Pd-catalyzed coupling of γ-C(sp3)-H bonds of oxalyl amide-protected amino acids with heteroaryl and aryl iodides

Article abstract of DOI:10.1021/acs.joc.6b00649

Pd-catalyzed regioselective coupling of γ-C(sp³)-H bonds of oxalyl amide-protected amino acids with heteroaryl and aryl iodides is reported. A wide variety of iodides are tolerated, giving the corresponding products in moderate to good yields. Various oxalyl amide-protected amino acids were compatible in this C-H transformation, thus representing a practical method for constructing non-natural amino acid derivatives.

Full text of DOI:10.1021/acs.joc.6b00649

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Note
Pd-catalyzed coupling of gamma-C(sp3)–H bonds in oxalyl
amide-protected amino acids with heteroaryl and aryl iodides
Jian Han, Yongxiang Zheng, Chao Wang, Yan Zhu, Zhi-
Bin Huang, Da-Qing Shi, Runsheng Zeng, and Yingsheng Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00649 • Publication Date (Web): 10 Jun 2016
Downloaded from http://pubs.acs.org on June 12, 2016
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The Journal of Organic Chemistry
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Pd-catalyzed coupling of γ
-C(sp3)–H bonds of oxalyl
amide-protected amino acids with heteroaryl and aryl iodides
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Jian Han, Yongxiang Zheng, Chao Wang, Yan Zhu, Zhi-Bin Huang, Da-Qing Shi, Runsheng Zeng* and Yingsheng
Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, China
*E-mail: zengrunsheng@suda.edu.cn; yszhao@suda.edu.cn
.
ABSTRACT: Pd-catalyzed regioselective coupling of γ-C(sp3)–H bonds of oxalyl amide-protected amino acids with heteroaryl
and aryl iodides is reported. A wide variety of iodides are tolerated giving the corresponding products in moderate to good yields.
Various oxalyl amide-protected amino acids were compatible in this C–H transformation, thus representing a practical method for
constructing non-natural amino acid derivatives.
In the past decade, direct C–H functionalization methodology has aroused widespread interest since it offers a concise
pathway towards the synthesis of key structures present in drugs and natural products.1-2 Recently, significant progress has
been made in the area of transition-metal-catalyzed functionalization of unactivated simple C(sp3)–H bonds assisted by
directing groups.3-4 The direct arylation of alkyl C–H bonds which is recognized as a powerful strategy to construct various
arylated alkyl compounds5-6 could help streamline the synthetic process and reduce the formation of by-products. In 2005,
Daugulis and co-workers had reported the use of N,N-bidentate directing groups in realizing the γ-arylation of amine
derivatives.7 Chen and co-worker also described an elegant Pd-catalyzed picolinamide-directed γ–functionalization of natural
amino acids.8 Ever since, different examples of N,N-bidentate directing groups for palladium-catalyzed γ-C(sp3)–H bonds
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arylation of amine/amino acid derivatives have emerged in literature9-11 (Scheme 1A). Very recently, Yu and co-workers
reported the γ–arylation of triflyl-protected amino acids with arylboron reagents using N-acetyl-L-isoleucine as a ligand.12
Heteroaryl compounds forms the core of many drugs, pesticides, dyes and plastics, and they usually play an important role
in synthetic chemistry and pharmaco-chemistry.13 However, reports on the direct functionalization of γ-C(sp3)–H bonds of
amine derivatives with heteroaryl iodides are still few. It is probable that heteroaryl compounds might coordinate with
palladium intermediate which could inhibit the C–H bond activation. Our group had previously demonstrated that oxalyl
amide could serve as an effective directing group for amine derivatives in promoting remote C–H transformation.14 As a
result, we proceed to address the challenge of γ-arylation of amino acids with heteroaryl iodides. This transformation would
represent a vital process since the resultant compounds frequently form the core of proteins, peptides, and pharmaceutical
agents.15-16 Herein, we report a new protocol for Pd-catalyzed selective coupling of γ-C(sp3)–H bonds of oxalyl
amide-protected amino acids with heteroaryl and aryl iodides under mild conditions (Scheme 1B). Both inert γ-CH3 and
-CH2 bonds could be well functionlized, giving synthetically useful arylated products in moderate to good yields.
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Scheme 1. Protecting Droup Directed C–H Activation
We began our initial study by treating amino ester 1a with 4-iodoanisole 2a in the presence of Pd(OAc)2 (5 mol %) and
o
Ag2CO3 (1.5 equiv) in mesitylene at 100 C for 24 h. Gratifyingly, 80% of highly selective γ-arylated amino ester 3a was
obtained (Table1, entry 1). However, a reduction in the catalyst loading resulted in only 55% yield of 3a (Table1, entry 2).
The introduction of pivalic acid17 as an additive slightly improved the reactivity of Pd-catalyzed γ-arylation, affording 3a in
85% yield. Further screening of other well-known additives,18 such as (BnO)2PO2H, HOAc, 1-AdCO2H, Ac-Gly-OH,
ortho-phenyl benzoic acid (o-PBA) and KHCO3, revealed their inefficacy under this process (Table 1, entries 4-9).
Inexpensive oxidants including K2S2O8, BQ, TBHP and Cu(OAc)2 were also tested but none gave a better result. Much to our
o
delight, we observed that reducing both the amount of Ag2CO3 used and lowering the temperature to 90 C further
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increased the yield of 3a to 89%. Control experiment revealed that the reaction could not proceed without a palladium
catalyst, indicating the irreplaceable role of Pd(OAc)2 in this newly developed protocol (entry 15). Finally, we found that
ArBPin could not replace aryl iodide as a coupling partner, which suggested that the Ag2CO3 and PivOH could not promote
C(sp3)–H arylation through a Pd(0)/Pd(II) catalytic manifold (entry 16).
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Table 1. Optimization Studies for Pd-Catalyzed C(sp3)–H Bond Arylationa
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entry
1
2c
oxidant
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
K2S2O8
BQ
additive
None
yield (%)b
80
55
85
66
62
73
51
57
68
23
0
None
PivOH
(BnO)2PO2H
HOAc
3
4
5
6
1-AdOH
Ac-Gly-OH
oPBA
7
8
9
KHCO3
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
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12
13
14d
15f
16g
TBHP
15
<5
89 (85)e
0
Cu(Oac)2
Ag2CO3
Ag2CO3
Ag2CO3
0
aConditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd(OAc)2 (5 mol %), oxidant (0.15 mmol), additive (0.03 mmol),
mesitylene (0.3 mL), 100 C, 24 h. bGC yield determined using tridecane as internal standard.cPd(OAc)2 (2.5 mol%).
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d Oxidant (0.1 mmol), 90 oC. eIsolated yield. fNo catalyst. gphenylboronic acid pinacol ester instead of 2a
.
With the optimized conditions in hand, various types of iodides were coupled with amino ester 1a (Table 2). Satisfyingly,
aryl iodides containing electron-donating or -withdrawing groups were well tolerated giving the corresponding products in
moderate to good yields (3a-l). It was worth noting that the compatibility of F, Cl and Br functional groups with this protocol
offered a great opportunity for further functionalization. The use of 1-iodo-4-nitrobenzene also afforded the product 3k in
o
good yield albeit under increased temperature and extended time (110 C, 36 h). Interestingly, the acetyl amide 2l, which
contained another coordination center for palladium catalyst12 also underwent arylation with 1a, giving an acceptable
synthetic yield of 3l under modified conditions.
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Encouraged by the excellent coupling ability of substrate 1a with aryl iodides, we extended this protocol to heteroaryl
iodides. We were pleased to find that several types of heteroaryl iodides could also undergo γ-arylation with 1a, as illustrated
in Table 3. In general, the heteroaryl iodides were less reactive compared with aryl iodides. The reaction could only proceed
at 110 oC with 10 mol % Pd(OAc)2 and 1.5 equiv Ag2CO3. For example, heteroaryl iodides 2m and 2n coupled well with 1a
affording the arylated products 3m and 3n in good yields respectively. The use of 2-acetyl-5-iodothiophene gave the
γ-functionalized product 3o in 65% yield. Iodopyridines bearing strong electron-withdrawing substituents also provided the
desired products in good yields (3p-q). Surprisingly, iodopyridines bearing the F, Cl, Br, and I groups were also successfully
incorporated into the alkyl scaffolds of amino acid esters under harsher conditions (3r-u). We reasoned that the iodopyridine
derivatives (2r-u) might coordinate with the palladium center and then enwrap/decompose the catalyst during the catalytic
cycle, thus resulting in the observed poor yields. To our delight, the coupling reaction of substrate 1a with methyl
5-bromo-2-furoate could also give 42% yield of the product (3w). Notably, all reactions proceeded quite cleanly, just
unreacted starting materials and products were observed in the transformation.
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Table 2.Substrate Scope of Aryl Iodidesa
aReaction conditions: 1a (0.2 mmol), ArI (0.3 mmol), Pd(OAc)2 (5 mol %), Ag2CO3 (0.2 mmol), PivOH (0.06 mmol),
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mesitylene (0.6 mL), 90 C, 24 h. Isolated yields. 110 C. Ag2CO3 (0.3 mmol), 110 C, 36 h. Ag2CO3(0.6 mmol), 130 C,
b
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c
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d
o
36 h.
Table 3.Substrate Scope of Heteroaryl Iodidesa
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aReaction conditions: 1a (0.2 mmol), heteroaryl iodide (0.3 mmol), Pd(OAc)2 (10 mol %), Ag2CO3 (0.3 mmol), PivOH
o
b
o
c
o
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(0.06 mmol), mesitylene (0.6 mL), 24 h, 110 C. Isolated yields. 90 C. Pd(OAc)2 (15 mol %), 150 C. Bromide (0.3
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mmol).
The substrate scope of amino acids was next explored and the results are shown in Table 4. We found that arylation
reaction of oxalyl amide protected isoleucine with 2a occurred at the γ-C(sp3)–H position by employing Pd(TFA)2 as catalyst,
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the monoarylated product 4a was obtained in 55% yield at 60 C. When we employed the Pd(OAc)2 as catalyst, the product
4a was isolated in lower yield, accompanied with the di-arylated product As expected, the coupling of valine derivative with
4-iodoanisole (3 equiv) in the presence of Pd(OAc)2 (10 mol %) after 36 hours gave the di-arylated product 4b in 83% yield.
The 1-aminocyclohexane-carboxylic acid derivative afforded the γ-monoarylated product in 61% yield (4c). Attempts to
increase the yield by increasing the reaction temperature resulted in the formation of both mono-and di-arylated products. To
further probe the substrate scope, a series of glycine derivatives were tested (4d-f).6c Unsurprisingly, cyclopropylglycine and
cyclobutylglycine gave the γ-arylated products (4d-e) in good yields under slightly modified reaction conditions.
Cyclohexylglycine could only give low yield of 4f after 36 hours at 130oC due to incomplete conversion of starting material.
These results indicated the difference in reactivity with the substrates of different ring sizes.
Table 4. Substrate Scope of Amino Acidsa
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aReaction conditions: 1 (0.2 mmol),2a (0.3 mmol), Pd(OAc)2 (10 mol %), Ag2CO3 (0.6 mmol), PivOH (0.06 mmol),
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mesitylene (0.6 mL), 130 C, 36 h. Isolated yields. Pd(TFA)2 (10 mol %), 60 C. 2a (0.6 mmol). Pd(OAc)2 (5 mol %),
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Ag2CO3 (0.3 mmol), 60 oC. ePd(OAc)2 (5 mol %), Ag2CO3 (0.3 mmol), 90 oC.
Scheme 2. Aryaltion of Oxalyl Amide Protected L-Amino Ester 1a’
Scheme 3. Synthesis of 3-Arylamino Acid Derivatives
To show the practical importance of this protocol, oxalyl amide protected L-amino ester 1a’ was reacted with
4-iodoanisole under standard reaction conditions. There was no significant racemization at the chiral centre, as determined by
high-performance liquid chromatography (Scheme 2). The significance of this Pd-catalyzed γ-arylation reaction was further
demonstrated by the preparation of homophenylalanine derivatives.19 For example, compound 3a could undergo a
Pd-catalyzed ortho-olefination reaction14b to give the alkenylated homophenylalanine derivative 5 in moderate yield.
Compound 3k could also be transformed to the synthetically useful alkynylated product 6 in moderate yield by coupling with
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bromoalkyne14e (Scheme 3). As we known, alkenes and alkynes are special building blocks in synthetic chemistry and in
materials chemistry because of their versatile transformation into multiple functional groups or linear structural motifs.
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Based on our previous studies and recent reports,14,20 a plausible mechanism is proposed in Scheme 4. The oxalyl amide 1a
reaction with Pd(OAc)2 generated the palladium amide complex 7, followed by C–H activation to give the intermediate 8.
Oxidative addition of aryl iodide to 8 produced a high-valent Pd intermediate 9. Subsequent rapid reductive elimination
followed by ligand exchange afforded the product, accompanied with active species of palladium intermediate 7. Ag2CO3
played an important role in catalyst regeneration via halide abstraction from a putative PdI2 species.21
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Scheme 4. Proposed Catalytic Cycle
Pd(OAc)2
1a
HOAc
MeO2C
O
N
N(i-Pr)2
3a
Pd
O
OAc
H
L
7
1a, Base
HOAc
MeO2C
MeO2C
O
O
N
N
N(i-Pr)2
N(i-Pr)2
I
Pd
L
Pd
L
O
O
Ar
8
10
MeO2C
O
ArI
N
N(i-Pr)2
I
Pd
L
O
Ar
9
CONCLUSION
In summary, we have developed a highly effective palladium-catalyzed coupling of γ-C(sp3)–H bonds in oxalyl
amide-protected amino acids with heteroaryl and aryl iodides. A wide variety of iodides are tolerated in this transformation.
Both unactivated γ–CH3 and –CH2 bonds are activated thus affording synthetically useful functionalized products in
moderate to good yields. This new development in the functionalization of C(sp3)–H bonds offers a new strategy towards
building non-natural amino acids derivatives.
EXPERIMENTAL SECTION
Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification.
HRMS analysis were carried out using TOF-MS instrument with ESI source. Multiplicities are recorded as: s = singlet, d =
doublet, t = triplet, dd = doublet of doublets, br s = broad singlet, m = multiplet. General procedures for the synthesis of
products are represented as follows:
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Preparation of S1. A solution of diisopropylamine (7.01 mL, 50 mmol, 1.0 equiv) in CH2Cl2 (50 mL) was added
dropwise to a solution of oxalyl chloride (6.44 mL, 75 mmol, 1.5 equiv) in CH2Cl2 (100 mL) at 0 °C. After 5 min of stirring,
triethylamine (7.30 mL, 52.5 mmol, 1.05 equiv) was added dropwise. The solution was warmed to room temperature and
stirred for 6 hours. Excess oxalyl chloride and solvent were removed under reduced pressure, and CH2Cl2 (30 mL) was added
and evaporated. This operation was performed twice to give S1 as a pale yellow solid. The crude product was used in the
next step without any purification.
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N,N-Diisopropyloxamoyl Chloride S1. Yield 95% (8.4 g); pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 3.77 (m, 1H),
3.51 (m, 1H), 1.41 (d, J = 6.9 Hz, 6H), 1.24 (d, J = 6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 158.8, 51.0, 46.5,
20.3, 19.8; HRMS calcd for C8H14ClNO2Na [M+Na+] 214.0611; found 214.0609.
General procedures for preparation of oxalyl amide protected amino acid(1a–1h).22-23 SOCl2 (4.35 mL, 60 mmol, 3.0
equiv) was added dropwise to a solution of amino acid (20 mmol, 1.0 equiv) in MeOH (30 mL) at 0 °C. The resulting
mixture was allowed to stir from 0 °C to room temperature overnight. The solvent was removed under reduced pressure to
give white solid, which was used directly for next step. A solution of amino ester (20 mmol, 1.0 equiv) in CH2Cl2 (40 mL)
was added dropwise to a solution of N,N–Diisopropyloxamoyl chloride S1 (25 mmol, 1.25 equiv) in CH2Cl2 (50 mL) at 0 °C.
After 30 min of stirring, triethylamine (5.84 mL, 42 mmol, 2.1 equiv) was added dropwise, and then the mixture was stirred
for 6 hours at room temperature before being quenched by water (50 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (20 mL × 3). The combined organic phase was washed with brine (30 mL) and dried over
anhydrous Na2SO4. Evaporation and column chromatography on silica gel afforded corresponding amide substrates as white
solid of colorless oil >70% yield.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (1a). Purified by column chromatography on silica gel with
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petroleum ester/ethyl acetate (12/1) as an eluent; Yield 81% (4.41 g); off-white solid; mp = 88–89 °C; H NMR (400 MHz,
CDCl3) δ 7.29 (d, J = 7.2 Hz, 1H), 4.65–4.58 (m, 1H), 4.51–4.46 (m, 1H), 3.73 (s, 3H), 3.52–3.45 (m, 1H), 1.94–1.88 (m,
1H), 1.80–1.73 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.20 (dd, J = 6.6, 2.6 Hz, 6H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 172.1, 163.1, 162.6, 53.5, 52.5, 49.8, 46.7, 25.5, 21.0, 20.9, 20.2, 20.1, 9.7; HRMS Calcd for C13H24N2NaO4
[M+Na+] 295.1634; Found: 295.1636.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-3-methylpentanoate (1b). Purified by column chromatography on silica
gel with petroleum ester/ethyl acetate (12/1) as an eluent; Yield 71% (4.26 g); off-white solid; mp = 54–56 °C; 1H NMR (400
MHz, CDCl3) δ 7.23 (br s, 1H), 4.69–4.63 (m, 1H), 4.52 (dd, J = 8.8, 5.0 Hz, 1H), 3.74 (s, 3H), 3.54–3.47 (m, 1H),
1.97–1.90 (m, 1H), 1.49–1.41 (m, 7H), 1.25–1.18 (m, 7H), 0.94–0.90 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 171.7, 163.0,
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162.6, 56.6, 52.3, 49.8, 46.7, 38.0, 25.3, 20.98, 20.96, 20.3, 20.2, 15.6, 11.7; HRMS Calcd for C15H28N2NaO4 [M+Na+]:
323.1947; Found: 323.1949.
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methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-3-methylbutanoate (1c). Purified by column chromatography on silica
gel with petroleum ester/ethyl acetate (12/1) as an eluent; Yield 79% (4.29 g); off-white solid; mp = 76–78 °C; 1H NMR (400
MHz, CDCl3) δ 7.23 (d, J = 8.4 Hz, 1H), 4.68–4.61 (m, 1H), 4.47 (dd, J = 8.9, 5.0 Hz, 1H), 3.74 (s, 3H), 3.54–3.47 (m, 1H),
2.25–2.17 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.21 (dd, J = 6.6, 3.9 Hz, 6H), 0.95 (dd, J = 9.7, 6.9 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 171.6, 163.2, 162.6, 57.2, 52.2, 49.7, 46.5, 31.2, 20.8, 20.1, 20.0, 19.0, 18.0; HRMS Calcd for
C14H26N2NaO4 [M+Na+]: 309.1790; Found: 309.1790.
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methyl 1-(2-(diisopropylamino)-2-oxoacetamido)cyclohexanecarboxylate (1d). Purified by column chromatography on
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silica gel with petroleum ester/ethyl acetate (12/1) as an eluent; Yield 80% (4.99 g); off-white solid; mp = 133–134 °C; H
NMR (400 MHz, CDCl3) δ 7.06 (br s, 1H), 4.72–4.65 (m, 1H), 3.71 (s, 3H), 3.54–3.47 (m, 1H), 2.07 (d, J = 13.5 Hz, 2H),
1.89–1.82 (m, 2H), 1.68–1.60 (m, 3H), 1.53–1.46 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H), 1.33–1.27 (m, 1H), 1.21 (d, J = 6.7 Hz,
6H); 13C NMR (101 MHz, CDCl3) δ 174.1, 162.9, 162.7, 59.1, 52.5, 49.6, 46.7, 32.2, 25.2, 21.4, 21.0, 20.2; HRMS Calcd for
C16H28N2NaO4 [M+Na+]: 335.1947; Found: 31951.
methyl 2-cyclopropyl-2-(2-(diisopropylamino)-2-oxoacetamido)acetate (1e). Purified by column chromatography on
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silica gel with petroleum ester/ethyl acetate (10/1) as an eluent; Yield 71% (4.03 g); off-white solid; mp = 62–63 °C; H
NMR (400 MHz, CDCl3) δ 7.49 (d, J = 6.7 Hz, 1H), 4.57–4.50 (m, 1H), 3.86–3.82 (m, 1H), 3.70 (s, 3H), 3.48–3.41 (m, 1H),
1.36 (d, J = 6.7 Hz, 6H), 1.16 (d, J = 6.5 Hz, 6H), 1.12–1.05 (m, 1H), 0.59–0.47 (m, 3H), 0.40–0.36 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 171.5, 163.0, 162.7, 56.1, 52.3, 49.6, 46.4, 20.8, 20.7, 20.1, 19.9, 13.3, 3.4, 3.3; HRMS Calcd for
C14H24N2NaO4 [M+Na+]: 307.1634; Found: 307.1639.
methyl 2-cyclobutyl-2-(2-(diisopropylamino)-2-oxoacetamido)acetate (1f). Purified by column chromatography on silica
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gel with petroleum ester/ethyl acetate (10/1) as an eluent; Yield 74% (4.41 g); off-white solid; mp = 102–103 °C; H NMR
(400 MHz, CDCl3) δ 7.25 (br s, 1H), 4.63–4.57 (m, 1H), 4.47 (t, J = 8.2 Hz, 1H), 3.70 (s, 3H), 3.52–3.45 (m, 1H), 2.71–2.62
(m, 1H), 2.01–1.76 (m, 6H), 1.40 (d, J = 6.8 Hz, 6H), 1.19 (dd, J = 6.6, 2.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.4,
163.3, 162.7, 55.9, 52.3, 49.8, 46.6, 37.7, 25.1, 24.8, 20.9, 20.2, 20.1, 18.0; HRMS Calcd for C15H26N2NaO4 [M+Na+]:
321.1790; Found: 321.1799.
methyl 2-cyclohexyl-2-(2-(diisopropylamino)-2-oxoacetamido)acetate (1g). Purified by column chromatography on silica
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gel with petroleum ester/ethyl acetate (10/1) as an eluent; Yield 76% (5.20 g); colorless oil; H NMR (400 MHz, CDCl3) δ
7.22 (d, J = 8.7 Hz, 1H), 4.68–4.61 (m, 1H), 4.45 (dd, J = 8.9, 5.5 Hz, 1H), 3.73 (s, 3H), 3.53–3.46 (m, 1H), 1.87–1.81 (m,
1H), 1.75–1.61 (m, 5H), 1.42 (d, J = 6.8 Hz, 6H), 1.24–1.04 (m, 11H); 13C NMR (101 MHz, CDCl3) δ 171.7, 163.0, 162.6,
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57.0, 52.3, 49.8, 46.7, 41.0, 29.6, 28.4, 26.0, 26.0, 20.97, 20.94, 20.2, 20.1; HRMS Calcd for C18H34N2NaO4 [M+Na+]:
365.2416; Found: 365.2428.
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General Procedure for Palladium-Catalyzed Arylation of 1a with Aryl Iodides (Table 2) (3a, 3b, 3d-3h, 3i-3k, 3l). A
mixture of 1a (54.5 mg, 0.2 mmol, 1.0 equiv), ArI (0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5 mol %), Ag2CO3 (55.2 mg, 1.0
equiv), PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene)
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(PTFE) cap] was heated at 90 C with vigorous stirring for 24 hours. The reaction mixture was cooled to room temperature,
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diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column
chromatography on silica gel to give the corresponding product.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(4-methoxyphenyl)butanoate (3a). 4-iodoanisole was used as
arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an eluent;
Yield 85% (64.3 mg); off-white solid; mp = 91–93 °C; H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.9 Hz, 1H), 7.08 (d, J =
8.4 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 4.68–4.62 (m, 1H), 4.59–4.54 (m, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.55–3.48 (m, 1H),
2.63 (t, J = 7.9 Hz, 2H), 2.23–2.14 (m, 1H), 2.07–1.98 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H), 1.23 (dd, J = 6.4, 4.1 Hz, 6H); 13C
NMR (101 MHz, CDCl3) δ 172.0, 163.2, 162.6, 158.2, 132.5, 129.5, 114.0, 55.3, 52.6, 52.0, 49.8, 46.7, 34.0, 30.8, 21.0, 20.9,
20.2, 20.1; HRMS Calcd for C20H30N2NaO5 [M+Na+] 401.2052; Found: 401.2066.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-phenylbutanoate (3b). iodobenzene was used as arylation reagent.
Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an eluent; Yield 70% (48.7 mg);
pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.31–7.21 (m, 3H), 7.16 (d, J = 6.9 Hz, 3H), 4.88–4.83 (m, 1H), 4.43–4.37 (m,
1H), 3.72 (s, 3H), 3.51–3.44 (m, 1H), 3.21–3.16 (dd, J = 13.9, 5.7 Hz, 1H), 3.11–3.06 (m, 1H), 1.74–1.72 (m, 2H), 1.40 (dd,
J = 6.8, 3.2 Hz, 6H), 1.16 (dd, J = 6.6, 1.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.3, 162.9, 162.6, 135.7, 129.4, 128.8,
127.3, 53.3, 52.6, 49.8, 46.6, 38.2, 21.0, 20.9, 20.2; HRMS Calcd for C19H28N2NaO4 [M+Na+] 371.1947; Found: 371.1954.
methyl 4-(3-chlorophenyl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (3d). 3-chloroiodobenzene was used as
arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (10/1) as an eluent;
Yield 86% (65.7 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 1H), 7.22–7.15 (m, 3H), 7.05 (d, J
= 7.1 Hz, 1H), 4.67–4.55 (m, 2H), 3.73 (s, 3H), 3.56–3.46 (m, 1H), 2.70–2.62 (m, 2H), 2.26–2.17 (m, 1H), 2.09–2.00 (m,
1H), 1.43 (d, J = 6.8 Hz, 6H), 1.23 (dd, J = 6.5, 5.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.8, 163.2, 162.5, 142.5,
134.3, 129.9, 128.7, 126.8, 126.6, 52.7, 51.9, 49.9, 46.8, 33.6, 31.4, 20.98, 20.95, 20.2, 20.1; HRMS Calcd for
C19H27ClN2NaO4 [M+Na+] 405.1557; Found: 405.1554.
methyl 4-(4-bromophenyl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (3e). 1-bromo-4-iodobenzene was used
as arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an eluent;
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Yield 83% (70.9 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.40–7.36 (m, 3H), 7.05 (d, J = 8.3 Hz, 2H), 4.67–4.60
(m, 1H), 4.59–4.54 (m, 1H), 3.72 (s, 3H), 3.56–3.49 (m, 1H), 2.68–2.60 (m, 2H), 2.24–2.15 (m, 1H), 2.07–1.98 (m, 1H),
1.43 (d, J = 6.8 Hz, 6H), 1.23 (dd, J = 6.6, 4.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.9, 163.1, 162.5, 139.4, 131.7,
130.3, 120.2, 52.7, 51.9, 49.8, 46.8, 33.7, 31.2, 20.99, 20.95, 20.2, 20.1; HRMS Calcd for C19H27BrN2NaO4 [M+Na+]
449.1052; Found: 449.1057.
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methyl
4-(4-bromo-3-chlorophenyl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate
(3f).
4-bromo-3-chloroiodobenzene was used as arylation reagent. Purified by column chromatography on silica gel with
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petroleum ester/ethyl acetate (8/1) as an eluent; Yield 74% (68.1 mg); pale yellow oil; H NMR (400 MHz, CDCl3) δ
7.51–7.47 (m, 2H), 7.26 (d, J = 2.0 Hz, 1H), 6.94–6.92 (m, 1H), 4.65–4.53 (m, 2H), 3.73 (s, 3H), 3.55–3.48 (m, 1H),
2.65–2.61 (m, 2H), 2.23–2.15 (m, 1H), 2.07–1.98 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.24–1.21 (m, 6H); 13C NMR (101 MHz,
CDCl3) δ 171.7, 163.2, 162.6, 141.5, 134.4, 133.8, 130.5, 128.3, 120.1, 52.7, 51.8, 49.9, 46.8, 33.4, 31.0, 21.0, 20.9, 20.2,
20.1; HRMS Calcd for C19H26BrClN2NaO4 [M+Na+] 483.0662; Found: 483.0669.
methyl
4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate
(3g).
6-iodo-1,4-benzodioxane was used as arylation reagent. Purified by column chromatography on silica gel with petroleum
ester/ethyl acetate (9/1) as an eluent; Yield 75% (60.9 mg); pale yellow solid; mp = 120–122 °C; 1H NMR (400 MHz, CDCl3)
δ 7.34 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.67–6.61 (m, 2H), 4.66–4.52 (m, 2H), 4.21 (s, 4H), 3.72 (s, 3H),
3.54–3.48 (m, 1H), 2.57 (t, J = 8.0 Hz, 2H), 2.21–2.12 (m, 1H), 2.05–1.95 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H), 1.22 (dd, J = 6.6,
3.5 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.0, 163.1, 162.6, 143.5, 142.0, 133.7, 121.4, 117.3, 117.1, 64.5, 64.4, 52.6,
52.0, 49.8, 46.7, 33.9, 31.0, 21.0, 20.2, 20.1; HRMS Calcd for C21H30N2NaO6 [M+Na+] 429.2002; Found: 429.2013.
methyl 4-(3-(2-(diisopropylamino)-2-oxoacetamido)-4-methoxy-4-oxobutyl)benzoate. (3h). Methyl 4-iodobenzoate was
used as arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (7/1) as an
eluent; Yield 81% (65.8 mg); pale yellow solid; mp = 68–70 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.2 Hz, 2H), 7.48
(d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 4.64–4.54 (m, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 3.54–3.47 (m, 1H), 2.73 (t, J =
7.8 Hz, 2H), 2.28–2.19 (m, 1H), 2.11–2.02 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.22 (dd, J = 6.6, 4.8 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 172.8, 167.1, 163., 162.6, 146.0, 129.9, 128.6, 128.3, 52.67, 52.1, 51.9, 49.9, 46.7, 33.4, 31.8, 21.0, 20.9,
20.2, 20.1; HRMS Calcd for C21H30N2NaO6 [M+Na+] 429.2002; Found: 429.2012.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(2-fluorophenyl)butanoate (3c). A mixture of 1a (54.5 mg, 0.2 mmol,
1.0 equiv), 2-fluoroiodobenzene 2c (0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5 mol %), Ag2CO3 (55.2 mg, 1.0 equiv),
PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap]
was heated at 110 oC with vigorous stirring for 24 hours. The reaction mixture was cooled to room temperature, diluted with
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ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on
silica gel with petroleum ester/ethyl acetate (10/1) to give the corresponding product 3c . Yield 82% (60.0 mg); pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.9 Hz, 1H), 7.19–7.14 (m, 2H), 7.06–6.96 (m, 2H), 4.66–4.56 (m, 2H), 3.72
(s, 3H), 3.55–3.48 (m, 1H), 2.73–2.69 (t, J = 7.9 Hz, 2H), 2.28–2.19 (m, 1H), 2.10–2.00 (m, 1H), 1.43 (dd, J = 6.8, 0.9 Hz,
6H), 1.23 (dd, J = 6.7, 2.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.9, 163.2, 162.6, 161.2 (d, JC−F = 243.0 Hz), 130.8 (d,
JC−F = 4.8 Hz), 128.2 (d, JC−F = 8.1 Hz), 127.3 (d, JC−F = 15.7 Hz), 124.2 (d, JC−F = 3.6 Hz), 115.4 (d, JC−F = 22.0 Hz), 52.6,
52.0, 49.9, 46.7, 32.3, 25.2, 21.0, 20.2, 20.2; HRMS Calcd for C19H27FN2NaO4 [M+Na+] 389.1853; Found: 389.1855.
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General Procedure for Palladium-Catalyzed Arylation of 1a with Aryl Iodides (Table 2) (3i-3k). A mixture of 1a
(54.5 mg, 0.2 mmol, 1.0 equiv), ArI (0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5 mol %), Ag2CO3 (82.8 mg, 1.5equiv),
PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap]
was heated at 110 oC with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature, diluted with
ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on
silica gel to give the corresponding product.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(3-(trifluoromethyl)phenyl)butanoate (3i). 3-iodobenzotrifluoride
was used as arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an
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eluent; Yield 72% (59.9 mg); pale yellow oil; H NMR (400 MHz, CDCl3) δ 7.46–7.36 (m, 5H), 4.70–4.64 (m, 1H),
4.62–4.57 (m, 1H), 3.73 (s, 3H), 3.56–3.50 (m, 1H), 2.81–2.69 (m, 2H), 2.30–2.21 (m, 1H), 2.12–2.03 (m, 1H), 1.44 (d, J =
6.8 Hz, 6H), 1.24 (dd, J = 6.3, 5.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.8, 163.1, 162.5, 141.4, 132.0 (d, JC−F =1.0
Hz), 130.9 (q, JC−F = 32.0 Hz), 129.1, 125.3 (q, JC−F = 32.0 Hz), 124.3 (q, JC−F = 270.0 Hz), 123.3 (q, JC−F = 4.0 Hz), 52.7,
51.9, 49.9, 46.8, 33.7, 31.6, 21.0, 20.9, 20.2, 20.1; HRMS Calcd for C20H27F3N2NaO4 [M+Na+] 439.1821; Found: 439.1829.
methyl 4-(4-acetylphenyl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (3j). 4-iodoacetophenone was used as
arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (7/1) as an eluent;
Yield 71% (55.4 mg); pale yellow solid; mp = 102–103 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 2H), 7.47 (d,
J = 8.0 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 4.65–4.55 (m, 2H), 3.72 (s, 3H), 3.55–3.48 (m, 1H), 2.74 (t, J = 7.9 Hz, 2H), 2.56
(s, 3H), 2.28–2.19 (m, 1H), 2.12–2.02 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.22 (dd, J = 6.1, 5.3 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 197.9, 171.8, 163.2, 162.6, 146.3, 135.5, 128.8, 52.7, 51.9, 49.9, 46.7, 33.4, 31.7, 26.7, 21.0, 20.9, 20.2, 20.1;
HRMS Calcd for C21H30N2NaO5 [M+Na+] 413.2052; Found: 413.2058.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(4-nitrophenyl)butanoate (3k). 4-iodo-1-nitrobenzene was used as
arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (7/1) as an eluent;
Yield 70% (55.1 mg); pale yellow solid; mp = 70–72 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.6 Hz, 2H), 7.53 (d, J =
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8.1 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 4.64–4.55 (m, 2H), 3.74 (s, 3H), 3.55–3.49 (m, 1H), 2.82–2.78 (m, 2H), 2.30–2.21 (m,
1H), 2.13–2.02 (m, 1H), 1.42 (dd, J = 6.8, 1.9 Hz, 6H), 1.24–1.21 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 171.6, 163.3,
162.5, 148.3, 146.7, 129.4, 123.9, 52.8, 51.8, 49.9, 46.8, 33.3, 31.7, 21.0, 20.9, 20.2, 20.1; HRMS Calcd for C19H27N3NaO6
[M+Na+] 416.1798; Found:416.1792.
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methyl 4-(4-acetamidophenyl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (3l). A mixture of 1a (54.5 mg, 0.2
mmol, 1.0 equiv), 4-iodoacetanilide 2l (0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5 mol %), Ag2CO3 (165.6 mg, 3.0 equiv),
PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap]
was heated at 130 oC with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature, diluted with
ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on
silica gel with petroleum ester/ethyl acetate (4/1) as an eluent to give the corresponding product 3c. Yield 45% (36.5 mg);
pale yellow solid; mp = 194–196 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (br s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.4
Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 4.57–4.50 (m, 2H), 3.70 (s, 3H), 3.54–3.47 (m, 1H), 2.60 (t, J = 7.9 Hz, 2H), 2.11 (s, 3H),
2.04–1.97 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H), 1.21 (dd, J = 6.6, 3.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.0, 168.8,
163.5, 162.9, 136.4, 136.2, 128.9, 120.3, 52.6, 51.9, 50.0, 46.6, 33.6, 31.1, 24.5, 20.9, 20.9, 20.2, 20.1; HRMS Calcd for
C21H31N3NaO5 [M+Na+] 428.2161; Found: 428.2170.
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methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(9-phenyl-9H-carbazol-2-yl)butanoate (3m). A mixture of 1a (54.5
mg, 0.2 mmol, 1.0 equiv), 3-iodo-9-phenylcarbazole 2m (0.3 mmol, 1.5 equiv), Pd(OAc)2 (4.5 mg, 10 mol %), Ag2CO3 (82.8
mg, 1.5 equiv), PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with
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poly(tetrafluoroethylene) (PTFE) cap] was heated at 90 C with vigorous stirring for 24 hours. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent to give the
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corresponding product 3m. Yield 83% (85.3 mg); pale yellow oil; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.7 Hz, 1H),
7.95 (d, J = 1.0 Hz, 1H), 7.61–7.54 (m, 4H), 7.47–7.43 (m, 1H), 7.39 (dd, J = 4.5, 1.0 Hz, 2H), 7.35–7.32 (m, 2H), 7.29–7.27
(m, 1H), 7.25–7.21 (m, 1H), 4.72–4.64 (m, 2H), 3.75 (s, 3H), 3.56–3.49 (m, 1H), 2.89 (t, J = 8.0 Hz, 2H), 2.39–2.30 (m, 1H),
2.22–2.13 (m, 1H), 1.44 (dd, J = 6.8, 2.1 Hz, 6H), 1.24 (dd, J = 6.6, 2.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.2,
163.2, 162.6, 141.3, 139.8, 137.9, 132.1, 123.0, 127.5, 127.1, 126.7, 126.0, 123.7, 123.3, 120.4, 120.0, 109.92, 109.88, 52.6,
52.2, 49.8, 46.8, 34.7, 31.9, 21.01, 20.99, 20.24, 20.17; HRMS Calcd for C31H35N3NaO4 [M+Na+] 536.2525; Found:
536.2521.
General Procedure for Palladium-Catalyzed Arylation of 1a with Heteroaryl Iodides (Table 2) (3n-3q). A mixture of
1a (54.5 mg, 0.2 mmol, 1.0 equiv), heteroaryl iodides (0.3 mmol, 1.5 equiv), Pd(OAc)2 (4.5 mg, 10 mol %), Ag2CO3 (82.8
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mg, 1.5 equiv), PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with
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poly(tetrafluoroethylene) (PTFE) cap] was heated at 110 C with vigorous stirring for 24 hours. The reaction mixture was
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cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel to give the corresponding product.
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methyl
2-(2-(diisopropylamino)-2-oxoacetamido)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)butanoate
(3n).
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3-iodo-1-(phenylsulfonyl)indole was used as arylation reagent. Purified by column chromatography on silica gel with
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petroleum ester/ethyl acetate (8/1) as an eluent; Yield 77% (81.3 mg); white oil; H NMR (400 MHz, CDCl3) δ 7.97 (d, J =
8.2 Hz, 1H), 7.88–7.86 (m, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.46–7.41 (m, 3H), 7.38–7.29 (m, 3H), 7.23 (t, J = 7.5 Hz, 2H),
4.73–4.66 (m, 1H), 4.65–4.60 (m, 1H), 3.70 (s, 3H), 3.57–3.50 (m, 1H), 2.81–2.68 (m, 2H), 2.34–2.25 (m, 1H), 2.16–2.07 (m,
1H), 1.61 (s, 2H), 1.45 (d, J = 6.8 Hz, 6H), 1.24 (dd, J = 6.6, 3.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.8, 163.1, 162.4,
138.3, 135.4, 133.8, 130.7, 129.4, 126.9, 125.0, 123.3, 123.2, 121.6, 119.5, 113.9, 52.7, 52.0, 49.9, 46.8, 31.6, 21.03, 21.00,
20.3, 20.2; HRMS Calcd for C27H33N3NaO6S [M+Na+] 550.1988; Found: 550.1984.
methyl 4-(5-acetylthiophen-2-yl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (3o). 5-acetyl-2-iodothiophene
was used as arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (7/1) as an
eluent; Yield 77% (81.3 mg); yellow solid; mp = 90–92 °C; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 3.8 Hz, 1H), 7.42 (d, J
= 8.0 Hz, 1H), 6.86 (d, J = 3.8 Hz, 1H), 4.67–4.58 (m, 2H), 3.75 (s, 3H), 3.56–3.49 (m, 1H), 2.99–2.87 (m, 2H), 2.50 (s, 3H),
2.35–2.26 (m, 1H), 2.16–2.09 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H), 1.24–1.21 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 189.6,
170.6, 162.2, 161.4, 151.9, 141.8, 132.0, 125.5, 51.8, 50.6, 48.9, 45.8, 32.7, 25.8, 25.6, 19.99, 19.95, 19.2, 19.1; HRMS
Calcd for C19H28N2NaO5S [M+Na+] 419.1617; Found: 419.1620.
methyl
2-(2-(diisopropylamino)-2-oxoacetamido)-4-(2-(trifluoromethyl)pyridin-4-yl)butanoate
(3p).
4-iodo-2-(trifluoromethyl)pyridine was used as arylation reagent. Purified by column chromatography on silica gel with
petroleum ester/ethyl acetate (8/1) as an eluent; Yield 67% (55.9 mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J =
5.0 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.31 (d, J = 4.8 Hz, 1H), 4.59–4.51 (m, 2H), 3.71 (s, 3H), 3.54–3.47 (m,
1H), 2.79 (t, J = 8.1 Hz, 2H), 2.30–2.21 (m, 1H), 2.15–2.05 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.21 (dd, J = 6.6, 4.5 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 171.4, 163.5, 162.8, 151.7, 150.2, 148.5 (q, JC−F = 34.0 Hz), 126.6, 121.6 (q, JC−F = 273.0
Hz), 120.7, (q, JC−F = 2.0 Hz), 52.7, 51.8, 50.0, 46.7, 32.3, 31.2, 20.9, 20.8, 20.2, 20.1; HRMS Calcd for C19H26F3N3NaO4
[M+Na+] 440.1773; Found: 440.1783.
methyl
4-(2,6-dichloropyridin-4-yl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate
(3q).
2,6-dichloro-4-iodopyridine was used as arylation reagent. Purified by column chromatography on silica gel with petroleum
ester/ethyl acetate (8/1) as an eluent; Yield 69% (57.7 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.1 Hz,
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1H), 7.11 (s, 2H), 4.66–4.56 (m, 2H), 3.76 (s, 3H), 3.56–3.50 (m, 1H), 2.75–2.62 (m, 2H), 2.28–2.19 (m, 1H), 2.10–2.03 (m,
1H), 1.43 (d, J = 6.8 Hz, 6H), 1.24 (t, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.3, 163.2, 162.4, 155.5, 150.8,
123.0, 52.9, 51.7, 49.9, 46.8, 32.4, 30.7, 21.0, 20.9, 20.2, 20.1; HRMS Calcd for C18H25Cl2N3NaO4 [M+Na+] 440.1120;
Found: 440.1121.
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General Procedure for Palladium-Catalyzed Arylation of 1a with Heteroaryl Iodides (Table 2) (3r-3x). A mixture of
1a (54.5 mg, 0.2 mmol, 1.0 equiv), heteroaryl iodides (0.3 mmol, 1.5 equiv), Pd(OAc)2 (6.6 mg, 15 mol %), Ag2CO3 (82.8
mg, 1.5 equiv), PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with
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poly(tetrafluoroethylene) (PTFE) cap] was heated at 150 C with vigorous stirring for 24 hours. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel to give the corresponding product.
methyl 4-(2-chloropyridin-4-yl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (3r). 2-chloro-4-iodopyridine was
used as arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an
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eluent; Yield 48% (36.9 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 5.1 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H),
7.14 (s, 1H), 7.03 (d, J = 5.0 Hz, 1H), 4.59–4.53 (m, 2H), 3.72 (s, 3H), 3.54–3.47 (m, 1H), 2.70–2.66 (m, 2H), 2.25–2.17 (m,
1H), 2.11–2.01 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.21 (t, J = 6.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.4, 163.4,
162.7, 153.0, 151.8, 149.7, 124.3, 122.7, 52.7, 51.7, 49.9, 46.7, 32.3, 30.8, 20.9, 20.9, 20.2, 20.1; HRMS Calcd for
C18H26ClN3NaO4 [M+Na+] 406.1510; Found: 406.1504.
methyl 4-(6-bromopyridin-3-yl)-2-(2-(diisopropylamino)-2-oxoacetamido)butanoate (3s). 2-bromo-5-iodopyridine was
used as arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an
1
eluent; Yield 47% (40.3 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.44 (d, J =
1.6 Hz, 2H), 4.70–4.59 (m, 2H), 3.79 (s, 3H), 3.61–3.54 (m, 1H), 2.75–2.67 (m, 2H), 2.30–2.21 (m, 1H), 2.14–2.04 (m, 1H),
1.47 (d, J = 6.8 Hz, 6H), 1.28 (t, J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.6, 163.2, 162.5, 150.3, 140.1, 138.8,
135.3, 128.0, 52.8, 51.7, 49.9, 46.8, 33.4, 28.3, 21.0, 20.9, 20.2, 20.1; HRMS Calcd for C18H26BrN3NaO4 [M+Na+] 450.1004;
Found: 450.1001.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(5-iodopyridin-2-yl)butanoate (3t). 2,5-diiodopyridinewas used as
arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an eluent;
Yield 36% (34.2 mg); brown oil; 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.2, 2.2 Hz, 1H), 7.80
(d, J = 7.8 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.63–4.54 (m, 2H), 3.72 (s, 3H), 3.54–3.47 (m, 1H), 2.82 (t, J = 7.5 Hz, 2H),
2.38–2.30 (m, 1H), 2.23–2.14 (m, 1H), 1.43 (dd, J = 6.8, 1.8 Hz, 6H), 1.21 (dd, J = 6.6, 2.3 Hz, 6H); 13C NMR (101 MHz,
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CDCl3) δ 171.8, 163.4, 162.8, 159.1, 155.3, 144.9, 125.2, 90.6, 52.6, 52.0, 49.8, 46.6, 33.3, 31.0, 21.0, 20.9, 20.2, 20.1;
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HRMS Calcd for C18H26IN3NaO4 [M+Na+] 498.0866; Found: 498.0863.
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methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(3-fluoropyridin-4-yl)butanoate (3u). 2-fluoro-4-iodopyridine was
used as arylation reagent. Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an
eluent; Yield 39% (28.7 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 8.1 Hz,
1H), 7.01–6.99 (m, 1H), 6.75 (s, 1H), 4.63–4.55 (m, 2H), 3.55–3.48 (m, 1H), 2.79–2.67 (m, 2H), 2.26–2.21 (m, 1H),
2.12–2.04 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.22 (dd, J = 6.5, 5.5 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.5, 164.3 (d,
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JC−F = 237.0 Hz), 163.3, 162.6, 155.6 (d, JC−F = 8.0 Hz), 147.7 (d, JC−F = 15.0 Hz), 121.7 (d, JC−F = 4.0 Hz), 109.3 (d, JC−F
=
37.0 Hz), 52.8, 51.7, 49.9, 46.7, 32.4, 30.98, 30.95, 20.94, 20.88, 20.2, 20.1; HRMS Calcd for C18H26FN3NaO4 [M+Na+]
390.1805; Found: 390.1816.
methyl
2-(2-(diisopropylamino)-2-oxoacetamido)-4-(1-tosyl-1H-indol-5-yl)butanoate
(3v).
5-iodo-1-(4-methylphenylsulfonyl)indole was used as arylation reagent. Purified by column chromatography on silica gel
with petroleum ester/ethyl acetate (7/1) as an eluent; Yield 52% (56.4 mg); brown oil; 1H NMR (400 MHz, CDCl3) δ 7.88 (d,
J = 8.5 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.11
(dd, J = 8.5, 1.5 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1H), 4.70–4.63 (m, 1H), 4.60–4.55 (m, 1H), 3.68 (s, 3H), 3.56–3.49 (m, 1H),
2.75–2.71 (m, 2H), 2.33 (s, 3H), 2.27–2.18 (m, 1H), 2.10–1.99 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.23 (dd, J = 6.6, 3.8 Hz,
6H); 13C NMR (101 MHz, CDCl3) δ 171.9, 163.1, 162.5, 145.0, 135.6, 135.4, 133.6, 131.2, 130.0, 126.9, 126.7, 125.4, 121.0,
113.6, 109.0, 52.6, 52.0, 49.8, 46.8, 34.3, 31.5, 21.7, 21.0, 21.0, 20.3, 20.2; HRMS Calcd for C28H35N3NaO6S [M+Na+]
564.2144; Found: 564.2162.
methyl
5-(3-(2-(diisopropylamino)-2-oxoacetamido)-4-methoxy-4-oxobutyl)furan-2-carboxylate
(3w).
methyl
5-bromo-2-furoate was used as arylation reagent. Purified by column chromatography on silica gel with petroleum
ester/ethyl acetate (7/1) as an eluent; Yield 42% (33.3 mg); brown oil; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.2 Hz, 1H),
7.07 (d, J = 3.4 Hz, 1H), 6.19 (d, J = 3.4 Hz, 1H), 4.68–4.57 (m, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.55–3.48 (m, 1H),
2.81–2.77 (m, 2H), 2.36–2.27 (m, 1H), 2.16–2.06 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.22 (dd, J = 6.6, 4.5 Hz, 6H); 13C NMR
(101 MHz, CDCl3) δ 171.5, 163.1, 162.3, 159.3, 159.0, 143.5, 119.3, 108.7, 52.8, 51.9, 51.6, 49.8, 46.8, 30.4, 24.6, 20.99,
20.95, 20.2, 20.1; HRMS Calcd for C19H28N2NaO7 [M+Na+] 419.1794; Found: 419.1808.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-3-(4-methoxybenzyl)pentanoate (4a). A mixture of 1b (0.2 mmol, 1.0
equiv), 4-iodoanisole (0.3 mmol, 1.5 equiv), Pd(TFA)2 (6.0 mg, 10 mol %), Ag2CO3 (165.6 mg, 3.0 equiv), PivOH (6.1 mg,
0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap] was heated at 60
oC with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and
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filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on silica gelwith
petroleum ester/ethyl acetate (8/1) as an eluent to give the corresponding product 4a. Yield 55% (44.7 mg); pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.11–7.07 (m, 3H), 6.84–6.81 (m, 2H), 4.64–4.58 (m, 2H), 3.77 (s, 3H), 3.71 (s, 3H),
3.56–3.49 (m, 1H), 2.61–2.47 (m, 2H), 2.21–2.15 (m, 1H), 1.46–1.35 (m, 8H), 1.23 (t, J = 6.4 Hz, 6H), 0.96 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 172.0, 163.4, 162.9, 158.2, 131.7, 130.2, 114.0, 55.3, 53.7, 52.5, 49.9, 46.7, 45.0, 36.1,
22.9, 21.02, 20.96, 20.3, 20.2, 11.9; HRMS Calcd for C22H34N2NaO5 [M+Na+] 429.2365; Found: 429.2364.
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methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)butanoate (4b). A mixture
of 1c (0.2 mmol, 1.0 equiv), 4-iodoanisole (0.6 mmol, 3.0 equiv), Pd(OAc)2 (4.5 mg, 10 mol %), Ag2CO3 (165.6 mg, 3.0
equiv), PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene)
(PTFE) cap] was heated at 130 oC with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature,
diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent to give the corresponding product 4b. Yield
83% (82.8 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 9.0 Hz, 1H), 7.06 (t, J = 8.5 Hz, 4H), 6.83–6.78
(m, 4H), 4.62–4.59 (m, 2H), 3.77 (d, J = 5.4 Hz, 6H), 3.61 (s, 3H), 3.56–3.49 (m, 1H), 2.65–2.54 (m, 5H), 1.46 (d, J = 6.8
Hz, 6H), 1.23 (dd, J = 7.9, 7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.6, 163.5, 162.9, 158.3, 158.2, 131.5, 131.15,
130.2, 130.2, 114.0, 55.33, 55.29, 53.6, 52.4, 49.8, 46.6, 45.5, 36.1, 35.5, 21.1, 20.9, 20.3, 20.2; HRMS Calcd for
C28H38N2NaO6 [M+Na+] 521.2628; Found: 521.2624.
methyl 1-(2-(diisopropylamino)-2-oxoacetamido)-3-(4-methoxyphenyl)cyclohexanecarboxylate (4c). A mixture of 1d
(0.2 mmol, 1.0 equiv), 4-iodoanisole (0.3 mmol, 1.5 equiv), Pd(TFA)2 (6.0 mg, 10 mol %), Ag2CO3 (165.6 mg, 3.0equiv),
PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap]
o
was heated at 60 C with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature, diluted with
ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on
silica gel with petroleum ester/ethyl acetate (9/1) as an eluent to give the corresponding product 4c. Yield 61% (51.1 mg);
yellow soid; mp = 163–165°C; 1H NMR (400 MHz, CDCl3) δ 7.25 (br s, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz,
2H), 4.71–4.64 (m, 1H), 3.77 (d, J = 1.2 Hz, 6H), 3.52–3.45 (m, 1H), 3.01–2.95 (m, 1H), 2.68 (d, J = 12.9 Hz, 1H), 2.49 (d, J
= 12.6 Hz, 1H), 1.89–1.80 (m, 2H), 1.73–1.69 (m, 1H), 1.58–1.49 (m, 2H), 1.43–1.34 (m, 7H), 1.19 (t, J = 6.4 Hz, 6H); 13
C
NMR (101 MHz, CDCl3) δ 172.9, 162.5, 162.2, 158.1, 138.1, 127.8, 113.9, 59.5, 55.4, 52.4, 49.6, 46.7, 41.7, 39.1, 34.1, 33.1,
22.7, 21.0, 20.9, 20.2; HRMS Calcd for C23H34N2NaO5 [M+Na+] 441.2365; Found: 441.2373.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-2-(2-(4-methoxyphenyl)cyclopropyl)acetate (4d). A mixture of 1e (0.2
mmol, 1.0 equiv), 4-iodoanisole (0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5 mol %), Ag2CO3 (82.8 mg, 1.5 equiv), PivOH
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(6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap] was
heated at 60 oC with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature, diluted with ethyl
acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on silica
gel with petroleum ester/ethyl acetate (9/1) as an eluent to give the corresponding product 4d. Yield 66% (51.5 mg); yellow
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oil; dr > 20:1 (determined by H NMR); H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H),
6.83 (d, J = 8.7 Hz, 2H), 4.67–4.60 (m, 1H), 3.79–3.75 (m, 4H), 3.60 (s, 3H), 3.53–3.47 (m, 1H), 2.33 (dd, J = 15.2, 8.4 Hz,
1H), 1.53–1.46 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.20 (dd, J = 9.7, 6.7 Hz, 6H), 1.14–1.04 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 171.6, 162.9, 162.6, 158.4, 130.1, 129.0, 113.7, 55.3, 52.3, 51.9, 49.7, 46.7, 22.0, 21.5, 21.0, 20.9, 20.2, 20.1, 8.0;
HRMS Calcd for C21H31N2O5 [M+H+] 391.2233; Found: 391.2226.
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methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-2-(2-(4-methoxyphenyl)cyclobutyl)acetate (4e). A mixture of 1f (0.2
mmol, 1.0 equiv), 4-iodoanisole (0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5 mol %), Ag2CO3 (82.8 mg, 1.5 equiv), PivOH
(6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap] was
heated at 90 oC with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature, diluted with ethyl
acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on silica
gel with petroleum ester/ethyl acetate (10/1) as an eluent to give the corresponding product 4e. Yield 70% (56.6 mg); pale
yellow oil; dr > 20:1 (determined by 1H NMR); 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.6 Hz, 2H), 6.83–6.81 (m, 2H),
6.65 (d, J = 7.6 Hz, 1H), 4.53–4.46 (m, 1H), 4.13 (dd, J = 10.1, 7.9 Hz, 1H), 3.78–3.72 (m, 4H), 3.65 (s, 3H), 3.48–3.41 (m,
1H), 3.10–3.01 (m, 1H), 2.41–2.25 (m, 2H), 2.15 (dd, J = 15.6, 7.9 Hz, 2H), 1.39 (dd, J = 8.7, 6.9 Hz, 6H), 1.13 (t, J = 6.5
Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.5, 162.3, 161.9, 158.4, 132.0, 129.2, 114.0, 55.3, 53.5, 52.3, 49.4, 46.6, 41.3,
40.9, 23.7, 22.4, 21.0, 20.9, 20.2, 20.1; HRMS Calcd for C22H32N2NaO5 [M+Na+] 427.2209; Found: 427.2204.
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-2-(2-(4-methoxyphenyl)cyclohexyl)acetate (4f). A mixture of 1g (0.2
mmol, 1.0 equiv), 4-iodoanisole (0.3 mmol, 1.5 equiv), Pd(OAc)2 (4.5 mg, 10 mol %), Ag2CO3 (165.6 mg, 3.0 equiv), PivOH
(6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap] was
heated at 130 oC with vigorous stirring for 36 hours. The reaction mixture was cooled to room temperature, diluted with ethyl
acetate and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography on silica
gel with petroleum ester/ethyl acetate(8/1) as an eluent to give the corresponding product 4f. Yield 34% (29.4 mg); yellow oil;
dr > 20:1 (determined by 1H NMR); 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.40 (d,
J = 8.0 Hz, 1H), 4.52–4.45 (m, 1H), 4.41 (t, J = 8.6 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.44–3.37 (m, 1H), 3.03–3.01 (m,
1H), 2.41–2.35 (m, 1H), 1.90–1.73 (m, 5H), 1.52–1.44 (m, 3H), 1.34 (dd, J = 13.1, 6.8 Hz, 6H), 1.14 (dd, J = 22.0, 6.6 Hz,
6H); 13C NMR (101 MHz, CDCl3) δ 172.1, 162.4, 161.9, 158.3, 135.7, 129.6, 114.0, 55.2, 54.5, 52.2, 49.4, 46.5, 42.7, 42.3,
27.5, 23.6, 23.4, 20.9, 20.9, 20.0; HRMS Calcd for C24H36N2NaO5 [M+Na+] 455.2522; Found: 455.2521.
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(S)-methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-phenylbutanoate (3a’).A mixture of oxalyl amide protected
L-amino ester 1a’ (54.5 mg, 0.2 mmol, 1.0 equiv), 4-iodoanisole (0.3 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 5 mol %),
Ag2CO3 (55.2 mg, 1.0 equiv), PivOH (6.1 mg, 0.3 equiv) and mesitylene (0.6 mL) in a 15 mL glass vial [sealed with
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poly(tetrafluoroethylene) (PTFE) cap] was heated at 90 C with vigorous stirring for 24 hours. The reaction mixture was
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cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an eluent to give the
corresponding product 3a’. Yield 82% (62.1 mg); yellow oil; >99.5% ee [Daicel Chiralcel OD-H, hexanes/i-PrOH = 85/15,
flow rate: 1.0 mL·min-1, λ = 254.4 nm, t (major)= 5.857, t (minor)= 6.330]. [α]D25 = 14.03 (c 1.06, acetone).
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(E)-methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-4-(2-(3,3-dimethylbut-1-en-1-yl)-4-methoxyphenyl)butanoate (5).
A mixture of 3a (75.7 mg, 0.2 mmol), 3,3-dimethyl-1-butene (2 equiv), Pd(OAc)2 (2.2 mg, 5 mol %), Ag2CO3 (165.6 mg, 3
equiv), (n-BuO)2PO2H (12.6 mg, 0.3 eq) and DCE (1 mL) in a 15 mL glass tube (sealed with PTFE cap) was heated at 140 oC
for 36 hours. The reaction mixture was cooled to room tempreture, and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel with petroleum ester/ethyl acetate (12/1) as an eluent to give the
alkenylated product 5. Yield 53% (48.8 mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 1H), 7.02 (d, J =
8.4 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 6.70 (dd, J= 8.4, 2.7 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 6.10 (d, J = 15.9 Hz, 1H),
4.76–4.69 (m, 1H), 4.60–4.55 (m, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.56–3.49 (m, 1H), 2.74–2.61 (m, 2H), 2.17–2.08 (m, 1H),
1.98–1.91 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.23 (dd, J = 6.6, 2.3 Hz, 6H), 1.12 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
172.0, 163.0, 162.3, 158.5, 144.5, 138.2, 130.6, 130.0, 120.0, 112.6, 111.6, 55.4, 52.6, 52.3, 49.7, 46.8, 33.8, 33.6, 29.7, 28.8,
21.0, 20.2, 20.2; HRMS Calcd for C26H40N2NaO5 [M+Na+] 483.2835; Found: 483.2835.
methyl 4-(3-(2-(diisopropylamino)-2-oxoacetamido)-4-methoxy-4-oxobutyl)-3-((triisopropylsilyl)ethynyl)benzoate (6). A
mixture of 3k (81.3 mg, 0.2 mmol), bromoalkyne (0.4 mmol, 2.0 equiv), Pd(OAc)2 (4.5 mg, 10mol %), AgOAc(0.4 mmol,
2.0 equiv), KOAc (0.6 mmol, 3.0 equiv) and toluene (1 mL) under Ar atmospherein a 15 mL glass tube (sealed with PTFE
cap) was heated at 120 oC for 36 hours. The reaction mixture was cooled to room tempreture, and concentrated in vacuo. The
resulting residue was purified by column chromatography on silica gel with petroleum ester/ethyl acetate (30/1) as an eluent
to give the alkynylated product 6. Yield 48% (48.8 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 1.7 Hz,
1H), 7.89 (dd, J = 8.0, 1.8 Hz, 1H), 7.30–7.25 (m, 3H), 4.74–4.68 (m, 1H), 4.57–4.51 (m, 1H), 3.91 (s, 3H), 3.69 (s, 3H),
3.56–3.49 (m, 1H), 2.95 (t, J = 7.8 Hz, 2H), 2.41–2.32 (m, 1H), 2.11–2.02 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.23 (dd, J = 6.6,
2.0 Hz, 6H), 1.14 (d, J = 2.4 Hz, 21H); 13C NMR (101 MHz, CDCl3) δ 171.9, 166.5, 163.1, 162.3, 147.7, 134.4, 129.7, 129.3,
128.6, 123.5, 104.2, 96.3, 52.6, 52.3, 52.0, 49.7, 46.8, 32.3, 31.2, 21.03, 20.99, 20.23, 20.16, 18.8, 11.4; HRMS Calcd for
C23H29BrN2NaO6 [M+Na+] 531.1107; Found: 531.1118..
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ASSOCIATED CONTENT
Supporting Information
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1H and 13C NMR spectra of all new compounds and HPLC trace for compound 3a’. This material is available free of
charge via theInternet at http://pubs.acs.org.
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported financially by the Natural Science Foundation of China (NO. 21572149) and the Young
National Natural Science Foundation of China (NO.21403148). The support of PAPD is also greatly acknowledged.
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