Competing amination and C-H arylation pathways in Pd/xantphos-catalyzed transformations of binaphthyl triflates: Switchable routes to chiral amines and helicene derivatives

Article abstract of DOI:10.1039/c6ob01102k

A Pd(OAc)₂/xantphos catalyst system was found effective for benzylaminations of binaphthyl 2-triflates bearing a variety of alkyl, benzyl, and substituted phenyl substituents at the 2′-position. With 2′-aryl substituents, an intramolecular Pd-catalyzed C-H arylation was observed as a competing side reaction under some conditions. By adjusting the solvent and quantity of the amine, the reaction was optimized to favor either the amination or the C-H arylation pathway, affording two distinct and potentially useful sets of products. The amines represent tunable chiral ligand precursors, while the C-H arylation pathway affords a series of benzofused [5]helicene derivatives. Kinetic studies and activation parameters for the C-H arylation pathway, supported by DFT calculations, are consistent with a concerted metalation-deprotonation (CMD) mechanism involving a Pd-bound carbonate as the base. Xantphos is proposed to facilitate the turnover-limiting inner-sphere CMD step by acting as a hemilabile ligand, while its wide bite angle engenders a low reductive elimination barrier.

Full text of DOI:10.1039/c6ob01102k

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Competing amination and C–H arylation pathways
in Pd/xantphos-catalyzed transformations of
binaphthyl triflates: switchable routes to chiral
amines and helicene derivatives†
Cite this: DOI: 10.1039/c6ob01102k
Aaron A. Ruch,a Sachin Handa,b Fanji Kong,a Vladimir N. Nesterov,a Dale R. Pahls,a
Thomas R. Cundaria and LeGrande M. Slaughter*a
A Pd(OAc)2/xantphos catalyst system was found effective for benzylaminations of binaphthyl 2-triflates
bearing a variety of alkyl, benzyl, and substituted phenyl substituents at the 2’-position. With 2’-aryl substi-
tuents, an intramolecular Pd-catalyzed C–H arylation was observed as a competing side reaction under
some conditions. By adjusting the solvent and quantity of the amine, the reaction was optimized to favor
either the amination or the C–H arylation pathway, affording two distinct and potentially useful sets of
products. The amines represent tunable chiral ligand precursors, while the C–H arylation pathway affords
a series of benzofused [5]helicene derivatives. Kinetic studies and activation parameters for the C–H aryla-
tion pathway, supported by DFT calculations, are consistent with a concerted metalation–deprotonation
(CMD) mechanism involving a Pd-bound carbonate as the base. Xantphos is proposed to facilitate the
turnover-limiting inner-sphere CMD step by acting as a hemilabile ligand, while its wide bite angle engen-
ders a low reductive elimination barrier.
Received 19th May 2016,
Accepted 1st August 2016
DOI: 10.1039/c6ob01102k
www.rsc.org/obc
systems for the amination of challenging substrate types, such
Introduction
as electron-rich and ortho-substituted aryl chlorides.7
The palladium-catalyzed coupling of aryl and vinyl electro-
An important aspect of the optimization of these catalysts
philes with protic nitrogen nucleophiles, commonly known as is suppression of competing palladium-catalyzed reactions
the Buchwald–Hartwig amination,1 has evolved into a versatile that lead to compounds other than the expected amination
method for the formation of carbon–nitrogen bonds.2 Notably, products. Such reactions include reduction of Ar–X to the
general conditions for this class of coupling reactions have arene8 (often accompanied by β-hydrogen elimination from
been elusive: the scope of amines and electrophiles that can the amine),9 conversion of Ar–X to the corresponding phenol
be coupled depends critically on the choice of ancillary ligand, (either by base hydrolysis of an aryl sulfonate10 or by adventi-
the base used, and other reaction parameters.3 The ligand is tious H2O outcompeting the amine as a nucleophile11) and
often the key variable, because it can be tailored to promote homocoupling of Ar–X to yield symmetrical biaryls.3 The
the turnover-limiting step of the catalytic cycle, which may vary latter two reactions have also been optimized into catalytic
depending on the electronic, steric, and acid/base (e.g., amine procedures that are synthetically useful in their own
pKa) properties of the substrates.4 Extensive studies of ligand right.12,13
effects on catalyst scope and activity,5 in parallel with mechan-
The palladium-catalyzed, base-assisted coupling of aro-
istic studies,6 have enabled development of efficient catalyst matic electrophiles with aromatic C–H bonds14 is one impor-
tant class of so-called “direct arylation” reactions, which
represent atom-economical alternatives to traditional cross-
coupling reactions.15 This reaction is commonly proposed to
proceed via a concerted metalation–deprotonation (CMD)
aDepartment of Chemistry, University of North Texas, 1155 Union Circle #305070,
Denton, Texas, USA. E-mail: legrande@unt.edu
mechanism14,16 that is conceptually similar to established
Pd-catalyzed amination mechanisms,6 but with a relatively
acidic C–H bond replacing the N–H bond in the catalytic cycle
(Scheme 1). Furthermore, this type of C–H arylation often
occurs under comparable conditions to those used for catalytic
amination (e.g., carbonate base, moderately polar solvents),
bDepartment of Chemistry, Oklahoma State University Stillwater, Oklahoma, USA
†Electronic supplementary information (ESI) available: Additional catalytic
results, synthetic procedures for binaphthyl alcohols, characterization data,
crystal data for compounds 4a, 5, and 9, DFT-calculated geometries, kinetic
data, copies of chiral HPLC traces and NMR spectra. CCDC 1479924–1479926.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ob01102k
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Results and discussion
Optimization of competing Pd-catalyzed reactions
We recently reported synthetic routes to a series of 1,1′-
binaphthalene-2-ols bearing various aryl, alkyl, and benzyl
substituents in the 2′-position (1a–j, Scheme 2).26 These were
envisioned as precursors for chiral carbene ligands in which
steric and/or noncovalent interactions of the binaphthyl
2′-substituent could be tuned, providing potential benefits in
enantioselective catalysis.19 Naphthols 1a–j were readily con-
verted into the corresponding triflates 2a–j by a modification
Scheme 1 Conceptual similarity of palladium-catalyzed amination and
C–H arylation.
suggesting that the two reactions could be competitive when a of literature procedures (Scheme 2),26,27 providing a starting
suitable C–H bond is present. Surprisingly, we are aware of point for further derivatization via Pd-catalyzed amination.
only one study in which this has been reported. Hartwig
Binaphthyl derivatives such as 2a–j can be viewed as extre-
observed intermolecular arylation at the C3 C–H bonds of mely bulky ortho-substituted aryl electrophiles, making them
indoles as a competing process with C–N coupling when hin- particularly challenging targets for the Buchwald–Hartwig
dered aryl halides were used as electrophiles.17,18
amination.7 Indeed, we are aware of only two studies in which
Herein, we report observation and optimization of an intra- C–N coupling of binaphthyl 2-triflates has been achieved.
molecular C–H arylation reaction that occurs as a side process Singer and Buchwald reported aminations of a 1,1′-binaphthyl
in intermolecular amination reactions of 2′-aryl-substituted 2-triflate derivative bearing a PMB protecting group at the
binaphthyl triflates, a challenging class of hindered electro- 2′-position using the wide bite-angle chelating diphosphine
philes for which effective amination methods are not currently ligand DPEphos28 in combination with Pd(OAc)2.29,30 More
available. This study initially sought to refine and broaden the recently, Zhu and co-workers found the chiral diphosphine
scope of preliminary amination conditions that we reported BINAP to be effective for aminations of a binaphthyl 2-triflate
for a limited set of these substrates.19 We have found that the having a smaller methoxy group at the 2′-position.31 Both
catalyst system can be optimized to favor either the amination, studies indicated a strong dependence of catalyst activity on
which affords an array of new enantiopure 2-aminobinaphthyl the nature of the 2′-substituent, and reversion of the triflate to
compounds that are potentially valuable ligand precursors, the alcohol was noted as a significant side reaction. Notably,
or the C–H arylation, which leads to a series of benzofused Meadows and Woodward reported that the hindered mono-
[5]helicene derivatives. The wide bite-angle chelating phos- dentate phosphine X-phos32 failed to promote amination with
phine ligand xantphos20 plays a key role in facilitating both 1,1′-binaphthyl 2-triflates,33 despite being effective for other
reaction pathways. The C–H arylation reaction occurs under types of ortho-substituted aryl triflates.34
fairly mild conditions and could potentially lead to more
Given these precedents, we focused primarily on chelating
efficient procedures for the synthesis of helicenes—chiral, phosphine ligands (Fig. 1) in our efforts to identify general
nonplanar polycyclic aromatic compounds21 that have many amination conditions for binaphthyl derivatives 2a–j.
potential uses22 but are typically prepared via lengthy multi- Binaphthyl 2-triflate 2a was chosen as a test substrate for
step syntheses.23
optimization of catalytic amination conditions, because the
An additional focus of this study was the mechanism of the steric influence of the bulky 3,5-bis(CF3)-phenyl substituent at
C–H arylation pathway. DFT studies, in combination with the 2′-position was expected to make amination particularly
experimental kinetic measurements and activation para- challenging.19 Benzylamine was utilized as the nucleophile, as
meters, implicate the ability of xantphos to act as a hemilabile the resulting C–N coupling products can be readily debenzyl-
ligand as a key requirement for effective catalysis of this reac- ated to yield the desired primary amines,35 and this route
tion. This permits one phosphine arm of the ligand to dis- avoids the cost and sensitivity issues associated with use of
sociate to accommodate a 6-centered, inner-sphere CMD
transition state for the C–H cleavage step,16 followed by rever-
sion to a κ2-chelate binding mode to facilitate reductive elimin-
ation leading to the helicene product. This scenario differs
from previous mechanistic proposals for C–H arylation reac-
tions involving bidentate phosphine/Pd catalysts24 but is
related to a recent report implicating hemilability by the
mono-phosphine oxide of xantphos as a key mechanistic
feature in an intermolecular C–H arylation reaction.25 Our
study suggests that ligand hemilability is important in promot-
ing C–H arylation even with non-oxidized xantphos, adding to
Scheme 2 Synthesis of 2’-substituted binaphthyl 2-triflate derivatives.
current understanding of the role of this wide bite-angle
chelate ligand in palladium catalysis.
Yields for 2a–j are crude yields; compounds were generally used
immediately in subsequent reactions without further purification.
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which has a rigid tricyclic structure that enforces a wider pre-
ferred bite angle compared with DPEphos,20,28a gave the
desired amine product 3a, in 61% yield. Xantphos has been
shown previously to provide improved yields compared with
other chelating diphosphines in several challenging C–N coup-
ling reaction classes,40 including couplings of di-ortho-substi-
tuted aryl bromides with nonhindered anilines40a and
reactions using amides40c–e,h or heteroarylamines40i as nucleo-
philes.41 Notably, no significant amounts of the reduced
binaphthyl product were detected in reactions of 2a using the
Pd/xantphos catalyst.42
Fig. 1 Phosphine ligands screened in palladium-catalyzed amination of 2a.
Further optimization studies showed that comparable
yields of 3a could be obtained with only a slight excess (1.2
equiv.) of amine (Table 2, entry 1). However, attempts to
reduce the catalyst loading from 10 mol% to 5 mol% Pd
resulted in lower conversion and increased formation of
phenol 1a (entry 2). Because polar solvents sometimes increase
yields in C–N coupling reactions,43 aminations of 2a were also
attempted in THF and DMF (Table 2, entries 3 and 4). Signifi-
cant quantities of a third, unexpected product were isolated
from these reaction mixtures. X-ray crystallographic analysis
identified this material as naphtho[1,2-g]chrysene derivative 4a
(Fig. S1, ESI†). This product evidently results from an intra-
molecular direct arylation24,44 of the binaphthyl triflate with the
ortho-C–H bond of the 3,5-bis(CF3)-phenyl group. Compound 4a
is a nonplanar, chiral molecule due to the helical twist resulting
from the steric interactions of the terminal rings and can be
benzophenone imine as a synthon for –NH2 groups.29 The rela-
tively mild base Cs2CO3 was employed, following previous
work showing that it minimizes formation of phenol bypro-
ducts via base hydrolysis of the aryl triflates.36,37 For ligand
screening reactions, Pd(OAc)2 was used as the precatalyst38 in
toluene solvent, because these conditions have been shown to
generally favor successful aminations of aryl triflate
substrates.10,36
Under these conditions, a strong dependence of catalytic
amination yields on the structure of the chelate ligand was
observed (Table 1). Attempted coupling reactions of 2a at
90 °C (ref. 39) using the simple alkyl-bridged diphosphines
dppm and dppe gave none of the desired 2-benzylamino
binaphthyl, with naphthol 1a as the only observed product
(entries 1 and 2). The monodentate ligand X-phos32 gave simi-
larly poor results (entry 3). Despite reports of successful amin-
ations of less bulky binaphthyl 2-triflates with catalysts
containing BINAP and DPEphos,29,31 these ligands were
ineffective with substrate 2a (entries 4 and 5). Only xantphos,
regarded as
a
benzannulated [5]helicene derivative.21a,23a
Solvent polarity appears to strongly influence the competing
amination and C–H arylation reactions. Amination product 3a
predominates in nonpolar toluene (Table 2, entry 1); roughly
equal amounts of 3a and arylation product 4a are obtained in
THF (entry 3), and 4a is the major product in DMF (entry 4).
In our efforts to optimize the selectivity of the Pd/xantphos
catalytic system for the C–H arylation product, it was found
that reducing benzylamine to a substoichiometric amount (0.2
equiv.) resulted in 4a being formed as the major product, even
in less polar solvents (Table 2, entries 5–8). Yields of 4a were
modest in toluene and dioxane (entries 5 and 6) and somewhat
better in THF (entry 7), but long reaction times (72 h) were
required. In DMF, a drastic acceleration in the reaction rate
was apparent, with complete conversion achieved in 3–4 h
even when the reaction temperature was lowered to 80 °C
(entry 8). In addition, DMF seemed to reduce apparent catalyst
degradation. In toluene, dioxane, and THF, a dark greenish-
brown color developed over 24–48 h, followed by precipitation
of black Pd concomitant with the end of substrate conversion.
For reactions of 1a in DMF, the supernatant remained a clear
green color, and no dark precipitate was observed. The palla-
dium loading could be reduced to 5 mol% in DMF, although a
50% excess of xantphos compared to Pd(OAc)2 was needed in
order to attain optimal rates (vide infra) and yields of 4a
(Table 2, entries 9 and 10).
Table 1 Effect of the phosphine ligand on product distribution in
palladium-catalyzed benzylamination of sterically hindered binaphthyl
2-triflate 2aa,b
Bite
Yield
Yield
Recovered
Entry
Ligand
anglec
3ad (%)
1ad (%)
2ae (%)
1
2
3
4
5
6
dppm
dppe
X-Phos
BINAP
DPEphos
Xantphos
72°
85°
—
92°
102°
107°
—
—
—
—
—
60
60
20
12
40
50
17
10
70
70
50
7
<5
a Reaction conditions: 2a (0.325 mmol), PhCH2NH2 (2.0 equiv.),
Pd(OAc)2 (10 mol%), ligand (10 mol%), Cs2CO3 (1.5 equiv.), toluene
(1.0 mL), 90 °C, 72 h. b ArF = 3,5-(CF3)2–C6H3. c Standardized average
bite angle derived from crystal structure data (ref. 20a). d Isolated
yields. e Remaining mass balance reflects losses during purification.
Additional studies were conducted to gain an improved
understanding of the reaction parameters favouring C–H aryla-
tion (Table S1, ESI†). Only a small amount (3%) of 4a was
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Table 2 Optimization of competing Pd-catalyzed amination and CH-arylation reactions of 2aa,b
Mol%
Pd(OAc)2
Mol%
xantphos
Equiv.
PhCH2NH2
Yield
Yield
Yield
Recovered
Entry
Solvent
t (h)
3ac (%)
1ac (%)
4ac (%)
2ad (%)
1
2
3
4
5
6
7
10
5
10
5
1.2
1.2
1.2
1.2
0.2
0.2
0.2
0.2
0.2
0.2
Toluene
Toluene
THF
72
61
28
37
—
—
—
<2
—
—
—
11
33
<2
20
11
14
20
19
9
<5
<5
41
67
46
44
64
72
63
74
15
31
14
8
15
20
<2
—
20
—
72e
72e
72e
72e
72e
72e
3
10
10
10
10
10
10
5
10
10
10
10
10
10
5
DMF
Toluene
1,4-Dioxane
THF
DMF
DMF
8f
9f
10f
3.5
3.5
5
7.5
DMF
18
a Reaction conditions: 2a (0.163 mmol), solvent (2.0 mL), 90 °C (unless otherwise specified). b ArF = 3,5-(CF3)2–C6H3. c Isolated yields.
d Remaining mass balance reflects losses during purification. e Reaction times not optimized. f Reaction conducted at 80 °C.
observed in the absence of benzylamine. This suggests that
The X-ray crystal structure of precatalyst 5 was determined
the amine is required for efficient conversion of PdII to catalyti- in order to gain information about the binding mode of xant-
cally active Pd0, consistent with previous studies implicating phos (Fig. S2, ESI†). This confirmed cis-bidentate (κ2) binding
aliphatic or benzylic amines as reducing agents via β-hydrogen of the diphosphine, with a bite angle of 102.4°. The mesylate
elimination from Pd–amido intermediates.9a,b,45 The putative anion is not bound to Pd and occupies the secondary coordi-
primary aldimine byproduct was not detected, likely due to the nation sphere. Similar cationic structures with κ2-bound ancil-
tendency of such compounds to polymerize rapidly.46 A reac- lary ligands have been determined for analogous palladacycles
tion using the Pd0 precatalyst Pd2(dba)3 gave no conversion to containing BINAP or dialkylbiaryl phosphine ligands,48a,b
3a and only a trace of 4a (5%), in agreement with previous although some complexes of the latter type show κ1 binding of
reports of inhibited oxidative addition47 and amination rates45 the phosphine and Pd-bound mesylate ions.48a
involving chelated diphosphine–Pd complexes ligated by dba
The use of CsHCO3 as the base (Table S1, ESI,† entry 4)
(dba = dibenzylideneacetone).
gave very similar yields to those obtained with Cs2CO3 in DMF
Further support for the importance of PdII-to-Pd0 reduction (Table 2, entry 10), and the reaction rate for a similar substrate
in the C–H arylation pathway was obtained by employing the was only slightly slower (by a factor of 1.25) when corrected for
xantphos palladacycle complex 5 (Fig. 2), which is one of a the lower solubility of CsHCO3 in DMF.49 This suggests that
family of precatalysts recently introduced by Buchwald and co- the deprotonating species under catalytic conditions may be a
2−
workers.48 Upon reaction with a base, precatalysts such as 5 form of carbonate with attenuated basicity—possibly CO3
rapidly generate active Pd0 species via reductive elimination of with associated Cs+ ions,50 or HCO3 generated in situ from
−
carbazole. Precatalyst 5 led to yields of 4a (64%) and phenol reaction of CO32− with adventitious H2O present in the base.
byproduct 1a (21%) that are comparable to those obtained
With reaction conditions that favor either the amination
with Pd(OAc)2/xantphos under analogous conditions (Table 2, or the C–H arylation pathway for 2a in hand, we examined
entry 10), but without the need for added benzylamine.
the scope of these catalytic reactions. The optimized amination
conditions were effective for a range of 2′-substituted binaphthyl
2-triflates (Table 3). The scope encompassed electron-deficient
(2a,e,f), unsubstituted (2b), and electron-rich aryls (2c,d)
although the yields were generally somewhat lower for electron-
deficient aryls. These conditions were also effective for catalytic
aminations of substrates with benzyl (2g), 3,5-bis(trifluoro-
methyl)benzyl (2h), and neopentyl (2i) 2′-substituents. Notably,
a binaphthyl triflate derivative with no 2′-substituent was
effectively aminated using DPEphos in combination with
Pd(OAc)2 (entry 10). This confirms that the use of xantphos is
not necessary in the absence of steric bulk at the 2′-position.
Fig. 2 Xantphos palladacycle precatalyst.
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Table 3 Scope of optimized Pd-catalyzed benzylamination of
binaphthyl 2-triflates 2a–j and subsequent debenzylation to give the
primary aminesa
Entry
1
Substrate
R
Yield 3b (%)
Yield 6b (%)
2a
61
89
2
3
4
5
6
2b
2c
2d
2e
2f
69
63
76
51
57
91
89
91
89
81
Scheme 3 Scope of optimized Pd-catalyzed intramolecular C–H aryla-
tion of 2’-aryl binaphthyl 2-triflates. aProduct 4e also formed upon reac-
tion of substrate 2f, in 71% yield (vide infra).
deficient, unsubstituted, or electron-rich. The [5]helicene
derivatives 4a–e were isolated as pure materials in 70–83%
yields by precipitation from the filtered reaction mixtures fol-
lowed by recrystallization from CH2Cl2.
7
8
2g
2h
83
62
88
86
An interesting outcome was observed in catalytic reactions
of 1,1′:2′,1″-ternaphthyl 2-triflate 8 (Scheme 4), which was pre-
pared from alcohol precursor 7 by the same procedures used
to obtain 1a–j (ref. 26) and 2a–j (Scheme 1). Compounds 7 and
8 exist as 50 : 50 mixtures of two diastereomers (7a/7b and
8a/8b) due to the adoption of two different atropisomeric
orientations of the 2′-(1″-naphthyl) group about the second
chiral axis. No amination products were observed upon sub-
jecting 8a/8b to optimized catalytic conditions, consistent with
the known steric sensitivity of Pd-catalyzed amination reac-
tions.33 However, optimized C–H arylation conditions afforded
the known helicene-like compound naphtho[1,2-s]picene (9),54
as confirmed by X-ray crystallography (Fig. S3, ESI†). A
50 : 50 mixture of the naphthol diastereomers (7a/7b) was the
only other material isolated from the reaction mixture.
9
2i
2j
76
92
82
94
10c
–H
a Reaction conditions: (i) 2 (0.53–0.90 mmol), PhCH2NH2 (1.2 equiv.),
Pd(OAc)2 (10 mol%), xantphos (10 mol%), Cs2CO3 (1.5 equiv.), toluene
(0.1 M), 90 °C, 72 h. (ii) 3 (1.3–8.0 mmol), H2 (1 atm), 10% Pd/C
(10 wt%, i.e. 1.0 wt% Pd, relative to 3), 1 : 2 MeOH/CH2Cl2 (33 mM),
25 °C, 12 h. b Isolated yields. c DPEphos used in place of xantphos in
the benzylamination step.
All binaphthyl benzylamines (3a–j) were readily debenzy-
lated by a modification of known procedures36,51 to give high
yields of primary amine derivatives 6a–j (Table 3). Chiral HPLC
analyses showed no detectable loss of stereochemistry in con-
versions of 2a–j to 3a–j and 6a–j, with enantiomeric ratios (er)
of 99 : 1 or higher observed for all amine derivatives (see the
ESI†). Primary amines 6a–j are potentially valuable new pre-
cursors to a variety of binaphthyl-based chiral auxiliaries and
ligands. For example, related derivatives have been used
to prepare chiral N-heterocyclic carbenes (NHCs),31,52 iso-
cyanides,19 and acyclic diaminocarbene (ADC) complexes.19,53
For all substrates containing 2′-aryl substituents (2a–f), the
reaction selectivity was completely switched to the C–H aryla-
tion product by conducting the reaction in DMF at 80 °C for
2–3.5 h with 5 mol% Pd(OAc)2, 7.5 mol% xantphos, and 0.2
equiv. of benzylamine (Scheme 3). Under these conditions, the
C–H arylation process appeared to be similarly facile whether
the 2′-aryl group of the binaphthyl triflate was electron-
The three-dimensional arrangement of the fused naphthyl
rings of 9 suggests that 9 could only arise from the diastereo-
meric conformation found in 7a and 8a, in which the 2- and
Scheme 4 Pd-catalyzed intramolecular C–H arylation of a diastereo-
meric mixture of 1,1’:2’,1’’-ternaphthyl 2-triflates 8a/8b. Reaction con-
ditions: (i) those specified in Scheme 2; (ii) those specified in Scheme 3.
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2″-positions are both oriented toward the same face of the
middle naphthyl moiety. The >50% yield observed for 9 thus
suggests interconversion of the two conformations. A 1D-EXSY
1H NMR spectroscopic experiment55 confirmed that this inter-
conversion occurs in the 7a/7b mixture of alcohol diastereo-
mers. After irradiation of one of the –OH peaks at 4.61 ppm,
spin inversion transfer to the other –OH peak at 4.48 ppm was
evident in the 1D gradient NOE spectrum of the mixture
(Fig. S4, ESI†), indicative of chemical exchange on the NMR
timescale.
Scheme 5 Regioselectivities of intramolecular C–H arylations of
binaphthyl triflates with meta-substituted 2’-aryl groups. Conditions: (i)
those specified in Scheme 3.
Despite being prepared from enantiomerically pure precur-
sors, benzannulated [5]helicene derivatives 4a–e and 9 exhibi-
ted very low specific rotations (e.g., [α]2D5 = 4–6° for 4a,b, and d
and 25–26° for 4c and e), and their chiral HPLC chromato-
grams indicated near-racemic mixtures of the two enantiomers
(see the ESI†). Preliminary dynamic HPLC data indicate that
this results from rapid racemization of the compounds in solu-
tion due to an intrinsic conformational instability of the
[5]helicene structure,56 as evidenced by a characteristic plateau
appearing between the two enantiomer elution peaks in the
chromatogram of 4a (Fig. S5†).57 A detailed analysis of this
phenomenon will be published elsewhere.58
Kinetic studies using the 2′-phenyl binaphthyl triflate sub-
strate (2b) provided further insights into the optimal catalytic
conditions for C–H arylation and the mechanism of the reac-
tion. First, the reaction rate was found to be significantly faster
when a xantphos : Pd(OAc)2 ratio of 1.5 : 1 was used, in com-
parison to identical conditions (26 mM 2b in DMF with
10 mol% Pd(OAc)2) with xantphos : Pd ratios of 1 : 1 and 2 : 1
(Fig. 3). We postulate that the lower rate at a 1 : 1 L : Pd ratio is
a result of partial degradation of the phosphine during catalyst
activation (vide infra), while the inhibition at 2 : 1 L : Pd may be
due to the formation of catalytically inert (xantphos)2Pd0;62
both processes would reduce the concentration of catalytically
active Pd species. In view of these results, a 1.5 : 1 ratio of xant-
phos to Pd(OAc)2 was used under the optimized catalytic con-
ditions and in all subsequent kinetic studies.
The rate of intramolecular C–H arylation of 2b was essen-
tially invariant with different initial concentrations of the sub-
strate and constant amounts of the catalyst and base (Fig. 4a),
suggesting that the reaction is zero order in the substrate.
However, the reaction rate increased with increasing catalyst
concentration. The slope of a plot of ln(k) versus ln[Pd]
(Fig. 4b) was close to unity, consistent with a rate law that is
first-order in palladium. The slower reaction rate measured for
a substrate isotopologue with a perdeuterated phenyl ring
[2b-d5, kD = (1.26 0.12) × 10−5 M s−1], in comparison to a sep-
arate rate measurement for undeuterated 2b [kH = (5.0 0.4) ×
10−5 M s−1], corresponds to a kinetic isotope effect (kH/kD)
of 4.0 0.5 at 90 °C (Scheme 6). This falls within the range of
Mechanism of C–H arylation
The arylation process leading to helicene derivatives 4 and 9
shows the characteristics of an intramolecular concerted meta-
lation–deprotonation (CMD) mechanism, in which the initial
formation of a palladium–carbon bond via oxidative addition
leads to directed, base-assisted activation of a C–H bond at a
second aromatic ring of the substrate.14 The reaction shares
key features with reported Pd-catalyzed intramolecular CMD
reactions,24,44 including the use of a carboxylate base and
amide solvent, regiospecific arylation of conformationally
accessible C–H bonds, and the similar facility of the process
with both electron-rich and electron-deficient aromatic
rings.59 The latter has been explained by Gorelsky and Fagnou
as a consequence of two counterbalancing effects: the energy
required to distort the substrate upon C–H activation (which is
less unfavorable for electron-deficient arenes), and the stabiliz-
ing interactions between the catalyst and substrate (which is
more favorable for electron-rich arenes).60
For additional comparison with reported catalyst systems,
the selectivity of the C–H arylation process for two accessible
but sterically and electronically different CH bonds was investi-
gated. When the 2′-aryl group of the binaphthyl triflate con-
tained a meta-fluoro substituent (2k, Scheme 5), arylation at
the more acidic61 ortho-CH bond adjacent to the fluorine was
favored over activation at the more remote ortho-CH bond by a
ratio of 9 : 1. When a meta-CF3 group was present (2f), the elec-
tronic preference for the more acidic CH bond was apparently
overridden by steric effects, and only the product resulting
from arylation at the CH bond para to CF3 was observed.
Similar regioselectivities have been reported for Pd-catalyzed
intramolecular C–H arylations of aryl 2-halobenzyl ethers in
the presence of the K2CO3 base, which are well-studied
examples of reactions that operate via CMD mechanisms.44d,h
Fig. 3 Product concentration versus time for C–H arylation of 2b with
varying L : Pd ratios (L
=
xantphos). Reaction conditions: 2b
(0.052 mmol), Pd(OAc)2 (10 mol%), xantphos, PhCH2NH2 (0.2 equiv.),
Cs2CO3 (1.5 equiv.), DMF (26 mM), 80 °C.
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Fig. 5 Eyring plot for C–H arylation of 2b to give 4b. Reaction rates
were measured for disappearance of 2b over the temperature range
50 °C–100 °C. Error bars are within the size of the markers for most
data points.
A notable feature of this CMD reaction is the presence of
the wide bite-angle, bidentate diphosphine ligand xantphos in
the catalyst system. The majority of reported intermolecular
and intramolecular Pd-mediated CMD processes utilize
either monodentate phosphines14,16c,44a,d–h,65 or no ligand.44b,i,
Fig. 4 Dependence of reaction rate on (a) substrate initial concen-
tration and (b) Pd concentration in intramolecular C–H arylation of 2b.
Rates are calculated based on the disappearance of 2b at 80 °C. Con-
ditions are the same as those specified in Fig. 3, with a 1 : 5 : 1 xantphos :
Pd ratio maintained. Error bars reflect uncertainties derived from least
squares fitting of the kinetic data at each concentration of 2b or Pd.
k
In a seminal study,24 Maseras, Echavarren and co-workers
reported that bidentate phosphines, including xantphos,
gave higher yields and reduced byproduct formation compared
with monodentate phosphines in Pd-catalyzed intramolecular
arylations of 2-bromobenzyl diarylmethanes.66,67 These
authors argued that an outer-sphere attack of the carbonate
base on the aryl C–H bond is likely in these systems (Fig. 6b),
in part because the bidentate phosphine occupies two co-
ordination sites and thus might inhibit the coordination of
the base to palladium.24 Relative reaction barriers calculated
by density functional theory (DFT) for the outer-sphere CMD
process were consistent with experimentally observed selecti-
vity ratios for intramolecular C–H arylations of differently sub-
stituted aryl rings when either monodentate44g or bidentate24
phosphines were included in the model. An inner-sphere
mechanism involving C–H deprotonation by a Pd-bound base
(Fig. 6a) was calculated to have similar energetic barriers but
exhibited poor agreement with the observed selectivity ratios
in the case of monodentate phosphine-ligated Pd. No compari-
son between inner-sphere and outer-sphere CMD processes
was presented for the systems with bidentate phosphines. By
contrast, computational studies of Pd-catalyzed intermolecular
C–H arylation reactions have focused on the inner-sphere
Scheme 6 Kinetic isotope effect on C–H arylation of 2b vs. 2b-d5.
Reaction conditions: (i) as specified in Scheme 3, but at 90 °C.
kH/kD values of 3.5–6.7 reported for other intramolecular Pd-
catalyzed C–H arylation reactions that have been proposed to
occur via CMD.24,44a,d–g A normal kH/kD in this range is gener-
ally thought to be inconsistent with an electrophilic aromatic
substitution (SEAr) mechanism, in which the formation of a
Wheland-type intermediate is commonly turnover-limiting
and precedes C–H cleavage.63,64
Taken together, the kinetic data point to a mechanism in
which the catalyst resting state occurs after oxidative addition
of the substrate, and C–H cleavage either is turnover-limiting
or precedes the turnover-limiting step. Thus, the concentration
of the resting state is limited by [Pd]total but not by [2b], imply-
ing a rate law that is 1st order in [Pd] and zero order in [2b]. To
gain further insights into the mechanism, an Eyring analysis
was performed using reaction rate data measured at seven
temperatures between 50 and 100 °C (Fig. 5). This analysis pro-
vides an activation enthalpy (ΔH‡) of 18 3 kcal mol−1. The
activation entropy (ΔS‡) is −15 9 cal mol−1 K−1 assuming a
first order overall rate law (r = k[Pd], vide infra).
Fig. 6 Inner-sphere versus outer-sphere CMD mechanisms.
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Fig. 7 DFT-calculated relative enthalpies and free energies (in kcal mol−1) of the transition state for inner-sphere CMD arylation of 2b (TS1), likely
resting states (I1, I2) and other potentially relevant intermediates. Calculations were done at the B3LYP/CEP-31G(d) level of theory with correction
for DMF solvation (SMD model). Relative energy levels are not drawn to scale.
CMD mechanism, in which the Pd-bound carboxylate base coordinated xanthene oxygen in I1 (Pd⋯O = 2.34 Å), which
abstracts a proton from the C–H bond via a 6-membered cyclic should be easily displaced by base. Three other identified
transition state (Fig. 6a).16,60,68
Pd-binaphthyl species (I3–I5) represent a plausible sequence
To aid in interpreting the kinetic data and to probe the of intermediates leading to the C–H activation step. Dis-
plausibility of different possible CMD mechanisms, we per- sociation of one phosphorus atom and a shift from κ1-bound
formed DFT calculations on potentially relevant intermediates to κ2-bound bicarbonate leads to a change from I2 to I3, fol-
and transition states in the catalytic cycle for intramolecular lowed by reversion of the bicarbonate to κ1-binding in I4 and
C–H arylation of 2b (Fig. 7). Starting geometries were taken I5, concomitant with changes in the xantphos binding mode.
from published X-ray crystal structure data and were delib- Interconversion of cis- and trans-bidentate xantphos via the
erately chosen to reflect the known propensity of xantphos to dissociation of one phosphine arm has been implicated in
adopt diverse binding modes at palladium, including cis- previous mechanistic studies of Pd/xantphos catalyst
bidentate,69 trans-bidentate,40h,70 and P–O–P tridentate.70a systems.70b,73 Intermediate I5 could also be accessible directly
Structures were optimized in the gas phase at the B3LYP/ from I2 or I3 upon κ2-to-κ1 shift of xantphos or bicarbonate,
CEP-31G(d) level of theory, and energetic corrections for DMF respectively.
solvation were performed via single point calculations on the
An inner-sphere CMD transition state involving proton
optimized geometries using the SMD continuum solvation abstraction by coordinated HCO3− (TS1) was identified (Fig. 8).
model (see the Experimental section for further details).71 The cyclic 6-membered Pd–O–C–O⋯H⋯C assembly in TS1 is
These calculations used bicarbonate (HCO3−) as a surrogate similar to previously calculated inner-sphere CMD transition
for the carbonate base to minimize energetic artefacts result- states16a,c,60a,68,74 and is characterized by a slightly greater
ing from charged intermediates. Bicarbonate was also used degree of bond-making (O⋯H = 1.25 Å) versus bond-breaking
as a model base in previous computational studies of Pd-cata-
lyzed CMD arylation,16c,24,44f,g and we found CsHCO3 to give
comparable results to Cs2CO3 experimentally (Table S1,
ESI†).49,72
The Pd-binaphthyl intermediate identified as the lowest in
free energy (I2) contains a trans-bidentate xantphos ligand and
a coordinated bicarbonate located opposite the binaphthyl
group. However, a cationic intermediate with xantphos in the
P–O–P tridentate coordination mode (I1) is only slightly higher
than I2 in free energy (Grel = +1.3 kcal mol−1), despite being
disfavored enthalpically (Hrel = +14 kcal mol−1), as a result of
the entropic benefit of expelling HCO3−. This small free energy
difference is within the error of DFT methods, making it plaus-
ible that I1 could be favored under experimental conditions or
Fig. 8 DFT-optimized geometries of transition states for arylation of
2b via inner-sphere CMD (TS1) and outer-sphere CMD (TS2). Xantphos
that I1 and I2 could be in a close equilibrium. Interconversion
phenyl rings and nonessential hydrogen atoms are omitted from the
of these two intermediates could be facilitated by the weakly figure for clarity.
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(C⋯H = 1.38 Å). A notable feature of TS1 is the dissociation of
one phosphine arm of the xantphos ligand (Pd⋯P = 3.98 Å) to
accommodate the base and incipient Pd⋯C bond. This obvi-
ates the need for a 5-coordinate PdII intermediate, which was
cited as an argument against an inner-sphere CMD process in
the seminal study of intramolecular C–H arylation with Pd/
bidentate phosphine catalysts.24 The Pd–C bond of the meta-
lated binaphthyl may play an important role in promoting
hemilabile behavior by the xantphos ligand, as judged by the
significant lengthening of the Pd–P bond trans to Pd–C in the
optimized geometry of I4 (2.54 Å, versus 2.38 Å for the Pd–P
bond trans to HCO3−; see the ESI†). The intermediate immedi-
ately preceding C–H activation (I5), which was identified via an
intrinsic reaction coordinate analysis75 starting from TS1, fea-
tures a partly dissociated (κ1) xantphos ligand, as well as a
weak η1 π-interaction between Pd and the binaphthyl moiety
−
(Pd⋯C1′ = 2.47 Å) at the coordination site adjacent to HCO3
.
Notably, the calculated activation enthalpy (ΔH‡) differs sig-
nificantly depending on whether cationic intermediate I1 or
bicarbonate-bound intermediate I2 is considered as the cata-
lyst resting state (Fig. 7). The ΔH‡ of 17 kcal mol−1 calculated
for the cationic resting state [(I1 + HCO3−) → TS1] is in close
agreement with the experimentally determined value of 18
3 kcal mol−1 (Fig. 5), whereas the ΔH‡ computed for I2 → TS1
is much higher (31 kcal mol−1). Due to the entropic unfavor-
ability of the overall bimolecular process leading from (I1 +
HCO3−) to TS1, the calculated free energy barrier (ΔG‡) of
29 kcal mol−1 is similar to that for the unimolecular I2 → TS1
pathway (31 kcal mol−1), despite the lower ΔH‡ for (I1 +
HCO3−) → TS1.
Fig. 9 DFT calculated relative enthalpies and free energies of the tran-
sition state for outer-sphere CMD arylation of 2b (TS2) along with rele-
vant intermediates identified from an intrinsic reaction coordinate
analysis. Energies are reported relative to I2 (see Fig. 7).
A CMD transition state corresponding to outer-sphere
attack by bicarbonate on a weakly Pd-bound η2-C–H bond
(TS2; Fig. 8 and 9) was also located, since this type of tran-
sition state was originally proposed for Pd/bidentate phos-
phine based C–H arylation systems.24 The calculated enthalpic
barriers are significantly higher for this mechanism: ΔH‡
=
23 kcal mol−1 for (I1 + HCO3−) → TS2 and ΔH‡ = 37 kcal mol−1
for I2 → TS2 (Fig. 9). We note that Echavarren and Maseras
−
chose intermediates containing HCO3 noncovalently pre-
associated with a [(κ2-diphosphine)Pd(aryl/η2-CH)]+ unit as the
reference states for computing relative energetic barriers for
outer-sphere CMD reactions.24,44g Our calculations show that
these types of intermediates are significantly higher in free
energy than the likely resting states in our system (15–25 kcal
Fig. 10 DFT calculated relative enthalpies and free energies of the tran-
sition state for reductive elimination to form 4b (TS3) along with relevant
intermediates identified from an intrinsic reaction coordinate analysis.
Energies are reported relative to I2 (see Fig. 7). a Free H2CO3 included in
mol−1 above I2; see I8 in Fig. 9 and other relevant intermediates thermodynamic calculations. b Dissociation to Pd0 + 4b is further down-
hill (Hrel = −13.3 kcal mol−1, Grel = −41.1 kcal mol−1).
in Fig. S7 in the ESI†), and thus any energetic barriers calculated
from them do not represent meaningful activation energies for
the overall catalytic cycle in the present catalyst system.76
Reductive elimination of helicene 4b from the (κ2-xantphos) highly effective for intermolecular C–H arylation of an acti-
palladacycle intermediate I10 (Fig. 10) was calculated to occur vated imidazole with a 3-bromopyrrole derivative under con-
with a very small energetic barrier (for TS3, ΔG2‡98K = 5 kcal ditions compatible with CMD (KOPiv base, DMA solvent).25
mol−1 from I10 and ΔG2‡98K = 8 kcal mol−1 from I2). Thus, the Experimental and computational studies of the mechanism
DFT study supports a turnover-limiting inner-sphere CMD step provided evidence that base-induced partial oxidation of the
via TS1.77
Pd-bound xantphos ligand to a mono-phosphine oxide78
While this study was in progress, Eastgate, Blackmond and (xantPO, Scheme 7a) is likely to be a key step leading to
co-workers disclosed a Pd/xantphos catalyst system that is effective catalysis in this system. The increased hemilability of
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trans-bidentate xantphos in combination with an anionic
ligand (Br−, I−, or N3−),70,73a,80 respectively. Thus, these reson-
ances are plausibly attributable to intermediates I1 and I2, in
agreement with the DFT studies identifying these as putative
catalyst resting states (Fig. 7). Small quantities of species with
chemical shifts at the expected locations for (xantphos)2Pd0
(2.5 ppm, 8% by integration)62 and free xantphos (−19 ppm,
<2%)28a were also detected.
Scheme 7 (a) Partial oxidation of Pd-bound xantphos to the mono-
phosphine oxide ligand xantPO, as reported by Eastgate, Blackmond
et al. (ref. 25); (b) displacement of xantPO in the presence of excess
The 31P NMR results indicate rapid, base-induced conver-
sion of most of the xantphos to the mono-phosphine oxide
form, xantPO. As noted in previous reports of phosphine
ligand oxidation in palladium-based catalyst systems, this
process likely depends on traces of water present in the base
xantphos (same ref.). ArBr
boxylic acid ethyl ester.
= 4-bromo-1-ethyl-5-nitropyrrole-2-car-
the xantPO ligand was suggested to be important in lowering and/or solvent.78 In contrast to Eastgate and Blackmond’s
the reaction barrier via adoption of a κ1-P binding mode in the study,25 our evidence does not support the involvement of
turnover-limiting inner-sphere CMD step.25
xantPO-ligated palladium in the catalytic C–H arylation reac-
In light of this report, we examined whether the mono-oxi- tion. These authors showed that xantPO is readily displaced
dized xantPO ligand might play a role in our intramolecular from PdII in the presence of free xantphos (Scheme 7b).25 This
CMD system. Unfortunately, several attempts to isolate Pd-con- is consistent with the presence of free xantPO but no Pd-
taining intermediates under catalytically relevant conditions bound xantPO in the 31P NMR experiment (Fig. 11), as well as
were unsuccessful. However, a 31P NMR analysis of a catalytic with the need for an excess of xantphos relative to Pd(OAc)2 to
reaction mixture was revealing. The reaction mixture was pre- achieve maximal rates in our system (Fig. 3). We postulate that
pared identically to that used for the 80 °C kinetic analysis of the very bulky binaphthyl ligands present in the likely catalyst
the 2b arylation reaction, but the mixture was removed from resting states (vide infra) might further increase the lability of
heating after 2 min and immediately filtered under nitrogen to the oxidized xantPO ligand through steric interactions, facili-
remove excess base. This time period was sufficient to initiate tating displacement by xantphos. The 31P NMR results also
the reaction and enter a regime with clean kinetic behavior, as imply that most of the palladium is converted into an inactive,
judged by concentration vs. time plots for the reaction at 80 °C as yet unidentified form during the initiation period, with only
(Fig. 3). The 31P NMR spectrum (Fig. 11) showed a major ≤35% of Pd (i.e. 23% of the xantphos based on 31P NMR inte-
species (76% by integration) with resonances at 23.6 and grations, at an initial 1.5 : 1 xantphos : Pd ratio) present as cata-
−23.0 ppm in a 1 : 1 ratio, consistent with non-coordinated lytically relevant (xantphos)Pd species.
mono-phosphine oxide (xantPO).25 No resonances at the
To further check whether Pd-bound xantPO could be
chemical shifts expected for Pd-coordinated xantPO (∼43 ppm involved in the catalytic reaction, we modelled potentially rele-
for PvO–Pd and ∼13 ppm for P–Pd)25 were detected.79 Two vant (xantPO)Pd intermediates and transition states at the
minor species were observed as singlets at 18.4 ppm (12% by same level of theory used for the (xantphos)Pd species dis-
integration) and 10.8 ppm (3% by integration). These chemical cussed above. With xantPO bound to Pd, an overall bimolecu-
shifts are very close to those previously reported for a cationic lar pathway with a cationic cis-bidentate (xantPO)Pd resting
arylpalladium complex containing P–O–P tridentate xant- state (I14, Fig. 12) had the most favorable energy profile, with
phos70a and for neutral arylpalladium complexes containing a calculated ΔH‡ of 9 kcal mol−1. The lowest energy transition
state (TS4) corresponds to a 6-centered inner-sphere CMD
process and is analogous to that calculated for unoxidized
xantphos (TS1), with the PvO unit undergoing hemilabile dis-
sociation. An overall unimolecular CMD pathway from an
alternative resting state with Pd-bound bicarbonate (I13) gives
a calculated ΔH‡ of 23 kcal mol−1. Because both calculated
ΔH‡ values are significantly different from the experimentally
determined value of 18 3 kcal mol−1, the DFT results provide
a further argument against Pd-bound xantPO being involved in
catalysis in the present system.
The experimental activation enthalpy and DFT-computed
energy barriers are thus most consistent with an inner-sphere
CMD process involving a Pd catalyst ligated by unoxidized
xantphos, although the cationic nature of the likely resting
Fig. 11 31P NMR spectrum of a catalytic reaction mixture for C–H aryla-
tion of 2b, after 2 min at 80 °C followed by filtration. Solvent: DMF with
state (I1) renders the overall reaction bimolecular. This is
also consistent with the negative activation entropy (ΔS‡)
C6D6 added (5% v/v). For the spectrum with integrations shown, see
Fig. S2 in the ESI.†
derived from the Eyring analysis, although a discussion of the
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Fig. 12 DFT-calculated relative enthalpies and free energies (in kcal mol−1) of the transition state and relevant intermediates for inner-sphere CMD
arylation of 2b with the mono-phosphine oxide ligand xantPO bound to Pd.
magnitude of ΔS‡ is warranted. The overall bimolecular reac- toluene, the free base would likely be present in too low a con-
tion from I1 implies a second-order rate law (r = k[Pd][base]). centration to compete with the amine for binding at Pd,83
Calculation of ΔS‡ based on experimental k values derived leading to amination as the favored reaction path.
from this rate law, with [base] = 2.7 mM based on solubility
measurements of Cs2CO3 in DMF,81 yields an activation
entropy of ΔS‡ = −3 9 cal mol−1 −1. Counter-intuitively, this
K
has a smaller negative magnitude compared with the value cal-
Conclusions
culated from first order rate constants assuming a first order This study highlights two conceptually related yet chemically
rate law, r = k[Pd] (ΔS‡ = −15 9 cal mol−1 K−1), i.e., for an distinct palladium-catalyzed transformations of binaphthyl tri-
overall unimolecular process with I2 as the catalyst resting flates that are competitive under some conditions. Both reac-
state. The ΔS‡ values derived from DFT-calculated relative free tions are enabled by the wide bite-angle xantphos ligand, and
energies for (I1 + HCO3−) → TS1 and I2 → TS1 are −40 cal each process can be separately optimized to yield potentially
mol−1 K−1 and +2.5 cal mol−1
K
−1, respectively (all species at useful products. The catalytic amination pathway affords a
1 M). We note that the experimental uncertainty on ΔS‡ is family of binaphthyl amines with sterically and electronically
large and likely to be underestimated, given that ΔS‡ is derived tunable 2′-substituents, which could be useful precursors to
from the y-intercept of the Eyring plot, which is highly sensi- new chiral auxiliaries and ligands for asymmetric syn-
tive to errors in individual rate constants and to the assumed thesis.19,31,52,53 The intramolecular C–H arylation pathway,
concentrations of catalytically active Pd and base, which are initially identified as a new type of side-reaction in Pd-cata-
not known.82 The experimental ΔH‡ value is determined from lyzed amination, becomes quite facile in polar solvents and
the slope of the Eyring plot, which is invariant to the assumed opens access to new members of the family of benzo-fused [5]
concentrations of Pd and the base. Thus, we regard ΔH‡ as the helicene derivatives.54,84–87 The reaction conditions are signifi-
more reliable metric for comparison with DFT-calculated acti- cantly less harsh compared with previously reported Pd-cata-
vation barriers.
lyzed C–H arylation routes to fused polycyclic aromatic
Although the amination pathway was not suitable for compounds, which typically require temperatures of
mechanistic studies due to low reaction rates and significant 120–180 °C.44h,88 In addition, our conditions allow the use of
catalyst decomposition, some insight into the factors leading readily accessible aryl triflates, which are relatively underdeve-
to the observed switchable reactivity can be drawn from the loped as coupling partners in direct arylation chemistry.65g,88a–c
DFT studies. Changing the continuum solvent from DMF (ε = Given the growing interest in applications of helicenes21 and the
37.22) to toluene (ε = 2.37) results in the nonassociated (I1 + scant attention given to C–H arylation routes to these
HCO3−) ion pair being drastically disfavored (Grel = +32 kcal materials,89 these results could form the basis for further develo-
mol−1) relative to I2, but the overall ΔG‡ for I2 → TS1 (27 kcal pment of efficient new synthetic routes to these chiral aromatic
mol−1) is surprisingly comparable to the ΔG‡ values calculated compounds.
for the inner-sphere CMD process in DMF solvent (Fig. 7).
Mechanistic studies of the C–H arylation reaction point out
Therefore, we propose that the switch to dominant C–H aryla- a unique role for the xantphos ligand. Its propensity for hemi-
tion reactivity in polar solvents is not due to large changes in labile behavior allows it to accommodate an inner-sphere
the relevant energetic barriers, but rather due to the increased CMD mechanism similar to those proposed for related inter-
solubility of the carbonate base. In nonpolar solvents such as molecular16a,c,60a,65,68 and intramolecular44a,b,d–i,k Pd-catalyzed
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arylation reactions that do not involve chelate ligands. This prior to reaction. For development of chiral HPLC separation
avoids the higher-energy outer-sphere CMD pathway.24,44g conditions used for confirmation of enantiomeric purity,
Although a recent report indicates that oxidation of xantphos racemic samples of 3a–j and 6a–j were prepared from commer-
to the mono-phosphine oxide xantPO can play a key role in cial rac-BINOL using methods identical to those for the
lowering the reaction barriers in some types of C–H arylation enantiopure products. General procedures for syntheses of all
reactions by increasing ligand hemilability,25 our results organic products are given below, with detailed characteri-
suggest that xantphos possesses sufficient hemilabile charac- zation data provided in the ESI.†
ter to accommodate inner-sphere CMD even without oxidation,
and indeed that the xantPO ligand is not bound to catalytically
Optimized synthetic procedures
relevant intermediates despite being present in the reaction
Synthesis of binaphthyl triflates (2a–2k, 8a/8b). Under an
mixture. We conclude that the effectiveness of xantphos as a inert atmosphere, binaphthyl alcohol precursor (1a–k or 7a/7b,
ligand in the amination and C–H arylation reactions arises 0.5–4.7 g) was placed in an oven-dried two-neck flask contain-
from a favorable combination of moderately strong donor ing dry CH2Cl2 (4 mL mmol−1 of alcohol) at 0 °C. NiPr2Et (1.2
ability (which likely facilitates oxidative addition of binaphthyl equiv.) was added, followed by gradual syringe addition of
triflate),90,91 hemilability, and wide bite angle. The latter is triflic anhydride (1.05 equiv.). The reaction mixture was stirred
expected to promote facile reductive elimination to form either at 0 °C. After complete consumption of the starting material as
the amine product (from a bulky Pd(amido)(binaphthyl) inter- monitored by TLC, the solution volume was doubled by
mediate) or helicene (from the rigid palladacycle formed upon addition of CH2Cl2. The mixture was washed with 1.0 N HCl,
C–H arylation),70b,73a,92 in agreement with the low calculated followed by water and saturated aqueous NaHCO3. The organic
barrier for TS3 (Fig. 10).
layer was then separated and dried over anhydrous sodium
sulfate. The solvent was evaporated to yield solid binaphthyl
triflate. The compounds were used immediately in subsequent
reactions without further purification.
Pd-catalyzed amination procedure for the synthesis of
binaphthyl benzyl amines (3a–j). In a nitrogen-filled glovebox,
Experimental section
General experimental methods
All manipulations were carried out under nitrogen in dried, Pd(OAc)2 (10 mol%) and xantphos (10 mol%) were added to a
distilled solvents unless otherwise mentioned. Toluene, THF, sealable glass reaction vessel equipped with a stir bar. For the
1,4-dioxane, and benzene-d6 were purified by distillation from unsubstituted binaphthyl triflate 2j, DPEphos was used in
sodium benzophenone ketyl. Dichloromethane was washed place of xantphos. Freshly distilled dry toluene (∼0.5 mL) was
with a sequence of concentrated H2SO4, deionized water, 5% added, and the mixture was stirred for 5 min. A solution of
Na2CO3 and deionized water, followed by pre-drying over an- binaphthyl triflate (2a–2k, 8a/8b, 0.14–0.50 g, 0.53–0.90 mmol)
hydrous CaCl2, and then refluxed over and distilled from P2O5 in toluene (sufficient volume to attain 0.1 M final concen-
under N2. DMF (99.8%, extra dry) was purchased pre-dried tration) was added, followed by Cs2CO3 (1.5 equiv.). The vessel
from Acros in septum-sealed bottles, which were sent into a was brought out of the glove box, benzylamine (1.2 equiv.) was
nitrogen glovebox immediately upon receipt. Methanol added under an argon counterflow, and the vessel was placed
(Pharmco, ACS grade) was used as received. Pd(OAc)2 (an- in a preheated (90 °C) oil bath for 72 h. The reaction mixture
hydrous, >99%) was purchased from Strem or Frontier Scientific, was then cooled to room temperature and filtered through
purified by recrystallization from chloroform according to pub- Celite, and the product was purified by flash column
lished procedures,93 and stored in a nitrogen glovebox.38 Xant- chromatography.
phos (min. 98%) was purchased from Strem. Cs2CO3 (Aldrich,
Conversion of benzyl amines 3a–j to primary amines 6a–j. In
99%) was transferred into a nitrogen glovebox immediately an oven-dried two-neck round bottom flask equipped with a
upon receipt, and the same container was used for all mechan- nitrogen balloon and a fresh septum, benzyl amine (3a–j,
istic studies. Preparative flash column chromatography was 0.7–3.2 g) was dissolved in a mixture of methanol (20 mL
performed on silica gel 60 (230–400 mesh) using solvent mix- MeOH per g of amine) and freshly distilled CH2Cl2 (40 mL
tures that gave optimal separations by TLC. Xantphos pallada- CH2Cl2 per g of amine). Under nitrogen counterflow, the
cycle 5 was prepared according to a published procedure.48a septum was removed, and 5% Pd–C (10 wt% with respect to
Triflic anhydride (Oakwood chemical, 98%) was placed in a 3a–j) was added. The septum was re-installed, and the reaction
sealable glass ampule under an Ar atmosphere immediately vessel was subjected to vacuum. The reaction mixture was then
upon receipt. The reagent was transferred under Ar counter- placed under an atmosphere of H2 (hydrogen balloon). The
flow at each use, and the ampule was stored at 4 °C. All other mixture was stirred for 1–6 h at RT, until complete consump-
reagents were purchased from Acros or Aldrich in the highest tion of the starting material as indicated by TLC. The hydrogen
available purity and were used as received.
atmosphere was then removed under vacuum, and the reaction
Binaphthyl alcohols 1a–k and 7a/7b were prepared by pub- vessel was flushed generously with nitrogen. The suspended
lished procedures26 or modifications thereof (see the ESI†) Pd/C was removed by filtration through Celite, the solvent was
starting from (R)-BINOL (>99%), which was purchased from evaporated, and the resulting solid product was purified by
Chem-Impex International, Inc and checked for optical purity flash column chromatography.
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Pd-catalyzed C–H arylation procedure for the synthesis of [5] constants by factoring out estimated concentrations of the
helicene derivatives (4a–e, 4k, 9). In a nitrogen-filled glovebox, active catalyst (0.91 mM)82 and base (2.7 mM Cs2CO3).81
Pd(OAc)2 (5 mol%) and xantphos (7.5 mol%) were added to a Uncertainties on rates and derived quantities were obtained
reaction vial or a sealable glass vessel equipped with a mag- from linear regression analyses of the concentration vs. time
netic stir bar. Dry DMF (0.5 mL per 100 mg of substrate) was data and are reported at the 95% confidence level.
added, and the reaction mixture was stirred for ∼5 min until
Kinetic isotope effect measurement. Pentadeuterated 2′-
the orange solution became yellow. A solution of binaphthyl phenyl binaphthyl alcohol 1b-d5 was prepared by the same pro-
triflate (100–400 mg) in dry DMF (1.5 mL per 100 mg of sub- cedure as 1b,26 but with bromobenzene-d5 (Cambridge Isotope
strate) was added, followed by Cs2CO3 (1.5 equiv.). The reaction Laboratories, 99.5% D) utilized in the Kumada coupling pro-
vessel was sealed and brought out of the glovebox. Benzyl- cedure. Compound 1b-d5 was converted to the triflate 2b-d5 by
amine (0.2 equiv.) was added, and the reaction vessel was the optimized procedure shown in Scheme 1. Separate rate
placed in a preheated (80 °C) aluminium block heater or an measurements of the C–H arylation reactions of 2b and 2b-d5
80 °C oil bath with magnetic stirring. Upon complete con- were performed at 90 °C under identical conditions, following
sumption of binaphthyl triflate as judged by TLC (2–3 h), the the general procedure described above.
hot reaction mixture was filtered through Celite, and the solu-
tion was cooled to precipitate the crude product. The product tion mixture of substrate 2b was prepared following the same
31P NMR analysis of C–H arylation reaction mixture. A reac-
was purified by recrystallization from CH2Cl2.
procedure used for the kinetic measurements (vide supra), but
with the HPLC internal standard omitted. After heating for
2 min at 80 °C, the entire reaction mixture was filtered to
Mechanistic studies
Representative kinetic procedure for intramolecular C–H remove any undissolved base, and half of the solution
arylation of 2b. In a nitrogen-filled glovebox, a stock precatalyst (∼1.0 mL) was transferred to a sealable NMR tube fitted with a
solution was prepared by adding Pd(OAc)2 (24 mg mL−1) to dry PTFE stopcock. A small amount of C6D6 (5% v/v) was added to
DMF and stirring until a transparent solution was obtained. A facilitate NMR locking and shimming. The NMR solution was
separate solution of xantphos (9.0 mg, 15 mol%) in 0.4 mL of degassed on a high-vacuum line via three freeze–pump–thaw
DMF was prepared in a 1 mL reaction vial, and 0.1 mL (10 mol cycles, and the sample was immediately analysed by 31P NMR
%) of the Pd(OAc)2 stock solution was added to it. The Pd spectroscopy.
(OAc)2/xantphos mixture was stirred until the solution turned
Solubility of bases in DMF. A 75 mg sample of Cs2CO3 or
from orange to yellow. Separately, substrate 2b (50 mg) and CsHCO3 was placed in a sealable reaction vessel containing a
2,7-dimethylnaphthalene (HPLC internal standard, 26 mg) magnetic stir bar, and 6 mL of dry DMF was added. The vessel
were dissolved in 1.5 mL of DMF, and this solution was com- was sealed, placed in an oil bath, and heated at the desired
bined with the Pd(OAc)2/xantphos mixture. The combined temperature for 3 h with vigorous stirring. The hot solution
mixture was stirred for 2 min. A 1 mL aliquot of this combined was filtered through a glass frit, and the filtrate was placed in
solution was transferred to a separate vial containing 1 mL of a tared round bottom flask. The DMF was removed by short
DMF and Cs2CO3 (25 mg, 1.5 equiv. with respect to halved con- path distillation, and the flask was further dried overnight on
centration of 2b). This halving of reagent concentrations was a high-vacuum line. The flask and solid contents were weighed
necessary in order to obtain usable kinetic data, as the reac- to determine the amount of solid residue present.
tion was too fast to monitor in its early stages under optimized
synthetic conditions. The reaction vial was sealed with a PTFE-
lined silicone septum and removed from the glovebox. Benzyl-
amine (1 μL, 20 mol%) was added via syringe through the
Computational methods
septum, and the vial was placed in a preheated aluminium DFT calculations were performed using the Gaussian 09 suite
block heater on a stir plate. Aliquots (10 μL) of the reaction of quantum chemistry programs94 with the B3LYP hybrid func-
mixture were withdrawn at regular time intervals, quenched tional.95 Palladium and main group elements were described
with 100 μL of isopropanol, and diluted with THF to a total using the relativistic effective core potentials (ECPs) and
volume of 1 mL. Quenched reaction aliquots were analyzed by valence basis sets (VBSs) of Stevens et al.96 The valence basis
HPLC using a Chiralpak-IA column (conditions: 90% hexane/ sets of non-hydrogen main group elements were augmented
10% isopropanol, flow rate 1.5 mL min−1, pressure 60 bar).
with d polarization functions, with exponents of 0.8 for carbon
The concentrations of reactant and products were deter- and oxygen and an exponent of 0.55 for P. This ECP/VBS com-
mined using HPLC integrated peak areas via multilevel con- bination, which is denoted variously in the literature as
centration versus response calibration plots for each CEP-31G(d), SBK(d), or CSDZ*, has been shown to reliably
compound in comparison with the internal standard. Plots of model structural and energetic properties of a wide range of
[2b] versus time were generally linear up to 70–75% conversion transition metal organometallic complexes, including catalyti-
following a brief induction period (<2 min at 80 °C). Pseudo cally relevant palladium species.97 Thermochemical quantities
zero-order rate constants were determined by linear least- were derived from frequency calculations on ground state and
squares fitting of reactant concentration versus time plots over transition state geometries optimized in the gas phase. Ener-
this region. These were converted to first- or second-order rate getic corrections for solvation were performed via single point
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calculations on gas phase-optimized geometries using the
SMD continuum solvation model.71 Full geometry optimi-
zations in DMF solvent were attempted but could not be
completed for several species, as the calculations failed to
converge. However, calculations on a key set of intermediates
and transition states (I1 + HCO3−, I2, TS2) showed that there
were minimal differences in relative enthalpies and free
energies (≤0.8 kcal mol−1) whether the optimizations were
performed in solvent or in the gas phase with solvent correc-
tion. The identities of ground states immediately preceding
and following calculated transition states were identified by
performing intrinsic reaction coordinate analyses75 and then
optimizing the endpoint geometries for the forward and
reverse reaction paths. Plots of optimized geometries were
prepared using GaussView.98
6 (a) S. Shekhar, P. Ryberg, J. F. Hartwig, J. S. Mathew,
D. G. Blackmond, E. R. Strieter and S. L. Buchwald, J. Am.
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J. Am. Chem. Soc., 2008, 130, 6686–6687; (e) C. Valente,
S. Çalimsiz, K. H. Hoi, D. Mallik, M. Sayah and
M. G. Organ, Angew. Chem., Int. Ed., 2012, 51, 3314–3332;
(f) S. M. Raders, J. N. Moore, J. K. Parks, A. D. Miller,
T. M. Leißing, S. P. Kelley, R. D. Rogers and
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3609–3612; (b) A. S. Guram, R. A. Rennels and
S. L. Buchwald, Angew. Chem., Int. Ed. Engl., 1995, 34,
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Acknowledgements
We gratefully acknowledge the National Science Foundation
(CHE-1360610 to LMS; CHE-1057785 and CHE-1464943 to
TRC) for financial support provided for this research. We
thank Prof. Guido Verbeck (UNT) for providing access to mass
spectrometry capabilities in the Laboratory for Imaging Mass
Spectrometry (UNT-LIMS). Prof. Wes Borden (UNT) is thanked
for helpful discussions. Prof. Daniel Armstrong and Zach Breit-
bach (University of Texas at Arlington) are thanked for sharing
expertise on chiral HPLC analyses of helicene derivatives.
9 (a) E. R. Strieter, D. G. Blackmond and S. L. Buchwald,
J. Am. Chem. Soc., 2003, 125, 13978–13980; (b) E. R. Strieter
and S. L. Buchwald, Angew. Chem., Int. Ed., 2006, 45,
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J. Org. Chem., 1997, 62, 1268–1273; (b) J. P. Wolfe and
S. L. Buchwald, J. Org. Chem., 1997, 62, 1264–1267.
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S. L. Buchwald, J. Am. Chem. Soc., 2006, 128, 10694–10695;
(b) T. Ikawa, T. E. Barder, M. R. Biscoe and S. L. Buchwald,
J. Am. Chem. Soc., 2007, 129, 13001–13007.
Notes and references
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Catalyzed Cross-Coupling Reactions, ed. A. De Meijere and 13 For optimized Pd-catalyzed homocoupling of aryl halides
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18 This side reaction has also been optimized to achieve selec-
tive catalytic C2- or C3-arylation of indole: M. V. Nikulin,
A. Y. Lebedev, A. Z. Voskoboinikov and I. P. Beletskaya,
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19 S. Handa and L. M. Slaughter, Angew. Chem., Int. Ed., 2012,
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31 S. Zhu, C. Wang, L. Chen, R. Liang, Y. Yu and H. Jiang, Org.
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1218–1224.
34 Another study reported that attempted aminations of a
1,1′-binaphthyl 2-nonaflate derivative failed despite the use
of several mono- and bidentate phosphines (including
xantphos) that often work well with hindered substrates:
P. N. M. Botman, O. David, A. Amore, J. Dinkelaar,
M. T. Vlaar, K. Goubitz, J. Fraanje, H. Schenk, H. Hiemstra
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22 Selected recent applications of helicene derivatives: as chir-
optical materials: (a) E. Anger, M. Srebro, N. Vanthuyne,
L. Toupet, S. Rigaut, C. Roussel, J. Autschbach, J. Crassous 35 P. N. Rylander, in Hydrogenation Methods, Academic Press,
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molecular electronic materials: (b) T. Hatakeyama, 36 J. Åhman and S. L. Buchwald, Tetrahedron Lett., 1997, 38,
S. Hashimoto, T. Oba and M. Nakamura, J. Am. Chem. Soc., 6363–6366.
2012, 134, 19600–19603. As chiral ligands for metal catalysts: 37 Cs2CO3 was also used previously in successful catalytic
(c) S. Cauteruccio, A. Loos, A. Bossi, M. C. Blanco Jaimes,
D. Dova, F. Rominger, S. Prager, A. Dreuw, E. Licandro and
aminations of 2′-substituted binaphthyl 2-triflates. See ref.
29–31.
A. S. K. Hashmi, Inorg. Chem., 2013, 52, 7995–8004; 38 Use of Pd(OAc)2 that was not rigorously purified led to non-
(d) K. Yavari, P. Aillard, Y. Zhang, F. Nuter, P. Retailleau,
A. Voituriez and A. Marinetti, Angew. Chem., Int. Ed., 2014,
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see: W. A. Carole and T. J. Colacot, Chem. – Eur. J., 2016, 22,
7686–7695.
M. Benaglia, A. Genoni, M. Orlandi and E. Licandro, 39 Reactions conducted at 100 °C or higher gave amine pro-
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(f) S. Cauteruccio, C. Bartoli, C. Carrara, D. Dova, C. Errico,
ducts that showed slight erosion of optical activity by
polarimetry.
G. Ciampi, D. Dinucci, E. Licandro and F. Chiellini, Chem- 40 (a) Y. Guari, D. S. van Es, J. N. H. Reek, P. C. J. Kamer and
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25 Y. Ji, R. E. Plata, C. S. Regens, M. Hay, M. Schmidt,
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26 S. Handa, Y. L. N. Mathota Arachchige and L. M. Slaughter,
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27 (a) Y. Uozumi, N. Suzuki, A. Ogiwara and T. Hayashi, Tetra-
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P. W. N. M. van Leeuwen, K. Goubitz and J. Fraanje,
Organometallics, 1995, 14, 3081–3089; (b) J. P. Sadighi,
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J. Org. Chem., 1999, 64, 6019–6022; (b) K. W. Anderson,
M. Mendez-Perez, J. Priego and S. L. Buchwald, J. Org.
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(e) L. Jean, J. Rouden, J. Maddaluno and M.-C. Lasne,
29 R. A. Singer and S. L. Buchwald, Tetrahedron Lett., 1999, 40,
1095–1098.
30 Another paper reported that the Singer and Buchwald’s
DPE-phos/Pd(OAc)2 amination conditions are also effective
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42 Xantphos has been reported to reduce the amount of arene 53 Y.-M. Wang, C. N. Kuzniewski, V. Rauniyar, C. Hoong and
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can lead to increased arene byproduct when C–N reductive
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