Mild and Regioselective Pd(OAc)2-Catalyzed C-H Arylation of Tryptophans by [ArN2]X, Promoted by Tosic Acid

Article abstract of DOI:10.1021/acscatal.6b03121

A regioselective Pd-mediated C-H bond arylation methodology for tryptophans, utilizing stable aryldiazonium salts, affords C2-arylated tryptophan derivatives, in several cases quantitatively. The reactions proceed in air, without base, and at room temperature in EtOAc. The synthetic methodology has been evaluated and compared against other tryptophan derivative arylation methods using the CHEM21 green chemistry toolkit. The behavior of the Pd catalyst species has been probed in preliminary mechanistic studies, which indicate that the reaction is operating homogeneously, although Pd nanoparticles are formed during substrate turnover. The effects of these higher order Pd species on catalysis, under the reaction conditions examined, appear to be minimal: e.g., acting as a Pd reservoir in the latter stages of substrate turnover or as a moribund form (derived from catalyst deactivation). We have determined that TsOH shortens the induction period observed when [ArN₂]BF₄ salts are employed with Pd(OAc)₂. Pd(OTs)₂(MeCN)₂ was found to be a superior precatalyst (confirmed by kinetic studies) in comparison to Pd(OAc)₂.

Full text of DOI:10.1021/acscatal.6b03121

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Research Article
pubs.acs.org/acscatalysis
Mild and Regioselective Pd(OAc)2‑Catalyzed C−H Arylation of
Tryptophans by [ArN2]X, Promoted by Tosic Acid
Alan J. Reay, L. Anders Hammarback, Joshua T. W. Bray, Thomas Sheridan, David Turnbull,
Adrian C. Whitwood, and Ian J. S. Fairlamb*
Department of Chemistry, University of York, York YO10 5DD, U.K.
S
* Supporting Information
ABSTRACT: A regioselective Pd-mediated C−H bond arylation methodology for
tryptophans, utilizing stable aryldiazonium salts, affords C2-arylated tryptophan
derivatives, in several cases quantitatively. The reactions proceed in air, without base,
and at room temperature in EtOAc. The synthetic methodology has been evaluated and
compared against other tryptophan derivative arylation methods using the CHEM21 green
chemistry toolkit. The behavior of the Pd catalyst species has been probed in preliminary
mechanistic studies, which indicate that the reaction is operating homogeneously, although
Pd nanoparticles are formed during substrate turnover. The effects of these higher order
Pd species on catalysis, under the reaction conditions examined, appear to be minimal: e.g., acting as a Pd reservoir in the latter
stages of substrate turnover or as a moribund form (derived from catalyst deactivation). We have determined that TsOH
shortens the induction period observed when [ArN2]BF4 salts are employed with Pd(OAc)2. Pd(OTs)2(MeCN)2 was found to
be a superior precatalyst (confirmed by kinetic studies) in comparison to Pd(OAc)2.
KEYWORDS: regioselectivity, cross-coupling, palladium, heteroarene, chirality, directing group, aryldiazonium salt
aromatic oxidation by CuII. This can be overcome using
INTRODUCTION
■
presynthesized [Ar1IAr2]X salts at 25 °C in EtOAc in air
Pd-catalyzed cross-couplings are well-established, versatile
(Scheme 1).10b However, in that chemistry the arylation
methods for the selective modification of natural products,1
selectivity emerged as an issue, where two arylation products,
macrocycles,2 and biomolecules.3 The intrinsic synthetic
derived from the transferring (Ar1 = phenyl) phenyl and static
methodology limitation is the requirement for substrate
(Ar2 = mesityl) aromatic groups, was found.
prefunctionalization, which adds synthetic complexity to a
multistep sequence, in addition to decreasing atom economy
In this study aryldiazonium salts, [ArN2]BF4, have been
examined as electrophilic arylating coupling partners with
and increasing downstream chemical waste. For these reasons,
tryptophan derivatives (1 + 2 → 3, Scheme 1). [ArN2]BF4 salts
the direct functionalization of C−H bonds has emerged as an
share similarities with [Ar1IAr2]X, in terms of both their
alternative to classical approaches,4,5 where high selectivities
structure and reactivity.12 As oxidative addition of [ArN2]BF4
can be achieved in complex systems such as pharmaceutical
to Pd0 is rapid,13,14 we anticipated development of a mild and
targets6 and biological probes involving metal catalysis.7,8
selective process, in the absence of an exogenous base. In this
The C2-selective Pd-mediated arylation of tryptophan
context, a mild methodology for the arylation of mainly indole
derivative 1, and tryptophan-containing peptides, has attracted
interest from several groups within the C−H activation field;9 a
derivatives was reported by Noel et al., employing aryldiazo-
nium salts and catalytic Pd(OAc)2.14d Noel et al. further
summary of our previous work10 and the key contributions of
Lavilla9b and Ackermann9c are given in Scheme 1. For all the
synthetic methodologies reported to date, one can be critical of
the stoichiometric byproducts (e.g., iodoarenes or Ag)
generated from these reactions, which complicate product
purification and in effect mask their global atom efficiency and
utility. For example, Pd-mediated processes using PhB(OH)2/
suggested a mechanism akin to Heck−Matsuda type coupling
reactions.14d For several years we have independently been
investigating synthetic protocols (Pd catalyst, solvent, temper-
atures) similar to those of Noel et al. for tryptophan
arylations.14h
A novel arylation protocol has therefore been developed that
provides a clean and mild synthetic method for the preparation
of arylated tryptophan derivatives. A significant initial rate
enhancement in arylation efficacy was found using catalytic
quantities of either TsOH or Pd(OTs)2(MeCN)2: i.e., in place
of Pd(OAc)2.
11
PhI(OAc)2 gave the arylated products in moderate yields, in
addition to PhI and other byproducts. The conditions require
that the aromatic group of the organoboronic acid be matched
with that of the IIII reagentan issue for the introduction of
substituted aromatics. This problem was in part obviated by
eliminating PhI(OAc)2 as reagent/oxidant, using instead
Cu(OAc)2 as a cocatalyst along with PhB(OH)2, with air
serving a role as a terminal oxidant.10a Under such conditions
specific tryptophan-containing peptides were susceptible to
Received: November 2, 2016
Revised: June 10, 2017
© XXXX American Chemical Society
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Scheme 1. Development of Conditions for the Direct C2-
Arylation of Tryptophan Derivatives and Peptides (Selected
Examples)
Table 1. Scope of Aryldiazonium Tetrafluoroborate Salts for
Direct Arylation of 1
a
RESULTS AND DISCUSSION
■
The aryldiazonium salts employed within this study are readily
available from the corresponding anilines by an oxidative
process to generate the tetrafluoroborate salts in excellent yields
(see the Supporting Information).15 Treatment of protected
tryptophan 1 with 1 equiv of [PhN2]BF4 (2a) in the presence
of catalytic Pd(OAc)2 in ethyl acetate gave the desired C2-
arylation product 3a in quantitative yield after 16 h at room
temperature (ca. 20 °C). This synthetic protocol was then
demonstrated on a series of substituted aryldiazonium salts,
which are collated in Table 1.
Alkylated, electron-donating, and halide-containing examples
provided good to excellent yields, while the sterically
encumbered 2,4,6-trimethylphenyl salts also proved effective,
giving 3e. The quantitative synthesis of the biphenyl-substituted
product 3d provided access to a product exhibiting fluorescence
at long-wave UV light (excitation at 365 nm), markedly distinct
from that of the single-arene-containing examples or the parent
compound 1.10 The tolerance of the synthetic protocol toward
halogenated arenes provides a useful orthogonality to further
functionalization to produce, for example, other biaryl
derivatives (from 3h−l). It is important to note that
aryldiazonium salts containing strongly electron withdrawing
substituents (3m,n) were not tolerated by this arylation
protocol, an observation also made by Correia and co-
workers,14b who described the formation of a diazo side
product generated by the nucleophilic attack of a C2-arylated
indole on electron-deficient aryldiazonium salts. These
electron-deficient aromatic groups can be installed via the
reported complementary conditions.10
a
All reactions conducted with 1 (0.192 mmol), 2 (0.192 mmol),
Pd(OAc)2 (5 mol %), and EtOAc (5 mL) at room temperature (ca. 20
°C). Reactions require Pd(OAc)2 for effective product conversion.
b
Reaction time extended to 24 h.
identical with that of the L-tryptophan starting material 1,
confirming that no racemization takes place at the chiral
center). In the examples where complete substrate conversion
was recorded (i.e., 3a−d,f−j), the desired arylation product
could be isolated without the need for column chromatography,
which provided a distinct practical benefit over the equivalent
diaryliodonium salt methodologies, in addition to the selective
formation of one arylation product. This advantage is reflected
in the green reaction metrics calculated for both this and our
previously published protocols (Table 2, conditions A−D),10
determined by the CHEM21 green metrics toolkit.16
In addition to an increase in product yield and decrease in
reaction temperature from the initial set of conditions, several
key mass-based metrics have been improved upon. Conditions
utilizing hypervalent iodine reagents (A and C) have noticeably
lower values for atom economy (AE): i.e., the theoretical
maximum efficiency for a particular transformation. While
Single-crystal X-ray diffraction structures of 3a,e,k were
obtained (see the Supporting Information); the absolute
stereochemistry of 3k was determined by the crystallographic
analysis and the product confirmed as S (stereochemistry
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a
Table 2. Comparison of Mass-Based Metrics for Several Direct Arylation Conditions
conditions, reagent
A, PhI(OAc)2/PhB(OH)2
B, PhB(OH)2 with CuII
C, [PhMesI]OTf
D, [PhN2]BF4
100
yield/%
temp/°C
solvent
AE
56
93
85
40
40
25
room temp (ca. 20)
AcOH
48
AcOH
88
EtOAc
46
EtOAc
74
RME
OE
16
62
24
74
33
70
52
100
602
MI
6902
4139
4504
a
Calculated using the CHEM21 unified metrics toolkit.16 Abbreviations: RME, reaction mass efficiency; AE, atom economy; OE, optimum
efficiency; MI, (total) mass intensity.
conditions B do not suffer from this, they do require the
undesirable addition of a second transition metal (in addition to
the drawbacks with certain peptides highlighted above). These
trends are also observed for the reaction mass efficiency
(RME), which incorporates yield and stoichiometry into the
simpler AE calculation, thus giving a measure of the observed
reaction efficiency, in comparison to the theoretical value
provided by AE. This can be rationalized through use of the
optimum efficiency metric, which directly correlates these two
factors, highlighting this new process (conditions D) as the
most atom and mass efficient overall.
Scheme 2. C2-Arylation of Two Selected Peptides with
Aryldiazonium Salt 2a
The most striking improvement can be seen in the mass
intensity (MI) value, which is an order of magnitude lower for
conditions D in comparison to our initial conditions A. The
primary reason for this dramatic increase is the removal of
purification by column chromatography (silica gel), with other
secondary effects including the number of equivalents of
arylating agent used for each set of conditions (a full
breakdown of the MI values can be found within the
Supporting Information). Finally, switching the reaction solvent
from neat acetic acid to the more benign ethyl acetate has a
demonstrable health impact, as acetic acid has been ranked as a
“problematic” reaction solvent by the recently published
CHEM21 solvent selection guide17 (ethyl acetate is ranked as
“recommended”).
Peptides (4 and 6) that had previously demonstrated
oxidative sensitivity to Pd0/CuII-mediated reaction condi-
tions10b were subjected to the new synthetic protocol. The
first arylation product 5 was isolated in excellent yield, with no
evidence of undesired aromatic hydroxylation, seen when CuII
was used (Scheme 2). A usable yield was recorded for 7 (45%).
Note that, for these complicated polar molecules, methanol was
used in place of ethyl acetate as the reaction solvent; the
catalyst loading was increased, primarily to ensure quantitative
conversion (thus, products 5 and 7 were isolated as the methyl
esters). The [α]D values for 5 and 7 were of magnitude similar
to those of the peptide starting materials 4 and 6, respectively,
showing that their stereochemical integrity was preserved under
the reaction conditions, in keeping with the previous arylations
of 1.
to understand the behavior of the catalyst system. The C2-
phenyl derivative 3a possesses a bathochromic shift of 62 nm
relative to 1,10a enabling the kinetic profile of the arylation
reaction to be examined by ex situ UV−visible spectroscopic
analysis. The evolution of 3a at 304 nm at 37 °C was monitored
against time (Figure 1a), reaching completion within ca. 2 h.
Product evolution exhibited a sigmoidal-like curve (Figure 1b),
in addition to a significant induction period (ca. 1 h).
Elimination of either substrate 1 or 2a for the duration of the
induction period produced kinetic profiles mirroring that found
in Figure 1b, upon addition of all substrates. Thus, both
substrates 1 and 2a are required for the formation of the active
catalyst.
Reported mechanistic work on the arylation of 3a using
conditions A indicated that palladium nanoparticles (PdNPs)
were formed in operando,10a where stabilized Pd(PVP)NP (ca.
2 nm, PVP = polyvinylpyrrolidinone) was found to be a viable
catalyst in this instance. It was postulated initially that the
sigmoidal curve observed in the current system could be
indicative of a quasi-heterogeneous process and autocatalysis.18
Preliminary mechanistic investigations for the arylation of
tryptophan derivatives by aryldiazonium salts were conducted
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Figure 1. (a) UV−visible spectra showing formation of 3a (ε = 17626
dm3 mol−1 cm−1) at 304 nm (between 5 min intervals) from reaction
of 1 with 2a at 37 °C. (b) Kinetic plot showing the evolution of 3a
over time (samples filtered through Celite; dilution ×104 in EtOAc for
direct analysis by UV−vis). General procedure: 1 (1.92 × 10−4 mol, 1
equiv), [PhN2]BF4 (2a; 1.92 × 10−4 mol, 1 equiv), Pd(OAc)2 (9.6 ×
10−6 mol, 5 mol %) in EtOAc (5 mL); overall concentration in [1] =
0.0384 mol dm−3 and [Pd] = 0.00192 mol dm−3. The water content in
the EtOAc solvent was found to be ∼430 ppm (Karl Fischer titration).
Established tests5 were therefore used to probe the catalytic
behavior in our system (Figure 2a). Excess Hg (200 equiv) was
added to the reaction mixture at 90 min (a well-known and
widely applied heterogeneous catalyst poison), which had no
effect on substrate turnover.19,20 The outcome suggests that
aggregated Pd nanoparticulate species are not required for
substrate turnover to occur. Addition of polyvinylpyridine
(PVPy, 200 equiv), thought to bind solubilized PdII ions,21 to
the reaction mixture during substrate turnover (at 90 min)
caused cessation of substrate conversion (1). The result of this
experiment gave the first indication that the reaction was likely
operating in a homogeneous manner. Filtration of the reaction
mixture through a preheated Celite pad (“hot filtration test” to
remove insoluble Pd black), again applied during substrate
turnover, similarly had no effect on substrate conversion (see
the Supporting Information). Finally, ex situ TEM images
(Figure 2b) of an aliquot taken from the reaction mixture
during substrate turnover showed the presence of a few
nanoparticles to the limit of detection (ca. 1 nm), which were
not commensurate with PdNPs observed in other C−H
functionalization reactions.5,10a,19c These findings, taken
together, led us to question whether heterogeneous Pd species
were playing a significant role in these tryptophan arylation
reactions at all: that is, beyond the aggregated Pd contributing
via an off-cycle catalyst reservoir or by a typical catalyst
deactivation process.
Figure 2. (a) Reaction profiles monitored by UV−vis spectroscopic
analysis, where addition of catalyst poison/filtration occurred at 90
min. (b) Transmission electron microscopy (TEM) image of particles
obtained from an aliquot of the reaction mixture at 90 min.
observation can be explained by formation of catalytically active
“Pd−OTs” complexes in the reactions; indeed cyclopalladated
tosylate Pd catalyst systems have been reported by both
Brown22 and Bedford.23 Therefore, Pd(OTs)2(MeCN)2 was
prepared and tested.24 Pd(OTs)2(MeCN)2 (5 mol %)
displayed the same accelerated reaction kinetic profile as that
determined when Pd(OAc)2 (5 mol %)/TsOH (5 mol %) was
used (Figure 3).
The induction period observed in the reaction of 1 + 2a →
3a mediated by Pd(OAc)2 suggested that other additives could
influence this process. Following a screen of different acids,
TsOH exhibited a profound positive effect, drastically reduced
the previously observed induction period seen with Pd(OAc)2
alone, and thus accelerated product conversion over time. This
Figure 3. Formation of 3a from reaction of 1 with 2a mediated by
either 5 mol % of Pd(OAc)2 with 5 mol % of TsOH (open circles) or
Pd(OTs)2(MeCN)2 (closed circles) at 37 °C. All data were obtained
by ex situ UV−vis spectroscopic analysis.
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Equivalent yields of the substrates previously tested (Table
1) were found when 5 mol % of Pd(OTs)2(MeCN)2 was used
in place of Pd(OAc)2 (see the Supporting Information).
Additionally, the catalyst loading of Pd(OTs)2(MeCN)2 could
be decreased to 1 mol %, providing the C2-phenyl arylation
product 3a in quantitative yield after 16 h at ambient
temperature (cf. 5 mol % when using Pd(OAc)2, Table 1).
We tentatively attribute the TsOH effect to more reactive Pd
catalyst species, while acknowledging that tosylate anion can
Ian J. S. Fairlamb: 0000-0002-7555-2761
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the Innovative Medicines Initiative Joint Undertaking under
grant agreement no. 115360 (Chem21 project), resources of
which are composed of financial contribution from the
European Union’s Seventh Framework Programme (FP7/
2007-2013) and EFPIA companies’ in kind contribution. We
acknowledge The Centre for Future Health funding initiative at
the University of York (with Wellcome Trust support) for
J.T.W.B.
influence the reactivity and stability of the ArN2 species.25
+
Finally, in our early screening studies we determined that the
N-protecting group in 1 exerts a profound influence on
arylation yield. For example, 1, possessing a NHBoc group,
1
gave arylated product with 53% conversion (by H NMR),
significantly lower than that when a NHAc group was
employed (resulting in quantitative yield). In addition,
employment of a NHTFA group in 1 appears to either
deactivate or inhibit arylation completely, resulting in no
arylation.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b03121.
■
S
Experimental procedures, characterization data of all new
compounds, and representative spectral data (PDF)
X-ray data for compound 3a (CCDC no. 1053549),
compound 3e (CCDC no. 1053551), and compound 3k
(CCDC no. 1053550) (CIF)
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AUTHOR INFORMATION
Corresponding Author
*I.J.S.F.: e-mail, ian.fairlamb@york.ac.uk; tel, +44 (0)1904
324091.
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ORCID
Joshua T. W. Bray: 0000-0003-2384-9675
Thomas Sheridan: 0000-0003-3795-8047
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DOI: 10.1021/acscatal.6b03121
ACS Catal. 2017, 7, 5174−5179