Ligand-Enabled β-C–H Arylation of α-Amino Acids Without Installing Exogenous Directing Groups

Article abstract of DOI:10.1002/anie.201610580

Herein we report acid-directed β-C(sp³)-H arylation of α-amino acids enabled by pyridine-type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc-protected unnatural amino acids in three steps. The pyridine-type ligands are crucial for the development of this new C(sp³)-H arylation.

Full text of DOI:10.1002/anie.201610580

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201610580
German Edition: DOI: 10.1002/ange.201610580
Homogeneous Catalysis Very Important Paper
Ligand-Enabled b-C–H Arylation of a-Amino Acids Without Installing
Exogenous Directing Groups
Gang Chen, Zhe Zhuang, Gen-Cheng Li, Tyler G. Saint-Denis, Yi Hsiao, Candice L. Joe, and
Jin-Quan Yu*
Abstract: Herein we report acid-directed b-C(sp3)-H arylation
of a-amino acids enabled by pyridine-type ligands. This
reaction does not require the installation of an exogenous
directing group, is scalable, and enables the preparation of
Fmoc-protected unnatural amino acids in three steps. The
pyridine-type ligands are crucial for the development of this
new C(sp3)-H arylation.
studies on oxazoline-directed C(sp3)-H activation,[8] in which
À
we used stereochemical information obtained in the C H
insertion step to deduce ideal geometric, steric, and electronic
requirements of the reaction pretransition-state.
This information has guided our efforts in the design of
novel monodentate directing groups, including A) CONHArF
(ArF = 4-(CF3)C6F4) and B) a more simple and practical
CONHOMe auxiliary (Scheme 1, [Eq. (1)]),[9,10] both of
C
ompared to directing groups that traditionally promote
cyclometallation, carboxylic acids form relatively weak inter-
actions with palladium (Pd), thereby hindering reactivity.
À
Practical C H activation directed by carboxylic acids would
represent a huge achievement for the field as carboxylic acids
are an important class of compounds widely prevalent in
natural products, pharmaceuticals, and materials. Moreover,
carboxylic acids are an important functional group handle,
which may be readily converted into orthogonal functional-
ity.[1] Insofar as acid-directed C H activation is concerned,
À
myriad examples of functionalization of C(sp2)-H bonds has
been detailed extensively and are reviewed elsewhere.[2] On
the contrary, examples of acid-directed C(sp3)-H activation
are sparse: Sen, Sames, and Chang have reported K2PtCl4-
catalyzed carboxyl-directed lactonization of aromatic[3] and
aliphatic acids, albeit with poor isolated yields. Our group first
reported Pd-catalyzed C(sp3)-H arylation with simple ali-
phatic acids, yet the substrate scope was limited.[4] Later,
Martin and colleagues reported Pd-catalyzed benzylic C(sp3)-
H activation/C(sp3)-O bond formation, producing benzolac-
tones.[5] Despite these significant advances, Pd-catalyzed b-
C(sp3)-H functionalization of aliphatic acids has not been well
developed, and is largely an unsolved problem.
Scheme 1. Arylation of a-amino acids.
which serve as carboxylate surrogates in the Pd-catalyzed
À
C H activation of alanine derivatives, enabling the prepara-
Previously, the research in our group has focused on
tion of unnatural a-amino acids. Both of these reactions
benefit from ligand acceleration by either pyridine- or
quinoline-based ligands, though the installation and removal
of these exogenous directing groups hampers the broad
application of these methods. To address this limitation, and
building upon our previous work in carboxylic acid-directed
À
monodentate weakly coordinating groups for C H activation;
these directing groups, compared to bidentate directing
groups[6] or strong monodentate-directing groups, offer the
advantage of benefiting from ligand-accelerated catalysis.[7]
Our work has been continuously influenced by our early
C(sp3)-H arylation,[4] we recently reported the enantioselec-
3
À
tive C(sp )-H arylation of methylene C H bonds with free
[*] Dr. G. Chen, Z. Zhuang, G.-C. Li, T. G. Saint-Denis, Prof. Dr. J.-Q. Yu
Department of Chemistry
carboxylic acids,[11] however, in both papers only aliphatic
acids with a-quaternary center could be applied to this
reaction [Eq. (2)].
The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
Given the weakly directing nature of carboxylic acids, we
elected to explore carboxylic acid-directed C(sp3)-H activa-
tion on N-phthaloyl alanine substrates by exploiting ligand
acceleration from pyridine- and quinoline-based ligands
[Eq. (3)]. Employing similar conditions to those reported in
our CONHOMe-directed arylation,[10] we were pleased to
find that L1 provided the desired arylated product in 45%
Dr. Y. Hsiao, Dr. C. L. Joe
Chemical and Synthetic Development
Bristol-Myers Squibb
1 Squibb Drive, New Brunswick, NJ 08903 (USA)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201610580.
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methyl group of L2 to a methoxy group (L4) the reaction
proceeded in 49% yield. An additional methoxy group at C6
(L5) failed to improve the yield (36%); L6, possessing
a methyl group at C6 improved the yield (58%); utilizing C5
acetylated ligand L8 resulted in a further increase in
reactivity. Neither 2-methyl quinoline (L9) nor quinoline-
based ligands (L10, L11) improved the yield. Since simple
substitutions on pyridine- and quinoline-based ligands failed
to increase reactivity; consequently, we prepared several
fused bicyclic pyridine ligands (L12–L15). Whereas ligands
with fused six-membered rings (L12, L13) afforded similar
results to those of L1, ligands with fused five-membered rings
afforded a dramatic increase in reactivity (L14, L15 = 79%
À
Scheme 2. Preliminary discovery for ligand-promoted C H arylation.
yield (Scheme 2). A control experiment showed that no
reaction occurred in the absence of ligand.
Encouraged by this initial result, we screened different
reaction conditions, including solvents and bases (see the
Supporting Information for details). It is evident that
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is crucial for the
reaction. HFIP has excellent hydrogen-bonding properties
and may be (A) aptly suited to interact with acidic directing
groups and/or (B) could serve as an ancillary ligand,
coordinating and stabilizing catalytically-active electrophilic
Pd-species, thereby improving the overall efficiency of the
reaction.[12] Base additives were very important in this
reaction: Na2HPO4·7H2O afforded the desired product in
62% yield. We suspect that this base is capable of deproto-
nating the acid substrates, allowing for adequate Pd coordi-
nation, as shown previously.[4]
With these results in hand, we began to screen various
ligands (Table 1). Surprisingly, 2-picoline (L2), which is highly
reactive in both CONHArF and CONHOMe directed aryla-
tion of amino acid substrates, was found to be inactive in this
C H arylation. However, the bulkier 2,6-lutidine (L3)
afforded the desired product in 42% yield. By changing the
À
yield). Inspired by multiligand promoted C N bond forma-
tion from the Buchwald group,[13] we tried a variety of mixed
ligands to further improve the yield (see the Supporting
Information). We discovered that a combination of L15
(10 mol%) and L8 (10 mol%) gave the desired product in
85% yield. While bidentate ligands that form five-membered
chelates with Pd were unreactive (L16), bidentate ligands that
form six-membered chelates—which were previously found
[11]
À
to promote enantioselective methylene C H activation
—
were also very reactive in this reaction (L17 = 71%, L18 =
75% yield). Efforts to change the heterocyclic nucleus of
these ligands (L19, L20) did not enhance reactivity, but still
afforded the desired product in high yields.
Various aryl iodides were next subjected to the optimized
reaction conditions (Table 2). Arylation of para- and meta-
methyl aryl iodides provided the corresponding products 2a
and 2b in 83% and 78% yields, respectively. Simple
iodobenzene gave 2c in 85% yield, and other electron-
À
Table 1: Screening of ligands for C(sp3)-H arylation.[a,b]
Table 2: Substrate Scope of Aryl Iodides of Arylation.[a,b]
[a] Experiments were performed with substrate 1 (0.1 mmol), Pd(OAc)2
(10 mol%), AgOAc (0.2 mmol), Ar-I (0.25 mmol), Na2HPO4·7H2O
(0.15 mmol), Ligand (20 mol%), HFIP (1.0 mL), 1008C, 24 h. [b] Deter-
mined by 1H NMR analysis of the crude product using CH2Br2 as an
internal standard. [c] HFIP (2.0 mL). [d] L15 (10 mol%)+L8 (10 mol%).
[e] Conditions: substrate (0.1 mmol), Pd(OAc)2 (10 mol%), Ag2CO3
(0.2 mmol), Ar-I (0.25 mmol), ligand (10 mol%), K2HPO4 (0.1 mmol),
HFIP (1.0 mL), 1008C, 24 h. [f] Ar=3,5-di-t-butylphenyl.
[a] Experiments were performed with substrate 1 (0.1 mmol), Pd(OAc)2
(10 mol%), AgOAc (0.2 mmol), Ar-I (0.25 mmol), Na2HPO4·7H2O
(0.15 mmol), L15 (20 mol%), HFIP (1.0 mL), 1008C, 24 h. [b] Isolated
yields are shown based on corresponding methyl ester. [c] L15
(10 mol%)+L8 (10 mol%).
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donating aryl iodides (methoxy, ethyl, iso-propyl) gave the
3 f and 3g: while 4 f was obtained in 23% yield, N-phthaloyl
desired products in good to excellent yields (2d, 2 f, 2g),
though meta-methoxy aryl iodide only produced 2e in
a moderate yield (52%). Different halogen substitution
patterns were all tolerated, and moderate-to-good yields
were obtained (2h–2l); these results are attractive in that the
chloro-, bromo-, and iodo- groups could be further function-
alized. Aryl iodides containing electron-withdrawing groups
(trifluoromethoxy, ester, trifluoromethyl) were also compat-
ible with the optimized reaction conditions, providing desired
product (2m–2p) in lower yields compared with electron-
donating aryl iodides (2d, 2 f, 2g). Di-substituted aryl iodides
afforded the arylation products (2q–2t) in good-to-excellent
yields. Unfortunately, heteroaryl iodides are presently incom-
patible with the arylation conditions.
We next tested acid-directed arylation in non-alanine
susbtrates (Table 3): Isovaline derivatives afforded mono-
arylation product (4a) in 45% yield under the same condition
for the arylation of the alanine substrate. Arylation of 1-
aminocyclobutane-1-carboxylic acid and 1-aminocyclopro-
pane-1-carboxylic acid under the same reaction conditions
proceeded in moderate yields (4b = 42% [mono: di = 2.2:1];
4c = 45%), but switching to L18 provided a boost in reactivity
(4b = 56% [mono: di = 2.5:1]; 4c = 63%). The b-amino acid
substrate 3d afforded the desired product 4d in poor yields
(35%). 3e was selected as a substrate to further test the
valine (3g) was not reactive. We suspect this is due to the
Thorpe–Ingold Effect which favors cyclopalladation.[14] It is
worth noting that this chemistry is applicable to a-quaternary
acid substrates: Gemfibrozil (3h), an oral drug used to lower
lipid levels,[15] was arylated in good yields (72%); in the
absence of ligand, 4h was only obtained in 30% yield. We
attempted to expand the substrate scope to other carboxylic
acids, however the yields were generally low (see Table S4 in
the Supporting Information).
There are several advantages to directly using free amino
acids as substrates for gram-scale preparation of unnatural
amino acids: the installation and removal of exogenous and
often times cumbersome directing groups are entirely
avoided, thus shortening synthetic routes and eliminating
chemical waste. To demonstrate the utility of the herein
reported reaction, we performed the reaction on gram scale
with 1 and para-tolyl iodides (Scheme 3) under the afore-
À
limitations of the acid-directed methylene C H arylation
(demonstrated in substrates 3b and 3c): Unfortunately, N-
phthaloyl phenylalanine produced 4e in 10% yield when L18
Scheme 3. Gram-scale synthesis of unnatural amino acids.
À
was used. g-C H arylation was next attempted with substrates
mentioned reaction conditions, the desired product 2a was
obtained in 75% yield. It is noteworthy that the a-center
chirality was preserved (see the Supporting Information). The
phthalimide group was next removed in the presence of
hydrazine to generate the free amine 2a-1, which was
subsequently converted to final Fmoc-protected amino acid
2a-2 (68% over two steps) which is widely used in peptide
synthesis.
Table 3: Arylation of Other Amino Acids and Carboxylic Acids.[a]
We propose that the transformation herein disclosed
proceeds through the mechanism[6a,9] outlined in Figure 1. PdII
coordinates the carboxylate of the substrate, followed by (1)
À
C H cleavage; (2) oxidative addition by aryl iodides,
generating a fleeting PdIV intermediate; (3) reductive elim-
ination, (4) product dissociation; (5) regeneration of the
active PdII species by silver salts. At this stage, we are
[a] Isolated yields are shown based on corresponding methyl ester.
[b] Conditions: substrate (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc
(0.2 mmol), Ar-I (0.25 mmol), Na2HPO4·7H2O (0.15 mmol), L15
(20 mol%), HFIP (1.0 mL), 1008C, 24 h. [c] Conditions: substrate
(0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar-I (0.25 mmol),
Na2HPO4·7H2O (0.15 mmol), L18 (12 mol%), HFIP (1.0 mL), 1008C,
24 h. [d] Conditions: substrate (0.1 mmol), Pd(OAc)2 (10 mol%),
Ag2CO3 (0.2 mmol), Ar-I (0.25 mmol), L18 (12 mol%), K2HPO4
(0.1 mmol), HFIP (1.0 mL), 1008C, 24 h. [e] Conditions: substrate
(0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar-I (0.25 mmol),
Na2HPO4·7H2O (0.15 mmol), L8 (20 mol%), HFIP (1.0 mL), 1008C,
24 h.
Figure 1. Plausible mechanism for C(sp3)-H arylation.
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currently investigating the precise role of monodentate
pyridine and bidentate heterocyclic ligands in enabling this
mechanism.
[1] For selected reviews and discussion on utility of carboxylic acids,
see: a) L. J. Gooßen, N. Rodriguez, K. Gooßen, Angew. Chem.
Int. Ed. 2008, 47, 3100; Angew. Chem. 2008, 120, 3144; b) T. Qin,
J. Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura,
B. D. Maxwell, M. D. Eastgate, P. S. Baran, Science 2016, 352,
801.
À
In conclusion, we have developed b-C H arylation of a-
amino acids using innate carboxylic acid functionality as
a directing group. This reaction was easily scaled up to
prepare unnatural amino acid building blocks. Further
development of more efficient ligands to expand the scope
[2] For reviews of acid-directed C(sp2)-H activation, see: a) K. M.
Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45,
788; b) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang,
Org. Chem. Front. 2015, 2, 1107.
À
À
of substrates—so as to achieve methylene-C H and g-C H
arylation—as well as coupling partners (e.g. heteroaryl
iodides) is ongoing in our laboratory.
[3] a) L. Kao, A. Sen, J. Chem. Soc. Chem. C 1991, 1242; b) B. D.
Dangel, J. A. Johnson, D. Sames, J. Am. Chem. Soc. 2001, 123,
8149; c) J. M. Lee, S. Chang, Tetrahedron Lett. 2006, 47, 1375.
[4] R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B.
Saunder, J.-Q. Yu, J. Am. Chem. Soc. 2007, 129, 3510.
[5] P. Novꢁk, A. Correa, J. Gallardo-Donaire, R. Martin, Angew.
Chem. Int. Ed. 2011, 50, 12236; Angew. Chem. 2011, 123, 12444.
[6] a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc.
2005, 127, 13154; b) O. Daugulis, H.-Q. Do, D. Shabashov, Acc.
Chem. Res. 2009, 42, 1074; c) L. D. Tran, O. Daugulis, Angew.
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Chen, B.-F. Shi, Angew. Chem. Int. Ed. 2013, 52, 13588; Angew.
Chem. 2013, 125, 13833.
Experimental Section
General procedure for arylation with aryl iodides: The starting
material 1 (0.1 mmol, 22 mg), Pd(OAc)2 (10 mol%, 2.2 mg), and
AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in
a sealed tube (10 mL) with a magnetic stir bar. To the reaction
mixture, aryl iodide (0.25 mmol), Na2HPO4 C7H2O (1.5 equiv), ligand
(20 mol%), HFIP (2.0 mL) were added. The reaction mixture was
first stirred at room temperature for 10 minutes and then heated to
1008C for 24 hours under vigorous stirring. Upon completion, the
reaction mixture was cooled to room temperature and AcOH was
added (0.05 mL), and filtered through celite using DCM. The solvents
were removed under reduced pressure and to the resulting mixture
was added with DCM (3 mL), cat. DMF, and (COCl)2 (2 equiv). After
2 hours, MeOH (0.5 mL) was added to the reaction mixture and the
mixture was stirred for another 1 hour. The solvents were removed
under reduced pressure and the resulting mixture was purified by
preparative TLC.
[7] K. M. Engle, J.-Q. Yu, J. Org. Chem. 2013, 78, 8927.
[8] R. Giri, X. Chen, J.-Q. Yu, Angew. Chem. Int. Ed. 2005, 44, 2112;
Angew. Chem. 2005, 117, 2150.
[9] J. He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A.
Homs, J.-Q. Yu, Science 2014, 343, 1216.
[10] G. Chen, T. Shigenari, P. Jain, Z. Zhang, Z. Jin, J. He, S. Li, C.
Mapelli, M. M. Miller, M. A. Poss, P. M. Scola, K.-S. Yeung, J.-Q.
Yu, J. Am. Chem. Soc. 2015, 137, 3338.
[11] G. Chen, W. Gong, Z. Zhuang, M. S. Andra, Y.-Q. Chen, X.
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1023.
Acknowledgements
We gratefully acknowledge the Scripps Research Institute
and Bristol-Myers Squibb for financial support. This work was
supported by NIH (NIGMS, 2R01 GM084019). We thank
SIOC, Zhejiang Medicine and Pharmaron (fellowships to G.
Chen). T. G. Saint-Denis is supported by the NSF GRFP and
the TSRI Deanꢀs Fellowship.
À
[12] For a review on HFIP-enabled C H activation, see the follow-
ing: J. Wencel-Delord, F. Colobert, Org. Chem. Front. 2016, 3,
394.
[13] B. P. Fors, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, 15914.
[14] a) S. Li, G. Chen, C.-G. Feng, W. Gong, J.-Q. Yu, J. Am. Chem.
Soc. 2014, 136, 5267; b) S. Li, R.-Y. Zhu, K.-J. Xiao, J.-Q. Yu,
Angew. Chem. Int. Ed. 2016, 55, 4317; Angew. Chem. 2016, 128,
4389.
Conflict of interest
[15] M. Jun, C. Foote, J. Lu, B. Neal, A. Patel, S. Nicholls, D. E.
Grobbee, A. Cass, J. Chalmers, V. Perkovic, Lancet 2010, 375,
1875.
The authors declare no conflict of interest.
À
Keywords: amino acids · arylation · C H activation · palladium ·
pyridine ligands
Manuscript received: October 28, 2016
Final Article published: && &&, &&&&
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Homogeneous Catalysis
G. Chen, Z. Zhuang, G.-C. Li,
T. G. Saint-Denis, Y. Hsiao, C. L. Joe,
J.-Q. Yu*
&&& — &&&
À
Ligand-Enabled b-C–H Arylation of a-
Amino Acids Without Installing
Exogenous Directing Groups
C H activation: The palladium(II)-cata-
lyzed b-C(sp3)-H arylation of a-amino
acids of free carboxylic acids enabled by
pyridine or quinoline-based ligands has
been developed. The arylation is highly
scalable and allows for the rapid syn-
thesis of unnatural amino acids.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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