Palladium-Catalyzed Regio- and Enantioselective Synthesis of Allylic Amines Featuring Tetrasubstituted Tertiary Carbons

Article abstract of DOI:10.1021/jacs.6b08841

The first asymmetric synthesis of α,α-disubstituted allylic N-arylamines based on a palladium-catalyzed allylic amination has been developed. The protocol uses highly modular vinyl cyclic carbonates and unactivated aromatic amine nucleophiles as substrates. The catalytic process features minimal waste production, ample scope in reaction partners, high asymmetric induction up to 97% ee, and operational simplicity.

Full text of DOI:10.1021/jacs.6b08841

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Communication
Palladium-Catalyzed Regio- and Enantio-Selective Synthesis
of Allylic Amines Featuring Tetrasubstituted Tertiary Carbons
Aijie Cai, Wusheng Guo, Luis Martínez-Rodríguez, and Arjan W. Kleij
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Oct 2016
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Palladium-Catalyzed Regio- and Enantio-Selective Synthesis of Al-
lylic Amines Featuring Tetra-Substituted Tertiary Carbons
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Aijie Cai,† Wusheng Guo,*,† Luis MartínezꢀRodríguez,† Arjan W. Kleij*,†,§
† Institute of Chemical Research of Catalonia (ICIQ), the Barcelona Institute of Science and Technology, Av. Països Cataꢀ
lans 16, 43007 – Tarragona, Spain.
§ Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 – Barcelona, Spain.
Supporting Information
Previous success in the palladiumꢀcatalyzed transformation of
ABSTRACT: The first asymmetric synthesis of
α,αꢀ
vinyl carbonates with various electrophiles showed wide potential
towards the construction of enantioꢀenriched compounds such as
furans, tertiary vinyl glycols and oxazolidinones.8 A key to this
success was the in situ formation of postulated zwitterionic πꢀallyl
palladium intermediates B and B´ that result from a Pdꢀcatalyzed
decarboxylation of vinyl cyclic carbonate A (Scheme 1b).
disubstituted allylic Nꢀarylamines based on a palladiumꢀcatalyzed
allylic amination has been developed. The protocol uses highly
modular vinyl cyclic carbonates and unactivated aromatic amine
nucleophiles as substrates. The catalytic process features minimal
waste production, ample scope in reaction partners, high asymꢀ
metric induction up to 97% ee and operational simplicity.
Scheme 1. Methodological Approach towards Chiral Al-
lylic Amines from Vinyl Carbonates and Amine Nucleo-
philes using Pd-Catalysis
Building chiral quaternary and/or tetraꢀsubstituted tertiary carꢀ
bons from simple and readily available starting materials under
mild reaction conditions continues to be one of the most challengꢀ
ing and attractive research goals in modern synthetic chemistry.1
Chiral allylic amines are fundamental building blocks in organic
synthesis and their preparation is of high synthetic and industrial
interest.2 Transition metal catalyzed allylic amination has up to
now been used as the most powerful and convenient tool for
construction of
α
ꢀmonoꢀfunctionalized chiral allyl amines,3 with
iridium based catalysts representing privileged systems in this
domain.3aꢀn
Despite significant progress in this area, the catalytic formation
of chiral
α,αꢀdisubstituted allylic amines incorporating tetraꢀ
substituted tertiary carbons attained through allylic amination has
proven to be very challenging and remains a largely unexplored
field of science.4,5 In this respect, Nguyen et al. recently reported
the first general allylic amination towards chiral α,αꢀdisubstituted
allylic amines based on rhodium catalysis (Scheme 1a).5 Howevꢀ
er, the use of economically more attractive palladium catalysis in
the context of allylic amination providing products with chiral
tetraꢀsubstituted tertiary carbons, continues to be an unsolved
problem.4 A key challenge is that nucleophilic attack on the steriꢀ
cally more crowded internal carbon center of the Pdꢀallyl species
is much more challenging than the attack on the terminal carbon
resulting preferably in linear rather than branched allylic amine
formation.4a New methodologies that can invert this selectivity
bias should undoubtedly trigger general interest in the synthetic
communities and revive the use of alternative strategies towards
these important chiral allylic scaffolds. In a wider context, the
We hypothesized that, in the presence of a suitable chiral ligand
and amine nucleophile,9 a dynamic kinetic asymmetric transforꢀ
mation (DYKAT) would be feasible if the isomerization of interꢀ
mediates B and B´ through π−σ−π interconversion occurs faster
than subsequent nucleophilic attack.2i The asymmetric environꢀ
ment around the Pd center would then kinetically favor the forꢀ
mation of one of the possible allylic amine enantiomers C or C´
(Scheme 1b) upon nucleophilic attack by amines. Herein we
disclose the first regioꢀ and enantioselective synthesis of
α,αꢀ
asymmetric synthesis of
via intramolecular rearrangement6 and the transition metal cataꢀ
lyzed synthesis of (rac)ꢀ
ꢀdisubstituted allylic amines7 further
show the limited progress and challenging nature of the asymmetꢀ
ric synthesis of ꢀdisubstituted allylic amines.
α,αꢀdisubstituted trifluoroacetimidates
disubstituted branched allylic arylamines based on a Pdꢀcatalyzed
allylic amination using substituted vinyl cyclic carbonates A and
unactivated aryl amine nucleophiles as reaction partners.
To challenge our mechanistic hypothesis, the reaction of pheꢀ
nylꢀsubstituted vinyl cyclic carbonate D and aniline was selected
as a model reaction (Table 1). Preliminary investigations (see SI,
α,α
α,α
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Table S1) suggested that a reaction temperature of 0ºC and a
results compared to the use of L1 under similar conditions (entries
1
2
3
4
5
6
7
8
combination of Pd2(dba)3⋅CHCl3/L1 (Table 1) is key to obtain an
appreciable yield of 1 (67%).10 At this temperature the formation
of a 1,4ꢀbutꢀ2ꢀene diol byꢀproduct11 is significantly suppressed.
Upon further decreasing the reaction temperature, very low conꢀ
version was noted.
7−12). The use of Pd(dba)2 was also productive (entry 13) but
showed poor reproducibility. The room temperature conversion
gave lower ee (91%, entry 14) and a significantly lower isolated
yield (38%). Similar erosion of the asymmetric induction was
noted when the reaction was performed at higher concentration
(entry 15, 71% ee). Lowering the concentration of the reactants
resulted in rather low conversions (entry 16). The use of a large
excess of aniline also led to a decrease of the enantioselectivity
(entry 17). The experimental observations reported in entries 14,
15 and 17 align well with the mechanistic hypothesis that the
asymmetric induction would be less efficient if the nucleophilic
attack by the amine is accelerated.12 Notably, base additives are
not required in this catalytic process which is crucial to control the
chemoselectivity of this transformation.13
Table 1. Selected Screening Data towards the Formation of
Chiral Allylic Amine 1 using Vinyl Cyclic Carbonate D
and Aniline as Substratesa
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Entry
1
Solvent
CH2Cl2
Toluene
CH3CN
Et2O
Yieldb [%]
67
eec [%]
64 (S)
59 (S)
76 (S)
75 (S)
95 (S)
84 (S)
68 (S)
73 (S)
ꢀ
L
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
2
52
3
52
4
67
5
THF
76
6
DMF
THF
37
7
39
8
THF
60
9
THF
<2
10
11
12
13d
14e
15f
16g
17h
THF
<2
ꢀ
THF
<2
ꢀ
THF
<2
ꢀ
THF
73
95 (S)
91 (S)
71 (S)
ꢀ
THF
38
Figure 1. Scope in aryl amine reaction partners. Reaction condiꢀ
tions: 0.2 mmol carbonate, 0.3 mmol of arylamine, [Pd] =
Pd2(dba)3⋅CHCl3 (1.25 mol%), L1 (5.0 mol%), 0.20 mL THF,
0oC, open to air, 12 h. All reported yields are isolated ones after
column purification. aPd2(dba)3⋅CHCl3 (2.5 mol%), L1 (10
THF
59
THF
<15
63
THF
71 (S)
b
mol%). 24 h. Note that in the Xꢀray structure for 1 (insert at the
aReaction conditions unless stated otherwise: 0.2 mmol (1
equiv) of carbonate, aniline (1.5 equiv), Pd2(dba)3⋅CHCl3
(1.25 mol%), L (5.0 mol%), 0.20 mL of solvent, 0ºC, open
top) only the alcoholꢀH is shown.
With the optimized conditions in hand, we then investigated the
scope in aryl amines towards the formation of the branched allylic
amines 1−15 (Figure 1).14 In general, the formation of these prodꢀ
ucts proceeds with excellent enantioselectivity of up to 97%
(except for allylic amine 15). The absolute configuration of allylic
amine 1 (S) was unambiguously confirmed by Xꢀray diffraction
studies (Figure 1).15 The protocol is quite efficient for various aryl
amine reaction partners, including those having aryl groups with
para- (2ꢀ5, 8, 9 and 12), meta- (6 and 11) and orthoꢀ (7 and 13)
substitutions. Both electronꢀdonating (3, 5−7 and 12) and −withꢀ
drawing groups (2, 4 and 9) are tolerated. The metaꢀnitro substiꢀ
tuted aniline was also tolerated affording allylic amine 11 in 63%
b
c
to air, 12 h. Isolated yield. Determined by HPLC (see SI
d
e
for details). Using Pd(dba)2 (2.5 mol%) as catalyst. Reacꢀ
f
g
h
tion at rt. 0.10 mL of THF. 0.30 mL of THF. 5 equiv of
aniline used.
Then the solvent and ligand effect was systematically optiꢀ
mized at 0ºC, and we were pleased to find that the yield of the
branched allylic amine 1 further increased to 76% with excellent
enantiocontrol (95% ee) using THF as solvent (Table 1, entries
1−6). The other phosphoramidite ligands L2−L7 gave inferior
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yield and 93% ee. The installation of indole (15) and 1,3ꢀ
in the allylic amine is feasible (25; 80% yield, 76% ee) albeit with
1
2
3
4
5
6
7
8
benzodioxole (14) fragments, which are frequently observed in
relevant pharmaceutical compounds,16 is also possible. The reacꢀ
tion with the orthoꢀmethoxyꢀaniline gave a lower yield (7: 37%)
indicating some steric limitations of present methodology. The
use of sterically demanding Nꢀmethyl aniline resulted in quantitaꢀ
tive linear product formation, while no reaction was observed
under the optimal conditions utilizing indole or pyrrole nucleoꢀ
philes. Further attempts to improve the enantioselectivity of prodꢀ
ucts 15 and 25 using chloride additives failed.17 Also, a linear
carbonate analogue was tested but gave as major product the
linear allylic amine under the optimized conditions (yield: 51%;
see the SI for details). This shows that vinyl cyclic carbonate
substrates have different intrinsic reactivity.
a lower degree of enantiocontrol. This may be explained by the
presence of an additional heteroꢀatom that could interact with the
Pd catalyst during the enantiodetermining stage of the reaction.
Similar effects were noted when other reaction partners (aryl
amines or carbonates) incorporating heteroatoms were utilized
(cf., preparation of 15 and 27). Under the optimized conditions
using ligand L1, the use of a furylꢀsubstituted carbonate afforded
allylic amine 27 with only 12% ee. The enantioselectivity could
be improved to 41% when bulkier ligand L7 was utilized at higher
catalyst/ligand loading. It is worth noting that in some cases the
linear product was observed and this resulted in a lower isolated
yield of the branched product (cf., syntheses of 7, 15, 22 and 26).
In order to further challenge the catalytic protocol, the enantioꢀ
selective synthesis of methylꢀ and nonꢀsubstituted (R = H) allylic
amines 28 and 29 was probed (Figure 3). Both allylic amine prodꢀ
ucts were isolated in good yields (71−77%) with moderate enanꢀ
tioꢀselectivity (46−60% ee); the use of ligand L7 did not improve
the enantioselectivity (see the SI). The introduction of a bulkier
cyclohexyl group (30: R = Cy) was not feasible.
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Figure 3. Preparation of methylꢀ and nonꢀsubstituted chiral allylic
amines 28 and 29, and attempted synthesis of 30.
In addition to the application potential of (chiral) allylic amines
reported previously,2 a further synthetic use of these branched
allylic amines was exemplified by the preparation of chiral ether
31, oxazolidinone 32, diamine 33 and carbamate 34 from allylic
amine 1 retaining the original chirality (Figure 4).
Figure 2. Scope in vinyl carbonate reaction partners. Reaction
conditions: 0.2 mmol carbonate, 0.3 mmol of aniline, [Pd] =
Pd2(dba)3⋅CHCl3 (1.25 mol%), L1 (5.0 mol%), 0.20 mL THF,
0oC, open to air, 12 h. All reported yields are isolated ones after
column purification. aPd2(dba)3⋅CHCl3 (2.5 mol%), L1 (10
mol%). bPd2(dba)3⋅CHCl3 (5 mol%), L7 (20 mol%).
Figure 4. Conversion of allylic amine 1. Reaction conditions: (i)
BnBr (1.1 equiv), NaH (2.0 equiv), THF (1 mL), 0−rt, 15 h; (ii)
pyridine (4.0 equiv), triphosgene (0.50 equiv), CH2Cl2, 0−rt, 3 h;
(iii) See SI for experimental details and further comments; (iv)
phenylisocyanate (1.3 equiv), Et3N (10 equiv), CH2Cl2, rt, 10 min.
We then focused on the investigation of the scope in vinyl carꢀ
bonates (Figure 2). We gratifyingly noted that a wide range of
arylꢀsubstituted vinyl cyclic carbonates were tolerated under the
reaction conditions giving access to the corresponding enantioenꢀ
riched allylic amines 16−27 in appreciable yields and good to
excellent levels of enantioselectivity. It is worth noting that comꢀ
pounds 1−27 also represent chiral vicinal amino alcohols which
are of high synthetic interest and have important applications in
biology.18
The presence of substituents with different steric and electronic
effects in the vinyl carbonate proved to be useful reaction partꢀ
ners. Generally, vinyl carbonates equipped with electronꢀdonating
aryl groups gave more productive catalysis with high levels of
enantioselectivity (16−17, 20−24; ≥ 88% ee). The carbonate
substrate having an orthoꢀBr substituent did not show any reactivꢀ
ity under the optimized conditions, while the metaꢀsubstituted
isomer gave the allylic amine product in 88% ee (see Supporting
information) though in low yield. Installation of thiophene moiety
In summary, we herein present the first regioꢀ and enantioselecꢀ
tive synthesis of α,αꢀdisubstituted allylic Nꢀarylamines based on a
palladiumꢀcatalyzed allylic amination protocol. This procedure
utilizes readily available and modular substituted cyclic vinyl
carbonates and unactivated aryl amines as reactants, can be operꢀ
ated without any special precautions and does not require any
additives. Therefore, this userꢀfriendly and efficient methodology
marks a significant step forward in the challenging synthesis of
these chiral allylic amine scaffolds.
ꢀ
ASSOCIATED CONTENT
Supporting Information
Complete experimental details, spectral data and HPLC analysis
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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5968. The challenge of controlling the regioꢀchemistry of palladiumꢀ
catalyzed allylic amination has a long history; even the regioꢀselective
synthesis of ꢀmonoꢀfunctionalized chiral allylic amines by allylic aminaꢀ
tion using palladium catalysis has been very difficult with only a few
notable exceptions, see refs. 3qꢀs.
ꢀ
AUTHOR INFORMATION
1
2
3
α
Corresponding Author
*wguo@iciq.es; *akleij@iciq.es
4
5
6
7
8
9
(5) Arnold, J. S.; Nguyen, H. M. J. Am. Chem. Soc. 2012, 134, 8380.
(6) (a) Fischer, D. F.; Xin, Z.; Peters, R. Angew. Chem. Int. Ed. 2007,
46, 7704. (b) Fischer, D. F.; Barakat, A.; Xin, Z.; Weiss, M. E.; Peters, R.
Chem. Eur. J. 2009, 15, 8722.
Notes
The authors declare no competing financial interests.
(7) Synthesis of (rac)ꢀα,αꢀdisubstituted allylic amines; Au catalysis:
ꢀ
ACKNOWLEDGMENT
(a) Kinder, R. E.; Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10,
3157. Ir catalysis: (b) Takeuchi, R.; Kashio, M. Angew. Chem. Int. Ed.
Engl. 1997, 36, 263. Pd catalysis: (c) Dubovyk, I.; Watson, I. D. G.;
Yudin, A. K. J. Am. Chem. Soc. 2007, 129, 14172. (d) Johns, A. M.; Liu,
Z.; Hartwig, J. F. Angew. Chem. Int. Ed. 2007, 46, 7259. Rh catalysis: (e)
Arnold, J. S.; Cizio, G. T.; Nguyen, H. M. Org. Lett. 2011, 13, 5576.
(8) (a) Khan, A.; Zheng, R.; Kan, Y.; Ye, J.; Xing, J.; Zhang, Y. J. An-
gew. Chem. Int. Ed. 2014, 53, 6439. (b) Khan, A.; Yang, L.; Xu, J.; Jin, L.
Y.; Zhang, Y. J. Angew. Chem. Int. Ed. 2014, 53, 11257. (c) Khan, A.;
Xing, J.; Zhao, J.; Kan, Y.; Zhang, W.; Zhang, Y. J. Chem. Eur. J. 2015,
21, 120. (d) Yang, L.; Khan, A.; Zheng, R.; Jin, L. Y.; Zhang, Y. J. Org.
Lett. 2015, 17, 6230.
We thank ICIQ, ICREA, and the Spanish MINECO through
projects CTQꢀ2014–60419ꢀR, and Severo Ochoa Excellence
Accreditation 2014–2018 through project SEVꢀ2013–0319. Eduꢀ
ardo C. EscuderoꢀAdán and Dr. Eddy Martin are acknowledged
for the X−ray analysis of compound 1. WG thanks the Cellex
foundation for funding of a postdoctoral fellowship.
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van Leeuwen, P. W. N. M. Inorg. Chim. Acta 2002, 327, 108. Please also
see review: (c) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem.
Res. 2006, 39, 747. Hydrogen bond promoted attack of the amine nucleoꢀ
philic onto the Pdꢀallyl species has previously been discussed by Trost et
al. (refs. 4aꢀb). We recently reported related hydrogen bond mediated
formation of linear allylic amines: (d) Guo, W.; MartínezꢀRodríguez, L.;
Kuniyil, R.; Martin, E.; EscuderoꢀAdán, E. C.; Maseras, F.; Kleij, A. W. J.
Am. Chem. Soc. 2016, 138, 11970.
(10) The choice for using chiral phosphoramidites was based on previꢀ
ous success with these ligands in asymmetric synthesis, refer to refs. 8aꢀb.
(11) Water can react with the vinyl cyclic carbonate in the presence of a
suitable palladium catalyst to afford a 1,4ꢀbutꢀ2ꢀene diol product, see:
Guo, W.; MartínezꢀRodríguez, L.; Martin, E.; EscuderoꢀAdán, E. C.;
Kleij, A. W. Angew. Chem. Int. Ed. 2016, 55, 11037.
(12) The increase of reaction temperature, concentration or aniline
amount would give faster nucleophilic addition. This combined with a
relatively slow equilibration between reactive species B and B´ (Scheme
1) will consequently lead to lower enantioꢀdiscrimination. For relevant
observations and/or a more detailed explanation please refer to refs. 4a
and 9c.
(13) Addition of external base may lead to 1,2ꢀdiol or carbamate forꢀ
mation, see: (a) Guo, W.; GónzalezꢀFabra, J.; Bandeira, N. A. G.; Bo, C.;
Kleij, A. W. Angew. Chem. Int. Ed. 2015, 54, 11686. (b) Laserna, V.;
Fiorani, G.; Whiteoak, C. J.; Martin, E.; EscuderoꢀAdán, E. C.; Kleij, A.
W. Angew. Chem. Int. Ed. 2014, 53, 10416.
(14) Alkyl amines can react with cyclic carbonates at room temperature
giving carbamate compounds. Such aminolysis behavior has been wellꢀ
documented, see for instance: (a) Blain, M.; JeanꢀGérard, L.; Auvergne,
R.; Benazet, D.; Caillol, S.; Andrioletti, B. Green Chem. 2014, 16, 4286.
(b) Guo, W.; Laserna, V.; Martin, E.; EscuderoꢀAdán, E. C.; Kleij, A. W.
Chem. Eur. J. 2016, 22, 1722. (c) Sopeña, S.; Laserna, V.; Guo, W.;
Martin, E.; EscuderoꢀAdán, E. C.; Kleij, A. W. Adv. Synth. Catal. 2016,
358, 2172. No branched allylic amine product was observed using deacꢀ
tivated alkyl amines of pꢀF and pꢀNO2 substituted benzylamines.
(15) For more details see: CCDCꢀ1496759.
(16) (a) Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wissner, A.;
Burns, M. G.; Largis, E. E.; Dolan, J. A.; Claus, T. H. J. Med. Chem.
1992, 35, 3081. (b) Ali, A.; Wang, J.; Nathans, R. S.; Cao, H.; Sharova,
N.; Stevenson, M.; Rana, T. M. ChemMedChem 2012, 7, 1217. (c)
Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A.
K.; Choi, E. H. Molecules 2013, 18, 6620.
(17) Chloride can increase the rate of π−σ−π process (Scheme 1) and
potentially improve the enantioselectivity, see: Trost, B. M.; Machacek,
M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005, 127, 7014. However, no
conversion of the substrates towards 15 and 25 was observed in the presꢀ
ence of Bu4NCl or N(Hex)4Cl (30 mol%).
(18) For recent relevant literature: (a) Shi, S.ꢀL.; Wong, Z. L.; Buchꢀ
wald, S. L. Nature 2016, 532, 353. (b) Orcel, U.; Waser, J. Angew. Chem.
Int. Ed. 2015, 54, 5250; See also ref. 8c.
(4) To the best of our knowledge, there is only one known example of
an enantioselective synthesis of α,αꢀdisubstituted allylic amine using
alkylamines via Pdꢀmediated allylic amination having, however, limited
substrate scope, see: (a) Trost, B. M.; Jiang, C.; Hammer, K. Synthesis
2005, 3335. Other relevant contributions using Pdꢀcatalysis and
phthalimide as nucleophile though with limited scope: (b) Trost, B. M.;
Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000, 122,
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