First total synthesis of N-(3-guanidinopropyl)-2-(4-hydroxyphenyl)-2- oxoacetamide

Article abstract of DOI:10.1002/hlca.201300318

The first total synthesis of the α-oxo amide-based natural product, N-(3-guanidinopropyl)-2-(4-hydroxyphenyl)-2-oxoacetamide (3), isolated from aqueous extracts of hydroid Campanularia sp., has been achieved. The α-oxo amide 12, prepared via the oxidative

Full text of DOI:10.1002/hlca.201300318

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First Total Synthesis of N-(3-Guanidinopropyl)-2-(4-hydroxyphenyl)-2-
oxoacetamide
by Satish S. Morea)b), Akula Raghunadha), Ramanathan Shankara), Navin B. Patelb),
Dinesh S. Bhaleraoc), and Unniaran K. Syam Kumar*c)
a) Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddyꢀs Laboratories Ltd.,
Miyapur, Hyderabad 500049, India
b) Department of Chemistry, Veer Narmad South Gujarat University, Udhana-Magdalla Road, Surat,
India
c) Integrated Product Development, Innovation Plaza, Dr. Reddyꢀs Laboratories Ltd., Bachupalli,
Qutubullapur, R.R. Dist., 500072, Andhra Pradesh, India (e-mail: syam_kmr@yahoo.com)
The first total synthesis of the a-oxo amide-based natural product, N-(3-guanidinopropyl)-2-(4-
hydroxyphenyl)-2-oxoacetamide (3), isolated from aqueous extracts of hydroid Campanularia sp., has
been achieved. The a-oxo amide 12, prepared via the oxidative amidation of 1-[4-(benzyloxy)phenyl]-
2,2-dibromoethanone (9a) with 4-{[(tert-butyl)(dimethyl)silyl]oxy}butan-1-amine (10a), has been used
as the key intermediate in the total synthesis of 3 as HBr salt. On the way, an expeditious total synthesis
of polyandrocarpamide C (2c), isolated from marine ascidian Polyandrocarpa sp., was carried out in four
steps.
Introduction. – The a-oxo amides are an intriguing class of reactive functionalities,
found in a number of natural products and pharmaceuticals [1]. Coscinamides 1a – 1c
[2] and polyandrocarpamides 2a – 2c [3] etc. posses a indol-3-yl oxo amide framework
in their structures. The polyandrocarpamides 2a – 2c were isolated by Lindquist and
Fenical from marine ascidian Polyandrocarpa sp. [3]. Recently, Houssen and Jaspars
isolated N-(3-guanidinopropyl)-2-(4-hydroxyphenyl)-2-oxoacetamide (3), an oxo
amide-based natural product, from aqueous extracts of marine invertebrates Campa-
nularia sp. [4]. Despite its structural resemblance to histone deacetylase (HDAC)
inhibitors such as suberoylanilide hydroxamic acid (SAHA; 4) and trichostatin A
(TSA; 5), 3 did not inhibit the growth of ARP-1 cells, presumably indicating its
diminished activity towards HDACs [5] (Fig.).
Results and Discussion. – As a part of our ongoing work on total syntheses of
biologically relevant natural products and their congeners [6], herein we report the first
total synthesis of N-(3-guanidinopropyl)-2-(4-hydroxyphenyl)-2-oxoacetamide (3) and
also the total synthesis of polyandrocarpamide C (2c).
The retrosynthetic strategy for the synthesis of 3, involving oxidative amidation
methodology as the key step, is outlined in Scheme 1. Deprotection of the OH group as
well as the amino groups in 6 with suitable reagents would yield the natural product 3.
The hydroxy protected natural oxo amide 6 in turn could be generated by Mitsunobu
reaction of an appropriately protected guanidine building block 7 with N-hydroxyalkyl
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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405
Figure. Natural products containing a-oxo moieties 1 – 3, and HDAC inhibitors 4 and 5
Scheme 1. Retrosynthetic Scheme for the Synthesis of 3
a-oxo amide 8. The latter could be prepared by oxidative amidation of 2,2-
dibromoethanone 9 with hydroxy-protected 4-aminobutan-1-ol (10).
The total synthesis of 3 was initiated with the synthesis of 1-[4-(benzyloxy)phenyl]-
2,2-dibromoethanone (9a; Scheme 2), which was prepared from 1-[4-(benzyloxy)phe-
nyl]ethanone (11) by bromination with Br2 in dioxane in 73% yield [7]. The oxidative
coupling of 9a with TBDMS-protected 4-aminobutan-1-ol 10a was carried out as
described in [8], and the a-oxo amide 12 was isolated in 55% yield. The removal of the
TBDMS groups in 12 was achieved by treatment with 1.0m solution of Bu4NF in THF
[9], and the free alcohol 8a was then isolated as pale-yellow solid in 93% yield. The

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Scheme 2. Synthesis of 14, the O-Benzyl Trifluoroacetic Acid Salt of 3
Mitsunobu reaction [10] of N,N’-di-Boc-guanidine 7a [11] and 8a was then attempted.
Initially, the reaction was performed with diisopropyl azodicarboxylate (DIAD) and
Ph3P. However, the required guanidino-substituted a-oxo amide 6a was obtained only
in 19% yield, whereas the major product formed in the reaction was identified as 13, a
transesterification product [12]. Our attempts to improve the yield of the Mitsunobu
reaction of 8a and 7a under various conditions utilizing different activating agents/
bases and solvent combinations were unsuccessful, and these reactions always gave 6a
in low yields (less than 20%). The removal of the N,N’-di-Boc group [13] in 6a with
CF3COOH (TFA) in CH2Cl2 yielded the O-Bn derivative of the natural product 3 as
TFA salt, i.e., 14, in 90% yield.
Though the synthesis of O-Bn derivative 14 of the natural product 3 was achieved
via oxidative amidation-Mitsunobu reaction strategy, we have attempted to develop an
alternative approach to address the low overall yield in the synthesis, especially in the
Mitsunobu reaction. Our solution was to introduce the guanidine unit in 3 via
displacement of the aminotriflate group in N,N’-di-Boc-N’’-triflylguanidine (7b; triflyl
(Tf), trifluoromethanesulfonyl) with the pre-constructed primary amino functionality
in a-oxo amide 15 (Scheme 3).
Thus, we started the total synthesis of 3 with 8a as the key intermediate (Scheme 4).
The mesyl (Ms; methanesulfonyl) protection of the primary OH group in 8a was

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Scheme 3. Modified Retrosynthetic Scheme for the Synthesis of 3
Scheme 4. Synthesis of 14 via N,Nꢀ-Di-Boc-N”-triflylguanidine
carried out with Et3N/CH2Cl2/MsCl [14], and the product 16 was used in situ for the
azidation. Thus, removal of the Ms group in 16 with NaN3 [15] gave the azido derivative
17, which, via Staudinger reduction, yielded the free amine 15 [16]. As the latter
underwent multiple reactions and decomposition during its isolation, especially while
concentrating the reaction mixture, our attempts to isolate the free amine in very pure
form were not successful. Hence, in situ guanidination of 15 was attempted with N,N’-
di-Boc-N’’-triflylguanidine (7b). Thus, 15 in CH2Cl2 was reacted directly with 7b and
the di-Boc guanidino a-oxo amide 6b was isolated in 65% overall yield over two steps

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starting from 17. The removal of the Boc groups in 6b was carried out with TFA in
CH2Cl2 at room temperature, and the free guanidino product was isolated as TFA salt
14 in 95% yield as white crystalline solid.
Thus, after the successful introduction of the guanidino moiety in very high yields,
our attempts were directed towards the removal of the O-Bn group in 14 (Scheme 5).
This was initially attempted with Pd/C-mediated hydrogenolysis; however, the major
product formed in this was identified as over-hydrogenated product 18. Our attempts to
prepare 3 under different hydrogenation reaction conditions (such as lower temper-
ature, different H2 pressures, and various grades of Pd/C, and % loading of Pd/C, etc.)
were not successful. However, when the reaction was carried out with HBr/AcOH at 08,
the debenzylation proceeded smoothly and 3 was isolated in 80% yield as HBr salt. The
deprotection of 14 went equally well with TMSBr/CH2Cl2, and 3 · HBr was isolated in
comparable yields. By this alternate approach, the total synthesis of 3 · HBr was
achieved in an overall yield of 15.67% over a seven-step process.
Scheme 5. Removal of the O-Benzyl Group
In the literature, a synthesis of polyandrocarpamide C (2c) has been reported using
(indol-3-yl)-2-oxoacetate or (2-indol-3-yl)-2-oxochloride as starting materials [17].
Herein, we report the total synthesis of 2c via oxidative amidation as key step of the
synthesis (Scheme 6). The 3-acetyl-1-tosyl-1H-indole (19) was subjected to dibromi-
Scheme 6. Synthesis of Polyandrocarpamide C (2c)

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nation with Br2 in dioxane to give 20 in 77% yield. The oxidative amidation of 20 with
2-(4-[(tert-butyl)(dimethyl)silyl]oxy}phenyl)ethanamine (21) was carried out as under
standard reaction conditions to yield the a-oxo amide 22. Detosylation and desilylation
of 22 yielded 2c in overall 23.4% yield starting from 19.
Conclusions. – We achieved the first total synthesis of the natural product N-(3-
guanidinopropyl)-2-(4-hydroxyphenyl)-2-oxoacetamide (3) as HBr salt in high yield.
The synthesis of polyandrocarpamide C (2c) was also carried out as a part of this study.
In the total synthesis of these two a-oxo amide-based natural products, oxidative
amidation has been employed as the key step of the process. The total syntheses of
these natural products were realized under mild reaction conditions and starting from
easily accessible starting materials. The synthesis of more natural products utilizing
oxidative amidationꢀMitsunobu reaction is under progress, and will be reported in due
course.
Authors are thankful to Dr. Vilas H. Dahanukar for the constant encouragement, support, and useful
discussions. We also thank to the analytical department of Dr. Reddyꢀs Laboratories for the analytical
support.
Experimental Part
General. All reactions were carried out in oven-dried glassware under N2, with magnetic stirring, and
the reactions were monitored by TLC, using Merck aluminum-backed plates pre-coated with silica gel
(SiO2; 0.25 mm, 60 F254). The TLC plates were visualized under UV light (254 nm) or developed using a
soln. of KMnO4 . Purifications were performed by column chromatography (CC) with SiO2 (60 –
120 mesh) purchased from SRL and eluted with hexanes/AcOEt.
M.p.: Electrothermal melting point apparatus; uncorrected. IR Spectra: a PerkinElmer 1650 Fourier
Transform spectrometer. NMR Spectra: in CDCl3, CD3OD, or (D6)DMSO (all with Me4Si as internal
standard) on Varian Gemini 200-MHz Fourier transform (FT) and 400-MHz FT spectrometers, chemical
shifts in ppm; and coupling constants (J) in Hz. MS: HP-5989A quadrupole mass spectrometer; in m/z.
2-[4-(Benzyloxy)phenyl]-N-(4-{[(tert-butyl)(dimethyl)silyl]oxy}butyl)-2-oxoacetamide (12). To a
stirred pre-cooled (20 – 258) mixture of 2,2-dibromo-1-[(4-benzyloxy)]phenylethanone (9a; 10.0 g,
0.026 mol), NaI (7.81 g, 0.052 mol), sulfolane (¼2,3,4,5-tetrahydrothiophene 1,1-dioxide; 50.0 ml), and
K3PO4 (13.81 g, 0.065 mol, powdered) were added, followed by 4-[(tert-(butyl)(dimethyl)silyloxy)]bu-
tan-1-amine (10a; 6.35 g, 0.031 mol) under N2. The mixture was stirred for ca. 1.5 – 2 h at r.t. A soln. of
tBuOOH (ca. 5.5m in decane, 5.9 ml, 0.033 mol) was added to the mixture within 10 min, and stirring was
continued for another 5 – 6 h at r.t. The mixture was diluted with H2O (200 ml) and extracted with AcOEt
(3 ꢁ 50 ml). The combined AcOEt extracts were washed with 10% aq. NaHSO3 soln. (2 ꢁ 50 ml), dil.
HCl (5%; 75 ml), and 10% NaCl soln. (100 ml). The org. layer was dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by CC (SiO2 (60 – 120 mesh); using AcOEt/hexanes)
20 :80 to afford 12 (6.31g, 55%). Pale-yellow solid. M.p. 91 – 928. IR (KBr): 3300, 3072, 2929, 1643, 1604,
1
1568, 1541, 1471, 1382, 1317, 1264, 1225, 1169, 1100. H-NMR (400 MHz, CDCl3): 0.05 (s, 6 H); 0.88 (s,
9 H); 1.59 – 1.69 (m, 4 H); 3.40 (q, J ¼ 6.6, 2 H); 3.60 (t, J ¼ 6.4, 2 H); 5.10 (s, 2 H); 7.00 (d, J ¼ 9.2, 2 H);
7.20 (br. s, NH); 7.44 – 7.34 (m, 5 arom. H); 8.41 (d, J ¼ 8.8, 2 H). 13C-NMR (100 MHz, CDCl3): 5.3; 18.2;
25.8; 29.9; 30.1; 39.0; 62.5; 70.0; 114.5; 126.5; 127.3; 128.1; 128.6; 133.8; 135.9; 162.2; 163.6; 185.8. ESI-
MS: 442 ([M þ H]þ).
2-[4-(Benzyloxy)phenyl]-N-(4-hydroxybutyl)-2-oxoacetamide (8a). To a soln. of 12 (6.3 g,
0.0142 mol) in THF (33 ml) was added Bu4NF soln. (1m in THF, 15.7 ml, 0.0156 mol) at 5 – 108. The
mixture was stirred for 2 h (monitored by TLC). After disappearance of 12 (TLC); the mixture was
diluted with H2O and extracted with tBuOMe (65 ml). The org. layer was washed with 10% NaCl soln.

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(35 ml) and concentrated under vacuum. The residue was purified by flash CC (SiO2; AcOEt/hexanes
30 :70) to give 8a (4.36 g, 93%). Pale-yellow solid. M.p. 97 – 1008. IR (KBr): 3102, 1670, 1636, 1603, 1573,
1510, 1455, 1426, 1386, 1317, 1264, 1176, 1117. 1H-NMR (400 MHz, CDCl3): 1.61 – 1.75 (m, 4 H); 3.40 (q,
J ¼ 6.8, 2 H); 3.71 (t, J ¼ 6.0, 2 H); 5.15 (s, 2 H); 7.00 – 7.04 (m, 2 H); 7.34 (s, NH); 7.42 – 7.39 (m, 5 arom.
H); 8.38 – 8.42 (m, 2 H). 13C-NMR (100 MHz, CDCl3): 25.8; 29.7; 39.1; 62.2; 70.1; 114.6; 126.4; 127.4;
128.2; 128.6; 133.8; 135.8; 162.4; 163.7; 185.8. ESI-MS: 328.2 ([M þ H]þ), 350.1 ([M þ Na]þ).
4-({2-[4-(Benzyloxy)phenyl]-2-oxoacetyl}amino)butyl Methanesulfonate (16). Under N2, to a soln.
of 8a (3.5 g, 0.010 mol) in CH2Cl2 (35 ml) was added Et3N (2.16 g, 0.0214 mol), and the mixture was
cooled to 0 – 58. MsCl (1.53 g, 0.0133 mol) in CH2Cl2 (30 ml) was added to the mixture slowly over a
period of 30 min at 0 – 58, and stirring was continued for 4 h at r.t. (monitored by TLC). The mixture was
then diluted with H2O. The CH2Cl2 layer was separated and washed with 10% aq. NaHSO3 soln.,
followed by 10% aq. NaCl soln. The CH2Cl2 layer was dried (Na2SO4) and concentrated under vacuum to
give 16, which was used as such for the next step of the reaction. An anal. pure sample of 16 was obtained
by purification of the crude product by CC (SiO2; AcOEt/hexanes 25 :75). Off-white solid. IR (KBr):
3098, 2943, 1670, 1638, 1603, 1572, 1509, 1459, 1353, 1265, 1168. 1H-NMR (400 MHz, CDCl3): 1.73 – 1.86
(m, 4 H); 2.99 (s, 3 H); 3.40 (q, J ¼ 6.8, 2 H); 4.24 (t, J ¼ 6.2, 2 H); 5.10 (s, 2 H); 7.20 (s, NH); 7.44 – 7.33
(m, 5 arom. H); 8.39 – 8.43 (m, 2 H). 13C-NMR (100 MHz, CDCl3): 25.5; 26.4; 37.3; 38.5; 69.1; 70.1; 114.6;
126.4; 127.4; 128.2; 128.6; 133.8; 135.8; 162.3; 163.8; 185.4. ESI-MS: 406.2 ([M þ H]þ).
N-(4-Azidobutyl)-2-[4-(benzyloxy)phenyl]-2-oxoacetamide (17). To a soln. of crude 16 in DMF
(20 ml), NaN3 (1.04 g, 0.0160 mol) was added at r.t., and the mixture was heated at 608 for 1 h (monitored
on TLC). After completion of the reaction, the mixture was diluted with H2O (80 ml) and extracted with
AcOEt (2 ꢁ 30 ml). The AcOEt layer was washed with 10% aq. NaCl soln. (2 ꢁ 25 ml) and concentrated
under vacuum. The crude product was purified by CC (SiO2; AcOEt/hexanes 25 :75) to give 17 (3.25 g,
85% over two steps). Light-cream solid. M.p. 83 – 858. IR (KBr): 2343, 2093, 1670, 1637, 1604, 1573, 1510,
1
1454, 1427, 1351, 1316, 1265. H-NMR (400 MHz, CDCl3): 1.63 – 1.73 (m, 4 H); 3.30 (t, J ¼ 6.4, 2 H);
3.39 – 3.44 (m, 2 H); 5.12 (s, 2 H); 7.01 – 7.04 (m, 2 H); 7.23 (s, NH); 7.44 – 7.39 (m, 5 arom. H); 8.39 – 8.43
(m, 2 H). 13C-NMR (100 MHz, CDCl3): 26.2; 26.5; 38.6; 50.9; 70.1; 114.6; 126.4; 127.4; 128.2; 128.6;
133.8; 135.9; 162.3; 163.8; 185.5. ESI-MS: 353.20 ([M þ H]þ).
Di(tert-butyl) [{[4-({2-[4-(benzyloxy)phenyl]-2-oxoacetyl}amino)butyl]amino}methylylidene]bis-
carbamate (6b). To a soln. of 17 (2.8 g, 0.0079 mol) in AcOEt (14 ml) were added H2O (1.4 ml) and
Ph3P (5.21 g, 0.0198 mol), and the mixture was stirred for 1 h at 308. The progress of the reaction was
monitored by TLC. After completion of the reaction, the mixture was dil. with H2O (20 ml). The layers
were separated, and the AcOEt layer was washed with 10% citric acid soln. The combined aq. layer was
basified with dilute aq. NaOH soln. and extracted with CH2Cl2 (2 ꢁ 20 ml). The CH2Cl2 layer was washed
with brine (30 ml) and dried (Na2SO4). The dry CH2Cl2 layer was cooled, and Et3N (1.6 g, 0.0158 mol)
was added, followed by addition of 7b (3.71 g, 0.00945 mol) at 0 – 58. The reaction was completed in ca.
2.5 h (monitored by TLC). The mixture was diluted with H2O, and CH2Cl2 layer was washed with 10%
NaCl soln. The CH2Cl2 layer was dried (Na2SO4) and concentrated under vacuum. The residue was
purified by CC (SiO2; AcOEt/hexanes 20 :80) to afford 6b (2.93 g, 65%, over two steps). White solid.
M.p. 99 – 1018. IR (KBr): 2347, 1726, 1644, 1604, 1572, 1455, 1422, 1368, 1326, 141261, 1227, 1168, 1135.
1H-NMR (400 MHz, CDCl3): 1.49 (s, 18 H); 1.61 – 1.66 (m, 4 H); 3.42 – 3.47 (m, 4 H); 5.15 (s, 2 H); 7.00
(d, J ¼ 9.2, 2 H); 7.30 (s, 1 H, NH); 7.43 – 7.37 (m, 5 arom. H); 8.35 (s, 1 H, NH); 8.40 (d, J ¼ 8.8, 2 H);
11.49 (s, 1 H, NH). 13C-NMR (100 MHz,CDCl3): 26.5; 26.7; 28.0; 28.2; 38.8; 40.2; 70.1; 79.2; 83.0; 114.2;
126.5; 127.4; 128.2; 128.6; 133.8; 135.9; 153.2; 156.1; 162.3; 163.4; 163.7; 185.58. ESI-MS: 569.40 ([M þ
H]þ).
tert-Butyl [4-({2-[4-(Benzyloxy)phenyl]-2-oxoacetyl}amino)butyl][N-(tert-butoxycarbonyl)carba-
mimidoyl]carbamate (6a). To a soln. 8a (0.60 g, 0.0018 mol), Ph3P (0.94 g, 0.0036 mol), and N,N’-di-
Boc-guanidine (7a; 1.4 g, 0.0054 mol) in dry THF (0.98 ml) was added dropwise a soln. of DIAD in THF
(0.74 g, 0.0036 mol) at ꢀ 58 under N2. The mixture was stirred for 1.5 – 2 h at ꢀ 58 to 08, warmed to r.t.,
and stirred at r.t. for ca. 48 h. The mixture was concentrated under reduced pressure, and the residue was
purified by CC (SiO2 (60 – 120 mesh) hexanes/AcOEt 3 :1) to furnish two products: 6a. and 13. Data of
1
6a Yield: 0.2 g (19%). White solid. M.p. 1188. H-NMR (400 MHz, CDCl3): 1.49 (s, 9 H); 1.51 (s, 9 H);
1.72 – 1.60 (m, 4 H); 3.91 (t, J ¼ 7.2, 4 H); 5.15 (s, 2 H); 7.02 (d, J ¼ 9.2, 2 H); 7.44 – 7.32 (m, 5 arom. H);

Helvetica Chimica Acta – Vol. 97 (2014)
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7.68 (t, J ¼ 6, 1 H, NH); 8.36 (d, J ¼ 8.8, 2 H); 9.20 (s, 1 H, NH); 9.37 (s, 1 H, NH). ESI-MS: 569.4 ([M þ
H]þ).
Data of 13 Yield: 0.63 g (66%). White solid. M.p. 1428. 1H-NMR (400 MHz, CDCl3): 1.49 (s, 9 H);
1.73 (m, 4 H); 3.42 (q, J ¼ 6.4, 2 H); 4.12 (t, J ¼ 5.6, 2 H); 7.02 (d, J ¼ 8.8, 2 H); 5.15 (s, 2 H); 7.22 (s, 1 H,
NH); 7.26 – 7.43 (m, 5 arom. H); 8.41 (d, J ¼ 8.8, 2 H). ESI-MS: 513.2 ([M þ H]þ).
2-[4-(Benzyloxy)phenyl]-N-(4-guanidinobutyl)-2-oxoacetamide Trifluoroacetate Salt (¼2-[4-(Ben-
zyloxy)phenyl]-N-(4-carbamimidamidobutyl)-2-oxoacetamide Trifluoroacetate; 14). Under N2, 2.2 g of
6b were added to a soln. of TFA in CH2Cl2 (1:1 mixture; 11 ml) at 08, and the mixture was stirred for ca.
3 h at r.t. The reaction was completed in 2 h (TLC). The mixture was concentrated under vacuum, and
t
the residue was co-distilled twice with BuOMe to remove traces of TFA. The residue was stirred with
tBuOMe, and the white precipitate so formed was filtered and dried under vacuum. Yield of 14: 1.78 g
(95%).
The synthesis of 14 was also achieved from 6a under identical reaction conditions in 90% yield. M.p.
115 – 1178. IR (KBr) 3368, 1704, 1667, 1645, 1604, 1574, 1547, 1509, 1473, 1455, 1427, 1381, 1316, 1250,
1231, 1268, 1203. 1H-NMR (400 MHz, CD3OD) : 1.66 (t, J ¼ 3.2, 4 H); 3.22 (t, J ¼ 6.6, 2 H); 5.20 (s, 2 H);
3.38 (t, J ¼ 6.2, 2 H); 7.12 (d, J ¼ 8.8, 2 H); 7.45 – 7.30 (m, 5 arom. H); 8.09 – 8.12 (m, 2 H). 13C-NMR
(100 MHz, CD3OD): 27.1; 27.3; 39.4; 42.0; 71.2; 115.9; 127.4; 128.6; 129.1; 129.5; 133.8; 137.7; 158.6; 165.3;
167.1; 189.2. ESI-MS: 369.20 ([M þ H]þ).
N-(4-Guanidinobutyl)-2-hydroxy-2-(4-hydroxyphenyl)acetamide (¼ N-(4-Carbamimidamidobutyl)-
2-hydroxy-2-(4-hydroxyphenyl)acetamide; 18). H2 Gas was bubbled through a suspension of 14 (0.5 g,
0.0013) in EtOH (7.5 ml) and 5% Pd/C (50% wet) at 0 – 58. After disappearance of starting material in ca.
7 h, the reaction mass was filtered, and filtrate was concentrated under vacuum to give 18 (0.48 g, 95%).
Pale-yellow oil. 1H-NMR (400 MHz, CDCl3): 1.40 – 1.42 (m, 4 H); 3.03 – 3.08 (m, 5 H); 4.04 (s, NH2); 4.76
(d, J ¼ 4.4, OH); 5.94 (d, J ¼ 4.4, 1 H); 6.70 (d, J ¼ 8.4, 2 H); 7.16 (d, J ¼ 8.4, 2 H); 7.56 (s, 1 H, NH); 7.96
(t, J ¼ 5.6, 1 H, NH); 9.34 (s, 1 H). 13C-NMR (100 MHz, CDCl3): 27.4; 28.0; 39.8; 42.4; 75.1; 116.7; 129.7;
133.0; 158.9; 156.0; 176.5. ESI-MS: 281.3 ([M þ H]þ).
N-(4-Guanidinobutyl)-2-(4-hydroxyphenyl)-2-oxoacetamide Hydrobromide (¼ N-{4-[(Aminoimi-
nomethyl)amino]butyl}-4-hydroxy-2-oxobenzeneacetamide Hydrobromide (1:1); 3 · HBr). TFA Salt
of guanidine derivative, 14 (1.5 g, 0.0031 mol), was added to a soln. of 33% HBr in AcOH (10 ml) at 0 –
58. The mixture was stirred for 2.5 h. The progress of the reaction was monitored by TLC, and after
completion, the mixture was concentrated under vacuum. The residue was diluted with AcOEt (20 ml)
and H2O (15 ml). The aq. layer was washed with Et2O (15 ml), and aq. layer containing product was
concentrated under vacuum completely. The residue was dissolved in MeOH (3 ml), and the product was
precipitated after addition of 15 ml of Et2O. The light-brown product was dried under vacuum at 508 to
furnish 3 (0.90 g, 80%). M.p. 154 – 1568. IR (KBr): 1664, 1644, 1612, 1594, 1528, 1474, 1437, 1372, 1337,
1310, 1282, 1257. 1H-NMR (400 MHz, CD3OD): 1.63 – 1.67 (m, 4 H); 3.22 (t, J ¼ 6.8, 2 H); 3.37 (t, J ¼ 6.2,
2 H); 6.84 – 6.88 (m, 2 H); 8.00 – 8.04 (m, 2 H). 13C-NMR (100 MHz, CD3OD): 27.1; 27.4; 39.4; 42.0;
116.5; 126.0; 134.1; 158.4; 165.0; 167.5; 189.2. ESI-MS: 279.15 ([M þ H]þ). HR-MS: 279.1471 ([M þ H]þ,
C13H19N4Oþ3 ; calc. 279.1457).
2,2-Dibromo-1-{1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}ethanone (20). To a pre-cooled dioxane
(100 ml) in a round-bottom flask was added Br2 (9.8 g, 0.0612 mol) under N2 at 208. To the yellow
suspension thus obtained was added 3-acetyl-N-[(4-methylphenyl)sulfonyl)]-1H-indole (19; 8.0 g,
0.025 mol) in 1 – 2 min and stirred for 2 – 3 h. After complete disappearance of starting material
(TLC), the mixture was poured into a mixture of ice and sat. aq. NaHCO3 soln. and stirred for 1 – 2 h.
The product was filtered and further purified by flash CC (SiO2; AcOEt/hexanes 20 :80) to give 20 (18 g,
77%). Light-pink solid. M.p. 162 – 1658. IR (KBr): 3128, 3015, 1656, 1531, 1383. 1173. 1H-NMR
(400 MHz, CDCl3): 2.37 (s, 3 H); 6.43 (s, 1 H); 7.20 – 7.51 (m, 4 H); 7.82 – 8.01 (m, 3 H); 8.28 – 8.35 (m,
1 H); 8.60 (s, 1 H). 13C-NMR (100 MHz, CDCl3): 21.6; 40.0; 113.1; 113.5; 123.0; 125.2; 126.2; 127.2; 127.8;
130.3; 133.2; 134.0; 134.5; 134.6; 146.2; 182.1. ESI-MS: 493.9 ([(M þ 2) þ Na]þ).
N-[2-(4-{[(tert-Butyl)(dimethyl)silyl]oxy}phenyl)ethyl]-2-{1-[(4-methylphenyl)sulfonyl]-1H-indol-
3-yl}-2-oxoacetamide (22). To a cooled suspesion of 2-{4-[(tert-butyl)(dimethyl)silyloxy]phenyl}ethan-
amine (21; 4.12 g, 0.0163 mol), K3PO4 (9.44 g, 0.0445 mol) and sulfolane (¼2,3,4,5-tetrahydrothiophene
1,1-dioxide; 35.0 ml) was added 20 (7.0 g, 0.0148 mol), and the mixture was stirred for 1 – 2 h under N2 at

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Helvetica Chimica Acta – Vol. 97 (2014)
r.t. tBuOOH soln. (5m in decane, 3.6 ml, 0.017 mol) was added and the mixture was stirred for 6 – 8 h. The
mixture was diluted with H2O (200 ml) and extracted with AcOEt (2 ꢁ 50 ml). The combined AcOEt
layer was washed with 10% aq. NaHSO3 soln., 10% aq. citric acid soln. (100 ml), and 10% aq. NaCl soln.
(100 ml). The org. layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was
purified by flash CC (SiO2; AcOEt/hexanes 20 :80) to give 22 (3.25 g, 38%). Off-white solid. M.p. 136 –
138.58. IR (KBr): 1690, 1645, 1608, 1509, 1477, 1443, 1377, 1290, 1251, 1190, 1176, 1132. 1H-NMR
(400 MHz, CDCl3): 0.19 (s, 6 H); 0.97 (s, 9 H); 2.36 (s, 3 H); 2.85 (t, J ¼ 7.2, 2 H); 3.60 (q, J ¼ 7.2, 2 H);
6.83 (d, J ¼ 8.4, 2 H); 7.12 (d, J ¼ 8.4, 2 H); 7.27 – 7.42 (m, 4 H); 7.87 (d, J ¼ 4.4, 2 H); 7.98 (dd, J ¼ 1.8, 6.8,
1 H); 8.32 (dd, J ¼ 1.4, 6.4, 1 H); 9.42 (s, 1 H). 13C-NMR (100 MHz, CDCl3): 4.4; 18.1; 21.2; 25.4; 34.6;
40.1; 113.9; 115.2; 120.7; 122.6; 125.4; 125.7; 127.7; 128.5; 129.4; 130.1; 130.5; 134.4; 134.5; 138.6; 145.5;
154.3; 161.5; 181.4. ESI-MS: 577.2 ([M þ H]þ).
N-[2-(4-Hydroxyphenyl)ethyl]-2-(1H-indol-3-yl)-2-oxoacetamide (2c). To a soln. of 22 (1.2 g,
0.0021 mol) in MeOH (24 ml) was added anh. CsCO3 (0.85 g, 0.0063 mol), and the mixture was stirred
at r.t. for 2 – 3 h. After disappearance of the starting material (TLC), the mixture was cooled, acidified to
neutral pH with AcOH, and concentrated under vacuum. The white residue thus obtained was suspended
in a mixture H2O/hexane, and the product was filtered after stirring. The product was further purified by
dissolving in MeOH, precipitating with H2O, and was dried at 508 under vacuum to give 2c (0.51 g, 80%).
1H-NMR (400 MHz, CDCl3): 2.83 (t, J ¼ 7.2, 2 H); 3.56 – 3.61 (m, 2 H); 6.78 – 6.81 (m, 2 H); 7.14 (d, J ¼
7.4, 2 H); 7.28 – 7.31 (m, 2 H); 7.45 – 7.49 (m, 1 H); 7.82 (s, 1 H); 8.32 – 7.35 (m, 1 H); 8.88 (s, 1 H).
13C-NMR (100 MHz, CD3OD): 36.7; 42.2; 113.2; 114.1; 116.4; 123.0; 123.9; 124.9; 128.0; 130.9; 131.1;
138.0; 139.6; 157.1; 165.7; 183.0. ESI-MS: 309.10 ([M þ H]þ). HR-MS: 307.1073 ([M ꢀ H]þ, C18H15N2O3þ ;
calc. 307.1083).
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Received August 16, 2013