Sequential Functionalization of meta-C-H and ipso-C-O Bonds of Phenols

Article abstract of DOI:10.1021/jacs.8b13403

The use of a template as a linchpin motif in directed remote C-H functionalization is a versatile yet relatively underexplored strategy. We have developed a template-directed approach to realizing one-pot sequential palladium-catalyzed meta-selective C-H olefination of phenols, and nickel-catalyzed ipso-C-O activation and arylation. Thus, this bifunctional template converts phenols to synthetically useful 1,3-disubstituted arenes.

Full text of DOI:10.1021/jacs.8b13403

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Communication
Sequential Functionalization of meta-C–H and ipso-C–O Bonds of Phenols
Jiancong Xu, Jingjing Chen, Feng Gao, Shuguang Xie, Xiaohua Xu, Zhong Jin, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Jan 2019
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Sequential Functionalization of meta-C–H and ipso-C–O Bonds of
Phenols
Jiancong Xu,┴,† Jingjing Chen,┴,† Feng Gao,† Shuguang Xie,† Xiaohua Xu,*,†,‡ Zhong Jin,*,†,‡ and Jin-
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Quan Yu*,⁋
†State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
⁋Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
United States
Supporting Information Placeholder
lifetime.3f For example, we3f,8 and others9 have found that the use
of a relatively ri-
ABSTRACT: The use of a template as a linchpin motif in
directed remote C–H functionalization is a versatile yet relatively
underexplored strategy. We have developed a template-directed
approach to realizing one-pot sequential palladium-catalyzed
meta-selective C–H olefination of phenols, and nickel-catalyzed
ipso-C–O activation and arylation. Thus, this bifunctional
template converts phenols to synthetically useful 1,3-disubstituted
arenes.
(a) Previous work (Chatani et al.):
O
FG2
FG1
[Rh] or [Ni]
O
H
[Pd]
N
N
FG1
ortho-C-H functionalization
ipso-C-O functionalization
(b) Sequential Functionalization of meta-C-H and ipso-C-O Bonds of Phenols:
O
N
OMe
R2
R
meta-C-H
ipso-C-O
N
N
directed remote C-H functionalized removal
m
H
N
functionalization
[Pd]
of directing template
[Ni]
Realizing remote selective C–H functionalization is essential
for broad application of directed C–H activation reactions in the
presence of multiple C–H bonds.1 Over the past two decades,
transition-metal-catalyzed arene ortho-C–H functionalization has
been extensively exploited via σ-chelation-assisted directing
effect.2 More recently, directed remote meta- and para-C–H
functionalization of arenes has also been achieved using distance
and geometry as the key recognition parameters.3–5 However, the
installation and removal of these templates for remote C–H
activation reduces the step economy in synthetic applications.
Therefore, a one-pot procedure that can both directly remove the
directing group and install additional desired functionality would
greatly improve the synthetic efficacy of directed arene C–H
activation. In this context, Chatani and others have demonstrated a
commendable example with the ortho-selective directing group 2-
pyridyloxy (OPy) (Figure 1a).6 Herein we report the development
of a palladium-catalyzed remote meta-C–H olefination of phenols
enabled by a novel bifunctional template, which can also be
directly converted into other functional groups, i.e. an aryl group
(vide infra), via the catalytic cleavage of the ipso-C–O bonds in
the meta-functionalized phenols (Figure 1b). Notably, this
template is easily installed in a single step from the commercially
available 2,4-dichloro-6-methoxy-1,3,5-triazine (Figure 1c).
R1
(c) Synthesis of Template:
OMe
N
OMe
N
OMe
2-CN-ArBpin
T
N
1 R = H
N
PdCl2(PPh3)2
N
N
T
T
2 R = 5-OMe
3 R = 4,5-(OMe)2
Cl
N
Cl
N
65-85%
R
Cl
N
Cl
NC
NC
> 10 g
Figure 1. Development of new bifunctional templates for
sequential meta-C–H/ipso-C–O functionalization of phenols.
gid template could functionalize remote meta-C–H bonds in long-
chain aromatic alcohols. Bearing in mind that the unreactive C–O
bonds in phenols may be directly functionalized via transition-
metal-catalyzed C–O cleavage of aryl ethers, such as 2-
pyridyloxy,6,10 and 2-triazinyloxy groups11, we strove to develop a
bifunctional template that could both direct the meta-C–H
functionalization of phenols and be subsequently removed
through
a
transition-metal-catalyzed ipso-C–O cleavage,
consisting of a 1,3,5-triazine-derived rigid biaryl scaffold (Figure
1b).
Initially, the biaryl templates T1–T3 were synthesized via a
Suzuki coupling from the commercially available 2,4-dichloro-6-
methoxy-1,3,5-triazine (Figure 1c), and the latter can also be
prepared from inexpensive cyanuric chloride in almost
quantitative yield (see the SI). The substrate bearing the template
T1 was subjected to the previously established meta-C–H
olefination conditions.3,8 Much to our delight, the C–H olefination
occurred exclusively at the meta-position with meta:others > 20:1
regioselectivity. Ortho-C–H functionalization directed by the
donor heteroatom of 1,3,5-triazine was not observed under the
reaction conditions.12 Not surprisingly, using templates T2 and T3
also afforded the products in >20:1 meta-selectivity. Increasing
the electron density of the phenyl rings in the templates T2 and T3
It is well established that the positional selectivity of template-
assisted remote C–H activation is highly associated with the
template geometry.3,4 An appropriate template facilitates the
assembly of a conformationally favored macrocyclic metallocycle
that enables the metal catalyst to activate the remote C–H bond of
the arene through an agnostic interaction.7 Moreover, a rigid
backbone in the template readily forms a large yet less strained
macrocyclic pre-transition state, and therefore provides the
palladacycle intermediate with higher stability and a longer
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did not significantly improve the reactivity, but led to a lower
arylboronic acid was investigated. Reaction parameters such as
metal catalysts, ligand, base, solvent, and temperature were
examined (see SI for details), showing that Ni(xantphos)Cl2 (10
mol%), K3PO4 (7.0 eq), in toluene at 120 oC comprised the
optimal reaction conditions.
1
2
3
ratio of mono- to di-olefinated products (Scheme 1). With the
template T1, however, the desired meta-C–H olefination product
could be obtained in 82% yield after an elongated reaction time
(36 h). Thus, T1 was selected as the optimal template.
4
5
6
Scheme 1. Design of New Template for meta-C-H
Table 1. Pd-Catalyzed Template-Directed meta-C–H
Olefination of Phenola
Olefination of Phenolsa
7
8
9
T1
T
T1
T
Pd(OAc)2 (10 mol%)
Ac-Gly-OH (20 mol%)
AgOAc (1.5 eq.)
Pd(OAc)2 (10 mol%)
Ac-Gly-OH (20 mol%)
AgOAc (2 eq.)
O
O
O
O
+
CO2Et
(3 eq.)
+
CO2Et
(3 eq.)
R
R
HFIP, 80 oC, 36 h
HFIP, 80 oC, 24 h
CO2Et
H
H
CO2Et
m
2
m
H
H
m'
m
m'
m
1
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T1
T1
T1
T1
OMe
N
OMe
OMe
N
O
O
O
O
Me
tBu
MeO
N
N
N
N
OMe
OMe
CO2Et
CO2Et
CO2Et
CO2Et
N
N
N
N
2a
2a
2b
: 81%
2c
: 89%
2d
: 75%
mono: 54%, di: 16%
OMe
N
T1
N
T1
T1
T1
T1
O
O
O
O
T2
T3
F
Cl
EtO2C
58% (mono:di = 2.6:1)
(meta:others > 20:1)
66% (mono:di = 2.3:1)
(meta:others > 20:1)
65% (mono:di = 2.8:1)
82% (mono:di = 3.4:1)b
(meta:others > 20:1)
CO2Et
CO2Et
mono: 68%
CO2Et
R
CO2Et
(R = Me): 65%
2e
mono: 75%
2f
2g
mono: 61%
2g
di: 17%
2h
2i
aYield and regioselectivity were determined by 1H NMR with
CH2Br2 as an internal standard. bReaction time: 36 h.
(R = OMe): 71%
2e
di: trace
2f
di: 17%
T1
T1
T1
T1
O
O
O
O
Having identified the optimal template, we further investigated
the generality of the template-assisted meta-C–H olefination
(Table 1). Both electron-donating and -withdrawing groups are
well tolerated with predominant meta-selectivity. Excluding alkyl
and alkoxyl groups, a variety of functional groups such as halogen
(2e, 2f, 2j, 2n and 2o), ester (2g), and acetyl (2p) groups afforded
the meta-olefinated products in isolated yields of 49–89%.
Substrates bearing two groups in different substitution patterns are
also compatible with the present protocol (2q–s). Compared with
meta- and para-substituted phenols, substrates derived from
ortho-substituted phenols delivered the meta-C–H olefination
products in higher yields (2b–g). The presence of an ortho-
substituent significantly improves the mono-selectivity as the di-
meta-C–H olefination will be subjected to steric hindrance from
the adjacent ortho-substituent. It is noteworthy that, using
template T1, naturally occurring L-tyrosine (2t) and estrone (2u)
also yielded the corresponding olefination products in exclusive
meta-selectivity. The synthetically valuable meta-olefinated
phenols could be readily obtained through removing the template
(See SI for details). In addition, the olefin coupling partner scope
was examined. Various α,β-unsaturated esters, amide, sulfone,
and phosphonate olefins were reactive, affording the meta-
olefinated products in good yields (2v1–2v6). Under the reaction
conditions, α- or β-substituted olefins proved to be compatible
substrates (2v7 and 2v8). Moreover, C–H olefination with cyclic
α,β-unsaturated esters and 2-amidoacrylates also provided the
desired meta-products with exclusive Z-selectivity in satisfactory
yields (2v9–2v12). The stereochemistry of the double bond is
determined by the two competing transition state energy of the -
hydride elimination, analogous to the Heck Coupling. The
transition state with the electron-withdrawing ester group being
anti to the phenyl group is generally favored which accounts for
the observed Z-selectivity of meta-C–H olefinated products (for
stereochemistry assignment, see the SI).
F
CO2Et F3C
CO2Et
CO2Et
CO2Et
Me
2l
OMe
2m
2j
: 67%
2k
: 62%
: 69%
T1
: 69%
T1
T1
T1
O
F
O
O
O
Me
CO2Et
CO2Et
CO2Et
CO2Et
Cl
COMe
2p
: 49%
Me
2n
2o
: 57%
2q
: 70%
: 71%
T1
O
T1
CO2Et
CO2Et
O
O
Me
Cl
H
CO2Me
Me
H
CO2Et
H
T1
T1
NPhth
CO2Et
Cl
O
O
2r
2s
: 53%
2t
: 59%
2u
: 65%
: 55%
olefin partner:
T1
T1
T1
T1
O
O
O
O
Me
Me
Me
Me
CO2R
R
CO2nBu
CO2Me
Me
2v
2v
2v
1 (R = Me): 73%
2 (R = Bn): 76%
3 (R = tBu): 44%
2v
2v
2v
4 (R = CONMe2): 69%
5 (R = SO2Ph): 76%
6 (R = P(O)(OEt)2): 79%
2v
7 : 68%
2v
8 : 66%
T1
T1
T1
T1
O
O
O
O
Me
Me
Me
Me
CO2Me
CO2Me
NHTFA
NHAc
CO2Me
CO2Me
2v
9 : 65%
2v
10 : 71%
2v
11 : 65%
2v
12 : 41%
aIsolated yield. Regioselectivity was determined to be meta:others
> 20:1 by 1H NMR using CH2Br2 as an internal standard.
Next, the substrate scope and the functional group tolerance of
this nickel-catalyzed transformation were also surveyed (Table 2).
Using p-methoxyl phenylboronic acid as a coupling partner, Ni-
catalyzed C–O cross-coupling with various o-, m-, and p-
substituted phenol substrates provided the biaryl products 3 in
good to excellent yields under the optimized reaction conditions
(3b–k). Various functional groups, such as alkyl, alkoxyl,
halogen, trifluoromethyl, and ester groups, are tolerated in this
transformation. Moreover, m-, m′-diolefinated phenol substrates
successf-ully underwent the reaction in good yield (3l). Using the
meta-C–H olefinated product of N-protected L-tyrosine, it was
also possible to synthesize an unnatural amino acid (3m). Single
crystal X-ray diffraction analyses of compounds 3i (p-OMe) and
3j (p-F) validated the exclusive meta-selectivity of C–H
functionalization and ipso-C–O cross-coupling (see SI for details).
In template-directed C–H functionalization, an additional step
is typically required to remove the template and release the C–H
functionalized product.3–5 We wonder whether the template could
serve as a linchpin to enable further elaboration of the product via
C–O activation. Undoubtedly, direct functionalization via
template-induced ipso-C–O bond cross-coupling will not only
reduce the cost of the process, but also improve the synthetic
efficacy. Therefore, transition-metal-catalyzed direct ipso-C–O
cross-coupling of the meta-C–H olefinated phenol 2a with
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T1
Ar
The scope of organoboron reagents was also evaluated: both m-
O
meta-C-H
ipso-C-O
1
2
3
4
5
6
7
8
and p-substituents on arylboronic acids including alkyl, halogen,
trifluoromethyl, and ester groups were tolerated (3n–t). Notably,
heteroarylboronic acid (3u) afforded the biaryl product in 83%
yield. Regrettably, o-substituted arylboronic acids give the target
products in poor yields, probably due to the steric congestion.
R
Pd
Ni
R
H
CO2Et
m
m
4
(intermediate not isolated)
2
Ar = 4-OMe-C6H4-
Ar
Ar
Ar
CO2Et
CONMe2
SO2Ph
Table 2. Ni-Catalyzed C–O Cross-Coupling of meta-
3a
4c
4a
, 55%
4b
, 58%
, 48%
Olefinated Phenolsa
Me
Me
Ar
Ar
MeO
Ar
MeO
CO2Me
CO2Bn
CO2Me
T1
Ar
O
Ni(Xantphos)Cl2 (10 mol%)
K3PO4 (7 eq)
9
ArB(OH)2
(4 eq)
R
R
+
4d
, 47%
4e
, 43%
, 54%
toluene, 120 oC, 24 h
Ar = 4-OMe-C6H4-
CO2Et
10
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CO2Et
MeO
m
m
2
3
aOverall yield for two steps.
Ar
Ar
Ar
Ar
F
Scheme 2. Recovery and Regeneration of Template
CO2Et
, 90%
Ar
CO2Et
CO2Et Me
CO2Et
3a
3b
, 73%
3c
, 80%
3d
, 88%
OMe
Ar
Ar
Ar
OMe
OMe
N
N
N
N
N
N
O
N
1) C-O coupling
2) 1N HCl
POCl3
3a
+
MeO
CO2Et
F
CO2Et F3C
EtO2C
CO2Et
CO2Et
HO
N
Cl
N
NC
PhNMe2
Me
3h
80 oC, 6 h, Ar
90%
b
NC
NC
3e
, 85%
3f
3g
, 86%
, 89%
, 78%
CO2Me
Ar
Ar
2a
5
T
1, 90%
, 88%
CO2Me
CO2Et
NPhth
Ar
Finally, this template-directed remote C–H functionalization
strategy was tested in the synthesis of key building blocks of
natural products. Template-assisted meta-C–H olefination of the
substrate derived from guaiacol afforded the olefinated product 6
in 68% yield. While direct C–O coupling of compound 6 with
arylboronate 9 under the present conditions gave the biaryl
scaffold 10 in low yield (18%), an alternative route featuring
quantitative removal of the template T1, borylation, and
palladium-catalyzed Suzuki coupling with bromide 8 efficiently
delivered the left-hand moiety 10 of TMC-95 A–D (Scheme 3), a
small class of naturally occurring selective proteasome inhibitors
with IC50 values of 5–60 nM.13 The synthetic strategy allows for
facile modification of the biaryl units and the amino acid residue,
for such purposes as a structure-activity relationship (SAR) study
for this family of natural products.
CO2Et
CO2Et
Ar
CO2Et
OMe
R
3i
, 89%
3l
3m
, 52%
, 85%
3j
(R = F), 87% (X-ray)
(X-ray)
Me
c
3k
(R = Cl), 70%
F
Cl
CO2Et
CO2Et
CO2Et
EtO2C
CO2Et
CO2Et
3n
, 89%
3o
, 85%
3p
, 75%
3q
, 85%
F
F3C
S
CO2Et
CO2Et
CO2Et
CO2Et
c
3r
3s
, 82%
3t
, 75%
3u
, 83%
, 81%
Scheme 3. Application to Synthesis of the Central Scaffold
of Natural Antibiotic TMC-95a
aIsolated yield. b110 oC, 36 h. c110 oC.
To improve the synthetic utility of this strategy and avoid the
tedious separation of C–H olefination products, a one-pot meta-
C–H/ipso-C–O functionalization procedure was pursued (Table
3). Following palladium-catalyzed meta-C–H olefination, the
unpurified intermediate was subjected to nickel-catalyzed ipso-C–
O cross-coupling reaction with an arylboronic acid. Gratifyingly,
this one-pot procedure furnished the desired m-substituted biaryls
in good overall yields (3a, 4a–e). These results further
demonstrated the synthetic applicability of this template-assisted
transformation. More importantly, template T1 can be recovered
and regenerated after nickel-catalyzed C–O coupling in excellent
yield (Scheme 2), which further enhances the synthetic efficacy
and atom-economy of the strategy.
T1
Bpin
OH
O
3) morpholine
4) Tf2O, py
MeO
T
1) 1, KOH
MeO
MeO
NHCbz
CO2Me
NHCbz
CO2Me
2)
meta-C-H
olefination
5) Pd(OAc)2/DPEphos
B2(pin)2
guaiacol
6
7
O
O
O
-C-O
7) ipso
coupling
6) Pd(dppf)Cl2
O
O
N
N
H
H
O
Bpin
Br
8
9
N
H
MeO
steps
NHCbz
CO2Me
TMC-95 A-D
10
aConditions: (1) T1 (1 eq), KOH (1 eq), THF, rt, 95%. (2) olefin
(3 eq), Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%), AgOAc (1.5
eq), HFIP (0.2 M), 80 oC, 36 h, 68%. (3) morpholine (1 eq),
Table 3. Template-Assisted Tandem meta-C–H/ipso-C–O
Functionalization of Phenolsa
o
dioxane, 100 C, 12 h, 99%. (4) Tf2O (1.1 eq), Pyridine (2.5 eq),
o
CH2Cl2, 0 C to rt, 3 h, 75%. (5) B2(pin)2 (2 eq), Pd(OAc)2 (10
o
mol%), DPEphos (20 mol%), TEA (4 eq), dioxane, 80 C, 16 h,
90 %. (6) ArBr 8 (1.1 eq), Pd(dppf)Cl2 (20 mol%), K2CO3 (4 eq),
DME, 80 oC, 14 h, 92%. (7) ArBpin 9 (4 eq), Ni(xantphos)Cl2 (10
mol%), K3PO4 (7 eq), toluene, 120 oC, 24 h, 18%.
In summary, a robust bifunctional template has been developed
for the palladium-catalyzed remote meta-C–H olefination of
phenols. The template can be synthesized concisely in a two-step
sequence from inexpensive cyanuric chloride, and is easily
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Journal of the American Chemical Society
Page 4 of 6
nitrile-based directing group and cleavable Si-tether. J. Am. Chem. Soc.
installed and removed. In addition, this bifunctional template is
amenable to nickel-catalyzed ipso-C–O cross-coupling. This
template-assisted one-pot sequential meta-C–H/ipso-C–O
functionalization methodology allows for the expedited synthesis
of multiply substituted arenes from simple phenol substrates.
Further applications of this template-assisted strategy are under
investigation in our laboratory.
2013, 135, 18778. (d) Tang, R.; Li, G.; Yu, J.-Q. Conformation-induced
remote meta-C–H activation of amines. Nature 2014, 507, 215. (e) Bera,
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2015, 54, 8515. (f) Chu, L.; Shang, M.; Tanaka, K.; Chen, Q.; Pissarnitski,
N.; Streckfuss, E.; Yu, J.-Q. Remote meta-C–H activation using a
pyridine-based template: achieving site-selectivity via the recognition of
distance and geometry. ACS Cent. Sci. 2015, 1, 394. (g) Li, S.; Cai, L.; Ji,
H.; Yang, L.; Li, G. Pd(II)-catalysed meta-C–H functionalizations of
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ASSOCIATED CONTENT
Supporting Information
9
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization data, NMR spectra for
new compounds (PDF)
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Crystal data for compounds 3i and 3j (CIF)
(4) Examples of template-directed para-C–H functionalization: (a)
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AUTHOR INFORMATION
Corresponding Author
*xiaohuaxu@nankai.edu.cn
*zjin@nankai.edu.cn
*yu200@scripps.edu
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Cho, J.-Y.; Tse, M.K.; Holmes, D.; Maleczka, R. E.; Jr.; Smith, M. R.; III.
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borylation of arenes. High turnover numbers, room temperature reactions,
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Koehn, G.; Whittlesey, M. K.; Frost, C. G. Ruthenium-catalyzed meta
sulfonation of 2-phenylpyridines. J. Am. Chem. Soc. 2011, 133, 19298. (f)
Hofmann, N.; Ackermann, L. meta-Selective C–H bond alkylation with
secondary alkyl halides. J. Am. Chem. Soc. 2013, 135, 5877. (g) Cheng,
C.; Hartwig, J. F. Rhodium-catalyzed intermolecular C–H silylation of
arenes with steric regiocontrol. Science 2014, 343, 853. (h) Kuninobu, Y.;
Ida, H.; Nishi, M.; Kanai, M. A meta-selective C–H borylation directed by
a secondary interaction between ligand and substrate. Nat. Chem. 2015, 7,
712. (i) Yang, Y.; Li, R.; Zhao, Y.; Zhao, D.; Shi, Z. Cu-catalyzed direct
C6-arylation of indoles. J. Am. Chem. Soc. 2016, 138, 8734. (j) Wang, P.;
Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M.
A.; Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. Ligand-accelerated non-
directed C–H functionalization of arenes. Nature 2017, 551, 489. (k)
Wang, X.; Leow, D.; Yu, J.-Q. Pd(II)-catalyzed para-selective C–H
arylation of monosubstituted arenes. J. Am. Chem. Soc. 2011, 133, 13864.
(l) Luan, Y.-X.; Zhang, T.; Yao, W.-W.; Lu, K.; Kong, L.-Y.; Lin, Y.-T.;
Ye, M. Amide-ligand-controlled highly para-selective arylation of
monosubstituted simple arenes with arylboronic acids. J. Am. Chem. Soc.
2017, 139, 1786.
(6) (a) Kinuta, H.; Tobisu, M.; Chatani, N. Rhodium-catalyzed
borylation of aryl 2-pyridyl ethers through cleavage of the carbon-oxygen
bond: Borylative removal of the directing group. J. Am. Chem. Soc. 2015,
137, 1593. (b) Tobisu, M.; Zhao, J.; Kinuta, H.; Furukawa, T.; Igarashi,
T.; Chatani, N. Nickel-catalyzed borylation of aryl and benzyl 2-pyridyl
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(7) Brookhart, M.; Green, M. L. H.; Parkin, G. Agostic interactions in
transition metal compounds. Proc. Natl. Acad. Sci. U.S.A. 2007, 104,
6908.
(8) Zhang, L.; Zhao, C.; Liu, Y.; Xu, J.; Xu, X.; Jin, Z. Activation of
remote meta-C–H bonds in arenes with tethered alcohols: A salicylonitrile
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meta-C–H functionalization of arenes across different linker lengths.
Angew. Chem., Int. Ed. 2018, 57, 7659.
Author Contributions
┴These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NSF of China (20502012, 21172111 and 21672116)
for financial support of this work. We gratefully acknowledge The
Scripps Research Institute, the NIH ((National Institute of General
Medical Sciences grant 5R01GM102265).
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Table of Contents (TOC)
1
2
3
4
5
6
7
8
9
OMe
N
meta-C-H
ipso-C-O
FG2
O
T
N
Pd
Ni
N
m
H
Enabled by
a bifunctional template
FG1
N
O
CO2Et
O
CO2Me
NPhth
CO2Et
O
N
H
Ar
H
MeO
H
H
NHCbz
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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29
30
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CO2Me
from guaiacol
from estrone
from L-tyrosine
6
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