Palladium-Catalyzed C–H Arylation of Amides by Triazole Assistance

Article abstract of DOI:10.1002/ejoc.201601045

Versatile palladium-catalyzed C–H arylations of benzamides were accomplished with the assistance of a removable triazole amine (TAM). The robustness of the palladium-catalyzed C–H functionalization protocol is reflected in its broad functional group tolerance, ample substrate scope, and ability to proceed under silver-free reaction conditions.

Full text of DOI:10.1002/ejoc.201601045

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Accepted Article
Title: Palladium-Catalyzed CH Arylation of Amides by Triazole Assistance
Authors: Darko Santrac; Stefano Cella; Wei Wang; Lutz Ackermann
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European Journal of Organic Chemistry
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Palladium-Catalyzed C−H Arylation of Amides by Triazole
Assistance
Darko Santrač,‘ Stefano Cella,‘ Wei Wang, and Lutz Ackermann*[a]
Abstract: Versatile palladium-catalyzed C‒H arylations of
benzamides were accomplished by triazole amine (TAM) assistance.
The robustness of the palladium-catalyzed C‒H functionalization
protocol was reflected by its broad functional group tolerance, ample
substrate scope and C‒H arylations under silver-free reaction
conditions.
facile removal[15] of the TAM group in a traceless fashion.
Results and Discussion
Optimization
At the outset, we explored reaction conditions for the desired C‒
H arylation of TAM-amide 1a (Table 1, and S-1 in the Supporting
Information).[16] Hence, the desired C‒H functionalization
occurred at reaction temperatures as low as 60 °C, with optimal
results being achieved at elevated temperatures (entries 1‒4).
High catalytic efficacy was guaranteed by the use of AgOAc as
the additive, but silver(I)-free reaction conditions proved also
viable (vide infra, entries 5‒7).
Introduction
Transition metal-catalyzed arylations of unactivated C‒H
bonds[1] have emerged as transformative alternatives to
traditional cross-coupling reactions of prefunctionalized
substrates.[2] The control of positional selectivity represents the
key challenge in the development of synthetically meaningful
intermolecular C‒H transformations, with considerable progress
realized by chelation-assisted C‒H activation.[3] Indeed,
particularly bidentate directing groups have proven instrumental
for site-selective C‒H functionalizations by palladium catalysis,[4]
with major contributions by inter alia Daugulis, Chatani and Shi
using 8-aminoquinoline (AQ) and (pyridin-2-yl)isopropyl (PIP)
amine-derived auxiliaries.[5]
Table 1. Optimization of the palladium-catalyzed CH arylation of amide 1aa
The copper-catalyzed[6] 1,3-dipolar cycloaddition[7] has been
identified as a powerful tool for the late-stage diversification in
medicinal chemistry, material sciences and biomolecular
chemistry.[8] With the prospect of providing an additional element
of complexity-increasing structural diversification, in 2008,[9] we
have introduced 1,2,3-trazoles as directing groups in positional-
selective C‒H functionalizations.[10] Guided by these findings, we
had developed modular triazole amines (TAM), which inter alia
enabled iron-[11] and ruthenium-catalyzed[12] arylations,
alkenylations and alkylations.[13] Within our own program on
palladium-catalyzed C‒H arylations,[14] we have now explored
the use of TAM amides for site-selective palladium-catalyzed C‒
H arylations, on which we report herein. Notable features of our
strategy are not limited to (i) efficient palladium-catalyzed C‒H
arylations, under (ii) silver-free reaction conditions, and (iii) a
Entry
Variation from standard condition
Yield [%][a]
1
2
3
4
5
6
---
94
35
80
95
---
---
60 °C
80 °C
150 °C
NaOAc instead of AgOAc
Me4NCl, nBu4NF, or nBu4NI instead of
AgOAc
7
KOAc/Me4NCl instead of AgOAc
50[b]
[a] Reaction conditions: 1a (0.50 mmol), 2a (2.00 mmol), Pd(OAc)2 (5.0
mol %), AgOAc (1.10 equiv), PhMe (4.0 mL), 16h, 110 °C. [b] 1a (0.50 mmol),
2a (2.00 mmol), Pd(OAc)2 (5.0 mol %), KOAc (2.8 equiv), Me4NCl (2.05
equiv), AcOH (1.5 equiv), 48 h, 120 °C.
[a]
D. Santrač,‘ S. Cella,‘ W. Wang, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August Universität
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax: (+49)551-39-6777
E-mail: Lutz.Ackermann@chemie-uni-goettingen.de
http://www.org.chemie.uni-goettingen.de/ackermann/
Thus, the optimization studies identified Pd(OAc)2 as the optimal
catalyst, along with AgOAc as the additive of choice (Scheme 1).
‘ These authors contributed equally.
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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Scheme 1. Optimized palladium-catalyzed C–H arylation by TAM assistance.
With the optimized reaction conditions in hand, we tested its
versatility in the palladium-catalyzed C‒H arylation of amides 1
that possess differently decorated TAM motifs (Scheme 2).
Interestingly, a considerable structural diversification on the
1,2,3-triazole scaffold was well accepted, thereby providing the
desired products 3aa‒3ea in excellent yields.
Scheme 3. Support for a mono-anionic bidentate coordination mode.
Substrate Scope
Encouraged by these results, we next explored the catalyst’s
versatility in the C‒H arylation process (Scheme 4). Indeed, the
C‒H functionalization protocol proved applicable to differently
substituted aryl iodides 2a-i, including sterically demanding
ortho-substituted derivatives. A variety of valuable electrophilic
functional groups, such as chloro, ester or ketone substituents,
was fully tolerated on the aryl iodides 2, thereby providing a
handle for further post-synthetic manipulation. The palladium-
catalyzed C‒H arylation occurred with high positional selectivity
within intramolecular competition experiments, solely cleaving
the less sterically congested C‒H bonds to furnish products
3ma, 3mg and 3na‒3ni.
Scheme 2. Influence of the TAM substitution pattern on C–H arylation.
The coordination mode of the TAM group was thereafter probed
by attempted palladium-catalyzed C‒H arylations with the
corresponding ester 1f and the tertiary amide 1g, highlighting
the importance of the NH-acidic secondary amide functionality.
Likewise, the secondary amides 1h and 1i being devoid of the
Lewis-basic 1,2,3-triazole motif failed to furnish the C‒H arylated
products (Scheme 3), revealing the bidentate coordination of the
TAM-amides 1a. Overall, these findings provide strong support
for a mono-anionic N,N-bidentate binding of the TAM amide to
the palladium(II) center.
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Table 2. Optimization of the silver-free CH arylation[a]
entry
additive
---
3aa [%][b]
1
2
3
4
5
6
NaOAc
CsOAc
MesCO2H
(1-Ad)CO2H
PivOH
53
77
80
89
83
[a] Reaction conditions: 1a (0.50 mmol), 2a (1.00 mmol), Pd(OAc)2 (5.0 mol %),
[b]
additive (30 mol %), PhMe (4.0 mL), 24h, 120 °C.
CH2Br2 as internal standard.
NMR conversion with
Subsequently, the scope of the silver-free palladium-catalyzed
C‒H arylation of TAM-amides 1 was explored. Indeed, the
optimized protocol turned out to be widely applicable (Scheme
5). Thus, para-, meta- and even sterically encumbered ortho-
Scheme 4. Scope of TAM-assisted C–H arylation.
substituted aryl iodides
2 were fully tolerated. Moreover,
valuable electrophilic functionalities, including ester, cyano and
ketone groups, were accepted by the optimized catalytic system.
In contrast, aryl bromides and chlorides were as of yet not
Silver-Free C‒H Functionalization
Given that the use of expensive silver(I) salts[17] as additives
generates undesired metal by-products, we became attracted to
establishing silver-free reaction conditions for the TAM-assisted
C‒H arylation. To this end, we probed various additives in the
palladium-catalyzed C‒H functionalization of amide 1a,
employing the mild base KHCO3 (Table 2). While catalytic
amounts of acetates allowed for the synthesis of desired biaryl
amide 3aa (entries 1‒3), optimal results were accomplished with
adamantyl and pivaloyl carboxylic acids (entries 4‒6). These
observations can be rationalized in terms of carboxylate-
assisted[18] C‒H activation being operative via a concerted
metalation−deprotonation (CMD),[19] ambiphilic metal-ligand
suitable
substrates.
The
palladium-catalyzed
C‒H
functionalization was characterized by high ortho-selectivity, as
became evident within TAM-assisted C‒H arylations on the
meta-substituted substrates 1m and 1n.
activation (AMLA),[20]
electrophilic substitution-type (BIES)[21] transition state.
or base-assisted intra-molecular
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Experimental Section
General Remarks
Catalytic reactions were carried out in Schlenk tubes under a N2
atmosphere using pre‐dried glassware. Toluene was dried over
Na and distilled under N2. All starting materials were synthesized
according to previously described methods.[12a] N-(2-[1-Benzyl-
1H-1,2,3-triazol-4-yl]propan-2-yl)-2-fluorobenzamide,
was
prepared according to
a
literature procedure.[12a] Other
chemicals were obtained from commercial sources and were
used without further purification, except aryl iodides, which were
sublimed twice before their use. Yields refer to isolated
1
compounds, estimated to be > 95% pure as determined by H-
NMR and GC-analysis. Chromatography: Merck silica gel 60
(40-63 µm). NMR: Spectra were recorded on Varian Unity 300,
Mercury 300, Inova 500, or Inova 600 in the solvent indicated;
chemical shifts (δ) are given in ppm. All IR spectra were
recorded on a Bruker FT-IR Alpha device. MS: EI-MS-spectra
were recorded with Finnigan MAT 95, 70 eV; High resolution
mass spectrometry (HRMS) with APEX IV 7T FTICR, Bruker
Daltonic. M. p.: Stuart melting point apparatus SMP3, Barlworld
Scientific, values are uncorrected.
Representative Procedure A for Palladium‐Catalyzed C‒H
Arylation
Scheme 5. Silver-free CH arylations of TAM-amides 1. [a] 1-AdCO2H as the
A mixture of amide 1 (0.50 mmol), aryl iodide 2 (2.00 mmol),
Pd(OAc)2 (5.0 mol %), AgOAc (0.55 mmol) and PhMe (4.0 mL)
under N2 was stirred at 110 °C for 16 h. At ambient temperature,
the mixture was diluted with EtOAc (20 mL), stirred for 10
minutes, filtered through a plug of celite (0.5 × 3.0 cm), and the
plug was washed with EtOAc (100 mL). The resulting solution
was concentrated in vacuo, and purified by column
chromatography on silica gel.
additive.
The practical utility of our strategy was illustrated by the removal
of the TAM group[11] in a traceless[15] fashion to deliver the biaryl
carboxylic acid 4 in high yield, featuring the sensitive ketone
functionality (Scheme 6).
Representative Procedure
B for Silver-free Palladium‐
Catalyzed C‒H Arylation
A mixture of amide 1 (0.50 mmol), aryl iodide 2 (1.00 mmol),
Pd(OAc)2 (5.0 mol %), KHCO3 (2.00 equiv), PivOH (30 mol %) in
PhMe (4.0 mL) under N2 was stirred at 120 °C for 24 h. At
ambient temperature, the mixture was diluted with EtOAc (20
mL), stirred for 10 minutes, filtered through a plug of celite (0.5 ×
3.0 cm), and the plug was washed with EtOAc (100 mL). The
resulting solution was concentrated in vacuo, and purified by
column chromatography on silica gel.
Scheme 6. TAM removal in a traceless fashion.
N-(2-[1-Benzyl-1H-1,2,3-triazol-4-yl]propan-2-yl)-4'-methoxy-
3-methyl-[1,1'-biphenyl]-2-carboxamide (3aa)
The representative procedure A was followed using 1a (167 mg,
0.5 mmol), 4-iodoanisole (2a) (468 mg, 2.00 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %), and AgOAc (91.8 mg, 0.55
mmol). Column chromatography on silica gel (npentane/EtOAc
3:1 → 1:1) yielded 3aa (207 mg, 94%) as a pale yellow solid.
Conclusions
In summary, we have reported on the unprecedented palladium-
catalyzed C‒H arylation by TAM-assistance. Thus, an
operationally simple C‒H functionalization of TAM-amides was
accomplished with excellent functional group tolerance and
ample substrate scope. The removable TAM-group enabled
silver-free C‒H arylations with KHCO3 as a mild[22] base through
a carboxylate assistance manifold.
1
M.p.: 114–115 °C. H-NMR (600 MHz, CDCl3) δ (ppm) = 7.35–
7.29 (m, 5H), 7.25–7.19 (m, 4H), 7.10 (t, J = 7.7 Hz, 2H), 6.80
(dd, J = 8.9, 2.1, 2H), 5.92 (s, 1H), 5.41 (s, 2H), 3.75 (s, 3H),
2.29 (s, 3H), 1.52 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ (ppm) =
168.7 (Cq), 158.7 (Cq), 153.1 (Cq), 138.5 (Cq), 136.8 (Cq), 135.1
(Cq), 134.6 (Cq), 132.8 (Cq), 130 (CH), 128.8 (CH), 128.7 (CH),
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1
128.4 (CH), 128.4 (CH), 127.7 (CH), 127 (CH), 120.4 (CH),
113.4 (CH), 55.2 (CH3), 53.8 (CH2), 51.6 (Cq), 27.5 (CH3), 19.2
(CH3). IR (ATR): 3294, 2977, 1651, 1512, 1456, 1178, 790, 721,
695, 533 cm-1. MS (EI) m/z (relative intensity): 440 (60) [M+], 397
(90), 240 (15), 225 (75), 200 (20), 182 (22), 153 (15), 91 (100).
HR-MS (EI) m/z calculated for C27H28N4O2 [M+]: 440.2212;
found: 440.2210. The analytical data were in accordance with
the data reported in the literature.[11c]
172 °C. H-NMR (600 MHz, CDCl3): δ = 7.67 (s, 1H), 7.66-7.62
(m, 2H), 7.32 (dd, J = 8.7, 2.0 Hz, 2H), 7.26 (dd, J = 7.6, 7.6 Hz,
1H), 7.21-7.17 (m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.7
Hz, 1H), 6.81 (dd, J = 8.9, 2.4 Hz, 2H), 5.86 (s, 1H), 3.72 (s, 3H),
2.37 (s, 3H), 1.64 (s, 6H). 13C-NMR (125 MHz, CDCl3): δ = 169.0
(Cq), 162.3 (Cq, JC-F = 248.5 Hz), 158.9 (Cq), 153.4 (Cq), 138.8
(Cq), 136.8 (Cq), 135.2 (Cq), 133.4 (Cq,JC-F = 3.1 Hz), 132.9 (Cq),
130.0 (CH), 128.9 (CH), 128.7 (CH), 127.3 (CH), 122.5 (CH,JC-F
= 8.5 Hz), 119.1 (CH), 116.5 (CH,JC-F = 23 Hz), 113.5 (CH), 55.2
(CH3), 51.7 (Cq), 27.7 (CH3), 19.3 (CH3). 19F-NMR (283 MHz,
CDCl3): δ = -112.40 (d, J = 4.5 Hz). IR (ATR): 3258, 1629, 1514,
1248, 1221, 1179, 1039, 817, 787, 538 cm-1. HR-MS (ESI) m/z
calcd for C26H25FN4O2 [M+H+] 445.2040, found 445.2034.
N-{1-(1-Benzyl-1H-1,2,3-triazol-4-yl)cyclohexyl}-4'-methoxy-
3-methyl-[1,1'-biphenyl]-2-carboxamide (3ba)
The representative procedure A was followed using 1b (113 mg,
0.3 mmol), 4-iodoanisole (2a) (280 mg, 1.2 mmol), Pd(OAc)2
(3.4 mg, 0.015 mmol, 5.0 mol %), and AgOAc (55.0 mg, 0.33
mmol). Column chromatography on silica gel (npentane/EtOAc
1/1) yielded 3ba (136.8 mg, 95%) as a white solid. M.p. = 174-
176. 1H-NMR (600 MHz, CDCl3): δ = 7.43 (s, 1H), 7.36-7.29 (m,
3H), 7.26 (dd, J = 8.8, 2.0, 2H), 7.24-7.21 (m, 3H), 7.08 (dd, J =
10.9, 7.5 Hz, 2H), 6.78 (dd, J = 8.8, 2.2 Hz, 2H), 5.46 (s, 2H),
5.44 (s, 1H), 3.78 (s, 3H), 2.26-2.17 (m, 2H), 2.14 (s, 3H), 1.95-
N-{2-(1-nButyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-4'-methoxy-
3-methyl-[1,1'-biphenyl]-2-carboxamide (3ea)
The representative procedure A was followed using 1e (150 mg,
0.5 mmol), 4-iodoanisole (2a) (468 mg, 2.0 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %), and AgOAc (91.8 mg, 0.55
mmol). Column chromatography on silica gel (n-pentane/EtOAc
1.84 (m, 2H), 1.36-1.24 (m, 3H), 1.24-1.16 (m, 1H), 1.15-1.04 (m, 1/1) yielded 3ea (194.6 mg, 96%) as a white solid. M.p. = 108-
2H). 13C-NMR (125 MHz, CDCl3): δ = 168.9 (Cq), 158.9 (Cq),
151.9 (Cq), 138.6 (Cq), 137.0 (Cq), 135.3 (Cq), 135.0 (Cq), 133.0
(Cq), 129.4 (CH), 128.9 (CH), 128.8 (CH), 128.4 (CH), 128.4
(CH), 127.7 (CH), 127.2 (CH), 121.9 (CH), 113.6 (CH), 55.3
(CH3), 53.9 (Cq), 53.8 (CH2), 34.8 (CH2), 25.2 (CH2), 21.3 (CH2),
21.2 (CH3). IR (ATR): 3258, 1629, 1514, 1464, 1151, 1048, 959,
846, 720, 458 cm-1. HR-MS (ESI) m/z calcd for C30H32N4O2
[M+Na+] 503.2423, found 503.2417.
109 °C. 1H-NMR (600 MHz, CDCl3): δ = 7.34 (dd, J = 8.6, 2.0 Hz,
2H), 7.24 (dd, J = 7.7, 7.7 Hz, 1H), 7.19 (s, 1H), 7.13-7.09 (m,
2H), 6.86 (dd, J = 8.6, 2.1 Hz, 2H), 5.94 (s, 1H), 4.23 (t, J = 7.3
Hz, 2H), 3.80 (s, 3H), 2.33 (s, 3H), 1.84-1.78 (m, 2H), 1.56 (s,
6H), 1.35-1.27 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C-NMR (125
MHz, CDCl3): δ = 168.8 (Cq), 158.9 (Cq), 152.8 (Cq), 138.7 (Cq),
137.0 (Cq), 135.2 (Cq), 133.0 (Cq), 130.1 (CH), 128.8 (CH), 128.5
(CH), 127.1 (CH), 120.2 (CH), 113.5 (CH), 55.2 (CH3), 51.7 (Cq),
49.8 (CH2), 32.2 (CH2), 27.5 (CH3), 19.6 (CH2), 19.2 (CH3), 13.4
(CH3). IR (ATR): 3258, 2959, 1610, 1539, 1512, 1458, 1244,
1178, 1031, 656 cm-1. MS (EI) m/z (relative intensity): 406 (30)
[M+], 363 (55), 240 (15), 225 (55), 224 (30), 182 (15), 166 (25),
58 (20), 57 (30). HR-MS (EI) m/z calcd for C24H30N4O2 [M+]
406.2369, found 406.2361.
4'-Methoxy-N-(2-{1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl}propan-2-yl)-3-methyl-[1,1'-biphenyl]-2-carboxamide (3ca)
The representative procedure A was followed using 1c (109 mg,
0.3 mmol), 4-iodoanisole (2a) (280 mg, 1.2 mmol), Pd(OAc)2
(3.4 mg, 0.015 mmol, 5.0 mol %), and AgOAc (55.0 mg, 0.33
mmol). Column chromatography on silica gel (npentane/EtOAc
1/1) yielded 3ca (126.2 mg, 90%) as a white solid. M.p. = 127-
N-(2-[1-Benzyl-1H-1,2,3-triazol-4-yl]propan-2-yl)-3-methyl-
128 °C. 1H-NMR (600 MHz, CDCl3): δ = 7.30 (dd, J = 8.8, 2.0 Hz, [1,1'-biphenyl]-2-carboxamide (3ab)
2H), 7.23 (dd, J = 7.7 Hz, 1H), 7.19-7.14 (m, 3H), 7.09 (t, J = 7.2
Hz, 2H), 6.85 (dd, J = 8.7, 2.0 Hz, 2H), 6.80 (dd, J = 8.7, 2.0 Hz,
2H), 5.94 (s, 1H), 5.34 (s, 2H), 3.76 (s, 6H), 2.29 (s, 3H), 1.51 (s,
6H). 13C-NMR (125 MHz, CDCl3): δ = 168.8 (Cq), 159.6 (Cq),
158.8 (Cq), 153.1 (Cq), 138.6 (Cq), 136.8 (Cq), 135.2 (Cq), 132.8
(Cq), 129.9 (CH), 129.3 (CH), 128.7 (CH), 128.4 (CH), 127.1
(CH), 126.6 (Cq), 120.1 (CH), 114.3 (CH), 113.4 (CH), 55.2
(CH3), 53.4 (CH2), 51.6 (Cq), 27.3 (CH3), 19.1 (CH3), 19.1 (CH3).
The representative procedure A was followed using 1a (167 mg,
0.50 mmol), iodobenzene (2b) (408 mg, 2.0 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 0.55
mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ab (188 mg, 92%) as a
1
white solid. M.p.: 177–178 °C. H-NMR (300 MHz, CDCl3): δ =
7.40–7.32 (m, 5H), 7.30–7.18 (m, 6H), 7.17–7.10 (m, 3H), 5.83
(s, 1H), 5.43 (s, 2H), 2.30 (s, 3H), 1.49 (s, 6H). 13C-NMR (125
IR (ATR): 3258, 2837, 1637, 1611, 1513, 1459, 1244, 1178, 833, MHz, CDCl3) δ = 168.7 (Cq), 153.5 (Cq), 140.7 (Cq), 139.2 (Cq),
665 cm-1. HR-MS (ESI) m/z calcd for C28H31N4O3 [M+H+]
471.2396, found 471.2391.
137.0 (Cq), 135.5 (Cq), 134.8 (Cq), 129.3 (CH), 129.1 (CH), 128.9
(CH), 128.7 (CH), 128.7 (CH), 128.1 (CH), 128.0 (CH), 127.3
(CH), 127.2 (CH), 120.5 (CH), 53.9 (CH2), 51.6 (Cq), 27.3 (CH3),
19.2 (CH3). IR (ATR): 3314, 2924, 1635, 1539, 1309, 1198, 1053,
760, 730, 632. MS (EI) m/z (relative intensity): 410 (35), 382 (15),
367 (85), 200 (16), 195 (80), 165 (42), 152 (35), 98 (24), 91
(100), 57 (22), 43 (52). HR-MS (EI) m/z calculated for C26H26N4O
[M+]: 410.2107; found: 410.2119. The analytical data were in
accordance with the data reported in the literature.[11c]
N-(2-{1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl}propan-2-yl)-4'-
methoxy-3-methyl-[1,1'-biphenyl]-2-carboxamide (3da)
The representative procedure A was followed using 1d (101 mg,
0.3 mmol), 4-iodoanisole (2a) (280 mg, 1.2 mmol), Pd(OAc)2
(3.4 mg, 0.015 mmol, 5.0 mol %), and AgOAc (55.0 mg, 0.33
mmol). Column chromatography on silica gel (npentane/EtOAc
1/1) yielded 3da (123.5 mg, 93%) as a white solid. M.p. = 170-
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European Journal of Organic Chemistry
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N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-4'-fluoro-3-
methyl-[1,1'-biphenyl]-2- carboxamide (3ac)
134.8 (Cq), 129.3 (CH), 129.1 (CH), 129.0 (CH), 128.6 (CH),
128.6 (CH), 127.8 (CH), 126.9 (CH), 121.2 (CH), 120.4 (CH),
114.0 (CH), 113.6 (CH), 55.1 (CH3), 53.8 (CH2), 51.6 (Cq), 27.2
(CH3), 19.1 (CH3). IR (ATR): 3304, 2836, 1652, 1497, 1456,
The representative procedure A was followed using 1a (167 mg,
0.50 mmol), 1-fluoro-4-iodobenzene (2c) (444 mg, 2.0 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 1299, 1222, 1046, 722, 698 cm-1. MS (EI) m/z (relative intensity):
0.55 mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ac (150 mg, 70%) as a
white solid. M.p.: 157–158 °C. 61 °C. 1H-NMR (300 MHz,
440 (10) [M+], 397 (85), 240 (10), 225 (55), 201 (22), 182 (20),
165 (15), 153 (15), 91 (100), 65 (8). HR-MS (EI) m/z calculated
for C27H28N4O2 [M+]: 440.2212; found: 440.2214. The analytical
CDCl3): δ = 7.39–7.30 (m, 5H), 7.26–7.18 (m, 4H), 7.17–7.05 (m, data were in accordance with the data reported in the
2H), 6.99–6.87 (m, 2H), 6.03 (s, 1H), 5.42 (s, 2H), 2.30 (s, 3H),
1.52 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 168.6 (Cq), 162.3
(Cq, JC-F = 246 Hz), 153.4 (Cq), 138.1 (Cq), 136.5 (Cq, JC-F = 3
Hz), 136.5 (Cq), 135.4 (Cq), 134.7 (Cq), 130.6 (CH, JC-F = 8 Hz),
129.4 (CH), 129.1 (CH), 128.7 (CH), 128.7 (CH), 128.0 (CH),
127.1 (CH), 120.2 (CH), 114.9 (CH, JC-F = 21 Hz), 54.1 (CH2),
51.8 (Cq), 27.4 (CH3), 19.2 (CH3). 19F-NMR (282 MHz, CDCl3) δ
(ppm) = -(115.6-115.7) (m). IR (ATR): 3289, 2980, 1634, 1539,
1508, 1218, 1194, 1051, 938, 529. MS (EI) m/z (relative
intensity): 428 (40) [M+], 385 (100), 213 (80), 212 (15), 183 (25),
165 (30), 91 (80), 43 (27). HRMS (EI) m/z calculated for
C26H25FN4O+: 428.2012; found: 428.2020. The analytical data
were in accordance with the data reported in the literature.[11c]
literature.[11c]
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-2'-methoxy-
3-methyl-[1,1'-biphenyl]-2-carboxamide (3af)
The representative procedure A was followed using 1a (167 mg,
0.50 mmol), 2-iodoanisole (2f) (487 mg, 2.00 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 0.55
mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3af (176 mg, 80%) as a
colorless solid. M.p. = 173–174 °C. 1H-NMR (600 MHz, CDCl3) δ
= 7.36–7.30 (m, 3H), 7.23 (dd, J = 7.6 Hz, 1H), 7.19–7.11 (m,
5H), 6.98 (d, J = 7.5 Hz, 1H), 6.88 (s, 1H), 6.83 (ddd, J = 7.4, 1.0
Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.30 (s, 1H), 5.37 (s, 2H), 3.62
(s, 3H), 2.31 (s, 3H), 1.45 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ
= 168.1 (Cq), 156.1 (Cq), 153.1 (Cq), 137.4 (Cq), 135.3 (Cq),
134.9 (Cq), 134.7 (Cq), 130.9 (CH), 129.6 (Cq), 129.2 (CH), 128.8
(CH), 128.7 (CH), 128.3 (CH), 128.0 (CH), 127.6 (CH), 127.4
(CH), 120.3 (CH), 120.1 (CH), 110.3 (CH), 55.2 (CH3), 53.8
(CH2), 51.4 (Cq), 27.5 (CH3), 19.3 (CH3). IR (ATR): 3391, 3116,
3079, 1646, 1515, 1455, 1228, 757, 729, 477 cm–1. MS (EI) m/z
(relative intensity): 440 (10) [M+], 397 (80), 225 (60), 210 (53),
201 (85), 181 (30), 165 (12), 152 (10), 91 (100), 65 (10). HR-MS
(EI) m/z calculated for C27H28N4O2 [M+]: 440.2212; found:
440.2211.
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-3-methyl-4'-
(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (3ad)
The representative procedure A was followed using 1a (167 mg,
0.50 mmol), 1-iodo-4-(trifluoromethyl)benzene (2d) (544 mg,
2.00 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and
AgOAc (91.8 mg, 0.55 mmol). Purification by column
chromatography on silica gel (n-pentane/EtOAc 3:1 → 1:1 )
yielded 3ad (217 mg, 91%) as a white solid. M.p. = 183–185 °C.
1H-NMR (300 MHz, CDCl3) δ = 7.55 – 7.47 (m, 4H), 7.42–7.15
(m, 8H), 7.11 (d, J = 7.5 Hz, 1H), 6.10 (s, 1H), 5.43 (s, 2H), 2.32
(s, 3H), 1.50 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 168.3 (Cq),
153.3 (Cq), 144.2 (Cq), 137.7 (Cq), 136.9 (Cq), 135.5 (Cq), 134.5
(Cq), 139.9 (CH), 129.4 (Cq, JC-F = 33.3 Hz), 129.2 (CH), 129.0
(CH), 128.8 (CH), 128.7 (CH), 127.9 (CH), 126.9 (CH), 124.9
(CH, JC-F = 3.3 Hz), 124.2 (Cq, JC-F = 272.0 Hz), 120.2 (CH),
54.0 (CH2), 51.7 (Cq), 27.0 (CH3), 19.1 (CH3). 19F-NMR (282
MHz, CDCl3) δ = -62.35 (s). IR (ATR): 3283, 2978, 1635, 1189,
1154, 1062, 848, 790, 716, 608 cm-1. MS (EI) m/z (relative
intensity): 478 (30) [M+], 450 (18), 435 (85), 263 (75), 215 (22),
165 (30), 91 (100), 65 (10), 43 (15). HR-MS (EI) m/z calculated
for C27H25F3N4O [M+]: 478.1980; found: 478.1967.
Methyl
2'-{(2-(1-benzyl-1H-1,2,3-triazol-4-yl)propan-2-
yl}carbamoyl)-3'-methyl-[1,1'-biphenyl]-4-carboxylate (3ag)
The representative procedure A was followed using 1a (167 mg,
0.50 mmol), methyl 4-iodobenzoate (2g) (524 mg, 2.00 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg,
0.55 mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ag (227 mg, 95%) as a
yellow-orange solid. M.p. = 136–138 °C. 1H-NMR (300 MHz,
CDCl3) δ = 7.95 (dd, J = 8.5, 1.9 Hz, 2H), 7.46 (dd, J = 8.5, 1.9
Hz, 2H), 7.40–7.08 (m, 9H), 6.07 (s, 1H), 5.42 (s, 2H), 3.88 (s,
3H), 2.30 (s, 3H), 1.49 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ =
168.5 (Cq), 167.0 (Cq), 153.3 (Cq), 145.3 (Cq), 138.0 (Cq), 136.8
(Cq), 135.5 (Cq), 134.7 (Cq), 129.9 (CH), 129.4 (CH), 129.1 (CH),
129.0 (CH), 128.9 (Cq), 128.8 (CH), 128.6 (CH), 127.9 (CH),
127.0 (CH), 120.3 (CH), 53.9 (CH2), 52.0 (CH3), 51.6 (Cq), 27.2
(CH3), 19.0 (CH3). IR (ATR): 3291, 2948, 1654, 1518, 1455,
1275, 1181, 1048, 768, 705 cm-1. MS (EI) m/z (relative intensity):
468 (32) [M+], 425 (100), 253 (18), 209 (25), 194 (18), 165 (40),
91 (95), 59 (8). HR-MS (EI) m/z calculated for C28H28N4O3 [M+]:
468.2161; found: 468.2163.
N-{2-[1-Benzyl-1H-1,2,3-triazol-4-yl]propan-2-yl}-3'-methoxy-
3-methyl-[1,1'-biphenyl]-2- carboxamide (3ae)
The representative procedure A was followed using 1a (167 mg,
0.50 mmol), 3-iodoanisole (2e) (487 mg, 2.00 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 0.55
mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ae (185 mg, 84%) as a
dark oil. 1H-NMR (600 MHz, CDCl3) δ = 7.35–7.30 (m, 3H), 7.25
(t, J = 7.6 Hz, 1H), 7.22–7.12 (m, 6H), 6.96–6.94 (m, 2H), 6.82–
6.80 (m, 1H), 5.90 (s, 1H), 5.42 (s, 2H), 3.73 (s, 3H), 2.30 (s, 3H),
1.50 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 168.7 (Cq), 159.2
(Cq), 153.4 (Cq), 142.0 (Cq), 139.0 (Cq), 136.9 (Cq), 135.4 (Cq),
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl}propan-2-yl)-4'-cyano-3-
methyl-[1,1'-biphenyl]-2-carboxamide (3ah)
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601045
FULL PAPER
Representative procedure A was followed using 1a (167 mg,
0.50 mmol), 4-iodobenzonitrile (2h) (458 mg, 2.00 mmol),
(EI) m/z (relative intensity): 476 (43) [M+], 433 (100), 276 (25),
261 (85), 218 (22), 189 (32), 91 (66). HR-MS (EI) m/z calcd for
+
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, C30H28N4O2 [M+] 476.2212, found 476.2193. The analytical data
0.55 mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ah (205 mg, 94%) as a
yellow-orange solid. M.p. = 143–145 °C. 1H-NMR (300 MHz,
CDCl3) δ = 7.52 (dd, J = 8.9, 2.2 Hz, 4H), 7.39–7.18 (m, 8H),
7.11–7.08 (m, 1H), 6.19 (s, 1H), 5.45 (s, 2H), 2.32 (s, 3H), 1.52
(s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 168.3 (Cq), 153.4 (Cq),
145.3 (Cq), 137.3 (Cq), 136.9 (Cq), 135.7 (Cq), 134.6 (Cq), 131.9
(CH), 130.4 (CH), 129.7 (CH), 129.2 (CH), 128.9 (CH), 128.8
were in accordance with the data reported in the literature.[11c]
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-3-chloro-4'-
methoxy-[1,1'-biphenyl]-2-carboxamide (3ka)
The representative procedure A was followed using 1k (177 mg,
0.50 mmol), 4-iodoanisole (2a) (468 mg, 2.00 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 0.55
mmol). Purification by column chromatography on silica gel
(CH), 128.1 (CH), 126.8 (CH), 120.1 (CH), 118.9 (Cq), 111.0 (Cq), (npentane/EtOAc 3:1 → 1:1) yielded 3ka (190 mg, 82%) as a
1
54.1 (CH2), 51.7 (Cq), 27.2 (CH3), 19.1 (CH3). IR (ATR): 3283,
2228, 1636, 1540, 1457, 1311, 1050, 848, 722, 666 cm-1. MS
(EI) m/z (relative intensity): 435 (30), 392 (70), 220 (65), 190
(22), 177 (12), 165 (25), 98 (10), 91 (100), 65 (65). HR-MS (EI)
m/z calculated for C27H25N5O [M+]: 435.2059; found: 435.2062.
white solid. M.p. = 137-139 °C. H-NMR (600 MHz, C6D6): δ =
7.28-7.21 (m, 5H), 7.21 – 7.20 (m, 1H), 7.19-7.17 (m, 2H), 7.14-
7.11 (m, 2H), 7.10 (dd, J = 7.0, 1.8 Hz, 2H), 6.73 (dd, J = 8.5,
1.9 Hz), 5.97 (s, 1H), 5.33 (s, 2H), 3.68 (s, 3H), 1.48 (s, 6H). 13C-
NMR (125 MHz, CDCl3): δ = 165.8 (Cq), 159.3 (Cq), 153.0 (Cq),
141.1 (Cq), 136.1 (Cq), 134.6 (Cq), 131.5 (Cq), 131.3 (Cq), 130.0
(CH), 129.7 (CH), 129.0 (CH), 128.6 (CH), 128.3 (CH), 128.0
(CH), 127.9 (CH), 120.6 (CH), 113.6 (CH), 55.3 (CH3), 53.9
(CH2), 52.3 (Cq), 27.6 (CH3) . IR (ATR): 3258, 1637, 1561, 1455,
1046, 840, 731, 704, 693, 583 cm-1. MS (EI) m/z (relative
4'-Acetyl-N-{2-(1-benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-3-
methyl-[1,1'-biphenyl]-2-carboxamide (3ai)
The representative procedure A was followed using 1a (167 mg,
0.50 mmol), 4-iodoacetophenone (2i) (492 mg, 2.00 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, intensity): 460 (15) [M+], 432 (15), 419 (30), 417 (80), 247 (15),
0.55 mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ai (210 mg, 89%) as a
yellow solid. M.p. = 130–132 °C. 1H-NMR (300 MHz, CDCl3) δ =
7.84 (dd, J = 8.2, 2.0 Hz, 2H), 7.48 (dd, J = 8.1, 2.3 Hz, 2H),
7.39–7.09 (m, 9H), 6.07 (s, 1H), 5.43 (s, 2H), 2.56 (s, 3H), 2.31
(s, 3H), 1.50 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 198.0 (Cq),
168.5 (Cq), 153.1 (Cq), 145.4 (Cq), 138.0 (Cq), 136.8 (Cq), 135.9
(Cq), 135.6 (Cq), 134.7 (Cq), 123.0 (CH), 129.1 (CH), 129.1 (CH),
128.8 (CH), 128.7 (CH), 128.2 (CH), 128.0 (CH), 127.0 (CH),
120.5 (CH), 54.0 (CH2), 51.6 (Cq), 27.2 (CH3), 26.6 (CH3), 19.1
(CH3). IR (ATR): 2977, 1636, 1538, 1359, 1270, 1184, 1050, 603
cm-1. MS (EI) m/z (relative intensity): 452 (42) [M+], 424 (22),
409 (100), 237 (20), 195 (50), 165 (20), 91 (90), 43 (50). HR-MS
(EI) m/z calculated for C28H28N4O2 [M+]: 452.2212; found:
452.2201.
245 (50), 210 (20), 139 (25), 91 (100). HR-MS (ESI) m/z calcd
for C26H25ClN4O2 [M+H+] 461.1744, found 461.1739.
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-3-fluoro-4'-
methoxy-[1,1'-biphenyl]-2-carboxamide (3la)
The representative procedure A was followed using 1l (169 mg,
0.50 mmol), 4-iodoanisole (2a) (468 mg, 2.00 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 0.55
mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3la (185 mg, 84%) as a
1
white solid. M.p. = 144-146 °C. H-NMR (600 MHz, CDCl3): δ =
7.36-7.30 (m, 6H), 7.28 (s, 1H), 7.23-7.20 (m, 2H), 7.09 (dd, J =
7.6, 1.1 Hz, 1H), 7.00 (dd, J = 8.7, 8.2, 1.1 Hz, 1H), 6.82 (dd, J =
8.7, 2 Hz, 2H), 6.18 (s, 1H), 5.43 (s, 2H), 3.77 (s, 3H), 1.61 (s,
6H). 13C-NMR (125 MHz, CDCl3): δ = 164.0 (Cq), 159.3 (Cq,d, JC-
F = 247.8 Hz), 159.3 (Cq), 153.0 (Cq), 141.3 (Cq, d, JC-F = 3.6 Hz),
134.6 (Cq), 131.2 (Cq,d, JC-F = 2.3 Hz), 130.1 (CH, d, JC-F = 8.9
Hz), 129.7 (CH), 128.9 (CH), 128.4 (CH), 127.7 (CH), 125.3 (CH,
d, JC-F = 3.0 Hz), 125.1 (Cq, d, JC-F = 18.0 Hz), 120.5 (Cq), 113.9
(CH, d, JC-F = 22.0 Hz), 113.6 (CH), 55.2 (CH3), 53.8 (CH2), 52.2
(Cq), 27.5 (CH3). 19F-NMR (283 MHz, CDCl3): δ = -116.64 (dd, J
= 9.1, 5.9 Hz). IR (ATR): 3258, 1608, 1581, 1450, 1235, 1027,
894, 815, 795, 486 cm-1. MS (EI) m/z (relative intensity): 444
(30) [M+], 416 (20), 402 (30), 401 (100), 229 (50), 186 (30), 91
(80) . HR-MS (ESI) m/z calcd for C26H25FN4O2 [M+H+] 445.2040,
found 445.2034.
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-3-(4-
methoxyphenyl)-2-naphthamide (3ja)
The representative procedure A was followed using 1j (111 mg,
0.30 mmol), 4-iodoanisole (2a) (280 mg, 1.2 mmol), Pd(OAc)2
(3.4 mg, 0.015 mmol, 5.0 mol %) and AgOAc (55 mg, 0.33
mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ja (140 mg, 98%) as a
1
white solid. M.p. = 202-203 °C. H-NMR (600 MHz, CDCl3): δ =
8.09 (s, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H),
7.70 (s, 1H), 7.50-7.43 (m, 2H), 7.35 (s, 1H), 7.34-7.28 (m, 5H),
7.23-7.19 (m, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.19 (s, 1H), 5.41 (s,
2H), 3.77 (s, 3H), 1.61 (s, 6H). 13C-NMR (125 MHz, CDCl3): δ =
168.2 (Cq), 159.0 (Cq), 153.1 (Cq), 136.5 (Cq), 134.7 (Cq), 134.4
(Cq), 133.5 (Cq), 132.5 (Cq), 131.5 (Cq), 130 (CH), 128.9 (CH),
128.8 (CH), 128.5 (CH), 128.4 (CH), 128 (CH), 127.8 (CH),
127.5 (CH), 127.2 (CH), 126.3 (CH), 120.5 (CH), 113.7 (CH),
55.2 (CH3), 53.8 (CH2), 51.5 (Cq), 27.3 (CH3). IR (ATR): 3281,
1630, 1545, 1244, 1207, 1176, 1050, 820, 718, 527 cm-1. MS
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-4,4'-
dimethyl-[1,1'-biphenyl]-2-carboxamide (3nj)
The representative procedure A was followed using 1n (167 mg,
0.50 mmol), 1-iod-4-methylbenzene (2j) (436 mg, 2.00 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg,
0.55 mmol). Purification by column chromatography on silica gel
(n-pentane/EtOAc 3:1 → 1:1) yielded 3nj (189 mg, 95%) as a
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601045
FULL PAPER
1
white solid. M.p. = 170-172 °C. H-NMR (600 MHz, CDCl3): δ =
The representative procedure A was followed using 1n (167 mg,
0.50 mmol), 4-iodoacetophenone (2i) (492 mg, 2.0 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg,
0.55 mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ni (185 mg, 95%) as a
colorless solid. M.p. = 141-143 °C. 1H-NMR (600 MHz, CDCl3): δ
= 7.82 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.34 (sbr, 1H),
7.32 (s, 1H), 7.31-7.24 (m, 3H), 7.22-7.15 (m, 4H), 6.23 (s, 1H),
5.39 (s, 2H), 2.51 (s, 3H), 2.32 (s, 3H), 1.55 (s, 6H). 13C-NMR
(125 MHz, CDCl3): δ = 197.5 (Cq), 168.3 (Cq), 152.9 (Cq), 144.9
(Cq), 137.8 (Cq), 136.3 (Cq), 135.6 (Cq), 135.6 (Cq), 134.5 (Cq),
130.5 (CH), 129.7 (CH), 128.8 (CH), 128.8 (CH), 128.6 (CH),
128.4 (CH), 128.1 (CH), 127.7 (CH), 120.4 (CH), 53.76 (Cq),
51.49 (CH2), 27.18 (CH3), 26.44 (CH3), 20.75 (CH3) . IR (ATR):
3260, 1671, 1637, 1604, 1554, 1221, 1185, 1005, 855, 502 cm-1.
MS (EI) m/z (relative intensity): 452 (5), 424 (30), 410 (35), 409
(100), 195 (60), 91 (85), 65 (10), 43 (50). HR-MS (EI) m/z calcd
for C28H28N4O2 452.2212 [M+], found 452.2205.
7.44-7.40 (m, 1H), 7.39-7.31 (m, 3H), 7.30 (s, 1H), 7.25-7.15 (m,
6H), 7.12-7.06 (m, 2H), 5.78 (s, 1H), 5.44 (s, 2H), 2.36 (s, 3H),
2.33 (s, 3H), 1.52 (s, 6H). 13C-NMR (125 MHz, CDCl3): δ = 168.5
(Cq), 153.2 (Cq), 137.3 (Cq), 137.1 (Cq), 137.1 (Cq), 136.7 (Cq),
135.9 (Cq), 134.8 (Cq), 130.6 (CH), 130.0 (CH), 129.1 (CH),
129.0 (CH), 128.9 (CH), 128.7 (CH), 128.5 (CH), 127.9 (CH),
120.6 (CH), 53.9 (CH2), 51.5 (Cq), 27.3 (CH3), 21.1 (CH3), 20.8
(CH3). IR (ATR): 3258, 1635, 1544, 1380, 1321, 1046, 813, 732,
693, 497 cm-1. MS (EI) m/z (relative intensity): 424 (15) [M+], 396
(15), 382 (30), 381 (100), 209 (65), 166 (35), 165 (45), 91 (75).
HR-MS (EI) m/z calcd for C27H28N4O [M+] 424.2263, found
424.2250.
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-4'-methoxy-
4-methyl-[1,1'-biphenyl]-2-carboxamide (3na)
The representative procedure A was followed using 1n (167 mg,
0.50 mmol), 4-iodoanisole (2a) (436 mg, 2.0 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 0.55
mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3na (185 mg, 84%) as a
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-3,4'-
dimethyl-[1,1'-biphenyl]-2-carboxamide (3aj)
1
colorless solid. M.p. = 166 °C. H-NMR (300 MHz, CDCl3) δ =
The representative procedure B was followed using 1a (167 mg,
0.50 mmol), 4-methyl-1-iodobenzene (2j) (218 mg, 1.00 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %), PivOH (15.3 mg,
0.15 mmol) and KHCO3 (100 mg, 1.00 mmol). Purification by
column chromatography on silica gel (n-pentane /EtOAc 3:1 →
7.44–7.23 (m, 4H), 7.32 (s, 1H), 7.29-7.16 (m, 6H), 6.84 (dd, J =
8.2, 2.0 Hz, 2H) 5.80 (s, 1H), 5.47 (s, 2H), 3.80 (s, 3H), 2.38 (s,
3H), 1.56 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 168.5 (Cq),
159.0 (Cq), 153.1 (Cq), 136.9 (Cq), 136.3 (Cq), 135.8 (Cq), 134.7
(Cq), 132.5 (Cq), 130.6 (CH), 130.0 (CH), 123.0 (CH), 129.1 (CH), 2:1 → 1:1) yielded 3aj (146 mg, 69%) as a white solid. M. p. =
129.0 (CH), 128.5 (CH), 127.9 (CH), 120.5 (CH), 113.8 (CH),
55.4 (CH3), 54.0 (CH2), 51.6 (Cq), 27.5 (CH3), 21.0 (CH3). IR
(ATR): 3294, 2995, 1609, 1458, 1242, 1174, 1044, 823, 781,
507 cm-1. MS (EI) m/z (relative intensity): 440 (30) [M+], 397
(100), 240 (12), 225 (60), 182 (20), 153 (15), 91 (80), 65 (10).
HR-MS (EI) m/z calculated for C27H28N4O2 [M+]: 440.2212;
found: 440.2210.
132–133 °C. 1H-NMR (300 MHz, CDCl3): δ = 7.35–7.29 (m, 3H),
7.28–7.15 (m, 6H), 7.16–6.95 (m, 4H), 5.90 (s, 1H), 5.41 (s, 2H),
2.31 (s, 3H), 2.29 (s, 3H), 1.51 (s, 6H). 13C-NMR (75 MHz,
CDCl3): δ = 168.7 (Cq), 153.3 (Cq), 139 (Cq), 137.6 (Cq), 136.8
(Cq), 135.3 (Cq), 134.7 (Cq), 128.9 (CH), 128.9 (CH), 128.7 (CH),
128.7 (CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 127.8 (CH),
127.1 (CH), 120.5 (CH), 53.9 (Cq), 51.6 (CH2), 27.3 (CH3), 21.0
(CH3), 19.2 (CH3). IR (neat): 3292, 1633, 1542, 1461, 1309,
1216, 1050, 826, 723, 649 cm-1. MS (EI) m/z (relative intensity):
424 (35) [M+], 381 (92), 209 (80), 165 (53), 91 (100). HR-MS (EI)
m/z calcd for C27H28N4O+[M+] 424.2263, found 424.2252. The
analytical data were in accordance with the data reported in the
Methyl
2'-[{2-(1-benzyl-1H-1,2,3-triazol-4-yl)propan-2-
yl}carbamoyl]-4'-methyl-[1,1'-biphenyl]-4-carboxylate (3ng)
The representative procedure A was followed using 1n (167 mg,
0.50 mmol), methyl-4-iodobenzoate (2g) (524 mg, 2.0 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, literature.[11c]
0.55 mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 1:1) yielded 3ng (193 mg, 82%) as a
colorless solid. M.p. = 173–175 °C. 1H-NMR (300 MHz, CDCl3) δ
= 7.97 (dd, J = 8.5, 1.9 Hz, 2H), 7.44-7.31 (m, 6H), 7.27 (s, 1H)
7.25-7.19 (m, 4H), 6.01 (s, 1H), 5.45 (s, 2H), 3.91 (s, 3H), 2.38
(s, 3H), 1.57 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 168.3 (Cq),
166.7 (Cq), 153.1 (Cq), 145.0 (Cq), 138.0 (Cq), 136.3 (Cq), 135.7
N-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-4’-methoxy-
4-(trifluoromethyl)-[1,1’-biphenyl]-2-carboxamide (3ma)
The representative procedure B was followed using 1m (194 mg,
0.50 mmol), 4-iodoanisole (2a) (234 mg, 1.00 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 5 mol %), PivOH (15.3 mg, 0.15 mmol)
and KHCO3 (100 mg, 1.00 mmol). Purification by column
(Cq), 134.6 (Cq), 130.6 (CH), 129.9 (CH), 129.5 (CH), 129.0 (CH), chromatography on silica gel (npentane /EtOAc 3:1 → 2:1 →
128.8 (Cq), 128.8 (2CH), 128.6 (CH), 127.9 (CH), 120.3 (CH),
54.1 (CH2), 52.1 (CH3), 51.8 (Cq), 27.4 (CH3), 21.0 (CH3). IR
(ATR): 3269, 1715, 1659, 1526, 1278, 1113, 826, 721, 535 cm-1.
MS (EI) m/z (relative intensity): 468 (5), 440 (30), 425 (100), 253
(15), 209 (25), 165 (30), 98 (12), 91 (65), 43 (10). HR-MS (EI)
m/z calculated for C28H28N4O3 [M+]: 468.2161; found: 468.2153.
1:1) yielded 3ma (226 mg, 91%) as a white solid. M.p. = 164–
165 °C. 1H-NMR (600 MHz, CDCl3) δ = 7.85 (s, 1H), 7.64 (d, J =
8.1 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37-7.33 (m, 3H), 7.32 (s,
1H), 7.27 (dd, J = 8.7, 2.1 Hz, 2H), 7.24-7.22 (m, 2H), 6.86 (dd,
J = 8.6, 2.2 Hz, 2H), 5.98 (s, 1H), 5.45 (s, 2H), 3.79 (s, 3H), 1.56
(s, 6H). 13C-NMR (125 MHz, CDCl3) δ = 167.1 (Cq), 159.9 (Cq),
152.9 (Cq), 136.7 (Cq), 142.8 (Cq) 134.7 (Cq), 131.1 (Cq), 130.7
(CH), 130.0 (CH), 129.4 (Cq, q, JC-F = 33.0 Hz) , 129.1 (CH),
128.7 (CH), 128.0 (CH), 126.5 (CH, q, JC-F = 4.0 Hz), 125.8 (CH,
4’-Acetyl-N-{2-(1-benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl}-4-
methyl-[1,1’-biphenyl]-2-carboxamide (3ni)
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European Journal of Organic Chemistry
10.1002/ejoc.201601045
FULL PAPER
q, JC-F = 3.9 Hz) , 123.8 (Cq, q, JC-F = 272.3 Hz) , 120.5 (CH),
114.1 (CH), 55.4 (CH3), 54.1 (CH2), 51.8 (Cq), 27.3 (CH3). 19F-
NMR (282 MHz, CDCl3) δ (ppm) = -62.54 (s). IR (ATR): 3278,
2983, 1634, 1338, 1302, 1255, 1172, 1150, 1120, 720 cm-1. MS
(EI) m/z (relative intensity): 494 (13) [M+], 466 (20), 451 (90),
279 (45), 236 (15), 91 (100). HRMS (EI) m/z calculated for
C27H25F3N4O2 [M+]: 494.1930; found: 494.1934.
Traceless Removal of the TAM Group
Aqueous HCl (37%, 5.0 mL) was added to 3mi (0.126 g, 0.25
mmol) in a pressure tube. The mixture was stirred at 140 °C for
12 h. At ambient temperature, H2O (20 mL) was added and the
mixture was extracted with CH2Cl2 (3 × 20 mL). The organic
layers were combined and washed with NaOH (2M, 3 × 20 mL).
The combined aqueous layer was acidified with 2M HCl until a
pH of 2, and the solution was extracted with CH2Cl2 (5 × 100
mL). The organic extracts were dried (Na2SO4) and filtered. The
filtrate was concentrated under reduced pressure to give 4'-
Methyl
2'-[{2-(1-benzyl-1H-1,2,3-triazol-4-yl)propan-2-
yl}carbamoyl]-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-
carboxylate (3mg)
The representative procedure A was followed using 1m (194 mg, (55 mg, 71 %) as a white solid. M. p. = 94-96 °C. H-NMR (300
acetyl-4-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 4mi
1
0.50 mmol), methyl 4-iodobenzoate (2g) (524 mg, 2.00 mmol),
MHz, CDCl3): δ = 8.30 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.87-
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %) and AgOAc (91.8 mg, 7.84 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.44-7.41 (m, 2H), 2.65 (s,
2.00 mmol). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 2:1 → 1:1) yielded 3mg (242 mg, 93%)
as a colorless solid. M.p. = 172–173 °C. 1H-NMR (300 MHz,
CDCl3) δ = 8.02 (dd, J = 8.3, 2.2 Hz, 2H), 7.84–7.83 (m, 1H),
7.72–7.68 (m, 1H), 7.48–7.42 (m, 3H), 7.38–7.32 (m, 3H), 7.25–
3H). 19F-NMR (282 MHz, CDCl3): δ = -62.78. 13C-NMR (75 MHz,
CDCl3): δ = 197.9 (Cq), 170.7 (Cq), 145.9 (Cq), 144.6 (Cq), 136.4
(Cq), 131.7 (CH), 130.4 (Cq, JC-F = 33.7 Hz), 129.7 (Cq), 128.8
(CH, JC-F = 3.4 Hz), 128.6 (CH), 128.3 (CH), 128.1 (CH, JC-F
=
3.8 Hz), 123.4 (Cq, JC-F = 270.0 Hz), 26.6 (CH3). IR (ATR): 1697,
7.21 (m, 3H), 6.18 (s, 1H), 5.46 (s, 2H), 3.92 (s, 3H), 1.57 (s, 6H). 1604, 1328, 1267, 1172, 1126, 1084, 830, 606 cm−1. HRMS m/z
13C-NMR (125 MHz, CDCl3) δ = 166.7 (Cq), 166.5 (Cq), 152.8
(Cq), 143.4 (Cq), 142.1 (Cq), 137.1 (Cq), 134.4 (Cq), 130.5 (CH),
130.3 (Cq, JC-F = 33.0 Hz), 129.8 (CH), 129.7 (CH), 129.0 (CH),
128.7 (CH), 128.7 (CH), 128.0 (CH), 126.6 (CH, JC-F = 4.0 Hz),
125.3 (CH, JC-F = 4.0 Hz) , 123.5 (Cq, JC-F = 272.0 Hz), 120.2
(CH), 54.2 (CH2), 52.3 (CH3), 52.1 (Cq), 27.4 (CH3). 19F-NMR
(282 MHz, CDCl3) δ (ppm) = -62.66 (s). IR (ATR): 3345, 3129,
1707, 1667, 1533, 1336, 1131, 1102, 1079, 727 cm-1. MS (EI)
m/z (relative intensity): 494 (35), 479 (100), 263 (25), 248 (12),
98 (10), 91 (100), 59 (20). HR-MS (EI) m/z calculated for
C28H25F3N4O [M+]: 522.1879; found: 522.1883.
calculated for C16H11F3O3 [M+H+] 309.0739, found 309.0734
[M+H+].
Acknowledgements
Generous support by the European Research Council under the
European Community`s Seventh Framework Program (FP7
2007-2013)/ERC Grant Agreement no. 307535, and the CSC
(fellowship to W.W.) is gratefully acknowledged.
Keywords: C‒H activation • amides • carboxylates • palladium •
4'-Acetyl-N-{2-(1-benzyl-1H-1,2,3-triazol-4-yl}propan-2-yl)-4-
(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (3mi)
triazoles
The representative procedure B was followed using 1m (194 mg,
0.50 mmol), 4-iodoacetophenone (2i) (246 mg, 1.00 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol %), PivOH (15.3 mg,
0.15 mmol, 30 mol %) and KHCO3 (100 mg, 1.0 mmol, 2.0
equiv). Purification by column chromatography on silica gel
(npentane/EtOAc 3:1 → 2:1 → 1:1) yielded 3mi (228 mg, 90 %)
as a colorless solid. M.p. = 154–155 °C. 1H-NMR (300 MHz,
CDCl3) δ = 7.90 (dd, J = 8.4, 2.0 Hz, 2H), 7.83 (s, 1H), 7.72–
7.67 (m, 1H), 7.49–7.41 (m, 3H), 7.38–7.30 (m, 4H), 7.24–7.19
(m, 2H), 6.29 (s, 1H), 5.45 (s, 2H), 2.58 (s, 3H), 1.58 (s, 6H).
13C-NMR (125 MHz, CDCl3) δ = 197.5 (Cq), 166.9 (Cq), 152.8
(Cq), 143.5 (Cq), 142.1 (Cq), 137.2 (Cq), 136.6 (Cq), 134.5 (Cq),
130.6 (CH), 130.3 (Cq, JC-F = 33.1 Hz), 129.1 (CH), 128.9 (CH),
128.7 (CH), 128.5 (CH), 128.0 (CH), 126.6 (CH, JC-F = 4.2 Hz),
125.3 (CH, JC-F = 4.1 Hz) , 123.6 (Cq, JC-F = 273.1 Hz), 120.4
(CH), 54.1 (CH2), 52.0 (Cq), 27.3 (CH3), 26.7 (CH3). 19F-NMR
(282 MHz, CDCl3) δ = -62.65 (s). IR (ATR): 3268, 2981, 1633,
1339, 1291, 1262, 1175, 1083, 719, 596 cm-1. MS (EI) m/z
(relative intensity): 506 (5), 478 (30), 463 (80), 249 (18), 98 (10),
91 (100), 65 (8), 43 (60). HRMS (EI) m/z calculated for
C28H25F3N4O2 [M+]: 506.1930; found: 506.1919.
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201601045
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Darko Santrač, Stefano Cella,
Wei Wang, and Lutz Ackermann*
C‒H Activation
Page No. – Page No.
Palladium catalyzed C − H arylations of
benzamides were accomplished by removable
triazole amines (TAM) with ample substrate
scope under silver-free reaction conditions.
Triazole-Assisted Palladium-
Catalyzed C−H Arylation of
Amides
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