Pd(II)-catalyzed C(sp3)-H arylation of amino acid derivatives with click-triazoles as removable directing groups

Article abstract of DOI:10.1039/c5ob00066a

By using click-triazoles as conveniently approachable and removable directing groups, the direct palladium-catalyzed C(sp³)-H arylation of amino acid derivatives with various aryl iodides bearing different electronic properties has been achieved. Notably, the desired amino acid molecule can be obtained by the cleavage of the tethered click-triazoles after the catalytic reaction, which aims to provide a practical protocol for the accessibility of both natural and synthetic amino acids.

Full text of DOI:10.1039/c5ob00066a

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Pd(II)-catalyzed C(sp3)–H arylation of amino acid
derivatives with click-triazoles as removable
directing groups†
Cite this: DOI: 10.1039/c5ob00066a
Guofu Zhang,a Xiaoqiang Xie,a Jianfei Zhu,a Shasha Li,a Chengrong Ding*a and
Ping Dingb
By using click-triazoles as conveniently approachable and removable directing groups, the direct palla-
dium-catalyzed C(sp3)–H arylation of amino acid derivatives with various aryl iodides bearing different
electronic properties has been achieved. Notably, the desired amino acid molecule can be obtained by
the cleavage of the tethered click-triazoles after the catalytic reaction, which aims to provide a practical
protocol for the accessibility of both natural and synthetic amino acids.
Received 13th January 2015,
Accepted 7th April 2015
DOI: 10.1039/c5ob00066a
www.rsc.org/obc
problem involve the utilization of a directing group that could
coordinate to a metal center, thus delivering the catalyst to the
Introduction
Optically active unnatural amino acids are important structural desired C–H bond, which in general formed a thermodynami-
motifs of pharmaceutical agents and biologically active com- cally stable five- or six-membered metallacyclic intermediate.
pounds.1 With the rapid development of protein engineering Compared with the monodentate directing group which gene-
and the discovery of amino acid-based drugs, synthesis of high rally works on C(sp2)–H activation, the bidentate directing
enantiopurity amino acid derivatives has attracted consider- groups have recently been demonstrated to be able to promote
able attention over the past few decades. Traditionally, un- metal-catalyzed C(sp3)–H bond activation (Scheme 1). In 2005,
natural amino acids can be obtained through enzymatic Daugulis and coworkers first described the Pd-catalyzed β-ary-
resolution of the corresponding racemates or through asym- lation of carboxylic acid and the γ-arylation of amine deriva-
metric synthesis. While considering the extensive availability tives by employing 8-aminoquinoline and picolinamide
of natural amino acids, a new approach of transition-metal- auxiliary as the directing groups.6 This methodology has
catalyzed direct C–H functionalization to access their un- gradually been applied to the preparation of synthetic amino
natural counterparts is in rapid development.2
acids, which have broad applications in drug discovery and
Transition-metal-catalyzed C–H functionalization repre- biotechnology. It is worth noting that Corey and coworkers
sents one of the most powerful methods for the direct con- demonstrated the pioneering examples of β- and γ-functionali-
version of ubiquitous C–H bonds into diverse functional zation of N-phthaloyl-α-amino amides with a similar strategy.7
groups selectively in organic synthesis over the past few An another elegant study was reported by Chen and coworkers
decades.3 Most efforts in this field have been focused on the
activation of C(sp2)–H bonds of (hetero)arenes for the for-
mation of new C–X bonds (X = C, O, N, F, Cl, Br, I, Si, P, B
etc.).4 In comparison, the direct functionalization of unreactive
C(sp3)–H remains challenging, mainly due to the inertness of
most C(sp3)–H bonds and the related difficulties in regioselec-
tive functionalization.5 To the best of our knowledge, the
most common strategies for addressing the aforementioned
aCollege of Chemical Engineering, Zhejiang University of Technology,
Hangzhou 310014, People’s Republic of China. E-mail: dingcr@zjut.edu.cn;
Fax: (+86)-571-88320147; Tel: (+86)-571-88320147
bSchool of Public Health, Central South University, Changsha 410078,
People’s Republic of China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Different bidentate directing groups for the arylation of
c5ob00066a
amino acid derivatives.
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on the Pd-catalyzed picolinamide-directed C(sp3)–H bond
functionalization, in which some cases of γ-arylation of
natural amino acids were described with moderate to excellent
yields.8 Other bidentate directing groups like N-(2-pyridyl)sulfa-
mide, 2-methoxyiminoacetyl and 2-(pyridine-2-yl)propan-2-
amine introduced by Carretero,9 Ma,10 and Shi11 respectively
have shown great reactivity in the palladium-catalyzed aryla-
tion of amino acid derivatives.
In spite of these achievements in the functionalization of
natural amino acids, there is still much more room for further
improvements regarding the catalytic efficiency of the process,
the scope of the amino acids, as well as designing easily acces-
sible yet novel directing groups.12 Recently, the‘click-1,2,3-tria-
zole’ unit has emerged as a chelator showing great potential
for metal coordination, and many metal ions like Cu, Ru, Pd,
etc. have been successfully explored. Our group also designed
some solid catalysts based on the utilization of the versatile
click-triazole, which not only works as a stable linker to graft
catalysts onto the supports but also as a good chelator to par-
ticipate in the catalytic reactions.13 Inspired by these attractive
findings, we wish to report a palladium-catalyzed C(sp3)–H ary-
lation of amino acid derivatives by employing click-1,2,3-tria-
zoles as the removable directing group, which are easily
accessible through copper(I)-catalyzed 1,3-dipolar Huisgen
cycloaddition between substituted alkynes and azides.
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
AgNO3
AgSbF6
Ag2O
DCE
DMF
o-Xylene
Toluene
t-BuOH
t-AmylOH
HFIP
HFIP
HFIP
HFIP
HFIP
39
Trace
NDc
ND
24
31
93
50
57
Trace
27
15
9
10
11
12
13
14
HFIP
HFIP
HFIP
ND
ND
a The reactions were conducted as follows unless otherwise
mentioned: 1a (0.20 mmol), Pd(OAc)2 (10.0 mol%), 2a (0.30 mmol),
additive (0.30 mmol) and solvent (1 mL), 5 h. b Determined by 1H
NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
standard. c Not detected.
Table 2 Pd(II)-catalyzed arylation of 1a with aryl iodidesa
Results and discussion
At the outset, a representative set of novel amino acids benza-
mides 1a containing 1,2,3-triazoles through [3 + 2] Huisgen
cycloaddition under mild conditions was prepared (for details,
please see the ESI†).11 With 1a as the model substrate, the con-
dition optimization for Pd(II)-catalyzed C(sp3)–H arylation was
carried out, and results are summarized in Table 1. Gratify-
ingly, the combination of 1a with 10 mol% Pd(OAc)2, AgOAc
(1.5 equiv.) and 1-iodo-4-methoxybenzene (2a, 1.5 equiv.) at
100 °C in 1,2-dichloroethane (DCE) can afford the desired
product 3aa in 39% yield (entry 1). With the initial result, we
then tested the solvent effect in this transformation. For those
solvents such as o-xylene, toluene, DMF, DMSO, t-BuOH, and
t-amyl-OH, there is no apparent improvement in terms of reac-
tion yield (entries 2–6). Yet, when 1,1,1,3,3,3-hexafluoroiso-
propanol (HFIP) was employed as the solvent, the desired
product could be achieved in 93% yield (entry 7). In addition,
other palladium catalysts and oxidants were also screened,
which were unable to yield the desired product with competi-
tive yield (entries 8–10). Generally Pd(TFA)2 shows higher cata-
lytic activity than Pd(OAc)2 in the C–H bond activation
reaction, but in this catalytic system the ligand exchange step
may reduce its catalytic activity. By switching from AgOAc to
other silver salts like Ag2CO3, AgNO3 or AgSbF6, decreased
yields were observed (entries 11–14, for details, please see the
ESI†). This result is in agreement with the findings by Ma and
coworkers.10
Entry
Ar
Product
Yieldb (%)
1
2
3
4
5
6
7
8
4-MeOC6H4
2-MeOC6H4
4-EtOC6H4
C6H5
4-FC6H4
4-ClC6H4
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
80
76
75c
83
84
83
86
87
90
86
88
82
80
76
82
68c,d
4-BrC6H4
2-F-4-BrC6H3
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CH3COC6H4
4-CF3C6H4
4-MeO2CC6H4
4-PhenylC6H4
1-Naphthyl
9
10
11
12
13
14
15
16
a The reactions were conducted with 0.40 mmol of 1a, Pd(OAc)2
(10.0 mol%), 2 (0.60 mmol), AgOAc(0.60 mmol), and HFIP(2 mL) and
stirred at 100 °C for 5 h unless otherwise mentioned. b Isolated yield.
c 12 h. d Pd(OAc)2 (20.0 mol%) was used.
With the optimal reaction conditions in hand, we next
examined the substrate scope of different aryl iodides and the
results are summarized in Table 2. In general, the demon-
strated transformation was found to be compatible with a
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variety of aryl iodides bearing either electron-withdrawing or form a five-membered cyclopalladated intermediate Pd(II) in
electron-donating groups, providing the corresponding ary- the reaction, but not a six-membered or seven membered ring
lated products with 68–90% isolated yields. For example, cyclopalladated intermediate.
fluoro (3ae), chloro (3af), bromo (3ag), nitro (3ai–3ak) and
To highlight the synthetic utility of this process in non-
ester (3an) groups are excellently tolerated, which are con- natural amino acid synthesis, we then explored the gram-scale
venient handles for further functionality. The electronic pro- synthesis of 4ai by using this protocol and removed the TAH
perties of the aryl iodides have an effect on their reactivity directing group under mild conditions.6d As shown in
toward arylation. Generally, electron-deficient aryl iodides Scheme 2, we were pleased to find that although the Pd-cata-
(3ae–3an) provided better yields than electron-rich aryl iodides lyzed arylation reactions were generally run on a 0.40 mmol
(3aa–3ac), probably due to the fact that electron-deficient aryl scale, a 3.0 mmol scale reaction provided 3ai with high yield
iodides are favorable to the reductive elimination step, while (93%, 1.41 g) and excellent enantiopurity (>96% ee). Then the
steric factors may not play an important role in the reaction TAH directing group could be removed in high yield with N-
reactivity (3ai–3ak). For reactions using less effective arylating phthaloylphenylalanine methyl ester 4ai being obtained in
reagents, more catalysts (3ap) and a prolonged reaction time 86% (0.86 g) isolated yield and 2-((((9H-fluoren-9-yl)methoxy)
(3ac, 3ap) were required. However, heteroaryl iodides like carbonyl)amino)-3-(4-nitrophenyl)propanoic acid 5ai can be
2-iodothiophene and 2-iodopyridine can’t transform smoothly obtained in 49% (0.51 g) yield with simple treatment, thus
for heteroatoms in heterocycles coordinate strongly to Pd(II) demonstrating the synthetically useful protocol.
catalysts and result in catalyst poisoning.
On the basis of the above observations and other reports,8
The present reaction was then applied to other substituted we proposed a plausible mechanism for the palladium-cata-
N-phthaloylalanine triazolylmethylhexyl (TAH) amide deriva- lyzed C(sp3)–H arylation of amino acid derivatives (Scheme 3).
tives (Table 3). When 1b was used as the substrate under the Similar to previously reported Pd-catalyzed N,N-bidentate-
optimal conditions, though there are two methyl groups that directed C–H functionalization systems, the TAH-directed ary-
are able to undergo arylation, the monoarylated product 3bj lation reaction likely proceeds through a PdII/IV catalytic cycle
was isolated in 70% yield. To our delight, the arylation of
β-amino acid 3-aminoisobutyric acid derivative 1c was also
possible, thus resulting in the formation of 3cg in 82% yield.
The cheering result indicated that this method can also be
applied to the arylation of β-amino acid derivatives, which are
key structural motifs of peptides and pharmaceutically impor-
tant compounds. However, other amino acid derivatives like
2-amino-2-phenylacetic acid (1d), 2-aminobutanoic acid (1e) or
phenylalanine (1f) couldn’t be arylated in this reaction. It may
Table 3 Pd(II)-catalyzed arylation of substituted N-phthaloylalanine-
TAH amide derivativesa
Scheme 2 Removal of the TAH group.
a The reactions were conducted with 0.40 mmol of 1, Pd(OAc)2
(10.0 mol%), 2 (0.60 mmol), AgOAc(0.60 mmol), and HFIP(2 mL) and
stirred at 100 °C for 5 h. ND = Not Detected.
Scheme 3 Plausible reaction mechanism.
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involving C–H palladation, oxidative addition (OA), and (t, J = 7.5 Hz, 2H), 4.61 (s, 2H), 5.26 (dd, J1 = 10.5 Hz, J2 = 5.5 Hz,
reductive elimination (RE). First, coordination of Pd(II) to the 1H), 6.69 (t, J = 7.0 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.98 (d, J =
N,N-bidentate directing group triggered the methyl C–H 6.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 2H), 7.68 (dd, J1 = 5.0 Hz, J2 =
palladation and formed a cyclopalladation intermediate Pd(II), 3.0 Hz, 3H), 7.75 (t, J = 5.5 Hz, 2H). 13C NMR (125 MHz,
then the five-membered cyclopalladated intermediate Pd(II) CDCl3): δ 13.9, 22.4, 26.1, 30.0, 30.4, 31.1, 34.8, 51.0, 52.4,
was oxidized to a high-valent Pd intermediate Pd(IV), which 55.2, 110.2, 120.5, 123.3, 125.0, 128.5, 130.9, 131.7, 134.0,
underwent a ligand exchange process. Subsequently, the ary- 157.5, 167.8, 169.2; HRMS (ESI) m/z calcd for C27H31N5O4 [M]+
lated product was formed by reductive elimination and 489.2449; found 489.2459.
1
released the Pd(II) catalyst, thus completing the whole catalytic
redox cycle.
3ac: H NMR (500 MHz, CDCl3): δ 0.89 (t, J = 7.0 Hz, 3H),
1.30–1.35 (m, 9H), 1.88 (t, J = 7.0 Hz, 2H), 3.43–3.54 (m, 2H),
3.88–3.93 (m, 2H), 4.30 (t, J = 7.5 Hz, 2H), 4.47–4.56 (m, 2H),
5.08 (dd, J1 = 11.0 Hz, J2 = 6.0 Hz, 1H), 6.68 (d, J = 8.5 Hz, 2H),
7.03 (d, J = 8.5 Hz, 2H), 7.13 (t, J = 5.5 Hz, 1H), 7.56 (s, 1H),
7.68 (dd, J1 = 5.5 Hz, J2 = 3.0 Hz, 2H), 7.75 (dd, J1 = 5.5 Hz, J2 =
3.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9, 14.7, 22.4,
26.1, 30.1, 31.1, 33.9, 35.1, 50.6, 55.5, 63.3, 114.6, 122.6, 123.5,
128.4, 129.9, 131.5, 134.2, 144.2, 157.8, 167.9, 168.8; HRMS
(ESI) m/z calcd for C28H33N5O4 [M]+ 503.2605; found 503.2627.
Conclusions
In summary, an effective Pd(II)-catalyzed C(sp3)–H arylation of
amino acid derivatives using removable 1,2,3-triazoles as the
removable directing group was developed. The demonstrated
protocol could be applied to synthesise some unnatural amino
acids in moderate to high yields and has shown a high level
compatibility with a variety of functional groups. Further
research to extend the applications of the click-triazole
directing group in the C–H activation field is currently
underway.
1
3ad: H NMR (500 MHz, CDCl3): δ 0.89 (t, J = 6.5 Hz, 3H),
1.31 (s, 6H), 1.86 (dd, J1 = 13.5 Hz, J2 = 7.0 Hz, 2H), 3.49–3.62
(m, 2H), 4.27 (t, J = 7.5 Hz, 2H), 4.50 (s, 2H). 5.12 (q, J = 5.5 Hz,
1H), 7.10–7.16 (m, 5H), 7.25 (s, 1H), 7.58 (s, 1H), 7.66 (dd, J1 =
5.5 Hz, J2 = 3.5 Hz, 2H), 7.73 (dd, J1 = 5.5 Hz, J2 = 3.5 Hz, 2H).
13C NMR (125 MHz, CDCl3): δ 13.9, 22.4, 26.1, 30.0, 31.1, 34.6,
51.0, 52.3, 123.4, 126.8, 128.5, 128.9, 131.6, 134.1, 136.8, 167.8,
168.9; HRMS (ESI) m/z calcd for C26H29N5O3 [M]+ 459.2343;
found 459.2320.
Experimental
1
The amino acid derivatives were synthesized according to the
procedure reported in the literature.2,12
3ae: H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 5.5 Hz, 3H),
1.33 (s, 6H), 1.90 (s, 2H), 3.47–3.59 (m, 2H), 4.32 (t, J = 7.0 Hz,
2H), 4.54 (s, 2H), 5.09 (dd, J1 = 11.5 Hz, J2 = 5.0 Hz, 1H), 6.84
(t, J = 8.0 Hz, 2H), 7.10 (dd, J1 = 8.5 Hz, J2 = 6.0 Hz, 2H), 7.60
(s, 1H), 7.70 (t, J = 4.0 Hz, 2H), 7.75 (t, J = 5.0 Hz, 2H).
General procedure for Pd(II)-catalyzed C(sp3)–H arylation of
amino acid derivatives
Pd(OAc)2 (9.0 mg, 0.04 mmol, 10 mol%), AgOAc (99.6 mg, 13C NMR (125 MHz, CDCl3): δ 13.9, 22.3, 26.1, 30.2, 31.1, 34.1,
0.60 mmol, 150 mol%), 1-iodo-4-methoxybenzene (140.4 mg, 35.3, 50.4, 55.2, 120.9, 122.2, 123.6, 130.6, 131.4, 131.8, 134.3,
0.60 mmol, 150 mol%), amino acid derivative 1a (153.3 mg, 135.9, 144.2, 167.8, 168.3. 19F NMR (376 MHz, DMSO-d6):
0.4 mmol, 100 mol%), and HFIP (2 mL) were introduced into a δ −115.75; HRMS (ESI) m/z calcd for C26H28FN5O3 [M]+
15 mL sealed tube equipped with a magnetic stirrer in air. The 477.2249; found 477.2267.
1
mixture was vigorously stirred at 100 °C for 5 h. After cooling
3af: H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 6.5 Hz, 3H),
to room temperature, the reaction was diluted with ethyl 1.33 (s, 6H), 1.92 (t, J = 7.0 Hz, 2H), 3.47–3.60 (m, 2H), 4.35 (t,
acetate (15 mL) and then filtered through a pad of Celite and J = 7.0 Hz, 2H), 4.52–4.62 (m, 2H), 5.09 (dd, J1 = 11.5 Hz, J2 =
washed with ethyl acetate (50 mL). The organic solvent was 5.0 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 7.12 (t, J = 8.5 Hz, 2H),
evaporated under vacuum and the crude product was purified 7.54 (s, 1H), 7.67 (s, 1H), 7.70 (dd, J1 = 6.0 Hz, J2 = 3.5 Hz, 2H),
by column chromatography using silica gel with n-hexane/ 7.76 (dd, J1 = 5.5 Hz, J2 = 2.5 Hz, 2H). 13C NMR (125 MHz,
ethyl acetate (v/v 1 : 2) as the eluent to provide the corres- CDCl3): δ 13.9, 22.4, 26.1, 29.9, 31.0, 33.9, 34.6, 51.2, 55.0,
ponding product 3aa (156.5 mg) in 80% yield.
123.3, 123.6, 128.7, 130.3, 131.5, 132.7, 134.4, 135.2, 143.6,
1
3aa: H NMR (500 MHz, CDCl3): δ 0.89 (s, 3H), 1.32 (s, 6H), 167.7, 168.6; HRMS (ESI) m/z calcd for C26H28ClN5O3 [M]+
1.91 (s, 2H), 3.43 (t, J = 11.0 Hz, 1H), 3.53 (d, J = 10.5 Hz, 1H), 493.1953; found 493.1939.
1
3.68 (s, 3H), 4.34 (s, 2H), 4.57 (s, 2H), 5.06 (s, 1H), 6.67 (d, J =
3ag: H NMR (500 MHz, CDCl3): δ 0.89 (t, J = 6.0 Hz, 3H),
7.5 Hz, 2H), 7.03 (d, J = 7.5 Hz, 2H), 7.66 (s, 2H), 7.72 (s, 2H), 1.31 (s, 6H), 1.86 (s, 2H), 3.48–3.58 (m, 2H), 4.27 (t, J = 6.5 Hz,
7.79 (s, 1H), 7.91 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 2H), 4.47 (s, 2H), 5.09 (dd, J1 = 11.5 Hz, J2 = 5.0 Hz, 1H), 7.01
22.3, 26.0, 29.8, 31.0, 33.7, 34.2, 51.5, 55.1, 55.2, 113.9, 123.4, (d, J = 8.5 Hz, 2H), 7.26 (s, 1H), 7.52 (s, 1H), 7.56 (s, 1H), 7.68
124.0, 128.6, 129.9, 131.6, 134.1, 158.3, 167.8, 169.1; HRMS (t, J = 3.0 Hz, 2H), 7.73 (t, J = 6.5 Hz, 2H). 13C NMR (125 MHz,
(ESI) m/z calcd for C27H31N5O4 [M]+ 489.2449; found 489.2467.
3ab: H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 6.5 Hz, 3H), 120.8, 123.5, 130.6, 131.4, 131.6, 134.2, 135.8, 167.7, 168.4;
1.33 (s, 6H), 1.92 (s, 2H), 3.41 (dd, J1 = 13.5 Hz, J2 = 10.5 Hz, HRMS (ESI) m/z calcd for C26H28BrN5O3 [M]+ 537.1448; found
1H), 3.60 (dd, J1 = 13.5 Hz, J2 = 4.5 Hz, 1H), 3.74 (s, 3H), 4.35 537.1451.
CDCl3): δ 13.9, 22.3, 26.1, 30.1, 31.1, 34.1, 35.1, 50.5, 55.0,
1
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1
3ah: H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 5.5 Hz, 3H), 30.1, 31.1, 34.4, 35.1, 50.4, 54.9, 123.5, 123.7, 128.2, 128.5,
1.32 (s, 6H), 1.87 (s, 2H), 3.50–3.61 (m, 2H), 4.28 (t, J = 7.0 Hz, 129.2, 131.4, 134.3, 134.5, 167.8, 168.2. 19F NMR (376 MHz,
2H), 4.50 (dd, J1 = 6.0 Hz, J2 = 1.5 Hz, 2H), 5.12 (dd, J1
=
DMSO-d6): δ −62.99; HRMS (ESI) m/z calcd for C27H28F3N5O3
11.5 Hz, J2 = 6.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 2H), 7.06 (dd, J1 = [M]+ 527.2217; found 527.2234.
1
8.0 Hz, J2 = 2.0 Hz, 1H), 7.12 (dd, J1 = 9.0 Hz, J2 = 1.5 Hz, 1H),
3an: H NMR (500 MHz, CDCl3): δ 0.87 (t, J = 6.5 Hz, 3H),
7.53 (s, 1H), 7.71 (dd, J1 = 5.5 Hz, J2 = 2.0 Hz, 2H), 7.78 (dd, J1 = 1.27 (s, 6H), 1.80 (s, 2H), 3.56–3.68 (m, 2H), 3.80 (s, 3H), 4.18
5.5 Hz, J2 = 3.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9, (t, J = 7.5 Hz, 2H), 4.38 (s, 2H), 5.13 (dd, J1 = 11.0 Hz, J2
=
22.4, 26.2, 28.4, 30.2, 31.2, 35.3, 50.5, 53.6, 119.0, 119.3, 122.3, 5.0 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 7.54 (s, 1H), 7.60 (t, J =
123.6, 127.5, 131.5, 132.3, 132.4, 134.4, 167.6, 168.0. 19F NMR 4.0 Hz, 2H), 7.65 (t, J = 4.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H),
(376 MHz, DMSO-d6): δ −114.56; HRMS (ESI) m/z calcd for 8.07 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 13.8, 22.3, 26.1,
C26H27BrFN5O3 [M]+ 555.1354; found 555.1365.
3ai: H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 6.0 Hz, 3H), 128.9, 129.7, 131.5, 134.0, 142.5, 144.4, 166.7, 167.7, 168.3;
1.32 (s, 6H), 1.86 (s, 2H), 3.65–3.74 (m, 2H), 4.26 (t, J = 7.0 Hz, HRMS (ESI) m/z calcd for C28H31N5O5 [M]+ 517.2398; found
30.0, 31.1, 34.6, 35.0, 50.4, 51.9, 54.8, 122.7, 123.3, 128.7,
1
2H), 4.48 (s, 2H), 5.16 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 517.2399.
1
2H), 7.56 (s, 2H), 7.70 (s, 2H), 7.73 (s, 2H), 8.02 (d, J = 8.5 Hz,
3ao: H NMR (500 MHz, CDCl3): δ 0.91 (t, J = 6.5 Hz, 3H),
2H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.5, 26.1, 30.2, 31.2, 1.35 (s, 6H), 1.99 (s, 2H), 3.52 (t, J = 11.0 Hz, 1H), 3.70 (dd, J1 =
34.6, 35.2, 50.7, 54.7, 123.7, 123.8, 129.9, 131.4, 134.6, 144.8, 13.0 Hz, J2 = 4.5 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.69 (d, J =
147.1, 167.7, 168.0; HRMS (ESI) m/z calcd for C26H28N6O5 [M]+ 13.0 Hz, 1H), 4.79 (d, J = 13.0 Hz, 1H), 5.20 (dd, J1 = 11.0 Hz,
504.2194; found 504.2186.
J2 = 4.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H),
1
3aj: H NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.5 Hz, 3H), 7.36–7.40 (m, 4H), 7.48 (d, J = 7.5 Hz, 2H), 7.66 (dd, J1 = 5.0 Hz,
1.29 (s, 6H), 1.83 (t, J = 6.5 Hz, 2H), 3.63–3.78 (m, 2H), 4.24 (t, J2 = 3.0 Hz, 2H), 7.75 (dd, J1 = 5.0 Hz, J2 = 3.0 Hz, 2H), 8.03
J = 7.0 Hz, 2H), 4.43 (t, J = 5.0 Hz, 2H), 5.15 (q, J = 5.5 Hz, 1H), (s, 1H), 8.38 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4,
7.34 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.51 (s, 1H), 26.2, 30.1, 31.1, 34.3, 35.1, 50.6, 55.3, 122.7, 123.5, 126.9,
7.66 (dd, J1 = 6.0 Hz, J2 = 3.5 Hz, 2H), 7.71 (dd, J1 = 6.0 Hz, J2 = 127.2, 128.7, 129.3, 131.5, 134.2, 135.8, 139.6, 140.5, 144.2,
3.5 Hz, 2H), 7.97 (dd, J1 = 9.0 Hz, J2 = 1.5 Hz, 1H), 8.02 (s, 1H), 167.8, 168.7; HRMS (ESI) m/z calcd for C32H33N5O3 [M]+
8.05 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4, 26.1, 535.2656; found 535.2663.
1
30.1, 31.1, 34.3, 34.8, 50.7, 54.7, 122.0, 123.5, 123.9, 129.5,
3ap: H NMR (500 MHz, CDCl3): δ 0.89 (t, J = 6.5 Hz, 3H),
131.4, 134.3, 135.2, 139.3, 148.2, 167.7, 168.1; HRMS (ESI) m/z 1.30 (s, 6H), 1.83 (t, J = 7.5 Hz, 2H), 3.84 (dd, J1 = 15.0 Hz, J2 =
calcd for C26H28N6O5 [M]+ 504.2194; found 504.2217.
11.0 Hz, 1H), 4.18–4.24 (m, 2H), 4.40–4.50 (m, 2H), 5.30 (dd,
1
3ak: H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 6.5 Hz, 3H), J1 = 10.5 Hz, J2 = 5.0 Hz, 1H), 7.15 (t, J = 3.0 Hz, 2H), 7.43–7.53
1.32 (s, 6H), 1.89 (t, J = 5.5 Hz, 2H), 3.67–3.73 (m, 1H), 4.05 (m, 4H), 7.61–7.67 (m, 5H), 7.78 (d, J = 7.5 Hz, 1H), 8.09 (d, J =
(dd, J1 = 14.5 Hz, J2 = 4.5 Hz, 1H), 4.30 (t, J = 7.5 Hz, 2H), 4.54 7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4, 25.9,
(d, J = 5.5 Hz, 2H), 5.31 (dd, J1 = 11.0 Hz, J2 = 4.5 Hz, 1H), 6.90 29.6, 30.0, 31.7, 33.5, 52.5, 54.1, 123.2, 123.4, 125.1, 125.8,
(s, 1H), 7.21 (dd, J1 = 7.5 Hz, J2 = 2.5 Hz, 1H), 7.33–7.35 126.4, 127.3, 127.8, 128.9, 131.6, 132.9, 133.8, 134.1, 167.7,
(m, 2H), 7.57 (s, 1H), 7.71 (dd, J1 = 5.0 Hz, J2 = 3.0 Hz, 2H), 169.3; HRMS (ESI) m/z calcd for C30H31N5O3 [M]+ 509.2500;
7.77 (dd, J1 = 5.0 Hz, J2 = 3.0 Hz, 2H), 8.00 (dd, J1 = 7.0 Hz, J2 = found 509.2510.
1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4,
3bj: 1H NMR (500 MHz, CDCl3): δ 0.89 (dd, J1 = 10.0 Hz, J2 =
26.1, 30.1, 31.1, 32.6, 35.2, 50.53, 53.5, 122.6, 123.4, 125.4, 6.5 Hz, 3H), 1.30 (d, J = 10.0 Hz, 6H), 1.83 (s, 3H), 1.86 (d, J =
128.3, 131.5, 132.8, 132.9, 133.3, 134.2, 149.0, 167.7, 168.0; 9.0 Hz, 2H), 3.40–3.64 (m, 1H), 3.89–4.03 (m, 1H), 4.12–4.28
HRMS (ESI) m/z calcd for C26H28N6O5 [M]+ 504.2194; found (m, 3H), 4.35–4.42 (m, 1H), 7.30–7.37 (m, 1H), 7.54–7.61 (m,
504.2170.
3H), 7.65–7.68 (m, 3H), 7.69–7.86 (m, 1H), 8.00–8.04 (m, 2H).
1
3al: H NMR (500 MHz, CDCl3): δ 0.89 (t, J = 6.5 Hz, 3H), 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4, 24.8, 26.1, 30.1, 31.2,
1.30 (s, 6H), 1.85 (s, 2H), 2.49 (s, 3H), 3.59–3.68 (m, 2H), 4.25 34.9, 39.7, 40.5, 50.4, 122.3, 123.0, 123.1, 125.6, 129.0, 131.4,
(t, J = 7.5 Hz, 2H), 4.46 (t, J = 15.0 Hz, 2H), 5.15 (q, J = 5.5 Hz, 134.0, 134.3, 136.9, 148.0, 168.5, 168.9; HRMS (ESI) m/z calcd
1H), 7.23 (d, J = 7.5 Hz, 2H), 7.55 (s, 2H), 7.66 (dd, J1 = 6.0 Hz, for C27H30N6O5 [M]+ 518.2350; found 518.2363.
1
J2 = 3.5 Hz, 2H), 7.71 (dd, J1 = 5.5 Hz, J2 = 3.5 Hz, 2H), 7.74 (d,
3cg: H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 7.0 Hz, 3H),
J = 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4, 26.1, 1.34 (t, J = 5.5 Hz, 6H), 1.90 (s, 2H), 2.83 (dd, J1 = 13.0 Hz, J2 =
26.5, 30.1, 31.1, 34.6, 35.1, 50.4, 54.8, 123.5, 128.6, 129.1, 4.0 Hz, 1H), 3.02 (dd, J1 = 14.0 Hz, J2 = 10.0 Hz, 1H), 3.11 (s,
131.4, 134.2, 135.8, 142.6, 167.8, 168.3, 197.7; HRMS (ESI) m/z 1H), 3.83 (dd, J1 = 14.0 Hz, J2 = 5.0 Hz, 1H), 3.96 (dd, J1 = 14.0
calcd for C28H31N5O4 [M]+ 501.2449; found 501.2465.
Hz, J2 = 7.5 Hz, 1H), 4.44 (d, J = 6.5 Hz, 4H), 7.10 (d, J = 7.5 Hz,
1
3am: H NMR (500 MHz, CDCl3): δ 0.89 (t, J = 6.5 Hz, 3H), 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.69 (q, J = 3.0 Hz, 3H), 7.75 (dd,
1.32 (s, 6H), 1.87 (t, J = 7.0 Hz, 2H), 3.59–3.69 (m, 2H), 4.27 (t, J1 = 5.5 Hz, J2 = 3.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
J = 7.0 Hz, 2H), 4.49 (t, J = 5.0 Hz, 2H), 5.15 (q, J = 5.5 Hz, 1H), δ 13.9, 22.3, 25.9, 29.5, 31.0, 32.3, 35.6, 40.0, 47.0, 53.3, 120.2,
7.26 (s, 1H), 7.32 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 123.3, 130.9, 131.4, 131.9, 134.1, 137.3, 168.4, 173.1; HRMS
7.69 (dd, J1 = 5.5 Hz, J2 = 3.0 Hz, 2H), 7.75 (dd, J1 = 5.5 Hz, J2 = (ESI) m/z calcd for C27H30BrN5O3 [M]+ 551.1604; found
3.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4, 26.1, 551.1608.
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Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (no. 20702051), the Natural
Science Foundation of Zhejiang Province (LY13B020017) and
the Key Innovation Team of Science and Technology in Zhe-
jiang Province (no. 2010R50018).
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