Synthesis of IAN-type N,N-Ligands via Dynamic Kinetic Asymmetric Buchwald-Hartwig Amination

Article abstract of DOI:10.1021/jacs.6b07972

The Pd⁰-catalyzed coupling of racemic heterobiaryl bromides, triflates, or nonaflates with aryl/alkyl primary amines using QUINAP as the ligand provides the corresponding axially chiral heterobiaryl amines with excellent yields and enantioselectivities. Reactivity and structural studies of neutral and cationic oxidative addition intermediates support a dynamic kinetic asymmetric amination mechanism based on the labilization of the stereogenic axis in the latter and suggest that coordination of the amine to the Pd center is the stereodetermining step.

Full text of DOI:10.1021/jacs.6b07972

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Communication
Synthesis of IAN-type N,N-ligands via Dynamic
Kinetic Asymmetric Buchwald–Hartwig Amination
Pedro Ramírez-López, Abel Ros, Antonio Romero-Arenas, Javier
Iglesias-Sigüenza, Rosario Fernandez, and José M. Lassaletta
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07972 • Publication Date (Web): 05 Sep 2016
Downloaded from http://pubs.acs.org on September 5, 2016
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Journal of the American Chemical Society
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Synthesis of IAN-type N,N-Ligands via Dynamic Kinetic Asymmetric
Buchwald–Hartwig Amination
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§,∑
§,∑
§
∫
∫
Pedro Ramírez-López, Abel Ros, Antonio Romero-Arenas, Javier Iglesias-Sigüenza, Rosario Fernández,*,
§
José M. Lassaletta*,
§Instituto Investigaciones Químicas (CSIC-US), C/ Américo Vespucio, 49, 41092 Sevilla, Spain.
∫Departamento de Química Orgánica, C/ Prof. García González, 1, 41012 Sevilla, Spain
Supporting Information Placeholder
ABSTRACT: The Pd0–catalyzed coupling of racemic hetero-
Scheme 1. Synthetic approaches to IAN amines
biaryl bromides, triflates or nonaflates with aryl/alkyl prima-
Previous synthesis of IAN amine
ry amines using QUINAP as the ligand provides the corre-
Ph
Me
H
N
N
sponding axially chiral heterobiaryl amines with excellent
yields and enantioselectivities. Reactivity and structural
studies of neutral and cationic oxidative addition intermedi-
ates support a dynamic kinetic asymmetric amination mech-
anism based on the labilization of the stereogenic axis in the
latter, and suggest that coordination of the amine to the Pd
center is the stereodetermining step.
H
N
1-chloroisoquinoline
AlMe3
N
Ph
Me
(1)
NH2
(R)-IAN, 96% ee
1:1 diastereomeric
mixture
Previous dynamic kinetic asymmetric cross-couplins (refs. 5 & 6)
+
Z
Z
Z
−
Y
Y
N
TfO
R
Y
R
ϕ1
ϕ2
R
Pd0L*n (cat)
N
L
N
ZM
(2)
Pd
base
Z
X
L'
ϕ1, ϕ2 >120°
I: Z = Ar
II: Z = PR2
X = TfO
In recent years, significant advances have been achieved in the field
of asymmetric cross–coupling, in particular for the synthesis of
axially chiral biaryls.1 In sharp contrast, the direct asymmetric het-
eroaryl-aryl cross–coupling remains as an unmet challenge,2 limit-
ing the access to functionalized heterobiaryls with appealing struc-
tures for their use as ligands in asymmetric catalysis. As a remarka-
ble example, the use Isoquinoline-Amino Naphthalene (IAN) and
related derivatives, which can be seen as N(sp2),N(sp3) analogues
of QUINAP, have been scarcely investigated.3 A plausible explana-
tion is the poor availability: there are no commercially available
representatives and their synthesis still requires chromatographic
separation of diastereomeric mixtures (Scheme 1, eq. 1),4 while the
lack of a general and practical method of synthesis has also limited
the structural diversity of known ligands of this type. Recently, we
have reported a novel strategy for the synthesis of functionalized
heterobiaryls based on dynamic kinetic asymmetric C–C5 and C–
P6 bond formations starting from heterobiaryl triflates to ensure the
formations of cationic oxidative addition intermediates (Scheme 1,
eq. 2). Stimulated by the growing potential of related axially chiral
heterobidentate ligands,7 we decided to focus on the development
of dynamic kinetic Buchwald-Hartwig (DYKAT: Dynamic Kinetic
Asymmetric Transformation) amination of heterobiaryl electro-
philes for the asymmetric synthesis of axially chiral IAN-type dia-
mines (Scheme 1, eq. 3).
Configurationally labile
This work
R
R
N
R
Pd0L*n (cat)
N
N
+
or
NH2R
(3)
X
Base
NHR
NHR
R1
5
R1
R1
1: X = ONf
2: X = OTf
3: X = Br
4: X = Cl
6
(ent)-6
biaryl triflates used in previous DYKAT processes. Second, the
racemization barriers for IAN amines are significantly lower than
those of arylated products I or QUINAP-type products II,8 making
necessary to work under exceptionally mild conditions.9 In order to
minimize the hydrolysis of the starting material, we started using
the coupling between nonaflate (±)-1A10 and aniline 5a as a model
reaction for the synthesis of IAN 6Aa, using NaOtBu as the base,
dry toluene as the solvent at 60 °C and 10 mol% Pd(dba)2/12
mol% ligand as the catalyst system (Scheme 2).
Ligands that showed a good performance in related processes
were selected for a preliminary screening: hydrazone–based ligands
L1-L2, which provided good to excellent enantioselectivities in
asymmetric Suzuki-Miyaura reactions,11 and TADDOL-derived
phosphoramidites L3, which exhibited an excellent behavior in
dynamic kinetic Suzuki-Miyaura couplings,5 showed a poor activity
and only in the case of ligand L2 a relatively high enantiomeric
excess (72% ee) was observed. Similarly, ferrocene–based ligands
L4-L5, previously used in C–P coupling reactions,6 or
The unprecedented asymmetric amination of heterobiaryls is a
particularly challenging goal due to the specific conditions re-
quired. First, a strong base is generally needed to achieve good
reactivities, so that compatibility issues might arise with the hetero-
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Scheme 2. Ligand Screening.a
Table 1. Optimization.a
1
2
3
4
5
6
7
8
X
PhNH2 5a
PhNH2 5a
N
L (12 mol%)
N
N
N
L (12 mol%)
L =
Pd(dba)2 (10 mol%)
N
PR2
Pd(dba)2 (10 mol%)
X
ONf
NHPh
NatBuO (2 equiv)
NHPh
Base (2 equiv)
22 h
toluene, 60 ˚C
17 h
(S)-L9b: X = C, R = (p-OMe-C6H4)
(S)-L9c: X = C, R = (p-Me-C6H4)
(S)-L9d: X = C, R = (p-F-C6H4)
(R)-L9e: X = C ,R = iBu,
(±)-1A, X = ONf
(±)-2A, X = OTf
(±)-3A, X = Br
(±)-4A, X = Cl
6Aa
(±)-1A
6Aa
Ph
Ph
(R)-L9f: X = C ,R = Cy
(S)-L9g: X = N, R = Ph
O
O
N
Ph
Ph
Ph2P
P
NMe2
Fe
N
Ph2P
N
9
N
N
PtBu2
O
O
Substrate Base
L
Yld. (%)
eeb
T (°C)
60
Ph
Ph
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60
Ph
Ph
L4: 60%, 67% ee
L2: 17%, 72% ee
L3: 8%, 8% ee
L1: 0%
1
Cs2CO3
Cs2CO3
(S)-L9a
99
81
95
84
90
92
99
98
98
26
77
78
88
92
89
90
91
89
84
77
61
50
68
20
(±)-1A
(±)-2A
(±)-3A
(±)-1A
(±)-3A
(±)-4A
(±)-3A
(±)-3A
(±)-3A
(±)-3A
(±)-3A
(±)-3A
OMe
2c
3d
4
50
(S)-L9a
(S)-L9a
(S)-L9a
(S)-L9a
(S)-L9a
(S)-L9bf
(S)-L9cg
(S)-L9d
(R)-L9e
(R)-L9f
(S)-L9gh
PPh2
N
PPh2
R
MeO
MeO
PPh2
PPh2
NaOtBu 60
Cs2CO3 50
PPh2
PPh2
Fe
Me2N
L9a: 45%, 87% ee
L7: R = PPh2; 61%, 19% ee
L8: R = OMe; 18%, 34% ee
OMe
L6: 44%, 4% ee
L5: 76%, 44% ee
5
NaOtBu 50
NaOtBu 50
NaOtBu 60
NaOtBu 60
NaOtBu 60
NaOtBu 60
NaOtBu 60
NaOtBu 60
6
a
Reactions conditions: 0.1 mmol 1A in toluene (2 mL), 2 equiv. of
5a, 2 equiv. of NaOtBu. Ee's were determined by chiral HPLC analysis.
See the Supporting Information for a more comprehensive screening.
7
8
commercially available axially chiral P,P and P,O-ligands such as
L6-L8 afforded moderate yields (18-76%) and variable enantiose-
lectivities (4-67% ee). Taking into account the poor results provid-
ed by the atropo P,N-ligand QUINAP L9a in dynamic kinetic C–P
bond formation,6a it was rather surprising to see the high level of
enantioselectivity (87% ee) observed in this case, although partial
hydrolysis of the starting (±)-1A resulted in an unsatisfactory 45%
yield. This undesired hydrolysis, however, could be avoided in two
ways. First, it was possible to use a less nucleophilic base such as
Cs2CO3, and the desired diamine (R)-6Aa was obtained in near
quantitative yields while maintaining the level of enantioselectivity
(Table 1, entry 1). At 50 °C, these mild conditions could also be
9
10
11
12
a Reactions conditions: 0.1 mmol scale in toluene (2 mL), 2 equiv. of
5a, 2 equiv. of base. b Determined by chiral HPLC analysis. c t: 48 h. d t:
17h. f 98% ee. g 96% ee. h 99% ee.
temperature of 60 °C was also needed for the latter, but in all cases
the corresponding products 6 were obtained in good yields and
enantioselectivities (88-93% ee). Interestingly, p-chloro- and p-
bromo-anilines 5e and 5f are suitable substrates, highlighting the
higher relative reactivity of the heterobiaryl bromide, which can be
attributed to the directing effect by the isoquinoline N atom. Ali-
phatic amines 5k-m could also be coupled using 4-10 equiv. of
amine and 4 equiv. of NaOtBu to give the desired products (R)-
6Ak-m in good to excellent yields (61-86%) and 86-91% ee after 72
applied to the amination of triflate (±)-2A with a slightly lower
yield (entry 2). Second, we speculated whether 1-(2-
bromonaphthalen-1-yl)isoquinoline (±)-3A could also be a suita-
ble substrate in this reaction. Although this material afforded dis-
appointing results in dynamic kinetic asymmetric Suzuki coupling,5
the reaction of (±)-3A with aniline 5a using NaOtBu as the base
under the above conditions afforded the desired product (R)-6Aa
in 95% yield with 89% ee in a shorter reaction time (17h, entry 3).
The reactions of (±)-1A, (±)-3A and even chloride (±)-4A could
also be performed at 50 °C, leading to slightly better enantioselec-
tivities (entries 4-6). Other QUINAP and QUINAZOLINAP-type
ligands L9b-g containing modified diaryl and dialkyl phosphino
groups6a were also tested in the model reaction but, unfortunately,
none of them led to improved enantioselectivities (entries 7-12).
Racemization studies performed with a toluene solution of 6Aa at
60, 80 and 100 °C showed that, after 48h, the product is configura-
tionally stable at 60 °C, but slowly racemizes at 80 °C and above.
hours at 60 °C. Bromide (±)-3B showed similar reactivity patterns
and the desired diamines 6Ba-m were obtained in good to excellent
yields and 86-93% ee. Finally, bromide (±)-3C was also used in
atroposelective amination with anilines 5a-d,g,j to afford C-series
products. A higher reaction temperature (60 °C) and longer reac-
tion time (45 h) were in general required, but good yields (72-
98%) and enantioselectivities (88-91% ee) were also achieved. As a
limitation, poor reactivity was observed when secondary amines
were used as reagents.
Compounds (R)-6Bf and (R)-6Bl were obtained in enantiopure
form (>99% ee) after crystallization. Additionally, X-ray analysis of
the former was used to assign the absolute Ra configuration. Simi-
larly, X-ray analysis of the cationic complex {Cu(I)[(R)-
With the optimized conditions (entry 5) at hand, the scope of
the methodology was explored using different bromides (±)-3A-C
–
6Aa]2}+PF6 was used to confirm the absolute R configuration of
and amines 5a-m (Table 2). The reaction of bromide (±)-3A
(Series A) and arylamines 5a-c and 5g-h worked well at 50 °C,
affording the coupling products 6Aa-c and 6Ag-h with excellent
yields and 90-96% ee in acceptable reaction times (∼25 hours).
Sterically hindered and electron-poor amines 5d-f and 5h-j re-
quired longer reaction times (30–48 h), and a higher reaction
(R)-6Aa. The absolute configuration of other products 6A-C was
assigned by analogy assuming a uniform reaction pathway.
The free IAN amine (R)-7 could be obtained after Pd-catalyzed
deprotection of allylamine (R)-6Am using N,N'-dimethylbarbituric
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Table 2. Dynamic Kinetic Asymmetric C-N Couplings: Scope.a
1
Ar(R)NH2 5 (2 equiv.)
2
3
4
X
Y
X
Y
X
Y
N
N
N
Pd(dba)2 (10 mol%) / (S)-L9a or (R)-L9a (12 mol%)
or
NHAr(R)
NHAr(R)
Br
(R)-6Bf:
t-BuONa or Cs2CO3 (2 equiv.)
toluene, 50-60 ˚C
5
(±)-3A-C
6A-C
ent-6A-C
6
(R)-6Aa: Z = H, 50 °C, 90%, 91% ee
7
8
9
(R)-6Ab: Z = Me, 50 °C, 89%, 96% ee
(R)-6Ag: Ar = 3,5-Xylyl, 50 °C, 88%, 90% ee
(R)-6Ah: Ar = o-Tol, 50 °C, 97%, 92% ee
(R)-6Ai: Ar = 1-Naphthyl, 50 °C, 91%, 93% ee
(R)-6Aj: Ar = 2-Naphthyl, 50 °C, 81%, 88% ee
N
(R)-6Akb R = Bn, 60 °C, 86%, 86% ee
(R)-6Al:b R = Cy, 60 °C, 63%, 91% ee
(R)-6Am:c R = All, 60 °C, 61%, 88% ee
N
N
(R)-6Ac: Z = OMe, 50 °C, 92%, 92% ee
H
N
H
H
N
N
(R)-6Ad: Z = F, 60 °C, 99%, 92% ee
(R)-6Ae: Z = Cl, 60 °C, 74%, 90% ee
(R)-6Af: Z = Br, 60 °C, 64%, 91% ee
R
Ar
Z
10
11
12
13
14
15
16
17
18
19
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60
(S)-6Ba:d Z = H, 50 °C, 84%, 89% ee
(S)-6Bb:d Z = Me, 50 °C, 98%, 90% ee
(S)-6Bc:d Z = OMe, 50 °C, 78%, 91% ee
(S)-6Bd:d Z = F, 50 °C, 89%, 92% ee
(R)-6Be: Z = Cl, 50 °C, 83%, 93% ee
(R)-6Bf: Z = Br, 50 °C, 67%, 89% eee
(S)-6Bg:d Ar = 3,5-Xylyl, 50 °C, 97%, 88% ee
(R)-6Bh: Ar = o-Tol, 50 °C, 94%, 90% ee
(S)-6Bi:d Ar = 1-Naphthyl, 50 °C, 94%, 92% ee
(S)-6Bj:d Ar = 2-Naphthyl, 50 °C, 83%, 86% ee
N
(S)-6Bk:b,d R = Bn, 60 °C, 94%, 93% ee
(S)-6Bl:b,d R = Cy, 60 °C, 60%, 91% ee
(S)-6Bm:b,c R = All, 60 °C, 59%, 92% ee
N
N
Me
Me
Me
H
H
H
N
N
N
R
Ar
Z
(R)-6Ca: Z = H, 60 ºC, 93%, 90% ee
(R)-6Cb: Z = Me, 60 ºC, 98%, 90% ee
(R)-6Cc: Z = OMe, 60 ºC, 94%, 91% ee
(R)-6Cd: Z = F, 60 ºC, 95%, 91% ee
N
N
N
H
N
H
N
H
N
Me
Me
(R)-6Cj: 60 ºC, 72%, 91% ee
(R)-6Cg: 60 ºC, 97%, 88% ee
Me
Me
Z
Me
a
b
Reaction conditions: 0.1 mmol scale in toluene (2 mL), 2 equiv. of 5, 2 equiv. of NaOtBu, t: 22-48h (see Supporting Information). 4 equiv. of
NaOtBu and 4 equiv. of 5 were used. c 4 equiv. of NaOtBu and 10 equiv. of 5 were used. d (R)-L9a was used. e >99% ee after crystallization.
Scheme 3. Representative transformations.
Scheme 4. Proposed amination mechanism.
Pd(PPh3)4 (10 mol%)
N
=
(S)-L9a
N
N
N
N
N
N,N'-dimethylbarbitutic acid
P
+
H
N
NHR
Br
Br
NH2
CH2Cl2
86%
N
Pd0
P
(R)-6Am (IAN), 88% ee
(R)-7A (IAN), 86% ee
+
+
N
−
N
O
m-CBPA (1.2 equiv.)
N
N
N
N
P
H
N
N
P
P
H
N
P
N
N
Pd
N
CH2Cl2, 0 °C→ rt
Pd
Pd
Pd
Br
71%
Br
NHR
Br
OAI+(Br)
(R)-8Aa (IAN), 91% ee
(R)-6Aa, 91
(R)-OAI(Br)
(S)-OAI(Br)
AI
acid as the reagent12 (Scheme 3). Additionally, products 6 are
direct precursors of axially chiral N-oxides7b by virtue of the selec-
tive N(sp2) oxidation performed with m-CPBA, as illustrated with
the synthesis of (R)-8. Compared to the previously developed
Suzuki coupling,5 the better performance of (±)-3A can be ex-
plained for the different reaction conditions applied in this case.
According to the mechanism depicted in Scheme 4, the base is
believed to play a dual role, behaving also as an efficient bromide
scavenger thanks to the low solubility of NaBr in toluene. In order
to provide some support for this hypothesis, we tackled the isola-
tion of the oxidative addition intermediates from heterobiaryl
triflate (±)-2A and bromide (±)-3A. The equimolar reaction of the
former with (S)-L9a and [Pd(Cp)(allyl)] afforded the cationic OA
intermediate OAI+(OTf) in 88% yield after crystallization (Scheme
5). The single–crystal X-ray diffraction analysis of this complex
showed the expected five-membered, cationic palladacycle struc-
ture and confirmed that the angles ϕ1 [C(39)-C(40)-C(41)] and
ϕ2 [C(40)-C(41)-C(42)] are significantly wider (127.6° and
125.0°, respectively) than the ideal value of 120°. The structure
reveals also a severe distortion of the square planar geometry at the
PdII center (torsion angle of 23.1° between the P-Pd-N(1) and the
C(50)-Pd-N(2) planes), with a Pd-N(1) bond longer than the Pd-
N(2) one (2.141 Å and 2.098 Å, respectively), as a consequence of
the stronger trans influence by the aryl ligand. This complex was
+
N
N
NatBuO
Pd
P
tBuOH
NaBr
tBuO
H2NR
OAI+(tBuO)
treated with aniline (20 equiv.) and Cs2CO3 (20 equiv.) to afford
(R)-6Aa after 7 h at 50 °C in 57% yield and 74% ee.13 Although an
apparent (Sa) configuration is observed, we assume that the afore-
said widening of angles ϕ1 and ϕ2 results in a rapid interconversion
of atropoisomers.14 In the same way, equimolar amounts of (S)-
L9a, bromide (±)-3A, and [Pd(Cp)(allyl)] were made to react
1
31
overnight at 80 °C in toluene; H-NMR and P NMR analysis of
the crude reaction mixture revealed a complex mixture15 in which
signals assigned to the cationic OA intermediate OAI+(Br) were
identified. Stoichiometric reaction of this mixture with aniline
quantitatively afforded the product (R)-6Aa with 87% ee. Addi-
tionally, crystals of the neutral intermediate (R)-OAI(Br) suitable
for X-ray diffraction analysis could be obtained from this mixture.
In this complex, the bromine atom remains attached to the Pd
center [Pd-Br bond length 2.491 Å] and the isoquinoline and 2-
naphthyl rings are placed in a near perpendicular arrangement. It is
assumed that the reaction of this mixture with the base results in a
–
–
Br to tBuO ligand exchange facilitated by the low solubility of
NaBr in toluene. Arguably, the poorer coordinating ability and
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Scheme 5. Synthesis and and X-ray structures of oxidative addition intermediates IOA+(OTf) and (S)-IOA(Br).
1
+
2
TfO−
P
C
3
4
5
6
7
8
N
[Pd(Cp)(η3−C3H5)], (±)-2A
127.6º
N
Pd
P
N
125.0º
Pd
Toluene, 80 °C
PPh2 phenyl rings & OTf
counteranion omitted
N
88%
N
OAI+(OTf)
PPh2
9
P
C
[Pd(Cp)(η3−C3H5)]
Pd
Br
N
10
11
12
13
14
15
16
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60
crystalization
(±)-3A
N
complex
mixture
P
Pd
PPh2 phenyl
rings omitted
Toluene, 80 °C
P
Br
N
N
N
(S)-L9a
(R)-OAI(Br)
(2) Mosquera, A.; Pena, M. A.; Pérez Sestelo, J.; Sarandeses, L. A., Eur. J.
Org. Chem. 2013, 2555.
(3) (a) Cortright, S. B.; Huffman, J. C.; Yoder, R. A.; Coalter, J. N.;
Johnston, J. N. Organometallics 2004, 23, 2238. (b) Cortright, S. B.;
Johnston, J. N. Angew. Chem., Int. Ed. 2002, 41, 345.
(4) Luesse, S. B.; Counceller, C. M.; Wilt, J. C.; Perkins, B. R.; Johnston,
J. N. Org. Lett., 2008, 10, 2445.
bigger size of the counteranion favors the formation of the cation-
ic intermediate OAI+(tBuO), from which the coordination of the
amine 5 generates the amination intermediate AI in the enanti-
oselectivity determining step. It is worth noting that the structure
of the proposed OAI+(tBuO) intermediate should closely mimic
that of the isolated complex IOA+(OTf), accounting for the
similar stereochemical result through both intermediates.
(5) Ros, A.; Estepa, B.; Ramírez-López, P.; Álvarez, E.; Fernández, R.;
Lassaletta, J. M. J. Am. Chem. Soc., 2013, 135, 15730.
(6) (a) Ramírez-López, P.; Ros, A.; Estepa, B.; Fernández, R.;, Fiser, B.;
Gómez-Bengoa, E.; Lassaletta, J. M. ACS Catal. 2016, 6, 3955. See also:
(b) Bhat, V.; Wang, S.; Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc., 2013,
135, 16829.
In summary, we have developed a new and efficient procedure
for the asymmetric synthesis of IAN-type N,N-ligands based on a
dynamic kinetic asymmetric Buchwald-Hartwig amination of
racemic heterobiaryl electrophiles. The use of QUINAP as the
ligand allowed the isolation of the products in high yields and
good to excellent enantioselectivities. The isolation of cationic
and neutral oxidative addition intermediates supports a mecha-
nism based in the labilization of the stereogenic axis in the former.
(7) (a) Fernández, E.; Guiry, P. J.; Connole, K. P. T.; Brown, J. M. J. Org.
Chem. 2014, 79, 5391. and references cited therein; (b) Malkov, A. V.;
Ramírez-López, P.; Biedermannová, L.; Rulíšek, L.; Dufková, L.; Kotora,
M.; Zhu, F.; Kočovský. P. J. Am. Chem. Soc. 2008, 130, 5341; (d) Tanaka,
S.; Seki, T.; Kitamura, M. Angew. Chem. Int. Ed. 2009, 48, 8948; (e)
Francos, J.; Grande-Carmona, F.; Faustino, H.; Iglesias-Sigüenza, J.;
Díez, E.; Alonso, I.; Fernández, R.; Lassaletta, J. M.; López, F.; Mascare-
ñas, J. L. J. Am. Chem. Soc. 2012, 134, 14322. (f) Liu, Y. E.; Lu, Z.; Li, B.;
Tian, J.; Liu, F.; Zhao, J.; Hou, C.; Li, Y.; Niu, L.; Zhao, B. J. Am. Chem.
Soc. 2016, DOI: 10.1021/jacs.6b03930.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and charac-
terization data for new compounds, crystallographic data for (R)-
6Bf, OAI+(OTf) and (S)-OAI(Br), and HPLC traces for com-
pounds 6, 7 and 8. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Cortright, S. B.; Yoder, R. A.; Johnston, J. N. Heterocycles 2004, 62,
223.
(9) Paradies, J. In Metal-Catalyzed Cross- Coupling Reactions and More; de
Meijere, A., Brase, S., Oestreich, M., Eds.; Wiley: Weinheim, 2014; Ch
13, pp 995-1060.
AUTHOR INFORMATION
(10) Nonaflates (nonafluorobutanesulfonates) have been used as an
alternative to triflates due to their higher stability and similar reactivity:
Högermeier, J.; Reissig H.-U. Adv. Synth. Catal. 2009, 351, 2747.
(11) (a) Ros, A.; Estepa, B.; Bermejo, A.; Álvarez, E.; Fernández, R.;
Lassaletta, J. M. J. Org. Chem. 2012, 77, 4740. (b) Bermejo, A.; Ros, A.;
Fernández, R.; Lassaletta, J. M.; J. Am. Chem. Soc. 2008, 130, 15798.
(12) Garro-Helion, F.; Merzouk, A.; Guibé; F. J. Org. Chem. 1993, 58,
6109. Deallylation with polymethylhydrosiloxane/ZnCl2/Pd(PPh3)4
(Chandrasekhar, S.; Reddy, C. R.; Rao, R. J. Tetrahedron 2001, 57, 3435)
or PhSO2Na/CSA/Pd(PPh3)4 (Honda, M.; Morita, H.; Nagakura, I. J.
Org. Chem. 1997, 62, 8932) afforded the product in racemic form, while
catalytic hydrogenation (H2, Pd/C) was uneffective.
Corresponding Author
ffernan@us.es, jmlassa@iiq.csic.es
Author Contribution
∑ P. R .-L. and A. R. contributed equally to this work.
ACKNOWLEDGMENT
We thank the Ministerio de Ciencia e Innovación (Grants
CTQ2013-48164-C2-1-P and CTQ2013-48164-C2-2-P,
contract RYC-2013-12585 for A.R.), European FEDER
Funds, and Junta de Andalucía (Grant 2012/FQM 10787) for
financial support.
(13) In spite of the evident strain in the structure of OAI+(OTf), no
reaction with aniline 5a (20 equiv.) was observed in the absence of
Cs2CO3 , even after heating at 70 °C overnight.
(14) Variable temperature 1H NMR (25 °C→ −78 °C) spectrometry did
not show a dynamic behavior, indicating that the barrier for the intercon-
version of atropoisomers is very low (see Supporting Information).
(15) We assume that the C(2)–Pd bond in neutral intermediates
OAI(Br) is a configurationally stable stereogenic axis and, therefore, four
possible isomers can be formulated.
REFERENCES
(1) Recent reviews: (a) Zhang, D.; Wang, Q. Coord. Chem. Rev., 2015,
286, 1. (b) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F.
Chem. Soc. Rev. 2015, 44, 3418. (c) Pauline, L.; Manoury, E.; Poli, R.;
Deydier, E.; Labande, A. Coord. Chem. Rev. 2016, 308, 131.
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R
R
N
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Pd(dba)2 (10 mol%), (S)-QUINAP (12 mol%)
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NHR
NatBuO or Cs2CO3 (2 eq.)
Toluene, 50-60 °C
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R = Aryl, Alkyl
R'
racemic
32 examples
high yields
X = TfO, NfO or Br
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