Synthesis of Ugi-4CR boronate analogues via microwave irradiation

Article abstract of DOI:10.1007/s11164-016-2433-y

The synthetic condition for the synthesis of boronate ester Ugi-4CR analogs under mild conditions was developed. The reported reactions were carried out in methanol and promoted by microwave heating. This synthetic strategy could provide unique access to a broad range of boron-containing chemical libraries.

Full text of DOI:10.1007/s11164-016-2433-y

Res Chem Intermed
DOI 10.1007/s11164-016-2433-y
Synthesis of Ugi-4CR boronate analogues
via microwave irradiation
Chao-Yu Hsiao1 Shi-Qing Huang1 Wan-Hsing Lien1 Chen-Yun Hsu1
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Kun-lin Hsieh1 Meng-Hsuan Lin1 Meng-Ju Wu1 Chia-Chieh Fu1
Hsien-Chi Chen1 Hao-Ping Fang1 Chia-Jung Li1 Po-Shen Pan1
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Received: 15 October 2014 / Accepted: 26 December 2014
Ó Springer Science+Business Media Dordrecht 2016
Abstract The synthetic condition for the synthesis of boronate ester Ugi-4CR
analogs under mild conditions was developed. The reported reactions were carried
out in methanol and promoted by microwave heating. This synthetic strategy could
provide unique access to a broad range of boron-containing chemical libraries.
Keywords Boron Á Multicomponent reaction Á Ugi reaction Á Suzuki–Miyaura
cross-coupling
Introduction
Compounds that contain a boron functional group have been broadly used as the key
building blocks in a wide range of organic reactions [1, 2]. In 2003, bortezomib
(VelcadeTM) became the first FDA-approved boron-containing agent to treat
multiple myeloma [3, 4] (Fig. 1). Since then, significant research efforts have been
focused on finding the next organoboron molecules to be used in medicinal
applications [5–8] (Fig. 1). Despite their structural differences, the current strategy
for the synthesis of organoboron compounds is mainly dependent on multi-step
operations. This strategy often requires extensive reaction time, as well as time-
consuming purification efforts. One alternative solution that could resolve this
hurdle is to utilize a multi-component reaction (MCR) [9–11], where three or more
reagents are put in one pot to yield the desired products. Although widely used in
many medicinal programs, it is underutilized in the making of organoboron
compounds. Westcott and co-workers reported one of the earliest examples of using
&
Po-Shen Pan
popan@mail.tku.edu.tw
1
Department of Chemistry, Tamkang University, No. 151 Yingzhuan Rd., Tamsui District,
New Taipei City 25137, Taiwan, ROC
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C.-Y. Hsiao et al.
(b)
(a)
(c)
(d)
(e)
Fig. 1 a Velcade; b TR150c; c PHX1149; d PT100; e Kerydin
Ugi-4CR to synthesize boronate esters [12]. Although, the desired compounds were
retrieved in good yields, it required 4–10 days to complete the reactions. Herein, we
report a microwave-assisted synthetic condition that could synthesize boron-
containing Ugi-4CR derivatives in 30 min.
Experimental section
General procedure for the synthesis of boronic ester-containing Ugi
analogues B1–B10
N-cyclohexyl-2-(N-phenylacetamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)acetamide (1) A 10-mL glass tube containing aniline (0.10 mL;
0.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (116 mg;
0.50 mmol), and 0.5 mL of methanol was first stirred for 5 min at room
temperature. Then, acetic acid (0.03 mL; 0.55 mmol) and cyclohexylisocyanide
(0.07 mL; 0.55 mmol) were added to the reaction mixture. Microwave irradiation
was applied for 30 min (45 °C, 150 W) under medium-speed magnetic stirring, and
the reaction mixture was concentrated and re-dissolved in dichloromethane. The
crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively.
The organic solution was collected and dried over MgSO4 and concentrated in
vacuo. The concentrated material was placed under vacuum at 40 °C for 8 h to
1
afford the desired product in a 93 % yield (221.94 mg) mp = 265 °C. H NMR
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Synthesis of Ugi-4CR boronate analogues via microwave…
(300 MHz, CDCl3) d: 7.62 (d, 2H), 7.19–7.12(m, 7H), 5.99 (s, 1H), 5.49 (br, 1H),
3.79–3.90 (m, 1H), 1.60–2.00 (m, 6H), 1.25–1.40 (m, 15H), 0.80–1.09 (m, 4H). 13
C
NMR (150.9 MHz, CDCl3) d: 175.85, 168.82, 138.49, 137.85, 135.04, 128.89,
128.35, 126.81, 126.08, 83.87, 63.00, 50.07, 48.51, 32.67, 27.32, 25.46, 24.84,
24.81, 24.73, 9.34. 11B NMR (192.5 MHz, CDCl3) d: 30.65. m/z HRMS (ESI,
positive ion): [M ? H]?, found 477.2937. C28H37BN2O4 requires 477.2923.
2-(N-benzylacetamido)-N-cyclohexyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)acetamide (2) The desired compound was prepared using benzylamine
(0.06 mL; 0.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzalde-
hyde (116 mg; 0.50 mmol), acetic acid (0.03 mL; 0.55 mmol), and cyclohexyliso-
cyanide (0.07 mL; 0.55 mmol) by general procedure (398.73 mg, 81 % yield).
mp = 183 °C. 1H NMR (300 MHz, CDCl3) d: 7.70 (d, 2H), 7.37 (d, 2H), 7.13–7.16
(m, 3H), 7.02–7.04 (m, 2H), 5.87 (s, 1H), 5.62 (br, 1H), 4.60 (dd, J = 42.0, 18.0, 2H),
3.77–3.79 (m, 1H), 2.04 (s, 3H), 1.82–1.92 (m, 2H), 1.59–1.65 (m, 3H), 1.23–1.32 (m,
15H), 1.01–1.07 (m, 2H). 13C NMR (150.9 MHz, CDCl3) d: 172.55, 168.44, 138.22,
137.44, 135.01, 128.80, 128.31, 126.80, 83.81, 62.90, 50.48, 48.44, 32.62, 25.36,
24.70, 22.40. 11B NMR (192.5 MHz, CDCl3) d: 30.88. m/z HRMS (ESI, positive ion):
[M ? H]?, 491.3079. C29H39BN2O4 requires 491.3079.
N-benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)propionamide (3) The desired compound was prepared using
benzylamine (0.06 mL; 0.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl) benzaldehyde (116 mg; 0.50 mmol), propanoic acid (0.05 mL; 0.55 mmol), and
cyclohexylisocyanide (0.07 mL; 0.55 mmol) by general procedure (401.56 mg,
80 % yield). mp = 210 °C. 1H NMR (300 MHz, CDCl3) d: 7.69 (br, 2H), 7.35 (br,
2H), 7.24–7.11 (m, 3H), 7.03 (br, 2H), 5.89 (s, 1H), 5.64 (br. 1H), 4.64 (dd,
J = 43.2, 17.3, 2H), 3.87–3.71 (m, 1H), 2.48–2.15 (m, 2H), 1.96–1.74 (m, 2H),
1.70–1.48 (m, 3H), 1.46–1.20 (m, 15H), 1.21–0.94 (m, 5H). 13C NMR (75.5 MHz,
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C.-Y. Hsiao et al.
CDCl3) d: 171.43, 168.77, 140.83, 137.86, 134.84, 130.47, 129.66, 129.05, 128.17,
113.90, 84.03, 65.43, 48.86, 32.87, 25.74, 25.57, 24.96, 24.83, 23.27. 11B NMR
(193 MHz, CDCl3) d: 30.79. m/z HRMS (ESI, positive ion): [M ? H]?, found
505.3232. C30H41BN2O4 requires 505.3236.
N-benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)isobutyramide (4) The desired compound was prepared using
benzylamine (0.06 mL; 0.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl) benzaldehyde (116 mg; 0.50 mmol), isobutric acid (0.05 mL; 0.55 mmol), and
cyclohexylisocyanide (0.07 mL; 0.55 mmol) by general procedure (286.21 mg,
55 % yield). mp = 78 °C. 1H NMR (300 MHz, CDCl3) d: 7.71 (d, 2 H), 7.36 (d, 2
H), 7.21–7.02 (m, 5H), 5.86 (s, 1H), 5.63 (br, 1H), 4.61 (dd, J = 56.6, 17.6, 2H),
3.88–3.69 (m, 1H), 2.75–2.60 (m, 1H), 1.96–1.80 (m, 2H), 1.74–1.48 (m, 3H), 1.32
(s, 15H), 1.21–1.15 (m, 2H), 1.11 (d, 3H), 1.05 (d, 3H). 13C NMR (150.9 MHz,
CDCl3) d: 179.28, 168.53, 138.42, 137.90, 135.04, 128.77, 128.39, 126.92,
126.0183.91, 63.20, 50.03, 48.50, 32.76, 32.71, 31.46, 25.49, 24.84, 24.71, 19.63,
19.28. 11B NMR (193 MHz, CDCl3) d: 30.68. m/z HRMS (ESI, positive ion):
[M ? H]?, found 519.3388. C31H43BN2O4 requires 519.3392.
N-benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-3-methylbutanamide (5) The desired compound was prepared
using benzylamine (0.06 mL; 0.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2- diox-
aborolan-2-yl)benzaldehyde (116 mg; 0.50 mmol), isovalic acid (0.07 mL;
0.55 mmol), and cyclohexylisocyanide (0.07 mL; 0.55 mmol) by general procedure
1
(433.59 mg, 83 % yield). mp = 169 °C. H NMR (300 MHz, CD3OD-d4) d: 7.67
(d, 2H), 7.33 (d, 2H), 7.18–7.02 (m, 5H), 5.90–5.75 (m, 1H), 4.60 (dd, J = 55.0,
17.6, 2H), 3.87–3.70 (m, 1H), 2.24–2.08 (m, 3H), 1.96–1.82 (m, 2H), 1.71–1.52 (m,
3H), 1.38–1.17 (m, 15H), 1.12–1.05 (m, 2H), 0.99–0.81 (m, 6H). 13C NMR
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Synthesis of Ugi-4CR boronate analogues via microwave…
(150.9 MHz, CDCl3) d: 174.62, 168.60, 138.37, 137.58, 135.06, 128.88, 128.39,
126.96, 126.26, 83.92, 63.59, 50.45, 48.56, 42.79, 32.71, 25.85, 25.48, 24.85, 22.62,
22.54. 11B NMR (193 MHz, CDCl3) d: 30.99. m/z HRMS (ESI, positive ion):
[M ? H]?, found 533.3532. C32H45BN2O4 requires 533.3549.
2-(N-phenylacetamido)-N-cyclohexyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)acetamide (6) The desired compound was prepared using aniline
(0.10 mL; 0.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde
(116 mg; 0.50 mmol), acetic acid (0.03 mL; 0.55 mmol), and cyclohexylisocyanide
(0.07 mL; 0.55 mmol) by general procedure (371.13 mg, 78 % yield). mp = 152 °C.
1H NMR (300 MHz, CDCl3) d: 7.61(s, 2H), 7.16(s, 4H), 7.09(s, 3H), 6.07(s, 1H),
5.58(br, 1H), 3.91–3.75(m, 1H), 1.95–1.79(m, 3H), 1.63–1.52(m, 4H), 1.38–1.23(m,
15H), 1.15–0.97(m, 3H). 13C NMR (150.9 MHz, CDCl3) d: 167.34, 164.93, 136.60,
133.17, 130.75, 130.12, 129.02, 126.50, 124.89, 124.02, 123.71, 79.98, 60.91, 44.75,
28.78, 21.55, 20.95, 19.25. 11B NMR (192.5 MHz, CDCl3) d: 30.30. m/z HRMS (ESI,
positive ion): [M ? H]?, found 477.2899. C28H37BN2O4 requires 477.2923.
2-(N-benzylacetamido)-N-cyclohexyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)acetamide (7) The desired compound was prepared using benzylamine
(0.06 mL; 0.55 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzalde-
hyde (116 mg; 0.50 mmol), acetic acid (0.03 mL; 0.55 mmol), and cyclohexyliso-
cyanide (0.07 mL; 0.55 mmol) by general procedure (355.08 mg, 72 % yield).
mp = 139 °C. 1H NMR (300 MHz, CDCl3) d: 7.70 (s, 1H), 7.62 (d, 1H), 7.48 (d, 1H),
7.25–6.96 (m, 6H), 5.98 (s, 1H), 5.48 (br, 1H), 4.58 (dd, J = 39.0, 17.8, 2H), 3.90–3.75
(m, 1H), 2.06 (s, 3H), 1.95–1.84 (m, 2H), 1.71–1.51 (m, 3H), 1.42–1.29 (m, 15H),
1.21–0.98 (m, 2H). 13C NMR (150.9 MHz, CDCl3) d: 172.63, 168.80, 137.63, 136.73,
134.80, 134.42, 132.24, 128.27, 128.09, 126.75, 126.11. 83.89, 62.66, 50.68, 48.53,
32.74, 25.49, 24.90, 22.27. 11B NMR (192.5 MHz, CDCl3) d: 30.65. HRMS (ESI,
positive ion): [M ? H]?, found 491.3077. C29H39BN2O4 requires 491.3079.
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C.-Y. Hsiao et al.
N-benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)propionamide (8) The desired compound was prepared using
benzylamine (0.06 mL; 0.55 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl) benzaldehyde (116 mg; 0.50 mmol), propanoic acid (0.04 mL; 0.55 mmol), and
cyclohexylisocyanide (0.07 mL; 0.55 mmol) by general procedure (430.82 mg,
1
85 % yield). mp = 88 °C. H NMR (300 MHz, CDCl3) d: 7.69 (s, 1H), 7.62 (d,
1H), 7.49 (d, 1H), 7.23–6.95 (m, 6H), 6.00 (s, 1H), 5.62 (br, 1H), 4.60 (dd,
J = 43.4, 17.9, 2H), 3.98–3.78 (m, 1H), 2.61–2.27 (m, 2H), 2.12–1.86 (m, 2H),
1.86–1.59 (m, 3H), 1.59–1.31 (m, 15H), 1.31–1.07 (m, 5H). 13C NMR (150.9 MHz,
CDCl3) d: 175.80, 168.96, 137.85, 136.74, 134.73, 132.24, 128.63, 128.05, 126.69,
126.0583.87, 62.83, 49.88, 48.51, 32.73, 27.30, 25.49, 24.90, 9.38. 11B NMR
(193 MHz, CDCl3) d: 30.79. m/z HRMS (ESI, positive ion): [M ? H]?, found
505.3243. C30H41BN2O4 requires 505.3236.
N-benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)isobutyramide (9) The desired compound was prepared using
benzylamine (0.06 mL; 0.55 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl) benzaldehyde (116 mg; 0.50 mmol), isobutric acid (0.05 mL; 0.55 mmol), and
cyclohexylisocyanide (0.07 mL; 0.55 mmol) by general procedure (443.32 mg,
1
86 % yield). mp = 79 °C. H NMR (300 MHz, CDCl3) d: 7.67 (s, 1H), 7.60 (d,
1H), 7.45 (d, 1H), 7.31–6.95 (m, 6H), 5.97 (s, 1H), 5.76 (br, 1H), 4.62 (dd,
J = 58.2, 17.9, 2H), 3.77–3.84 (m, 1H), 2.67–2.77 (m, 1H), 1.82–1.97 (m, 2H),
1.58–1.72 (m, 3H), 1.31–1.43 (m, 15H), 1.21–1.12 (m 8H). 13C NMR (150.9 MHz,
CDCl3) d: 179.19, 168.79, 138.05, 136.54, 134.57, 132.13, 128.21, 127.96, 126.70,
125.91. 11B NMR (193 MHz, CDCl3) d: 30.60. m/z HRMS (ESI, positive ion):
[M ? H]?, found 518.3320. C31H43BN2O4 requires 518.3313.
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Synthesis of Ugi-4CR boronate analogues via microwave…
N-benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-3-methylbutanamide (10) The desired compound was prepared
using benzylamine (0.06 mL; 0.55 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)benzaldehyde (116 mg; 0.50 mmol), isovalic acid (0.07 mL;
0.55 mmol), and cyclohexylisocyanide (0.07 mL; 0.55 mmol) by general procedure
1
(411.02 mg, 77 % yield). mp = 78 °C. H NMR (300 MHz, CDCl3) d: 7.67 (s,
1H), 7.61 (d, 1H), 7.66 (d, 1H), 7.24–6.97 (m, 6H), 5.91 (s, 1H), 5.64 (br, 1H), 4.61
(dd, J = 62.0, 17.8, 2H), 3.79–3.73 (m, 1H), 2.29–2.13 (m, 3H), 1.97–1.89 (m, 2H),
1.69–1.56 (m, 3H), 1.37–1.26 (m, 15H), 1.16–1.04 (m, 2H), 1.04–0.97 (m, 6H). 13
C
NMR (150.9 MHz, CDCl3) d: 174.50, 168.85, 137.78, 136.59, 134.61, 132.22,
128.19, 126.72, 126.15, 83.83, 63.05, 50.07, 48.49, 42.77, 32.70, 25.88, 25.51,
24.89, 24.77, 24.70, 22.65, 22.60. 11B NMR (193 MHz, CDCl3) d: 30.46. m/z
HRMS (ESI, positive ion): [M ? H]?, found 533.3566. C32H45BN2O4 requires
533.3549.
General procedure F for the synthesis 11–14
N-benzyl-N-(2-(cyclohexylamino)-1-(30-methoxy-[1,10-biphenyl]-3-yl)-2-oxoethyl)isobu-
tyramide (11) Compound 9 (100.5 mg, 0.194 mmol), 1-bromo-3-methoxybenzene
(0.031 mL, 0.25 mmol), and Pd(PPh3)2Cl2 (5.09 mg, 0.0194 mmol) were added to a
flask containing a magnetic stir with EtOH (1.90 mL). Triethylamine (0.06 mL,
0.426 mmol) was then added to the reaction mixture and this mixture was stirred
under reflux conditions for 10 h under a N2 atmosphere. After cooling the mixture to
room temperature, solvent was removed in vacuo. The crude material was diluted
with ethyl acetate (5.00 mL) and water (5.00 mL). The aqueous layer was separated
from the organic layer, and the aqueous layer was extracted with ethyl acetate
(2 9 15 mL). Organic layers were then combined, washed with brine solution, and
dried with MgSO4, and solvent was removed in vacuo. The crude material was then
purified by flash column chromatography on silica gel using n-hexane/ethyl
acetate = 1:1 as the eluent to give the desired product 11 as an oil (m.p. 180 °C) in
1
61 % yield (59 mg); H NMR (600 MHz, CDCl3) d: 7.47–6.85 (m, 13H), 6.01 (s,
1H), 5.73 (br, 1H), 4.67 (dd, J = 18, 103.2, 2H), 3.82 (s, 3H), 3.79–3.76 (m, 1H),
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C.-Y. Hsiao et al.
2.70 (quint, J = 6.6, 1H), 1.92–1.86(m, 2H), 1.66–1.54 (m, 2H), 1.35–1.22 (m, 4H),
1.12 (dd, J = 6.6, 30, 8H). 13C NMR (150.9 MHz, CDCl3) d: 179.42, 168.83,
160.10, 142.23, 141.62, 138.13, 135.88, 129.92, 129.16, 128.88, 128.70, 128.47,
127.35, 127.05, 126.06, 119.81, 113.10, 112.99, 62.73, 55.49, 49.88, 48.73, 33.05,
32.95, 31.65, 25.67, 24.99, 24.91, 19.96, 19.52.
N-benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(3-(thiophen-2-yl)phenyl)ethyl)propionamide
(12) Following general procedure F, the desired compound was synthesized
utilizing 8 (98.1 mg, 0.193 mmol), 2-bromothiophene (0.023 ml, 0.251 mmol),
Pd(PPh3)2Cl2 (5.05 mg, 0.019 mmol), and triethylamine (0.059 ml, 0.424 mmol),
1
giving compound 12 as a white solid (m.p. 177 °C) in 78 % yield (69.5 mg); H
NMR (600 MHz, CDCl3) d: 7.53–6.98 (m, 12H), 6.01 (s, 1H), 5.79 (br, 1H), 4.65
(dd, J = 18, 81.6, 2H), 3.79 (s, 1H), 2.39–2.23(m, 2H), 1.91–1.85(m, 2H),
1.63–1.53(m, 4H), 1.40–1.08(m, 7H). 13C NMR (150.9 MHz, CDCl3) d: 176.03,
168.82, 143.77, 137.88, 136.21, 134.96, 129.35, 128.73, 128.51, 128.20, 127.62,
127.04, 126.21, 126.11, 125.34, 123.61, 62.78, 50.17, 48.77, 32.98, 32.93, 27.49,
25.65, 24.98, 24.91, 9.61.
N-benzyl-N-(2-(cyclohexylamino)-1-(30-nitro-[1,10-biphenyl]-4-yl)-2-oxoethyl)-3-
methylbutanamide (13) Following general procedure F, the desired compound
was synthesized utilizing 5 (133 mg, 0.25 mmol), 1-bromo-3-nitrobenzene
(0.065 mg, 0.325 mmol), Pd(PPh3)2Cl2 (6.557 mg, 0.025 mmol), and triethylamine
1
(0.08 mL, 0.55 mmol), giving compound 13 as an oil in 42 % yield (55.8 mg); H
NMR (600 MHz, CDCl3) d: 8.12 (s, 1H), 7.96 (d,1H), 7.59 (d, 1H), 7.36 (t, 2H),
7.04 (s, 1H), 6.95 (quint, J = 6.6, 7.8, 5.4, 6.6, 4H), 6.80 (d, 3H), 5.71 (s, 1H), 5.66
(br, 1H), 4.47 (dd, J = 7.2, 126, 2H), 3.57 (s, 1H), 2.09–1.71(m, 4H), 1.69–0.66(m,
15H). 13C NMR (150.9 MHz, CDCl3) d: 174.79, 168.68, 148.93, 142.28, 138.76,
137.69, 135.95, 133.11, 130.60, 129.97, 128.57, 127.41, 127.21, 126.43, 122.45,
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Synthesis of Ugi-4CR boronate analogues via microwave…
122.09, 62.85, 50.56, 48.82, 42.97, 33.04, 32.96, 26.12, 25.69, 25.08, 24.98, 24.93,
22.85, 22.78.
2-([1,10-biphenyl]-3-yl)-N-cyclohexyl-2-(N-phenylacetamido)acetamide (14) Fol-
lowing general procedure F, the desired compound was synthesized utilizing 6
(119.1 mg, 0.25 mmol), bromobenzene (0.034 ml, 0.325 mmol), Pd(PPh3)2Cl2
(6.55 mg, 0.025 mmol), and triethylamine (0.076 mL, 0.55 mmol), giving com-
pound 14 as a white solid (mp = 79 °C) in 60 % yield (64 mg); 1H NMR
(600 MHz, CDCl3) d: 7.61 (s, 1H), 7.41–7.06 (m, 13H), 6.10 (s, 1H), 5.66 (br, 1H),
3.81–3.80 (m, 1H), 1.93–1.53 (m, 7H), 1.34–0.99 (m, 6H). 13C NMR (150.9 MHz,
CDCl3) d: 171.51, 168.95, 141.44, 140.83, 140.59, 135.44, 133.19, 130.65, 129.44,
129.40, 129.13, 128.95, 128.31, 127.68, 127.33, 127.20, 65.07, 49.01, 33.08, 33.01,
25.69, 25.03, 24.95, 23.49.
Results and discussion
Experiments were performed to find the optimum synthetic conditions. The results
are shown in Table 1. It should be noted that all boronic acid building blocks (R-
B(OH)2) used in the synthesis were protected by pinacol as the boronate ester
analogues (R-Bpin). First, ranges of solvents were selected (entry 1–4), and it was
found that methanol provided the best result (entry 4, 62 %). Second, when the
reaction was carried out with an elevated temperature (45 °C), the yields improved
from 62 % (entry 4) to 68 % (entry 5). In addition, it was found that the reaction
could finish earlier if microwave irradiation was applied (entry 6). It is important to
note that further reducing the reaction period from 0.5 h (entry 6) to 0.25 h (entry 7)
significantly lowered the overall yield from 78 to 42 %. After the optimal condition
was determined, ranges of building blocks were used to synthesize boron-containing
Ugi derivatives (Table 2). In all cases, the desired products 1–10 were synthesized
in good to excellent yields (55–93 %).
One of the advantages of synthesizing boron-containing Ugi analogs was that
post-Ugi modification could be accomplished via a palladium-catalyzed Suzuki–
Miyaura reaction. Four examples were included in this report where aryl/heteroaryl
halides were successfully coupled to the boronate esters to yield the desired
products 11–14 in moderate to good yields (Scheme 1).
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C.-Y. Hsiao et al.
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Synthesis of Ugi-4CR boronate analogues via microwave…
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C.-Y. Hsiao et al.
Conclusions
In summary, a microwave-assisted Ugi-4CR reaction that could synthesize boron-
containing compounds was developed. Further, post-Ugi modification was also
successfully demonstrated, making this strategy suitable for chemical library
synthesis. More boron-containing analogs are being synthesized and their biological
activity will be tested and reported in due course.
Scheme 1 Pd-mediated Suzuki–Miyaura cross-coupling of boron containing Ugi-4CR substrates
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Synthesis of Ugi-4CR boronate analogues via microwave…
Acknowledgments This research was supported by the Ministry of Science and Technology in Taiwan
(MST-103-2113-M-032-010). We thank the Department of Chemistry of Tamkang University for the
equipment and financial support. We thank Ms. Shen–Shen Chen for conducting the 11B NMR
experiments.
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