Ligand-accelerated ortho -C-H alkylation of arylcarboxylic acids using alkyl boron reagents

Article abstract of DOI:10.1021/ja409014v

A protocol for the Pd(II)-catalyzed ortho-C-H alkylation of phenylacetic and benzoic acids using alkylboron reagents is disclosed. Monoprotected amino acid ligands (MPAA) were found to significantly promote reactivity. Both potassium alkyltrifluoroborates and alkylboronic acids were compatible coupling partners. The possibility of a radical alkyl transfer to Pd(II) was also investigated.

Full text of DOI:10.1021/ja409014v

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Article
Ligand-Accelerated ortho-C–H Alkylation of
Arylcarboxylic Acids using Alkyl Boron Reagents
Peter S. Thuy-Boun, Giorgio Villa, Devin Dang, Paul F Richardson, Shun Su, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja409014v • Publication Date (Web): 14 Oct 2013
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Ligand-Accelerated ortho-C–H Alkylation of Arylcarboxylic
Acids Using Alkyl Boron Reagents
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Peter S. Thuy-Boun,† Giorgio Villa,† Devin Dang,† Paul Richardson,‡ Shun Su,§ Jin-Quan Yu†*
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
‡Pfizer Global Research and Development, 10770 Science Center Dr. San Diego, CA 92121, USA
§Bristol-Myers Squibb Company, 311 Pennington Rocky Hill Road, Pennington, NJ 08534, USA
ABSTRACT: A protocol for the Pd(II)-catalyzed ortho-C–H alkylation of phenylacetic and benzoic acids using alkylboron reagents is dis-
closed. Mono-protected amino acid ligands (MPAA) were found to significantly promote reactivity. Both potassium
alkyltrifluoroborates and alkylboronic acids were compatible coupling partners. The possibility of a radical alkyl transfer to Pd(II) was
also investigated.
Table 1. Standard Conditions and Deviations
1.Introduction
The importance of the aryl–alkyl motif is exemplified by its
abundance in natural products1 and pharmaceuticals,2 and many
methods for its construction have been described.3,4 A comple-
mentary approach that is rapidly gaining traction utilizes C–H
bonds as coupling partners.5,6 Notable progress has been made
on this front despite the propensity for intermediate metal-alkyl
fragments to undergo undesired β-hydride elimination and
homocoupling side reactions. Our early efforts focused on the
development of C(sp2)–H alkylation reactions using model sub-
strates containing strongly coordinating pyridine and oxazoline5
directing groups (Scheme 1, A) with the long-term goal of im-
parting reactivity on more synthetically useful substrates.6 Thus
far, we have achieved C–H alkylation using removable amide6h
,
and O-methylhydroxamic acid7 directing groups which are capa-
ble of outcompeting unproductive side reactions. We have also
reported a single example of electron-rich benzoic acid C(sp2)–H
methylation;6a however, the ortho-alkylation of arylcarboxylic
acids using other alkylboron reagents is in general, hampered by
the -hydride elimination pathway. Inspired by Fu’s successful
development of tailored ligands for alkyl–alkyl cross-coupling,4a-
d
we sought to utilize the accelerated C–H cleavage reactivity
imparted by mono–N-protected amino acids to similar ends.8
Herein, we report the ligand-accelerated C(sp2)–H alkylation of
phenylacetic and benzoic acids using Pd(II) as a catalyst (Scheme
1, B). This protocol provides a one-step route to ortho-alkylated
benzoic9 and phenylacetic acids, which are useful building blocks
for the preparation of medicinally relevant compounds. Fur-
thermore, we demonstrate the utility of this protocol by using it
to install a “magic methyl”10 group onto a biaryl scaffold gener-
ating lead compound BMS-98947-055-01.
Reaction Conditions: carboxylic acid substrate (0.5 mmol), alkyl
trifluoroborate (0.75 mmol), Li2CO3 (1.0 mmol), Ag2CO3 (1.0 mmol), BQ
(0.025 mmol), Ligand (0.1 mmol), Pd(OAc)2 (0.05 mmol), t-BuOH (2.5 mL).
adetermined by 1H-NMR. bmaterial balance determined based on isolated 3a
and recovered starting material (1a).
2.Results and Discussion
2.1 Initial Discovery and Optimizations
Initial studies were guided by conditions optimized from our
previous C–H arylation work using aryltrifluoroborates as cou-
pling partners.8d For alkyltrifluoroborate coupling, three key
modifications were essential for providing alkylated 3a in good
yields: (1) Exchanging KHCO3 for Li2CO3 (Table 1, entry 14), (2)
conducting reactions under an O2 free atmosphere (entries 4, 5),
and (3) employing an optimized ligand (Boc-Thr(tBu)-OH). Ex-
amination of various inorganic salts indicated that both Li+ and
CO32- are beneficial for this reaction. In addition to promoting C–
H insertion,6a salt additives were previously shown to impact the
transmetallation step (entries 13-18).11 Alkylated 3a was ob-
served with or without Ag2CO3 but the inclusion of Ag2CO3 in-
Scheme 1. Development of C(sp2)–H Alkylation
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creased yields significantly. O2 was found to decrease yields
With respect to benzoic acids, we rescreened ligands and
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(entries 4, 5). An optimized ligand, Boc-Thr(tBu)-OH, was identi-
fied from an extensive screen of commercially available mono-
N-protected amino acids (see supporting information, SI: S6-S7).
Although sterically demanding ligands can discourage -hydride
elimination in alkylation reactions,4 substrate-ligand matching
may also be important for promoting C–H activation. During the
ligand screen using model substrates 1a and 1e, non-N-
protected amino acids and amino acids with strongly coordinat-
ing side chains such as methionine, histidine, or tryptophan were
found to generally inhibit this reaction (see supporting infor-
mation, SI: S6-S7 for ligand screen).
found Ac-Val-OH to be most effective. It is also interesting to
note that electron poor substrates (Table 4, 5a and 5b) benefited
most from the application of ligands where alkylation of electron
rich substrates varied depending on arene substitution pattern
(5c-f). Notably, monoselectivity increased for 5d with the appli-
cation of a ligand (mono:di from 1.9:1 to 7.7:1). For unsubstituted
benzoic acid, the di product (5g’) was formed as the major prod-
uct in the presence of ligands. Efforts to suppress the di alkyla-
tion of benzoic acid to selectively form mono alkylated product
were unsuccessful (see SI: S25-S26).
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Table 3. Phenylacetic Acid Substrate Scope
Table 2. Alkylboronic Acid Compatibility
Reaction Conditions: carboxylic acid substrate (0.5 mmol),
nPr–B (OH)2 (0.75 mmol), Li2CO3 (1.0 mmol), Ag2CO3 (1.0 mmol),
Ligand (0.1 mmol), Pd(OAc)2 (0.05 mmol), t-BuOH (2.5 mL).
Further optimization studies based upon these three modifi-
cations yielded two sets of standard conditions: one utilizing
catalytic benzoquinone (Std-BQ, Table 1, entry 1) and the other
utilizing dimethylformamide (Std-DMF, Table 1, entry 11). Dif-
ferences in conversion were observed depending on the additive
employed, but in general, these additives increased the repro-
ducibility of reaction outcomes; the effects of these additives
were also studied in detail (see SI: S22-S24) and the observa-
tions were consistent with many previously reported cross-
coupling reactions.12-14 Importantly, with a simple inorganic base
modification, alkyl boronic acids were found to be compatible
coupling partners under the reported protocol (Table 2, also see
SI: S10-S11).
2.2 Substrate Scope
Reaction Conditions (Std-DMF): carboxylic acid substrate (0.5 mmol),
alkyl trifluoroborate (0.75 mmol), Li2CO3 (1.0 mmol), Ag2CO3 (1.0 mmol),
DMF (0.5 mmol), Ligand (0.1 mmol), Pd(OAc)2 (0.05 mmol), t-BuOH (2.5
mL).; Quantification: Isolated yields; a: Ligand = Boc-(L)-Thr(tBu)-OH; b: No
Ligand; c: Ligand = Boc-Leu-OH; d: Ligand = Boc-(D)-Thr(tBu)-OH; e: 2 equiv
nBu–BF3K, 3 equiv Ag2CO3.
Substrate scope was investigated using the Std-DMF condi-
tions. Electron poor (Table 3, 3a-d) and electron rich (Table 3, 3e-
l) phenylacetic acids were generally well tolerated. Ligand en-
hancement effects were consistently pronounced for electron
poor arenes (3a-d). With respect to electron rich arenes, yields
varied depending on ring-substitution: 3i (72%), 3j (13%), and 3k
(70%) and importantly, ortho-substituents appear to have a posi-
tive effect. We also note that ligand optimization may still be
necessary for particular substrates. For example, when Boc-Leu-
OH was applied in place of Boc-Thr(tBu)-OH for the coupling of
1g, the yield nearly tripled from 22% to 64% (3g). Notably over-
the-counter NSAID drugs, naproxen (1l) and ketoprofen (1o)
were compatible substrates and the alkylation of enantiopure 1l
proceeded without erosion of stereochemistry at the adjacent
acidic α-carbon. The presence of large α-substituents hampered
this reaction (3m). In general, mono:di selectivities of phenyl
acetic acids were poor in the absence of ortho- or meta- substitu-
tion (3n-mono:3n’-di 1:0.6). However, the use of excess
alkyltrifluoroborate and Ag2CO3 led to the predominant for-
mation of di product (3n-mono:3n’-di 1:17).
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Table 4. Benzoic Acid Substrate Scope
Table 5. Potassium Alkyltrifluoroborate Scope
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Reaction Conditions (Std-DMF): carboxylic acid substrate (0.5 mmol),
alkyl trifluoroborate (0.75 mmol), Li2CO3 (1.0 mmol), Ag2CO3 (1.0 mmol),
DMF (0.5 mmol), Ligand (0.1 mmol), Pd(OAc)2 (0.05 mmol), t-BuOH (2.5
mL); Quantification: a: Ligand = Ac-Val-OH, Isolated yield; b:No Ligand, 1H-
NMR conversion; c: 5 mol% BQ, no DMF; d: 3 equiv nBu–BF3K, 3 equiv
Ag2CO3.
An exploration of potassium alkyltrifluoroborate scope was
undertaken using both Std-DMF and Std-BQ conditions (Table
5). Non-coordinating primary alkyltrifluoroborates (methyl,
trifluoropropyl, phenethyl) were compatible coupling partners
(7a-c) along with benzyl (7d), methylcyclohexyl (7e), and
methylcyclopentyl (7f). However, the coupling of 1e with
methylcyclobutyl boron gave only trace amounts of desired
product (7g) and methylcyclopropyl did not couple at all. There
is a possibility that the alkyl intermediates underwent -carbon
scission instead of reductive elimination. Alkyltrifluoborates
containing functional handles (protected amine, ketone, ester)
were also compatible coupling partners (7h-j). Unfortunately,
alkyltrifluoroborates containing α-heteroatoms, olefins, or al-
kynes did not yield desired coupled products. It was also found
that with the exception of cyclopropyltrifluoroborate (7k and 7l)
and cyclopentyltrifluoroborate (7m’15 and 7n), reactions with
secondary alkylborons were problematic.16 We anticipate that
extensive ligand development could provide a solution to this
problem in the future. A GC/MS sampling of organic phase ex-
tracted from reactions using cyclohexyltrifluoroborate yielded
cyclohexene and bicyclohexyl suggesting that β-hydride elimina-
tion17 and homocoupling could be competing pathways.
Reaction Conditions: aStd-BQ: carboxylic acid substrate (0.5 mmol), al-
kyl trifluoroborate (0.75 mmol), Li2CO3 (1.0 mmol), Ag2CO3 (1.0 mmol), BQ
(0.025 mmol), Ligand (0.1 mmol), Pd(OAc)2 (0.05 mmol), t-BuOH (2.5 mL), 4
h reaction time or bStd-DMF: carboxylic acid substrate (0.5 mmol), alkyl
trifluoroborate (0.75 mmol), Li2CO3 (1.0 mmol), Ag2CO3 (1.0 mmol), DMF (0.5
mmol), Ligand (0.1 mmol), Pd(OAc)2 (0.05 mmol), t-BuOH (2.5 mL), 4 h
reaction time; Quantification: Conv. determined by 1H-NMR, isolated yields in
parenthesis.
2.3 Mechanistic Considerations
The ineffective coupling of methylcyclobutyl and
methylcyclopropyl borons, and the need for an O2 free atmos-
phere prompted us to investigate the possibility of alkyl radical
formation.18 First, nearly complete inhibition of this reaction by
TEMPO was observed (Scheme 2, A) and without substrate 1e,
phenethylTEMPO adduct was obtained in 67% GC yield (see SI:
S12-S14). A control experiment revealed that only Ag2CO3 was
necessary to generate alkyl radicals as evidenced by the for-
mation of phenethylTEMPO adduct (see SI: S12-S14).19 Second,
homocoupling product 8a was formed by treating
phenethyltrifluoroborate (6c) with Ag2CO3 in the absence of
TEMPO (Scheme 2, B). The incompatibility of methylcyclopropyl
boron could stem from a radical ring-opening/isomerization to
the terminal radical olefin species which could then unproduc-
tively polymerize.
Radical alkyl intermediacy poses an interesting mechanistic
dilemma.6n,20 Following C–H cleavage, a transmetallation event
could occur to give R–Pd(II)–Ar species. Alternatively, alkyl radi-
cal capture by Ar–Pd(II)–Y (where Y may be any anionic species
present in solution such as OAc- or OtBu-) may provide interme-
diate R–Pd(III)–Ar which could then reductively eliminate to give
the alkylated products (Scheme 2, C). While evidence for the
latter sequence is scarce, the possibility cannot be ruled out at
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this time. The coupling of α-stereogenic alkyl borons could pro-
Figure 1. Ligand Effect: Rate Profile for Conversion of 1a to 3a.
vide more definitive evidence.18,21,22 Unfortunately, they are
incompatible under the reported conditions (see SI).
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Table 6. Effects of Ligand Loading
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Scheme 2. (A) Reaction Inhibition by TEMPO (B)
Alkyltrifluoroborate Homocoupling (C) Putative Reaction
Pathways
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Reaction Conditions: carboxylic acid substrate (0.5 mmol), alkyl
trifluoroborate (0.75 mmol), Li2CO3 (1.0 mmol), Ag2CO3 (1.0 mmol), Ligand
(0.1 mmol), Pd(OAc)2 (0.05 mmol), t-BuOH (2.5 mL). adetermined by 1H-
NMR. bmaterial balance determined based on isolated 3a and recovered
starting material (1a).
2.4 Application in Medicinal Chemistry
Finally, with practicality in mind, we sought to apply this pro-
tocol in a medicinal chemistry setting. From the perspective of
small molecule therapeutics, the installation of methyl groups
has long been recognized as a method for significantly attenuat-
ing the biological activity of a molecule while minimally perturb-
ing its sterics and electronics. For example, the addition of a
single methyl group to the piperidine ring of Merck’s orexin-1/2
(OX1R/OX2R) antagonist was found to increase potency by >480
fold.23 In this case, methylation was thought to induce a critical
conformational change in the antagonist, but in general, this
may not be true as the origin of these effects require case-by-
case examination. Colloquially, these beneficial methyl additions
have been termed “magic methyl” effects and to fully under-
stand their origins, a diverse and robust repertoire of methyla-
tion methods is required.10 Here we apply this alkylation proto-
col to rapidly and selectively ortho-methylate a biaryl carboxylic
acid generating a medicinally relevant compound BMS-98947-
055-01 (9b) in 45% yield (Scheme 3). The use of Boc-Phe-OH as a
ligand, lower temperature (90 °C), and an extended reaction
time (12 h) improved yield (55%) over our standard condition
(STD-BQ) for this particular substrate.
With the application of amino acid ligands, significant accel-
eration effects were observed in contrast to reactions where
ligands were not applied (Figure 1). Additives BQ and DMF were
not used in order to isolate the effects of the amino acid ligands
on this C–H alkylation reaction. Reactivity was probed using a
set of electronically diverse substrates (Table 6). A ligand loading
survey revealed unusual trends where for electron poor sub-
strates (1a, 1b), a Ligand:Pd ratio of 0.5:1 was as effective as a
ratio of 2:1. In contrast, for electron-rich substrates (1e and 1f),
conversion correlatively increased with increased ligand loading.
To understand the origin of the substrate-dependent ligand
effects, we attempted to identify the rate-determining steps for
the nbutylation of 1a and 1e. KIE (kinetic isotope effect) values
for the nbutylation of electron-poor 1a were found to be 1.5 and
3.4 when 20 mol% and 2.5 mol% ligand were used, respectively.
These results suggest that for electron poor 1a, C–H cleavage is
slow (relative to other elementary steps) at low ligand loading,
and with sufficient amounts of ligand, C–H cleavage is signifi-
cantly accelerated to the extent that C–H cleavage is no longer
rate-limiting. In contrast, KIE values of electron-rich 1e were
small under both conditions (20 mol% ligand: 1.4; 2.5 mol% lig-
and: 0.9) suggesting that C–H cleavage may not be involved in
rate limiting step in either case with this substrate. However, the
alkylation of electron rich 1e and 1f are enhanced by the applica-
tion of ligand thus suggesting that ligands may play an addition-
al role in catalysis beyond accelerating the C–H cleavage step.
For a more extensive treatment, see SI S15-S24.
Scheme 3. Selective C–H Methylation of Biaryl 9a Gener-
ates 9b, BMS-98947-055-01.
100
20% Boc-Thr(tBu)-OH
No Ligand
80
Reaction Conditions: aStd-BQ: 1.5 equiv MeBF3K, Ligand
= Boc-
Thr(tBu)-OH, 110 °C, 2 h; b3 equiv MeBF3K, Ligand = Boc-Phe-OH, 90 °C,
60
40
20
0
12 h.
3. Conclusion
In summary,
a ligand-accelerated C–H alkylation of
phenylacetic and benzoic acids is disclosed. Both electron rich
and poor substrates are reactive. Alkyl trifluoroborates and alkyl
0
20
40
60
Time (min)
80
100
120
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Feng, J.; Li, C.-J. J. Am. Chem. Soc. 2008, 130, 2900-2901. (c) Deng,
boronic acids are compatible coupling partners. A variety of pri-
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fragments possessing trifluoromethyl, phenyl, Boc-amine, ester,
or ketone functional groups. Unusual ligand acceleration effects
were noted. Despite these advances, coupling with α-secondary
or α-tertiary alkylborons remains a challenge, and achievement
of this goal will enable a more conclusive investigation of alkyl
radical intermediacy within the context of this C–H functionali-
zation manifold.
9
ASSOCIATED CONTENT
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Supporting Information. Experimental procedures and analyti-
cal data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) O-Methylhydroxamic Acid Directed C(sp3)–H alkylation: Wang,
D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(8) (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2012, 45, 788-802. (b) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q.
Science, 2010, 327, 315-319. (c) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J.
Am. Chem. Soc. 2010, 132, 14137-14151. (d) Engle, K. M.; Thuy-Boun,
P. S.; Dang, M.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 18183-18193.
(9) While this manuscript was under preparation, this protocol
was applied to methylation of a benzoic acid intermediate in the
total synthesis of (+)-Hongoquercin A: Rosen, B. R.; Simke, L. R.;
Thuy-Boun, P. S.; Dixon, D. D.; Yu, J.-Q.; Baran, P. S. Angew. Chem.
Int. Ed. 2013, 52, 7317-7320.
AUTHOR INFORMATION
Corresponding Author
E-mail: yu200@scripps.edu (J.-Q.Y.)
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Acknowledgement. We gratefully acknowledge The Scripps
Research Institute, the NIH (NIGMS, 2R01GM084019) and Bris-
tol-Myers Squibb Co. for financial support. We thank the US EPA
(STAR predoctoral fellowship for P.S.T.-B. Assistance Agree-
ment no. FP917296-01-0), Swiss National Science Foundation
(postdoctoral fellowship for G.V.), ACS SEED Program (high
school internship program for D.D.) and Frontier Scientific (for
the generous donation of alkylboron reagents). TSRI Manuscript
No. 25052.
(10) For the importance of “magic methyl” groups, see: Leung, C.
S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgenson, W. L. J. Med. Chem.
2012, 55, 4489-4500.
(11) For a discussion of base/salt additives in Suzuki coupling: (a)
Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302-4214. (b)
Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-Jones, G.
C.; Murray, P. M. Angew. Chem Int. Ed. 2010, 49, 5156-5160. (c)
Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116-2119.
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2503. (e) Amatore, C.; Jutand, A.; Le Duc, G. Angew. Chem. Int. Ed.
2011, 50, 1-5. (f) Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V. Russ.
J. Gen. Chem. 2011, 81, 1573-1574. (g) Lennox, A. J. J.; Lloyd-Jones,
G. C. J. Am. Chem. Soc. 2012, 134, 7431-7441.
(12) Johnson, J. B.; Rovis, T. Angew. Chem. Int. Ed. 2008, 47, 840-
871.
(13) Excess BQ reduced conversion (Table 1, entry 10) presumably
through coordinative saturation of Pd and due to an undesired side
reaction. A GC/MS analysis of crude reaction mixtures revealed
masses correlating to variably alkylated benzoquinones.
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