128.3 (CH), 128.4 (C), 128.7 (2 CH), 128.8 (4 CH), 128.9 (4 CH),
129.0 (CH), 129.2 (2 CH), 129.7 (2 CH), 135.7 (2 C), 137.0 (C), 137.2 (C),
149.2 (C). HRMS (ESI-TOF) cald for C38H39N2O5S2: 667.2295 [M + H]+;
found: 667.2289.
Phenyl
2-benzyl-4-[2-(phenylsulfonyl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-4-sulfonate (3aa). Yellow foam. 1H NMR
(CDCl3, 400 MHz) δ 2.62 (td, J = 13.6 and 4.4 Hz, 1H), 2.80-2.91 (m, 2H),
3.13 (dd, J = 12.4 and 2.0 Hz, 1H), 3.26 (d, J = 12.4 Hz, 1H), 3.50 (ddd, J
= 14.4, 13.2 and 4.4 Hz, 1H), 3.53 (d, J = 15.6 Hz, 1H), 3.60 (d, J = 12.8
Hz, 1H), 3.73 (d, J = 15.6 Hz, 1H), 3.74 (d, J = 12.8 Hz, 1H), 6.79 (m, 2H),
7.09 (d, J = 7.6 Hz, 1H), 7.13-7.38 (m, 10H), 7.51-7.59 (m, 3H), 7.66 (tt, J
= 7.6 and 1.2 Hz, 1H), 7.79 (m, 2H). 13C NMR (CDCl3, 100.5 MHz) δ 31.2
(CH2), 52.1 (CH2), 56.6 (CH2), 57.0 (CH2), 62.7 (CH2), 68.1 (C), 121.9 (2
CH), 127.0 (CH), 127.4 (CH), 127.6 (CH), 127.9 (CH), 128.0 (CH), 128.1
(C), 128.2 (2 CH), 128.8 (2 CH), 129.1 (CH), 129.4 (2 CH), 129.5 (2 CH),
129.7 (2 CH), 134.0 (CH), 136.9 (C), 137.3 (C), 138.6 (C), 149.1 (C).
HRMS (ESI-TOF) cald for C30H30NO5S2: 548.1560 [M + H]+; found:
548.1567.
2,N,N-Tribenzyl-4-[2-(phenylsulfonyl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-4-sulfonamide (3ba). Yellow oil. 1H NMR
(CDCl3, 400 MHz) δ 2.63 (ddd, J = 13.6, 12.8 and 4.8 Hz, 1H), 2.79 (ddd,
J = 13.6, 12.8 and 3.6 Hz, 1H), 2.86 (d, J = 12.4 Hz, 1H), 2.89 (ddd, J =
13.6, 12.8 and 3.6 Hz, 1H), 3.16 (d, J = 12.4 Hz, 1H), 3.44 (d, J = 12.8
Hz, 1H), 3.49 (ddd, J = 13.6, 12.8 and 4.8 Hz, 1H), 3.49 (d, J = 14.8 Hz,
1H), 3.57 (d, J = 14.8 Hz, 1H), 3.70 (d, J = 12.8 Hz, 1H), 4.01 (broad s,
4H), 6.77 (d, J = 6.8 Hz, 4H), 7.06-7.35 (m, 14H), 7.55 (tt, J = 7.6 and 1.2
Hz, 2H), 7.65 (tt, J = 7.6 and 1.2 Hz, 1H), 7.76 (dd, J = 8.0 and 1.2 Hz,
1H), 7.83 (m, 2H). 13C NMR (CDCl3, 100.5 MHz) δ 31.6 (CH2), 52.4 (CH2),
52.5 (2 CH2), 56.4 (CH2), 57.1 (CH2), 63.0 (CH2), 69.7 (C), 127.4 (CH),
127.5 (CH), 127.6 (2 CH), 127.9 (CH), 128.2 (2 CH), 128.3 (4 CH), 128.5
(4 CH), 128.6 (CH), 128.8 (2 CH), 128.9 (CH), 129.5 (2 CH), 129.6 (C),
129.7 (2 CH), 133.9 (CH), 135.7 (2 C), 136.5 (C), 137.2 (C), 138.7 (C).
HRMS (ESI-TOF) cald for C38H39N2O4S2: 651.2346 [M + H]+; found:
651.2349.
Phenyl
2-benzyl-4-[2-(methylsulfonyl)ethyl]-1,2,3,4-
1
tetrahydroisoquinoline-4-sulfonate (3ab). Yellow Oil. H NMR (CDCl3,
400 MHz) δ 2.67-2.78 (m, 2H), 2.75 (s, 3H), 2.90-3.01 (m, 1H), 3.22 (dd,
J = 12.4 and 1.6 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 3.37-3.47 (m, 1H),
3.60 (d, J = 12.8 Hz, 1H), 3.61 (d, J = 14.8 Hz, 1H), 3.82 (d, J = 12.8 Hz,
1H), 3.83 (d, J = 14.8 Hz, 1H), 6.85 (m, 2H), 7.14 (dd, J = 8.0 and 1.2 Hz,
1H), 7.18-7.40 (m, 10H), 7.79 (dd, J = 8.0 and 1.2 Hz, 1H). 13C NMR
(CDCl3, 100.5 MHz) δ 31.1 (CH2), 40.5 (CH3), 50.7 (CH2), 56.5 (CH2),
56.9 (CH2), 62.6 (CH2), 68.1 (C), 122.0 (2 CH), 127.1 (CH), 127.5 (CH),
127.7 (CH), 128.0 (CH), 128.1 (CH), 128.5 (C), 128.9 (2 CH), 129.2 (CH),
129.6 (2 CH), 129.8 (2 CH), 137.0 (C), 137.2 (C), 149.1 (C). HRMS (ESI-
TOF) cald for C25H28NO5S2: 486.1403 [M + H]+; found: 486.1403.
2,N,N-Tribenzyl-4-[2-(methylsulfonyl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-4-sulfonamide (3bb). Yellow oil. 1H NMR
(CDCl3, 400 MHz) δ 2.73-2.91 (m, 3H), 2.81 (s, 3H), 2.94 (dd, J = 12.4
and 1.2 Hz, 1H), 3.18 (d, J = 12.4 Hz, 1H), 3.42-3.51 (m, 1H), 3.45 (d, J =
12.8 Hz, 1H), 3.55 (d, J = 14.8 Hz, 1H), 3.66 (d, J = 14.8 Hz, 1H), 3.77 (d,
J = 12.8 Hz, 1H), 4.08 (broad s, 4H), 6.80 (d, J = 6.4 Hz, 4H), 7.09-7.17
Phenyl
2-benzyl-4-[2-(methoxycarbonyl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-4-sulfonate (3ac). Pale yellow solid. 1H NMR
(CDCl3, 400 MHz) δ 2.22 (ddd, J = 16.2, 11.2 and 5.2 Hz, 1H), 2.65 (ddd,
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European Journal of Organic Chemistry
10.1002/ejoc.201601300
FULL PAPER
(m, 7H), 7.24-7.36 (m, 7H), 7.99 (dd, J = 7.6 and 1.6 Hz, 1H). 13C NMR
(CDCl3, 100.5 MHz) δ 31.7 (CH2), 40.4 (CH3), 50.9 (CH2), 52.4 (2 CH2),
56.6 (2 CH2), 62.9 (CH2), 69.7 (C), 127.4 (CH), 127.5 (CH), 127.6 (2 CH),
127.9 (CH), 128.3 (4 CH), 128.5 (4 CH), 128.6 (CH), 128.8 (2 CH), 129.0
(CH), 129.7 (2 CH), 130.0 (C), 135.7 (2 C), 136.5 (C), 137.1 (C). HRMS
(ESI-TOF) cald for C33H37N2O4S2: 589.2189 [M + H]+; found: 589.2199.
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taken into account using the hybrid functional usually denoted as
B3LYP[14] in conjunction with the D3 dispersion correction suggested by
Grimme and co-workers[15] using the double- quality plus polarization
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characterized by frequency calculations,[17] and have positive definite
Hessian matrices. Transition structures (TS’s) show only one negative
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associated eigenvectors were confirmed to correspond to the motion
along the reaction coordinate under consideration using the Intrinsic
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account using the Polarizable Continuum Model (PCM).[19] Single point
calculations on the PCM(THF)-B3LYP-D3/def2-SVP geometries were
performed to estimate the change in the Gibbs energies at the B3LYP-D3
level using the triple- quality plus polarization def2-TZVP basis set[16] for
all atoms. This level is denoted PCM(THF)-B3LYP-D3/def2-
TZVP//PCM(THF)-B3LYP-D3/def2-SVP.
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Acknowledgements
We gratefully acknowledge financial support for this work from
the MINECO-FEDER (CTQ2013-44303-P, CTQ2015-64937-R,
and CTQ2014-51912-REDC). Y.G.-R. acknowledges the
MINECO for a FPI grant.
[13] Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
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Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery,
Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
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Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
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D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D.
J. Fox, Gaussian, Inc., Wallingford CT, 2009.
Keywords: arylation • palladium-catalyzed • Domino reactions •
Nitrogen heterocycles • density functional calculations
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Entry for the Table of Contents (Please choose one layout)
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Domino -arylation/Michael
addition reactions: Sulfonates,
sulfonamides and phosphonates are
useful partners for the -
arylation/Michael addition process
leading to tetrahydroisoquinolines
Domino -arylation/Michael addition
reactions
Daniel Solé,* Ferran Pérez-Janer, Yago
García-Rodeja, and Israel Fernández*
Page No. – Page No.
Exploring New Partners for the
Domino -Arylation/Michael Addition
Reaction Leading to
Tetrahydroisoquinolines
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