Palladium-Catalyzed, Enantioselective Formal Cycloaddition between Benzyltriflamides and Allenes: Straightforward Access to Enantioenriched Isoquinolines

Article abstract of DOI:10.1021/jacs.8b12636

Benzyl and allyltriflamides can engage in Pd-catalyzed oxidative (4+2) annulations with allenes, to produce highly valuable tetrahydroisoquinoline or dihydropyridine skeletons. The reaction is especially efficient when carried out in the presence of designed N-protected amino acids as metal ligands. More importantly, using this type of chiral ligands, it is possible to perform desymmetrizing, annulative C-H activations of prochiral diarylmethylphenyl amides, and thus obtain the corresponding isoquinolines with high enantiomeric ratios.

Full text of DOI:10.1021/jacs.8b12636

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Communication
Palladium-catalyzed, enantioselective formal
cycloaddition between benzyltriflamides and allenes:
Straightforward access to enantioen-riched isoquinolines
Xandro Vidal, José L. Mascareñas, and Moisés Gulías
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12636 • Publication Date (Web): 13 Jan 2019
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Palladium-catalyzed, enantioselective formal cycloaddition between
benzyltriflamides and allenes: Straightforward access to
enantioenriched isoquinolines
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Xandro Vidal, José L. Mascareñas,* Moisés Gulías*
Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química
Orgánica. Universidade de Santiago de Compostela. 15782 Santiago de Compostela (Spain).
Supporting Information Placeholder
tetrahydroisoquinoline products can be assembled in an efficient
and highly enantioselective manner via desymmetrization of
prochiral starting materials (Scheme 1A). While several
desymmetrizing C-H activation/functionalization processes have
been described, especially under Pd-catalysis, 7,8,9 to the best of our
ABSTRACT: Benzyl and allyltriflamides can engage in Pd-
catalyzed oxidative (4+2) annulations with allenes, to produce
highly valuable tetrahydroisoquinoline or dihydropyridine
skeletons. The reaction is especially efficient when carried out in
presence of designed N-protected amino acids as metal ligands.
More importantly, using this type of chiral ligands, it is possible to
perform desymmetrizing, annulative C-H activations of prochiral
diarylmethylphenyl amides, and thus obtain the corresponding
isoquinolines with high enantiomeric ratios.
knowledge,
palladium-catalyzed
enantioselective
formal
cycloadditions relying on C-H activations are unknown.10
Moreover, the number of reports on any desymmetrizing metal-
mediated annulations involving C-H activations is marginal.11
Scheme 1. An asymmetric C-H activation/annulation
approach to isoquinoline skeletons
The metal-catalyzed functionalization of non-activated C–H bonds
has emerged as an extremely powerful synthetic tool.1 Moreover,
if the C-H activation is appropriately harnessed to encompass a
concomitant annulation reaction, the methodology allows a direct
assembly of cyclic skeletons from simple, non-functionalized
acyclic starting materials.2 In this context, we have reported several
Rh and Pd-catalyzed annulations of alkenylphenols and
alkenylanilides with different unsaturated partners. These
strategies allow to build a variety of heterocyclic products in a
straightforward manner.3 The use of allenes as annulation partners
is particularly attractive owing to their inherent reactivity, and
because they favor reductive elimination versus β-hydride
elimination steps in key metallacyclic intermediates.4
A. Desymmetrizing Annulation. Allenes favor the reductive elimination step.
Ar
Ar
R
R
Pd(II),[O], L*
NTf
R
Ar
+
·
NHTf
(4+2)
Ar
L*:2,6-F,F-Bz-Leu-OH
R
reductive
elimination
enantioselective
C-Hactivation
R
NTf
regioselective
diastereoselective
enantioselective
Pd
R
allene insertion
R
B. Natural products and drugs with the tetrahydroisoquinoline core.
OMe
O
Quinocarcin
Owing to this special reactivity, we wondered if allenes could
engage in annulative C–H functionalizations of benzyl- or
allylamines, as this would allow to build highly valuable
tetrahydroisoquinoline and tetrahydropyridine skeletons from
simple precursors. Achieving these transformations is far from
obvious, not only because of the difficulties associated to the C-H
activation and allene insertion steps, but also because of competing
benzylic or allylic oxidation reactions. Indeed, the only precedent
in this type of annulations involves the use of α,α-disubstituted
benzylamines (which can´t be oxidized) and monosubstituted
allenes, and provides mixtures of isomeric adducts.5,6
(antitumoral)
Me
N
H
HO
HO
N
H
MeO
MeO
N
CO2H
Me
N
Ph
O
Crispine A
(antitumoral)
N
N
O
Solifenacin
Apomorphine
(antimuscarinic)
(Parkinson)
Finally, it is important to note that tetrahydroisoquinoline skeletons
are privileged scaffolds present in a vast amount of bioactive
natural products and drugs (Scheme 1B), and therefore the
development of enantioselective approaches to these cyclic
products is of major significance.12
Herein, we report the discovery of conditions that allow to carry
out efficient Pd-catalyzed annulations between benzylamides and
allenes. The reaction works for α-unsubstituted and
monosubstituted benzyltriflamides, and different types of allene
partners, and takes place with excellent regio- and
stereoselectivities. The annulation can be extended to allyl and
even homoallylamines, thereby allowing to build dihydropyridine
and azepine skeletons. More importantly, we demonstrate that the
Considering our previous work on the annulation of alkenylanilides
and allenes under palladium catalysis,3e we began our research by
exploring the reaction between benzyltriflamide 1a and
vinylidenecyclohexane (2a) in presence of 1.5 equiv. of Cs2CO3,
and using Pd(OAc)2 as catalyst, and Cu(OAc)2 as reoxidant. With
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tert-amyl alcohol as solvent, the desired (4+2) cycloadduct was
Table 2. Pd(II)-catalyzed annulation of N-Benzyltrifli-mides
with allenesa
1
2
3
4
5
6
7
8
isolated in a modest 15% yield. The use of other solvents, at the
same temperature (80ºC), allowed for little improvements (up to
23-25% yield, Table 1, entries 1-5). Although the presence of the
triflyl substituent in the amine slows down the benzylic oxidation,
the formation of undesired benzylaldehyde was still significant.
While the addition of DMSO in toluene allowed a slight increase
in the yield to 34%, we found that adding protected amino acids
(entries 6-10), and especially 2,6-F,F-Bz-Leu-OH (L, 40 mol%),
boosts the yield up to 85% (entry 11). This could be further
improved by adding 15 equiv of DMSO to the reaction mixture
(95% yield, entry 12), with the reaction being complete after only
40 minutes. The role of the DMSO is unclear, but it may help to
stabilize Pd(0) intermediates, and therefore favor a more effective
reoxidation to Pd(II). Finally, the amount of Cu(OAc)2 can be
decreased to 50 mol% without significantly affecting the yield
(entry 13).
Pd(OAc)2 (10 mol%)
R1
R2
R4
R3
NTf
NHTf
L
(40 mol%)
+
·
Cu(OAc)2 (2 equiv)
Cs2CO3 (1.5 equiv)
toluene/DMSO, 90ºC
R4
R3
R2 R1
1a
2 equiv.
2a-h
3
NTf
NTf
NTf
Ph
NTf
Me
H
, 80%
NTf
H
9
nBu
nBu
Ph
iPr
Ph
Ph
3ae
(E:Z = 3.3:1)c
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3ab
3ac
3ad
, 85%
, 86%
, 74%
Et
NTf
Me
NTf
NTf
Me
Me
Table 1. Optimization of the reaction conditions.a
Ph
Ph
(E:Z = 1.1:1)c
, 85%
2a
(
)
·
O
3af
3ag
3ah
3ba,
91%, 93:7 er
, 80%
, 90%
F
NTf
Pd(OAc)2 (10 mol%)
NH
CO2H
NHTf
a
b
F
Cu(OAc)2·H2O (2 equiv)
Cs2CO3 (1.5 equiv), air
Solvent, T, Ligand
Isolated yield based on allenes, after 16h. E:Z and
c
regioisomeric ratios are >20:1, unless otherwise noted.
Inseparable isomers. Regioisomeric ratio determined by crude
1H-NMR.
3aa
1a
2 equiv.
L
)
2,6-F,F-Bz-Leu-OH (
Entry
1
Solvent
T
Ligandb
Yieldc
15%
23%
24%
9%
t-AmyOH
Dioxane
DCE
80 ºC
80 ºC
80 ºC
80 ºC
90ºC
90ºC
90ºC
90ºC
90ºC
90ºC
-
-
-
-
-
-
The reaction is not limited to unsubstituted benzyltriflamides, and
thereby -alkyl benzyltriflamides can participate in the
annulations, providing for efficient kinetic resolutions. Therefore,
treatment of 2 equiv of (1-phenylpropyl)triflamide (1b) with allene
2a, using standard conditions, produced a 91% yield of cycloadduct
3ba (45% yield based on the allene 2a, Table 2) with a very good
93:7 enantiomeric ratio (er). We also isolated a 40% yield of
enantioenriched starting amide (er = 86:14).
2
3
4
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
5
6d
25%
34%
37%
31%
58%
69%
7
Boc-Leu-NHOMe
Boc-Phe-NHOMe
Boc-Ala-OH
Table 3. Pd(II)-catalyzed annulation between N-allyl (and
8
homoallyltriflamides) and allenes.a
9
R1
R2
Pd(OAc)2 (10 mol%)
( )n
R3
R4
R5
R6
10
11
12d
13d
Boc-Val-OH
( )n
R1
NHTf
L
(40 mol%)
NTf
R6
+
·
90ºC 2,6-F,F-Bz-Leu-OH 85%
90ºC 2,6-F,F-Bz-Leu-OH 95%e
90ºC 2,6-F,F-Bz-Leu-OH 86%e,f
Cu(OAc)2 (2 equiv)
Cs2CO3 (1.5 equiv)
toluene/DMSO, 90ºC
R5
R2
R3
R4
1c-e
2a 2g
or
3
, n = 0,1
2 equiv.
a Conditions: 0.333 mmol 1a, 0.167 mmol of allene 2a, 2 mL
Me
NTf
NTf
NTf
of solvent, under air, 16h. b 40% of ligand. c Yields based on 2a,
NTf
Me
Me
d
calculated by using an internal standard. 15 equiv of DMSO
added. e Isolated yield based on 2a. f 0.5 equiv. of Cu(OAc)2·H2O
Ph
b
b,c
3ca
3da
3cg
3ea
, 83%
, 71%
, 88%
, 90%
Using the optimized conditions, we found that the reaction can be
extended to different types of allenes (see table 2). Thus, other 1,1-
dibsubstituted allenes like 5-vinylidenenonane (2b) or (4-
methylpenta-1,2-dien-3-yl)benzene (2c) led to the corresponding
isoquinolines 3ab and 3ac in 85 and 86% yield. 1,1’-Disubstituted
allenes 2d and 2e provided the corresponding adducts 3ad and 3ae,
as only one stereo- and regioisomer (80 and 74% yield,
respectively). Monosubstituted allenes like propa-1,2-dien-1-
ylcyclohexane also work, to give 3af as 1.1:1 mixture of E:Z
isomers. More impressively, trisubstituted allenes led to only one
cycloadduct in a very efficient manner (3ag and 3ah, 80 and 90%
yield, respectively). It is important to note that diphenylacetylene
or styrene failed to react with 1a under the standard reaction
conditions, which supports the special reactivity of allenes in this
type of palladium catalyzed annulations.
Isolated yields based on allenes 2 after 16h. 105 ºC. c An
equimolar amount of 1e and 2a was used.
a
b
Next, we wondered if the annulation could be extended to more
challenging triflamides bearing alkenyl instead of benzyl pendants.
Palladium-catalyzed activations of olefinic C(sp2)-H bonds has
been much less developed than that of their aromatic counterparts,
in part because of competing alkene addition reactions.
Gratifyingly, using the above conditions, allene 2a reacted
efficiently with allylamines 1c and 1d to produce the expected
tetrahydropyridines 3ca and 3da in 71 and 88% yield.13 This
reaction is general for other allenes as exemplified with
trisubstituted derivative 2g that led to the formation of 3cg in an
excellent 90% yield.
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Interestingly, in a rare example of a formal (5+2) annulation, the
unsubstituted benzyltriflamide (Table 2), we only observed the Z
1
2
3
4
5
6
7
8
transformation can be extended to homoallylic amines, as
demonstrated with the assembly azepine 3ea (83%). This
preliminary result proposes one of the more trivial and practical
entries to seven-membered azaheterocycles, and warrants further
future research to explore the scope of the process.
isomer.
Other prochiral substrates featuring different substituents at the aryl
moiety also participated in the annulation. Therefore, products like
3ga or 3gf, in which the phenyl groups have ortho methyl
substituents, were produced in excellent yields and with
enantiomeric ratios of 97:3 and 98:2. A crystal structure of 3ga
allowed to stablish the absolute configuration of the chiral center
(table 4). For the case of para substituted aromatic rings, the
reaction was also very efficient, and products 3ha, 3hb, 3ia and
3ib, were isolated in yields of 86-95% yields, and enantiomeric
ratios of up to 95:5. Finally, cycloadducts with methoxy
substituents in para or meta positions of the aromatic rings were
also efficiently formed (3ja and 3ka), although the enantiomeric
ratio slightly dropped to 90:10 for the latter.
Table 4. Enantioselective Pd(II)-desymmetrization of
diarylmethyltriflamide.a,b
Ar
Ar
9
Pd(OAc)2 (10 mol%)
R1
NTf
L
(40 mol%)
10
11
12
13
14
15
16
17
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20
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Ar
+
·
NHTf
Cu(OAc)2 (2 equiv)
Cs2CO3 (1.5 equiv)
toluene/DMSO, 90ºC
R2
Ar
R1 R2
3
1f-1k
2 equiv.
2
Ph
Scheme 2. Mechanistic proposal
Ph
Ph
Ph
NTf
NTf
NTf
NTf
Pd(OAc)2L2
O
NH OH
Cs2CO3
Ar
1
nBu
nBu
H
iPr
Ph
L
O
R
O
O
N
E:Z = 1:4.9
Cu(OAc)2
Pd
O
-
3fc,c 66% yield
3ff, 81% yield
HCO3
L
R
3fa
3fb, 95% yield
, 85% yield
Cs2CO3
94:6 er
95:5 er
93:7 er
Me Ar
O
95:5 er
CF3
Ar
S
Me Ar
N
O-Cs
NTf
base
L = AcOH or DMSO
O
NTf
Pd
N
NTf
L
L
H
O
3gae
Pd
R2
O
O
CF3
R1
R
S
Ar
N
3
I
O-Cs
Pd
L
O
R
HO
HN
OCOR
Tf
3gf d
IIa
,
95% yield
3ga d
,
66% yield
N
98:2 er
97:3 er
Pd
L
O
Ar
NTf
Pd
Ar
Ar
Ar
Ar
L
R1
MeO
R2
L
NTf
NTf
MeO
NTf
L
NTf
Cl
NTf
IV
IIb
R1
R2
Pd
L
R1
R2
Me
·
III
·
R
R
R
R
3ia
, R = -(CH2)5-,
3ha
, R = -(CH2)5-,
93% yield, 91:9 er
95% yield, 94:6 er
3ja
3ka
, 90% yield
90:10 er
, 93% yield
94:6 er
A hypothetical catalytic cycle depicted in Scheme 2 allows to
infer key elements that are critical for the success of the above
annulations. The triflyl group should favor deprotonation at the
nitrogen, and the formation of intermediates like I, in which
eliminations of benzylic hydrogens might be not especially easy.14
The amino acid ligand likely plays a key role in facilitating the C-
H activation to give palladacycle IIb, which after coordination of
the allene would form intermediate III. This intermediate evolves
by migratory insertion to give a π-allylic palladacycle (IV), which
undergoes a N-Csp2 reductive elimination, favored by the presence
of the coordinating exo-alkene group. Pd(0) is reoxidized to the
active Pd(II) catalyst through a combination of Cu(OAc)2 and air.
3ib
, R = nBu,
3hb
, R = nBu,
92% yield, 95:5 er
86% yield, 91:9 er
a Conditions: 0.333 mmol of amides 1, 0.167 mmol of allenes
b
2, under air, 16h. Isolated yields based on 2. Structure of the
major product shown. E:Z and regioisomeric ratios are >20:1,
c
d
unless otherwise noted. 70 ºC, 3 days. 0.167 mmol of
triflamide 1g, 0.333 mmol of allenes 2a and 2d. Yield based on
e
1g. Hydrogens omitted for clarity. Note: Ar represents the
same aromatic ring than that undergoing the transformation, as
corresponds for a symmetric substrate
In the case of the desymmetrization process, the palladacycle
intermediate II is chiral, and the preferred formation of one of the
enantiomer over the other must be attributed to steric clashing
effects in the step from I to II, as proposed for simple
functionalization reactions.14
While the above examples demonstrate that using N-triflyl
protected amines and allenes it is possible to achieve very
appealing annulative C-H activations, the efficiency of the kinetic
resolution to give optically active isoquinoline 3ba, called for
exploring asymmetric variants based on desymmetrization
strategies. Gratifyingly, treatment of the diphenylmethylamide 1f
with allene 2a, under standard conditions at 90 ºC, gave the
expected cycloadduct 3fa with an excellent 85% yield and a very
good 94:6 enantiomeric ratio. Similar results were obtained with
other disubstituted allenes such 2b and 2c, which gave the products
3fb and 3fc with yields between 66 and 95%, and 95:5 er ratios.
Remarkably, using a monosubstituted allene (propa-1,2-dien-1-
ylcyclohexane, 2f) we obtained an excellent yield (81%) and er
(93:7) of the adduct 3ff, and, contrary to the reaction with the
In conclusion, we have developed a straightforward access to
highly valuable tetrahydroisoquinoline and tetrahydropyridine
skeletons through
cycloaddition of benzyl and allylamines to allenes. The reaction
relies on a Pd-catalyzed C sp2 -H activation, and presents excellent
levels of chemo- and regioselectivity; being also highly appealing
in terms of atom economy. More important, the annulation can be
performed in an enantioselective fashion using prochiral
diarylmethylamines, leading to enantiomeric ratios up to 98:2. This
a
palladium-catalyzed formal (4+2)
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Del Rio, K. P.; García-Fandiño, R.; Mascareñas, J. L.; Gulías M. ACS
Catal., 2016, 6, 3349–3353. (e) Cendón, B., Casanova, N., Comanescu, C.,
García-Fandiño, R., Seoane, A., Gulías, M., Mascareñas, J. L. Palladium-
catalyzed formal (5 + 2) annulation between ortho-alkenylanilides and
allenes. Org. Lett, 2017, 19, 1674-1677. (f) Font, M.; Cendón, B.; Seoane,
A.; Mascareñas, J. L.; Gulías, M. Rhodium(III)‐catalyzed annulation of
2‐alkenylanilides with alkynes via C‐H activation: a direct access to
2‐substituted indolines. Angew. Chem. Int. Ed. 2018, 57, 8255-8259.
(4) For a discussion on the role of the geometry of the metal center and
the π-allyl system in favoring the reductive elimination see ref 3d.
(5) Rodríguez, A.; Albert, J.; Ariza, X.; Garcia, J.; Granell, J.; Farràs, J.;
La Mela, A.; Nicolás, E. J. Catalytic C–H activation of phenylethylamines
or benzylamines and their annulation with allenes. J. Org. Chem. 2014, 79,
9578-9585.
(6) For selected examples of metal-catalyzed C-H functionalization with
allenes, see: (a) Zeng, R.; Wu, S.; Fu, C.; Ma, S. Room-temperature
synthesis of trisubstituted allenylsilanes via regioselective C–H
functionalization. J. Am. Chem. Soc. 2013, 135, 18284−18287. (b)
Gandeepan, P.; Rajamalli P.; Cheng, C.-H. Rhodium(III)‐catalyzed [4+1]
annulation of aromatic and vinylic carboxylic acids with allenes: an
efficient method towards vinyl‐substituted phthalides and 2‐furanones.
Chem. - Eur. J. 2015, 21, 9198−9203. (c) Nakanowatari, S.; Ackermann, L.
Ruthenium(II)‐catalyzed C-H functionalizations with allenes: versatile
allenylations and allylations. Chem. - Eur. J. 2015, 21, 16246−16251. (d)
Thrimurtulu, N.; Dey, A.; Maiti, D.; Volla, C. M. R. Cobalt‐catalyzed
sp2‐C−H activation: intermolecular heterocyclization with allenes at room
temperature. Angew. Chem. Int. Ed. 2016, 55, 12361-12365. (e) Zeng, R.;
Fu, C.; Ma, S. Highly Selective Mild Stepwise Allylation of N-
Methoxybenzamides with Allenes. J. Am. Chem. Soc. 2012 134, 9597-
9600. (f) Wang, H.; Glorius, F. Mild Rhodium(III)‐Catalyzed C-H
Activation and Intermolecular Annulation with Allenes. Angew. Chem. Int.
Ed., 2012, 51, 7318-7322. (g) Wu, L.; Meng, Y.; Ferguson, J.; Wang, L.;
type
of
palladium-catalyzed
annulative
C-H
1
2
3
4
5
6
7
8
activation/desymmetrization processes, which had not been
previously reported, represents an important new addition to the
armory of catalytic asymmetric methods.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and spectroscopic data for new
compounds (PDF)
CIF files for compounds and 3ba and 3ga
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AUTHOR INFORMATION
Corresponding Author
*E-mail: moises.gulias@usc.es
joseluis.mascarenas@usc.es
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work has received financial support from Spanish grants
(SAF2016-76689-R, CTQ2016-77047-P and FPU fellowship to X.
V.), the Consellería de Cultura, Educación
Universitaria (ED431C 2017/19, 2015-CP082 and Centro Singular
de Investigación de Galicia accreditation 2016-2019, ED431G/09),
the European Regional Development Fund (ERDF), and the
European Research Council (Advanced Grant No. 340055). The
orfeo-cinqa network CTQ2016-81797-REDC is also kindly
acknowledged.
Zeng; F.
Palladium-Catalyzed Oxidative Annulation of ortho-
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(11)For formal annulations based on the enantioselective
desymmetrizing functionalizations with rhodium catalysts, see: (a) Tran, D.
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aromatic ketimines induced by directed C-H activations. Angew. Chem. Int.
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dynamic kinetic asymmetric transformations of racemic allenes by the
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regioselective
Ar
Ar
Pd(II),[O]
2,6-F,F-Bz-Leu-OH
H
NTf
R
·
diastereoselective
enantioselective
+
Ar
(4+2) annulation
NHTf
R
R
Ar
H
R
via:
Ar
NTf
Ar
Pd
L
R
R
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