Amine Activation: N-Arylamino Acid Amide Synthesis from Isothioureas and Amino Acids

Article abstract of DOI:10.1002/adsc.201700134

N-arylamino acid amides have been synthesized via a novel method based on N-arylamine activation into isothioureas followed by reaction with amino acids under iron catalysis. The activated N-arylamines are easily prepared using a three-component reaction with commercial reagents, tert-butylisocyanide and S-phenyl benzenethiosulfonate. The protocol shows a broad functional group compatibility, with respect to side chain functionality of the amino acid (e. g. aliphatic and aromatic OH, (hetero)aromatic NH, amide NH, thioether), and the chiral amino acids do not undergo epimerization. The mechanism of the new amide synthesis has been studied. (Figure presented.).

Full text of DOI:10.1002/adsc.201700134

UPDATES
DOI: 10.1002/adsc.201700134
1
2
3
4
5
6
Amine Activation: N-Arylamino Acid Amide Synthesis from
Isothioureas and Amino Acids
7
8
9
Yan-Ping Zhu,a Pieter Mampuys,a Sergey Sergeyev,a Steven Ballet,b and Bert U.
W. Maesa,*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
a
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
E-mail: bert.maes@uantwerpen.be
Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel,
Pleinlaan 2, B-1050 Brussels, Belgium
b
Received: February 3, 2017; Revised: May 16, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201700134
Abstract: N-arylamino acid amides have been
synthesized via a novel method based on N-aryl-
amine activation into isothioureas followed by
reaction with amino acids under iron catalysis. The
activated N-arylamines are easily prepared using a
three-component reaction with commercial re-
agents, tert-butylisocyanide and S-phenyl benzene-
thiosulfonate. The protocol shows a broad func-
tional group compatibility, with respect to side
chain functionality of the amino acid (e.g. aliphatic
and aromatic OH, (hetero)aromatic NH, amide
NH, thioether), and the chiral amino acids do not
undergo epimerization. The mechanism of the new
amide synthesis has been studied.
Keywords: amine activation; amino acid; amide;
iron; catalysis; carbodiimide; steric hindrance
Figure 1. Examples of N-heteroarylamide containing active
ingredients of agrochemicals and medicines.
Introduction
Despite the significant number of methods which
43 The amide functionality is one of the most important have been reported in the past decades, several
44 units in organic chemistry. It is the basic structural limitations and challenges remain for amide synthesis
45 unit of proteins, but is also widely present in various such as: a) mild reaction conditions, avoiding epimeri-
46 polymers (e.g. chitin, nylon), natural products (e.g. zation of a stereocenter at the alpha methylene of the
47 paclitaxel, penicillin), top-selling drugs (e.g. Atorvas- carboxylic acid; b) challenging amides e.g. featuring
48 tatin, Valsartan, Sitagliptin) and agrochemicals (e.g. sterically hindered carboxylic acids and/or electron
49 Boscalid, Fluxapyroxad) (Figure 1).[1] It is present in deficient (hetero)aromatic amines; c) versatile meth-
50 more than 25% of all launched pharmaceuticals and ods compatible with unprotected functional groups
51 2/3 of the drug candidates.[2] Moreover, it has been (e.g. NH2 and OH groups); d) use of (at least)
52 estimated that 16% of all reactions performed in stoichiometric amounts of often toxic and hazardous
53 pharma industry involve amide bond formation.[3] coupling/activating reagents, and associated genera-
54 Around 10 years ago, the ACS Green Chemistry tion of the corresponding stoichiometric waste which
55 Institute (GCI) Pharmaceutical roundtable identified is not always (easily) separable and usually not
56 amide synthesis as a key area of interest for the recoverable into the reagent. New synthetic ap-
57 industry, and this has not changed since then.[4]
Adv. Synth. Catal. 2017, 359, 1–19
1
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
2
3
4
5
6
7
8
9
proaches tackling one or more of these aspects are
therefore highly sought after by organic chemists.
Amide synthesis from a surrogate of an amine or
carboxylic acid is an important area studied. Up to
now, many innovative strategies have been reported
which do not rely on an amine and carboxylic acid:
aminocarbonylation of alkenes or alkynes,[5] coupling
of (activated) thioacids with amines or azides,[6]
various reactions of azides with N-tosyl aldimines or
10 ketones,[7] oxidation of in situ generated aminals from
11 alcohols and amines,[8] reaction of a-bromo nitro-
12 alkanes with amines and NIS,[9] radical based coupling
13 from a-keto acids with amines and aldehydes with Scheme 1. Amide synthesis based on amine activation.
14 N,N-disubstituted formamides[10] and reaction of
15 Grignard reagents with isocyanates or NCAs.[11]
16
However, procedures starting from carboxylic acids tion we herein report our findings on the use of
17 and amines are still the most interesting due to the sensitive side chain unprotected chiral amino acids
18 widespread availability of these building blocks. The using our recently disclosed method.[16a] After all, N-
19 acylation of amines with activated carboxylic acids heteroarylamino acid amide reaction products are
20 (C!N direction), such as, acyl chloride, acyl imidazole, important structural entities as exemplified by the
21 anhydride or activated ester (obtained by classical amino acid based APIs Lidocaine, Tocainide, Mepiva-
22 coupling reagents, such as carbodiimides, phosphonium caine, Prilocaine and Bentiromide (Figure 1).[1] In this
23 salts, uronium/guanidinium reagents),[12a] is still the manuscript, we also study the reaction mechanism of
24 most common route for amide synthesis. They gener- our new amide synthesis based on fundamental studies
25 ally allow mild reaction conditions and result in often with model compounds.
26 good yields. Sometimes, the activated carboxylic acids
27 are generated in an extra step and activation requires
28 unstable, expensive and waste-intensive reagents. Re-
Results and Discussion
29 cent advances in this field use acetylenes and a N-Protected a-amino acids 2 were evaluated under
30 transition metal and ynamides to activate the carbox- the standard conditions for amide synthesis disclosed
31 ylic acid or Si ligation with 9-silafluorenyl dichlor- in our communication (Fe(acac)3 (2.5 mol%), i-PrOH
32 ides.[12b–d] Epimerization of sensitive a-chiral acids (2 mL), 838C, air, 24 h).[16a] Reaction of amino acids l-
33 through the formation of oxazolone intermediates is 2 with the model activated aniline N-tert-butyl-S,N’-
34 difficult to suppress with carboxylic acid activation. diphenylisothiourea (1a) gave the corresponding N-
35 Lewis acids catalysis involving boron species or metal phenyl amino acid amides l-3 in moderate to excellent
36 salts is an interesting relatively new approach for amide yield (57–97%) (Scheme 2). The reaction proved to be
37 synthesis, but the substrate scope is unfortunately still fully compatible with standard nitrogen protective
38 limited to standard amides.[12e–g]
groups for amino acids (Boc, Cbz and Fmoc). Acid
39
As an alternative approach, amine activation (N! labile Boc did not deprotect under these reaction
40 C direction) has been developed. Its main advantage conditions though a Lewis acid at a higher temper-
41 is that epimerization of a-chiral acids such as amino ature is used. Remarkably, even very challenging
42 acids is expected to be easily avoided. But up to now amino acids, such as Boc-l-Gln-OH (l-2g), Boc-l-
43 only a few procedures have been reported based on Thr-OH (l-2i), Boc-l-Tyr-OH (l-2p), Boc-l-Trp-OH
44 this approach (Scheme 1). Amine activation as (l-2r), and Boc-l-His-OH (l-2s) featuring a nucleo-
45 isocyanide (a),[13] N-(imidazolylcarbonyl)amine (b),[14] philic group in the side chain could be used, without
46 and iminophosphorane (in situ obtained from azides requiring any protection. Boc-l-Thr-OH (l-2i) was
47 and phosphines) (c)[15] have been developed.
48
selected as model to test amide synthesis with other
Within our program on amide synthesis,[16] we have isothioureas. N’-Tert-butyl-S-phenyl-N’-(hetero)aryli-
49 recently reported isothiourea as a new class of sothiourea featuring sterically hindered substituents
50 activated amines suitable for N-(hetero)arylamide (N-2,6-diisopropylphenyl, 1x), strong electron-with-
51 synthesis (Scheme 1, route d).[17] The protocol uses an drawing substituents (N-4-methoxycarbonylphenyl,
52 iron catalyst under mild reaction conditions and is 1o) and heteroaromatic cores (N-pyridin-3-yl, 1r)
53 especially suitable for the synthesis of very challenging afforded the threoninamides l-3j–l-3l in good yields.
54 N-heteroarylamides, from the point of view of sterics Similarly, d-amino acids d-2 were successfully applied
55 and electronics, which are not (or only in poor yield) as exemplified for some selected representatives
56 accessible via classical coupling reagents. Realizing (Scheme 3). Importantly, no epimerization occurred
57 that N-activation strategies should avoid epimeriza-
Adv. Synth. Catal. 2017, 359, 1–19
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
2
3
4
5
6
7
8
9
with the l- and d-amino acids tested (Supporting
Information).
Unnatural amino acids as exemplified by Cbz-Aib-
OH (2t), Boc-b-Ala-OH (2u), and Boc-Inp-OH (2v)
also worked equally well (Scheme 4). Finally, we
tested this protocol to transform the a-carboxylic acid
group of a short peptide into an amide (Scheme 5).
Rewardingly, N-Boc-triglycine (2w) readily reacted
with N-aryl-N’-tert-butyl-S-phenylisothioureas (N-
phenyl 1d, N-t-butylphenyl 1y, and N-4-bromophenyl
1m) and the corresponding triglycinamides (3aa–3ac)
were obtained in 79–87%. When more challenging
tripeptides N-Boc-L-Pro-L-Val-L-Pro-OH (2x) and N-
Boc-L-Trp-L-Gln-L-Ala-OH (2y) reacted with N-tert-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
butyl-S,N’-diphenylisothiourea
standard condition, the desired tripeptides 3ad and
3ae were obtained in a very good yield.
(1a)
under
the
Scheme 2. l-Amino acid (l-2) scope. Reaction conditions:
isothiourea 1 (0.30 mmol), l-amino acid l-2 (0.36 mmol),
Fe(acac)3 (2.5 mol%), isopropanol (2 mL), 838C, air, 24 h.
[a] 72 h. [b] Fe(acac)3 (5 mol%). [c] Fe(acac)3 (10 mol%). [d]
48 h.
Scheme 4. Unnatural amino acid scope. Reaction conditions:
isothiourea
1 (0.30 mmol), amino acid 2 (0.36 mmol),
Fe(acac)3 (2.5 mol%), isopropanol (2 mL), 838C, air, 24 h.
Scheme 5. N-Boc-triglycine. Reaction conditions: isothiourea
1 (0.30 mmol), N-Boc-triglycine (2w) or N-Boc-L-Pro-L-Val-
L-Pro-OH (2x) (0.36 mmol), Fe(acac)3 (2.5 mol%), isopropa-
nol (2 mL), 838C, air, 24 h. [a] isothiourea 1 (0.15 mmol), N-
Boc-L-Trp-L-Gln-L-Ala-OH (2y) (0.18 mmol), 48 h.
In order to demonstrate the potential of the new
methodology for amino-acid amide synthesis, we
applied it for the synthesis of the antiarrythmic drug
Tocainide (3x) (Scheme 6). This drug is sold as a
racemate but the R-enantiomer is 4 times as potent as
the S-enantiomer. Classically, 3x is made by acylation
Scheme 3. d-Amino acid scope. Reaction conditions: iso-
thiourea 1 (0.30 mmol), d-amino acid d-2 (0.36 mmol),
Fe(acac)3 (2.5 mol%), isopropanol (2 mL), 838C, air, 24 h.
[a] 72 h. [b] Fe(acac)3 (5 mol%). [c] Fe(acac)3 (10 mol%). [d]
48 h.
of 2,6-dimethylaniline with
bromide, followed by nucleophilic substitution of the
2-bromopropanoyl
Adv. Synth. Catal. 2017, 359, 1–19
3
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Scheme 6. Synthesis of R-Tocainide. [a] Reaction conditions: Fe(acac)3 (10 mol%), isopropanol (2 mL), 838C, air, 72 h.
16 remaining bromine atom with ammonia.[18] Our ap- mide serve as intermediates in the reaction mecha-
17 proach starts from Boc-protected alanine (2c), of nism. Also FeII proved to be a suitable catalyst as
18 which both the l- and d-enantiomer are readily illustrated by a reaction of N-tert-butyl-S,N’-diphenyli-
19 commercially available. N-tert-Butyl-N’-2,6-dimethyl- sothiourea (1a) with pivalic acid (5e) in the presence
20 phenyl-S-phenylisothiourea (1v) was easily prepared of Fe(acac)2, which also afforded N-phenylpivalamide
21 in very high yield from 2,6-dimethylaniline, S-phenyl (6e) but in a slightly lower yield than with Fe(acac)3
22 benzenethiosulfonate and tert-butyl isocyanide.[17] Re- (compare F with G). This indicates a Lewis acid role
23 action of 1v and d-2c in 2-butanol yielded (R)-N-Boc for iron.
24 Tocainide in 93%. When the reaction was performed
25 in isopropanol at 838C 95% isolated yield was
26 obtained but more Fe(acac)3 catalyst (10 mol%) and a
27 longer reaction time (72 h) were needed to achieve
28 full conversion. Starting from l-2c the S enantiomer
29 was easily obtained in a similar manner (91% yield).
30 No epimerization occurred under the reaction con-
31 ditions (Supporting Information). Boc deprotection of
32 (R)-N-Boc Tocainide finally delivered (R)-Tocainide.
33 An overall yield of 80% was obtained for the most
34 active enantiomer, (R)-N-Boc Tocainide. Interestingly,
35 the PhSSPh by-product formed from PhSH under the
36 reaction conditions could be isolated in 81% yield. It
37 can be transformed into S-phenyl benzenethiosulfo-
38 nate reagent according to a literature procedure.[19]
39
To gain insight in the reaction mechanism of our
40 new amide synthesis and to identify possible reaction
41 intermediates, a set of control experiments were
42 performed (Scheme 7). The synthesis of N-phenyl-
43 benzamide (6a) was selected as model. When N-tert-
44 butyl-N’-phenylurea (4) was treated with benzoic acid
45 (5a) under the standard conditions no reaction
46 occurred (Scheme 7, A). When N-benzoyl-N’-tert-
47 butyl-N-phenylurea (7) was used as substrate, 6a was
48 obtained in excellent yield (B). Reaction of N-tert-
49 butyl-N’-phenylcarbodiimide (8) with 5a yielded a
50 mixture of amide 6a and urea 4 in 85% and 8%,
51 respectively (C). A similar result was obtained without
52 Fe catalyst (C). When the same reaction was
53 performed in the presence of the by-products formed
54 during the amide synthesis [phenyldisulfide (D) and
55 thiophenol (E)] similar results were obtained. These
Scheme 7. Control experiments to support the mechanism of
the amide formation. Isolated yields. [a] 1H NMR yield, using
1,3,5-trimethoxybenzene as internal standard.
On the basis of the above results, a reaction
56 experiments indicate that N-acyl-N’-tert-butyl-N- (het- mechanism is proposed in Scheme 8 (left). Initially,
57 ero)arylurea and N-tert-butyl-N’-(hetero)arylcarbodii- the isothiourea-Fe complex B is formed. This com-
Adv. Synth. Catal. 2017, 359, 1–19
4
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Scheme 8. Reaction mechanism: carbodiimide as an intermediate (A) versus reagent (B).
25 plexation activates the substrate for elimination, activation process, while it is a carboxylic acid
26 yielding carbodiimide C. Reaction of C with carbox- activating reagent in the classical approach. This
27 ylic acid affords O-acylisourea D, which undergoes an difference clearly reflects in the efficiency of both
28 O!N acyl migration (Mumm rearrangement)[20] to protocols (vide infra, Scheme 11).
29 form N-acyl-N-(hetero)aryl-N’-tert-butylurea E. Fi-
Two different amides can in principle be formed in
30 nally, E eliminates tert-butyl isocyanate yielding N- our protocol as the reaction mechanism involves O!
31 (hetero)arylamide. The avoidance of racemization in N migration in the O-acylisourea intermediate D.[20] In
32 reactions with amino acids is in accordance with a our reactions, however, only one amide was always
33 very fast O!N acyl migration, which protects the a- selectively formed. The features of such migrations
34 position of the carbonyl. The formation of urea side remain largely unstudied, as it is an undesired side
35 product F with electrophilic or more sterically hin- reaction when using carbodiimide as coupling reagents
36 dered acyl groups can be explained by reaction of D (Scheme 8, right) (vide infra), diminishing the yield of
37 with isopropanol (solvent). Alcoholysis of O-acylisour- the desired amide.[21] Therefore, we studied the acyl
38 ea can for those cases be suppressed by using a more migration on a series of isothiourea substrates in the
39 sterically hindered alcohol (2-butanol) or a non- reaction with benzoic acid under the same reaction
40 nucleophilic solvent (o-xylene) as we have disclosed in conditions (Scheme 9). Isothioureas with an alkyl and
41 our communication.[16a] It is actually remarkable that aryl group on nitrogen (9, 11) always gave the N-
42 in the majority of reported examples alcoholysis with arylbenzamide irrespective of the sterics of the alkyl
43 isopropanol does not compete with O!N acyl migra- group (Scheme 9AꢀB). Even in 11, which features two
44 tion and no F is formed, again pointing to very fast ortho methyl’s in the arene and an unbranched
45 acyl transfer.
aliphatic chain, selective migration to the arylated
46
Although our protocol and the one based on nitrogen occurred. This supports the complete regio-
47 carbodiimide coupling reagents activating carboxylic selectivity obtained in our N-(hetero)arylamide syn-
48 acid (e.g. DCC) both involve an O-acylisourea inter- thesis featuring an alkyl and (hetero)aryl nitrogen
49 mediate they are mechanistically completely different substituent in the isothiourea substrate. This can be
50 (Scheme 8, right). In the latter case, O-acylisourea rationalized by protonation of the most basic nitrogen
51 does not undergo O!N acyl migration, but reacts of the carbodiimide intermediate by carboxylic acid.
52 directly in an intermolecular reaction with amine or
Next, substrates containing two N-alkyl groups
53 another molecule of carboxylic acid. Often a nucleo- were studied (12, 15 and 17[17]). Isothiourea 12,
54 philic additive such as HOBt, HOAt or DMAP is containing a tert-butyl and an ethyl group, gave N-tert-
55 added to form an “active ester”, explicitly avoiding butylbenzamide (13) as minor and N-ethylbenzamide
56 the migration. Moreover, the carbodiimide (inter- (14) as major product (Scheme 9C). With an electron-
57 mediate) in our protocol results from the amine withdrawing ester in the b-position (15), selectivity
Adv. Synth. Catal. 2017, 359, 1–19
5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
would be a solution. However, as our previously
developed three-component reaction for isothiourea
synthesis does not tolerate the activation of aliphatic
amines, this would require a synthesis involving the
corresponding carbodiimides.[17] We envisioned that
the use of symmetrical carbodiimides directly, which
can be accessed from alkylamines, would be a
potential strategy to overcome these limitations and,
therefore, represents an interesting alternative amine
activation.[22] They can for instance be synthesized by
reaction of an alkylamine and an alkylisocyanide using
I2 as catalyst and cumene hydroperoxide as stoichio-
metric oxidant.[22c] Pleasingly, when N,N’-dicyclohexyl-
(23a), N,N’-diisopropyl- (23b), N,N’-di-tert-butyl-
(23c) and N,N’-diadamantylcarbodiimide (23d) were
reacted with 2,2,2-triphenylacetic acid (5d) the target
sterically encumbered aliphatic amides were obtained
in good yield (Scheme 10). The process starting from
carbodiimide does not require an iron catalyst though
a non-nucleophilic solvent, avoiding urea side product
formation, and a higher reaction temperature are
essential. This strategy can also be used for (hetero)
aromatic amines as exemplified for the reaction of
N,N’-(2,6-diisopropylphenyl)carbodiimide (23e) with
5d.
Scheme 9. Selectivity of amide formation in the reaction of
N,Nꢁ-disubstituted-S-phenylisothiourea with carboxylic acids.
Isolated yields. [a] 1H-NMR yield, using 1,3,5-trimethoxyben-
zene as internal standard.
30 was lost and an almost equal amount of the two
31 amides was obtained (Scheme 9D). When the elec-
32 tron-withdrawing character was further increased by
33 building in three b-fluorine atoms (17), instead of an
34 ester, almost exclusive formation of 13 was observed
35 (Scheme 9E).
36
Subsequently, the sterics of the acyl group were
37 altered by changing the carboxylic acid in a reaction
38 with 17. More sterically hindered diphenylacetic acid
39 (5b), 2,2-diphenylpropionic acid (5c) and triphenyl-
40 acetic acid (5d) completely reversed the selectivity
41 observed with benzoic acid (Scheme 9E) and gave the
42 corresponding N-trifluorethylamide as major compo-
43 nent (Scheme 9 FꢀH). From all these experiments we
44 can conclude that in the absence of electronic effects,
Scheme 10. Synthesis of amides from carbodiimides and
carboxylic acids. Reaction conditions: 23 (0.30 mmol), 5d
(0.36 mmol), o-xylene (2 mL), 1308C, air, 24 h.
When we attempted to synthesize amino acid
45 sterics always govern the acyl transfer but strong amides 3 with Boc-l-Thr-OH (L-2i) and Boc-l-His-
46 electron-withdrawing groups can overrule sterics in OH (l-2s) featuring a nucleophilic group in the side
47 reactions with less bulky carboxylic acids. With two chain or sterically hindered aliphatic amides 24 via
48 alkyl groups on the nitrogen atoms in the isothiourea classical reaction of amine and carboxylic acid with
49 simple nitrogen basicity of the in-situ formed carbodii- DCC no or only a low amount of the target amides
50 mide cannot explain the experimental observations.
was obtained (Scheme 11). The new amide synthesis
51
Based on the regio-selectivity observed for the O! disclosed is therefore complementary with classical
52 N acyl transfer in O-acylisourea, extension of the protocols. While both protocols will provide standard
53 protocol towards challenging amides based on ali- amides only the new protocol gives efficient access to
54 phatic amines seems to be limited by the steric the challenging representatives. Though the classical
55 properties of the carboxylic acid, and no generally and new procedure both involve a carbodiimide, the
56 applicable protocol could be identified (Scheme 9). efficiency difference reflects the different reaction
57 Use of symmetrical isothiourea as activated amines mechanism (vide supra).
Adv. Synth. Catal. 2017, 359, 1–19
6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
2
3
acylisourea intermediate they are mechanistically
completely different, based on a different substrate,
explaining the very poor results obtained for the latter
approach in challenging amide synthesis.
4
5
6
7
Experimental Section
The general information of the equipment used to character-
ize the synthesized compounds can be found in the support-
ing information. The synthesis and characterization of
compounds 1v,[16a] 6e[16a] and 17[17] has previously been
described by us.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
General procedure
A for the synthesis of N-(hetero)
arylamides: A 10 mL pressure vial was charged with N-aryl-
N’-tert-butyl-S-phenylisothiourea (1) (0.30 mmol), carboxylic
acid (0.36 mmol), Fe(acac)3 (2.7 mg, 2.5 mol%) and isopro-
panol (2.0 mL) or 2-butanol (2.0 mL). The vial was sealed
and the reaction mixture was respectively stirred at 838C or
988C for 24 h under an air atmosphere. The mixture was
cooled down to room temperature, concentrated under
reduced pressure and dried under vacuum. The residue was
purified by flash column chromatography on silica gel or
recrystallized (compounds 3v–3x) to yield the corresponding
N-(hetero)arylamide.
Scheme 11. Synthesis of examples of Scheme 2 and 10 using
classical method from carboxylic acids and amines with
DCC. [a] Method A. Reaction conditions: amino acid 2
(1.0 mmol), HOBt hydrate (1.1 mmol), DCC (1.1 mmol),
aniline (1.1 mmol), anhydrous THF (5 mL), 258C, 24 h. [b]
Method B. Reaction conditions: R1CO2H 5 (1.05 mmol),
DCC (1.08 mmol), DMAP (0.25 mmol), amine (1.0 mmol),
CH2Cl2 (10 mL), 0–258C, 24 h.
Benzyl [2-oxo-2-(phenylamino)ethyl]carbamate (3a):[23] Pre-
pared from N-tert-butyl-S,N’-diphenylisothiourea (1d)
(85 mg, 0.30 mmol, 1.0 equiv.) and Z-Gly-OH (2a) (75 mg,
0.36 mmol, 1.2 equiv.) according to the general procedure A.
The residue was purified by column chromatography on
silica gel with heptane/EtOAc=1:1 as eluent. Benzyl [2-oxo-
2-(phenylamino)ethyl]carbamate was obtained in 60% yield
(51 mg). White solid, m.p.: 122–1248C (lit.:[23] 144–1458C), 1H
NMR (400 MHz, DMSO-d6): d (ppm) 9.95 (s, 1H), 7.61 (d,
J=7.6 Hz, 2H), 7.53 (s, 1H), 7.38 (br s, 3H), 7.31 (t, J=
7.6 Hz, 4H), 7.05 (t, J=7.2 Hz, 1H), 5.07 (s, 2H), 3.85 (d, J=
5.6 Hz, 2H); 13C NMR (101 MHz, DMSO-d6): d (ppm) 167.9,
156.6, 138.9, 137.0, 128.7, 128.3, 127.74, 127.67, 123.2, 119.1,
65.5, 44.1; HRMS (ESI): m/z [M+H]+ calcd for C16H17N2O3:
285.1239; found 285.1250.
Conclusion
30 A novel protocol for amino acid amide synthesis was
31 developed based on rarely explored amine rather than
32 carboxylic acid activation which does not require
33 rigorously dried solvents or an inert atmosphere.
34 (Hetero)arylamines are easily activated as bench
35 stable N-tert-butyl-N’-(hetero)aryl-S-phenylisothiour-
36 ea via a three-component reaction with commercially
37 available reagents, tert-butylisocyanide and S-phenyl
38 benzenethiosulfonate.
N-(hetero)arylamino
acid
39 amides can be obtained in high selectivity and yield
40 from these isothioureas via reaction with amino acids
41 under iron catalysis, showing a broad functional group
42 compatibility (e.g. aliphatic and aromatic OH, (het-
43 ero)aromatic NH, amide NH, thioether) without any
44 racemization. The potential of the new methodology
45 has been exemplified by the synthesis of the API
46 Tocainide. Mechanistic studies revealed that the
47 reaction involves a N-tert-butyl-N’-(hetero)arylcarbo-
48 diimide and is based on a selective O!N acyl transfer
49 in the O-acyl-N-tert-butyl-N’-(hetero)arylisourea inter-
50 mediate, formed via reaction of the carbodiimide with
51 carboxylic acid. Such selective transfer cannot be
52 achieved in the corresponding N,N’-dialkyl systems
53 and therefore challenging aliphatic amides were in
54 this case prepared from alternative activated amines,
55 namely symmetrical carbodiimides. Although our
56 protocol and the one based on classical carbodiimide
57 coupling reagents (e.g. DCC) both involve an O-
(9H-Fluoren-9-yl)methyl
[2-oxo-2-(phenylamino)ethyl]
carbamate (3b) Prepared from N-tert-butyl-S,N’-diphenyliso-
thiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and N-Fmoc-
Gly-OH (2b) (107 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by
recrystalization with EtOAc/MeOH=9:1. (9H-Fluoren-9-yl)
methyl [2-oxo-2-(phenylamino)ethyl]carbamate was obtained
in 77% yield (86 mg). White solid, m.p.: 186–1898C, 1H
NMR (400 MHz, DMSO-d6): d (ppm) 9.94 (s, 1H), 7.89 (d,
J=7.2 Hz, 2H), 7.74 (d, J=7.2 Hz, 2H), 7.60 (d, J=8.0 Hz,
3H), 7.40 (t, J=7.2 Hz, 2H), 7.29–7.35 (m, 5H), 7.04 (t, J=
7.2 Hz, 1H), 4.32 (d, J=7.2 Hz, 2H), 4.25 (t, J=7.2 Hz, 1H),
3.82 (d, J=6.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d
(ppm) 167.9, 156.6, 143.8, 140.7, 138.9, 128.7, 127.6, 127.0,
125.2, 123.2, 120.0, 119.1, 65.7, 46.6, 44.0; HRMS (ESI): m/z
[M+H]+ calcd for C23H21N2O3: 373.1547; found 373.1557.
tert-Butyl
(2S)-[1-oxo-1-(phenylamino)propan-2-yl]
carbamate (l-3c)[24] Prepared from N-tert-butyl-S,N’-diphe-
nylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-
Adv. Synth. Catal. 2017, 359, 1–19
7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
(l)-Ala-OH (l-2c) (68 mg, 0.36 mmol, 1.2 equiv.) according
to the general procedure A. The residue was purified by
column chromatography on silica gel with heptane/EtOAc=
2:1 as eluent. tert-Butyl (S)-[1-oxo-1-(phenylamino)propan-2-
yl]carbamate was obtained in 96% yield (76 mg). White
solid, m.p.: 142–1448C, 1H NMR (400 MHz, DMSO-d6): d
(ppm) 9.87 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.30 (t, J=
7.6 Hz, 2H), 7.04 (t, J=7.6 Hz, 1H), 6.99 (s, 1H), 4.14 (quint,
J=7.2 Hz, 1H), 1.39 (s, 9H), 1.27 (d, J=6.8 Hz, 3H); 13C
NMR (101 MHz, DMSO-d6): d (ppm) 171.8, 155.2, 139.1,
128.6, 123.1, 119.1, 78.0, 50.4, 28.2, 18.0; HRMS (ESI): m/z
[M+H]+ calcd for C14H21N2O3: 265.1547; found 265.1555.
28.2, 19.2; HRMS (ESI): m/z [M+Na]+ calcd for C16H24N2O3
Na: 315.1685; found 315.1681.
1
2
3
4
5
6
7
8
9
tert-Butyl [(2S,3S)-3-methyl-1-oxo-1-(phenylamino)pentan-
2-yl]carbamate (l-3e)[25] Prepared from N-tert-butyl-S,N’-
diphenylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and
Boc-(l)-Ile-OH (l-2e) (83 mg, 0.36 mmol, 1.2 equiv.) accord-
ing to the general procedure A. The residue was purified by
column chromatography on silica gel with heptane/EtOAc=
1:1 as eluent. tert-Butyl [(2S,3S)-3-methyl-1-oxo-1-(phenyl-
amino)pentan-2-yl]carbamate was obtained in 96% yield
(88 mg). White solid, m.p.: 161–1638C (lit.:[25] 124–1258C), 1H
NMR (400 MHz, CDCl3): d (ppm) 9.17 (s, 1H), 7.50 (d, J=
8.0 Hz, 2H), 7.17 (t, J=7.6 Hz, 2H), 7.02 (t, J=7.6 Hz, 1H),
5.82 (s, 1H), 4.29 (s, 1H), 1.96 (d, J=5.6 Hz, 1H), 1.69 (br s,
1H), 1.43 (s, 9H), 1.23–1.29 (m, 1H), 1.04 (d, J=6.8 Hz, 3H),
0.93 (t, J=7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3): d
(ppm) 171.3, 156.5, 137.9, 128.6, 123.9, 120.0, 79.8, 60.0, 37.2,
28.3, 25.0, 15.4, 10.8; HRMS (ESI): m/z [M+H]+ calcd for
C17H27N2O3: 307.2022; found 307.2020.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
tert-Butyl
(2R)-[1-oxo-1-(phenylamino)propan-2-yl]
carbamate (d-3c)[25] Prepared from N-tert-butyl-S,N’-diphe-
nylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-
(d)-Ala-OH (d-2c) (68 mg, 0.36 mmol, 1.2 equiv.) according
to the general procedure A. The residue was purified by
column chromatography on silica gel with heptane/EtOAc=
2:1 as eluent. tert-Butyl (2R)-[1-oxo-1-(phenylamino)propan-
2-yl]carbamate was obtained in 95% yield (75 mg). White
solid, m.p.: 142–1448C, 1H NMR (400 MHz, CDCl3): d (ppm)
8.77 (s, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H),
7.05 (t, J=7.2 Hz, 1H), 5.39 (d, J=7.6 Hz, 1H), 4.41 (br s,
1H), 1.45 (s, 9H), 1.43 (s, 3H); 13C NMR (101 MHz, CDCl3):
d (ppm) 171.2, 156.1, 137.8, 128.8, 124.1, 119.8, 80.4, 50.7,
28.3, 17.8; HRMS (ESI): m/z [M+H]+ calcd for C14H21N2O3:
265.1547; found 265.1557.
tert-Butyl (2S)-2-(phenylcarbamoyl)pyrrolidine-1-carboxy-
late (l-3f)[27] Prepared from N-tert-butyl-S,N’-diphenyliso-
thiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-(l)-
Pro-OH (l-2f) (77 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:1 as
eluent. tert-Butyl (S)-2-(phenylcarbamoyl)pyrrolidine-1-car-
boxylate was obtained in 97% yield (84 mg). Brown solid,
m.p.: 186–1888C (lit.:[27] 187–1888C), 1H NMR (400 MHz,
CDCl3): d (ppm) 9.49 (br s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.25
(m, 2H), 7.03 (m, 1H), 4.47 (m, 1H), 3.48 (m, 2H), 2.44 (m,
1H), 1.91–1.99 (m, 3H), 1.49 (s, 9H); 13C NMR (101 MHz,
CDCl3): d (ppm) 170.1, 156.4, 138.0, 128.9, 123.9, 119.7, 80.8,
60.4, 47.2, 28.4, 27.3, 24.1; HRMS (ESI): m/z [M+H]+ calcd
for C16H23N2O3: 291.1703; found 291.1715.
tert-Butyl-(2S)-[3-methyl-1-oxo-1-(phenylamino)butan-2-yl]
carbamate (l-3d)[26] Prepared from N-tert-butyl-S,N’-diphe-
nylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.), Boc-(l)-
Val-OH (l-2d) (78 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3
(2.65 mg, 2.5 mol%) according to the general procedure A.
The residue was purified by column chromatography on
silica gel with heptane/EtOAc=1:1 as eluent. tert-Butyl (2S)-
[3-methyl-1-oxo-1-(phenylamino)butan-2-yl]carbamate was
obtained in 95% yield (83 mg). White solid, m.p.: 120–1218C
tert-Butyl (2R)-2-(phenylcarbamoyl)pyrrolidine-1-carboxy-
late (d-3f) Prepared from N-tert-butyl-S,N’-diphenyliso-
thiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-(d)-
Pro-OH (d-2f) (77 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:1 as
eluent. tert-Butyl (2R)-2-(phenylcarbamoyl)pyrrolidine-1-car-
boxylate was obtained in 90% yield (78 mg). White solid,
1
(lit.:[26] 120–1228C), H NMR (400 MHz, CDCl3): d (ppm)
9.00 (s, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.19 (t, J=7.6 Hz, 2H),
7.03 (t, J=7.6 Hz, 1H), 5.74 (d, J=8.4 Hz, 1H), 4.23 (s, 1H),
2.21 (t, J=6.8 Hz, 1H), 1.44 (s, 9H), 1.06 (d, J=7.2 Hz, 3H),
1.05 (d, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): d
(ppm) 171.0, 156.5, 137.8, 128.7, 124.0, 120.0, 80.0, 61.0, 31.0,
28.3, 19.3; HRMS (ESI): m/z [M+Na]+ calcd for C16H24N2O3
Na: 315.1685; found 315.1681.
1
m.p.: 186–1888C, H NMR (400 MHz, CDCl3): d (ppm) 9.43
(br s, 1H), 7.51 (d, J=7.6 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H),
7.08 (t, J=6.4 Hz, 1H), 4.45 (br s, 1H), 3.44 (br s, 2H), 2.54
(br s, 1H), 1.91 (br s, 2H), 1.58 (br s, 1H), 1.49 (s, 9H); 13C
NMR (101 MHz, CDCl3): d (ppm) 167.7, 132.4, 130.8, 128.8,
123.7, 119.6, 80.8, 68.1, 47.1, 28.3, 23.7, 22.9; HRMS (ESI):
m/z [M+H]+ calcd for C16H23N2O3: 291.1703; found
291.1710.
tert-Butyl-(2R)-(3-methyl-1-oxo-1-(phenylamino)butan-2-yl)
carbamate (d-3d)[26] Prepared from N-tert-butyl-S,N’-diphe-
nylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.), Boc-(d)-
46 Val-OH (d-2d) (78 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by column
47
chromatography on silica gel with heptane/EtOAc=1:1 as
eluent. tert-Butyl-(2R)-(3-methyl-1-oxo-1-(phenylamino)bu-
tan-2-yl)carbamate was obtained in 90% yield (88 mg).
48
49
50
51
52
53
54
55
56
57
tert-Butyl (2S)-[5-amino-1,5-dioxo-1-(phenylamino)pentan-
2-yl]carbamate (l-3g) Prepared from N-tert-butyl-S,N’-di-
phenylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.), Boc-
(l)-Gln-OH (l-2g) (89 mg, 0.36 mmol, 1.2 equiv.) and Fe(a-
cac)3 (5.3 mg, 5 mol%) according to the general procedure A
with 72 hours reaction time. The residue was purified by
column chromatography on silica gel with heptane/EtOAc=
1:3 as eluent. tert-Butyl (2S)-[5-amino-1,5-dioxo-1-(phenyl-
amino)pentan-2-yl]carbamate was obtained in 83% yield
1
White solid, m.p.: 120–1218C (lit.:[26] 120–1228C), H NMR
(400 MHz, CDCl3): d (ppm) 9.28 (br s, 1H), 7.47 (d, J=
7.6 Hz, 2H), 7.12 (br s, 2H), 6.99–6.97 (m, 1H), 5.97 (d, J=
8.4 Hz, 1H), 4.28 (br s, 1H), 2.18–2.16 (m, 1H), 1.40 (s, 9H),
1.05 (d, J=6.4 Hz, 6H); 13C NMR (101 MHz, CDCl3): d
(ppm) 171.2, 156.5, 137.8, 128.5, 123.9, 120.0, 79.7, 61.0, 31.1,
Adv. Synth. Catal. 2017, 359, 1–19
8
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
(80 mg). White solid, m.p.: 174–1768C, H NMR (400 MHz,
DMSO-d6): d (ppm) 9.91 (s, 1H), 7.59 (d, J=7.6 Hz, 2H),
7.30 (t, J=7.6 Hz, 3H), 7.04 (t, J=7.2 Hz, 1H), 6.98 (d, J=
6.8 Hz, 1H), 6.75 (br s, 1H), 4.04 (m, 1H), 2.15–2.16 (m, 2H),
1.79–1.90 (m, 2H), 1.38 (s, 9H); 13C NMR (101 MHz, DMSO-
d6): d (ppm) 174.2, 171.4, 155.9, 139.4, 129.2, 123.8, 119.8,
78.6, 55.3, 32.0, 29.0, 28.7; HRMS (ESI): m/z [M+H]+ calcd
for C16H24N3O4: 322.1761; found 322.1765.
67.1, 66.6, 55.4, 40.2, 31.8, 29.2, 22.3; HRMS (ESI): m/z [M+
1
2
3
4
5
6
7
8
9
H]+ calcd for C18H32N3O5: 490.2336; found 490.2344.
tert-Butyl [(2S,3R)-3-hydroxy-1-oxo-1-(phenylamino)butan-
2-yl]carbamate (l-3i) Prepared from N-tert-butyl-S,N’-diphe-
nylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.), Boc-(l)-
Thr-OH (l-2i) (79 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3
(5.3 mg, 5 mol%) according to the general procedure A with
72 hours reaction time. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:1 as
eluent. tert-Butyl [(2S,3R)-3-hydroxy-1-oxo-1-(phenylamino)
butan-2-yl]carbamate was obtained in 88% yield (78 mg).
White solid, m.p.: 101–1038C, 1H NMR (400 MHz, CDCl3): d
(ppm) 8.87 (s, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.29 (t, J=
8.0 Hz, 2H), 7.10 (t, J=7.6 Hz, 1H), 5.85 (d, J=7.6 Hz, 1H),
4.42 (q, J=5.6 Hz, 1H), 4.28 (d, J=6.4 Hz, 1H), 3.96 (s, 1H),
1.48 (s, 9H), 1.24 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d (ppm) 169.6, 156.8, 137.3, 128.8, 124.5, 120.2, 80.6,
67.0, 59.0, 28.2, 18.2; HRMS (ESI): m/z [M+H]+ calcd for
C15H23N2O4: 295.1652; found 295.1663.
tert-Butyl (2R)-[5-amino-1,5-dioxo-1-(phenylamino)pentan-
2-yl]carbamate (d-3g) Prepared from N-tert-butyl-S,N’-di-
phenylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.), Boc-
(d)-Gln-OH (d-2g) (89 mg, 0.36 mmol, 1.2 equiv.) and
Fe(acac)3 (5.3 mg, 5 mol%) according to the general proce-
dure A with 72 hours reaction time. The residue was purified
by column chromatography on silica gel with heptane/
EtOAc=1:3 as eluent. tert-Butyl (2R)-[5-amino-1,5-dioxo-1-
(phenylamino)pentan-2-yl]carbamate was obtained in 83%
yield (80 mg). White solid, m.p.: 174–1768C, 1H NMR
(400 MHz, DMSO-d6): d (ppm) 9.92 (s, 1H), 7.60 (d, J=
7.6 Hz, 2H), 7.31 (t, J=7.6 Hz, 3H), 7.05 (t, J=7.2 Hz, 1H),
7.00 (d, J=7.2 Hz, 1H), 6.75 (s, 1H), 4.05 (m, 1H), 2.13–2.19
(m, 2H), 1.79–1.90 (m, 1H), 1.88–1.94 (m, 1H), 1.39 (s, 9H);
13C NMR (101 MHz, DMSO-d6): d (ppm) 173.4, 171.0, 155.4,
139.0, 128.7, 123.2, 119.2, 78.1, 55.9, 31.6, 28.2, 27.6; HRMS
(ESI): m/z [M+H]+ calcd for C16H24N3O4: 322.1761; found
322.1768.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
tert-Butyl
{(2S,3R)-1-[(2,6-diisopropylphenyl)amino]-3-
hydroxy-1-oxobutan-2-yl}carbamate (l-3j) Prepared from N-
tert-butyl-N’-(2,6-diisopropylphenyl)-S-phenylisothiourea
(1x) (133 mg, 0.30 mmol, 1.0 equiv.), Boc-(l)-Thr-OH (l-2i)
(79 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3 (5.3 mg,
5 mol%) according to the general procedure A with 72 hours
reaction time. The residue was purified by column chroma-
tography on silica gel with heptane/EtOAc=1:1 as eluent.
Dibenzyl-(2S)-[6-oxo-6-(phenylamino)hexane-1,5-diyl]dicar-
bamate (l-3h) Prepared from N-tert-butyl-S,N’-diphenyliso-
thiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and Z-(l)-Lys
(Z)-OH (l-2h) (149 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:2 as
Dibenzyl-(2S)-[6-oxo-6-(phenylamino)hexane-1,5-
diyl]dicarbamate was obtained in 74% yield (109 mg). White
solid, m.p.:126–1288C, H NMR (400 MHz, CDCl3): d (ppm)
8.78 (br s, 1H), 7.52 (d, J=7.6 Hz, 2H), 7.31–7.33 (m, 9H),
7.27 (d, J=7.2 Hz, 2H), 7.24 (s, 1H), 7.09 (t, J=7.6 Hz, 1H),
6.02 (d, J=6.4 Hz, 1H), 5.08–5.11 (m, 5H), 4.40 (br s, 1H),
3.16 (d, J=5.2 Hz, 2H), 1.93–1.90 (m, 1H), 1.77–1.72 (m,
1H), 1.51–1.43 (m, 2H); 13C NMR (101 MHz, CDCl3): d
(ppm) 170.5, 156.7, 137.6, 136.5, 136.0, 128.8, 128.4, 128.37,
128.1, 127.9, 127.87, 127.83, 124.3, 120.0, 67.1, 66.5, 55.4, 40.2,
31.8, 29.2, 22.3; HRMS (ESI): m/z [M+H]+ calcd for C18H32
N3O5: 490.2336; found 490.2344.
tert-Butyl
{(2S,3R)-1-[(2,6-diisopropylphenyl) amino]-3-
hydroxy-1-oxobutan-2-yl}carbamate was obtained in 82%
yield (93 mg). White solid, m.p.: 156–1588C, 1H NMR
(400 MHz, CDCl3): d (ppm) 7.97 (s, 1H), 7.28 (t, J=7.6 Hz,
1H), 7.16 (d, J=7.6 Hz, 2H), 5.67 (d, J=7.6 Hz, 1H), 4.48 (d,
J=6.4 Hz, 1H), 4.22 (d, J=7.6 Hz, 1H), 3.64 (s, 1H), 3.03
(sep, J=6.8 Hz, 2H), 1.49 (s, 9H), 1.27 (d, J=6.4 Hz, 3H),
1.19 (d, J=7.6 Hz, 6H), 1.17 (d, J=7.6 Hz, 6H); 13C NMR
(101 MHz, CDCl3): d (ppm) 171.7, 157.0, 146.0, 130.4, 128.5,
123.4, 80.6, 66.4, 57.7, 28.7, 28.3, 23.7, 23.4, 18.5; HRMS
(ESI): m/z [M+H]+ calcd for C21H35N2O4: 379.2591; found
379.2599.
eluent.
1
Methyl 4-{(2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydrox-
ybutanamido}benzoate (l-3k) Prepared from N-tert-butyl-
N’-(4-methoxycarbonylphenyl)-S-phenylisothiourea
(1o)
(103 mg, 0.30 mmol, 1.0 equiv.) and Boc-(l)-Thr-OH (l-2i)
(79 mg, 0.36 mmol, 1.2 equiv.) with 72 hours reaction time
according to the general procedure A. The residue was
purified by column chromatography on silica gel with
heptane/EtOAc=1:1 as eluent. Methyl 4-{(2S,3R)-2-[(tert-
butoxycarbonyl)amino]-3-hydroxy butanamido}benzoate was
obtained in 57% yield (60 mg). White solid, m.p.: 135–1378C,
1H NMR (400 MHz, CDCl3): d (ppm) 9.08 (s, 1H), 7.93 (d,
J=8.8 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.78 (d, J=7.6 Hz,
1H), 4.42 (d, J=4.4 Hz, 1H), 4.25 (d, J=5.2 Hz, 1H), 3.87 (s,
3H), 2.02 (s, 1H), 1.45 (s, 9H), 1.23 (d, J=2.4 Hz, 3H); 13C
NMR (101 MHz, CDCl3): d (ppm) 171.2, 170.0, 166.5, 141.6,
130.7, 125.8, 119.1, 80.9, 66.7, 60.4, 51.9, 28.2, 14.1; HRMS
(ESI): m/z [M+H]+ calcd for C17H25N2O6: 353.1707; found
353.1728.
Dibenzyl-(2R)-[6-oxo-6-(phenylamino)hexane-1,5-diyl]dicar-
bamate (d-3h) Prepared from N-tert-butyl-S,N’-diphenyliso-
thiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.) and Z-(d)-Lys
46 (Z)-OH (d-2h) (149 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:2 as
eluent. Dibenzyl- (2R)-[6-oxo-6-(phenylamino)hexane-1,5-
diyl]dicarbamate was obtained in 76% yield (110 mg). White
47
48
49
50
51
52
53
54
55
56
57
1
solid, m.p.:126–1288C, H NMR (400 MHz, CDCl3): d (ppm)
8.75 (br s, 1H), 7.46 (d, J=7.5 Hz, 2H), 7.27–7.19–7.26 (m,
12H), 7.04 (t, J=7.2 Hz, 1H), 5.99 (d, J=6.5 Hz, 1H), 5.08–
5.03 (m, 5H), 4.35 (br s, 1H), 3.10 (br s, 2H), 1.88–1.86 (m„
1H), 1.73–1.69 (m, 1H), 1.45–1.38 (m, 4H), 13C NMR
(101 MHz, CDCl3): d (ppm) 170.5, 156.7, 137.6, 136.5, 136.0,
128.8, 128.4, 128.4, 128.1, 128.0, 127.9, 127.9, 124.3, 120.0,
tert-Butyl [(2S,3R)-3-hydroxy-1-oxo-1-(pyridin-3-ylamino)
butan-2-yl]carbamate (l-3l) Prepared from N-tert-butyl-N’-
Adv. Synth. Catal. 2017, 359, 1–19
9
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
(3-pyridinyl)-S-phenylisothiourea (1r) (86 mg, 0.30 mmol,
1.0 equiv.), Boc-(l)-Thr-OH (l-2i) (79 mg, 0.36 mmol,
1.2 equiv.) and Fe(acac)3 (5.3 mg, 5 mol%) according to the
general procedure A with 72 hours reaction time. The residue
was purified by column chromatography on silica gel with
heptane/EtOAc=1:1 as eluent. tert-Butyl [(2S,3R)-3-
hydroxy-1-oxo-1-(pyridin-3-ylamino)butan-2-yl]carbamate
was obtained in 77% yield (68 mg). White solid, m.p.: 127–
on silica gel with heptane/EtOAc=1:1 as eluent. tert-Butyl
(2S)-[4-(methylsulfanyl)-1-oxo-1-(phenylamino)butan-2-yl]
carbamate was obtained in 89% yield (87 mg). White solid,
1
2
3
4
5
6
7
8
9
1
m.p.: 103–1058C, H NMR (400 MHz, CDCl3): d (ppm) 8.99
(s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.23 (s, 2H), 7.07 (d, J=
7.2 Hz, 1H), 5.81 (s, 1H), 4.56 (s, 1H), 2.64 (t, J=7.2 Hz, 2H),
2.22–2.15 (m, 1H), 2.10 (s, 3H), 2.08–2.03 (m, 1H), 1.44 (s,
9H); 13C NMR (101 MHz, CDCl3): d (ppm) 170.6, 156.2,
137.7, 128.7, 124.2, 119.9, 80.3, 54.2, 31.8, 30.2, 28.2, 15.2;
HRMS (ESI): m/z [M+H]+ calcd for C16H25N2O3S:
325.1586; found 325.1598.
1
1298C, H NMR (400 MHz, CDCl3): d (ppm) 9.08 (s, 1H),
8.60 (s, 1H), 8.29 (d, J=4.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H),
7.21 (dd, J=8.0, 4.8 Hz, 1H), 5.82 (d, J=7.6 Hz, 1H), 4.47–
4.45 (m, 2H), 4.28 (d, J=6.0 Hz, 1H), 1.47 (s, 9H), 1.24 (d,
J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): d (ppm) 170.3,
10
11
12
tert-Butyl (2R)-[4-(methylsulfanyl)-1-oxo-1-(phenylamino)
butan-2-yl]carbamate (d-3n) Prepared from N-tert-butyl-
S,N’-diphenylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.),
and Boc-(d)-Met-OH (d-2n) (90 mg, 0.36 mmol, 1.2 equiv.)
according to the general procedure A with 72 hours reaction
time. The residue was purified by column chromatography
on silica gel with heptane/EtOAc=1:1 as eluent. tert-Butyl
(2R)-[4-(methylsulfanyl)-1-oxo-1-(phenylamino)butan-2-yl]
carbamate was obtained in 85% yield (83 mg). White solid,
13 156.8, 145.0, 141.1, 134.5, 127.3, 123.7, 80.9, 66.7, 59.2, 28.3,
18.5; HRMS (ESI): m/z [M+H]+ calcd for C14H22N3O4:
14
296.1605; found 296.1608.
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
tert-Butyl (2R)-[3-(benzylsulfanyl)-1-oxo-1-(phenylamino)
propan-2-yl]carbamate (l-3m) Prepared from N-tert-butyl-
S,N’-diphenylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.),
Boc-(l)-Cys(Bn)-OH (l-2m) (112 mg, 0.36 mmol, 1.2 equiv.)
and Fe(acac)3 (10.6 mg, 10 mol%) according to the general
procedure A with 72 hours reaction time. The residue was
purified by column chromatography on silica gel with
heptane/EtOAc=1:1 as eluent. tert-Butyl (2R)-[3-(benzylsul-
fanyl)-1-oxo-1-(phenylamino)propan-2-yl]carbamate was ob-
1
m.p.: 103–1058C, H NMR (400 MHz, CDCl3): d (ppm) 8.99
(s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.23 (s, 2H), 7.07 (d, J=
7.2 Hz, 1H), 5.81 (s, 1H), 4.56 (s, 1H), 2.64 (t, J=7.2 Hz, 2H),
2.22–2.15 (m, 1H), 2.10 (s, 3H), 2.08–2.03 (m, 1H), 1.44 (s,
9H); 13C NMR (101 MHz, CDCl3): d (ppm) 170.5, 156.2,
137.6, 128.8, 124.2, 119.9, 80.4, 54.2, 31.7, 30.2, 28.3, 15.2;
HRMS (ESI): m/z [M+H]+ calcd for C16H25N2O3S:
325.1586; found 325.1590.
1
tained in 91% yield (105 mg). White solid, m.p.: 94–968C, H
NMR (400 MHz, CDCl3): d (ppm) 8.18 (br s, 1H), 7.53 (d,
J=7.9 Hz, 2H), 7.36–7.23 (m, 7H), 7.11 (t, J=7.3 Hz, 1H),
5.33 (d, J=6.4 Hz, 1H), 4.34 (d, J=5.8 Hz, 1H), 3.83–3.69
(m, 2H), 2.99–2.80 (m, 2H), 1.1.47 (s, 9H); 13C NMR
(101 MHz, CDCl3): d (ppm) 168.8, 155.7, 137.9, 137.4, 129.0,
128.7, 127.3, 124.6, 120.0, 80.8, 54.6, 36.7, 33.4, 28.3; HRMS
(ESI): m/z [M+H]+ calcd for C21H27N2O3S: 387.1737; found
387.1744.
Na-(tert-butoxycarbonyl)-N-phenyl-l-phenylalaninamide (l-
3o)[29] Prepared from N-tert-butyl-S,N’-diphenylisothiourea
(1a) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-(l)-Phe-OH (l-
2o) (95 mg, 0.36 mmol, 1.2 equiv.) according to the general
procedure A. The residue was purified by column chroma-
tography on silica gel with heptane/EtOAc=1:1 as eluent.
Na-(tert-butoxycarbonyl)-N-phenyl-l-phenylalaninamide was
obtained in 94% yield (96 mg). White solid, m.p.: 138–1398C
(lit.[29] 138–1398C), 1H NMR (400 MHz, CDCl3): d (ppm)
8.75 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.28–7.25 (m, 5H), 7.22
(t, J=7.6 Hz, 2H), 7.07 (t, J=7.2 Hz, 1H), 5.75 (d, J=8.0 Hz,
1H), 4.73 (br s, 1H), 3.21 (dd, J=13.6, 6.4 Hz, 1H), 3.10 (dd,
J=13.6, 8.4 Hz, 1H), 1.41 (s, 9H); 13C NMR (101 MHz,
CDCl3): d (ppm) 170.4, 156.1, 137.5, 136.7, 129.2, 128.7,
128.5, 126.7, 124.1, 120.0 80.2, 56.7, 38.8, 28.2; HRMS (ESI):
m/z [M+Na]+ calcd for C20H24N2O3Na: 363.1685; found
363.1680.
tert-Butyl
(2S)-[3-(benzylsulfanyl)-1-oxo-1-(phenylamino)
propan-2-yl]carbamate (d-3m) Prepared from N-tert-butyl-
S,N’-diphenylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.),
Boc-(d)-Cys(Bn)-OH (d-2m) (112 mg, 0.36 mmol, 1.2 equiv.)
and Fe(acac)3 (10.6 mg, 10 mol%) according to the general
procedure A with 48 hours reaction time. The residue was
purified by an automated flash chromatography system using
heptane/EtOAc (from 100% heptane to 25% EtOAc, 25 mL/
min) as eluent. tert-Butyl (2S)-[3-(benzylsulfanyl)-1-oxo-1-
(phenylamino) propan-2-yl]carbamate was obtained in 95%
yield (111 mg). White solid, m.p.: 106–1078C, 1H NMR
(400 MHz, CDCl3): d (ppm) 8.23 (br s, 1H), 7.49 (d, J=
7.8 Hz, 2H), 7.34–7.23 (m, 7H), 7.11 (t, J=7.4 Hz, 1H), 5.37
(d, J=7.1 Hz, 1H), 4.34 (d, J=5.5 Hz, 1H), 3.81–3.73 (m,
2H), 2.98–2.81 (m, 2H), 1.47 (s, 9H); 13C NMR (101 MHz,
CDCl3): d (ppm) 168.8, 155.7, 137.9, 137.4, 129.0, 128.7,
127.3, 124.6, 120.0, 80.8, 54.6, 36.7, 33.5, 28.3; HRMS (ESI):
m/z [M+H]+ calcd for C21H27N2O3S: 387.1737; found
387.1743.
Na-(tert-butoxycarbonyl)-N-phenyl-d-phenylalaninamide (d-
3o)[29] Prepared from N-tert-butyl-S,N’-diphenylisothiourea
(1a) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-(d)-Phe-OH (d-
2o) (95 mg, 0.36 mmol, 1.2 equiv.) according to the general
procedure A. The residue was purified by column chroma-
tography on silica gel with heptane/EtOAc=1:1 as eluent.
Na-(tert-butoxycarbonyl)-N-phenyl-d-phenylalaninamide was
obtained in 95% yield (97 mg). White solid, m.p.: 138–1398C
(lit.[29] 138–1398C), 1H NMR (400 MHz, CDCl3): d (ppm)
8.63 (br s, 1H), 7.35 (d, J =7.8 Hz, 2H), 7.22–7.16 (m, 7H),
7.02 (t, J=7.1 Hz, 1H), 5.66 (d, J=7.4 Hz, 1H), 4.67 (br s,
1H), 3.19–3.14 (m, 1H), 3.08–3.03 (m, 1H), 1.37 (s, 9H); 13C
NMR (101 MHz, CDCl3): d (ppm) 170.2, 156.0, 137.5, 136.8,
129.3.9, 128.7, 128.5, 126.8, 124.2, 120.1, 80.3, 56.7, 38.7, 28.2;
tert-Butyl
(2S)-[4-(methylsulfanyl)-1-oxo-1-(phenylamino)
butan-2-yl]carbamate (l-3n)[28] Prepared from N-t-butyl-
S,N’-diphenylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.)
and Boc-(l)-Met-OH (l-2n) (90 mg, 0.36 mmol, 1.2 equiv.)
according to the general procedure A with 72 hours reaction
time. The residue was purified by column chromatography
Adv. Synth. Catal. 2017, 359, 1–19
10
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
HRMS (ESI): m/z [M+Na]+ calcd for C20H24N2O3Na:
363.1685; found 363.1681.
ethyl)carbamate was obtained in 91% yield (89 mg). White
solid, m.p.: 116–1198C (lit.:[31b] 120–1218C), 1H NMR
(400 MHz, CDCl3): d (ppm) 8.64 (br s, 1H), 7.48 (d, J=
6.4 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 7.34–7.26 (m, 3H), 7.15
(t, J=7.5 Hz, 2H), 6.99 (t, J=7.1 Hz, 1H), 6.04 (d, J=4.5 Hz,
1H), 5.54 (br s, 1H), 1.41 (s, 9H); 13C NMR (101 MHz,
CDCl3): d (ppm) 168.9, 155.7, 137.6, 137.4, 128.9, 128.7,
128.4, 127.3, 124.3, 119.9, 80.5, 59.1, 28.3; HRMS (ESI): m/z
[M+H]+ calcd for C19H23N2O3: 327.1703; found 327.1712.
1
2
3
4
5
6
7
8
9
Na-(tert-Butoxycarbonyl)-N-phenyl-l-tyrosinam
(l-3p)[30]
Prepared from N-tert-butyl-S,N’-diphenylisothiourea (1a)
(85 mg, 0.30 mmol, 1.0 equiv.), Boc-(l)-Tyr-OH (l-2p)
(101 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3 (5.3 mg,
5 mol%) according to the general procedure A with 72 hours
reaction time. The residue was purified by column chroma-
tography on silica gel with heptane/EtOAc=1:3 as eluent.
Na-(tert-butoxycarbonyl)-N-phenyl-l-tyrosinam was obtained
in 96% yield (103 mg). White solid, m.p.: 117–1208C, 1H
NMR (400 MHz, CDCl3): d (ppm) 8.15 (br s, 1H), 7.38 (d,
J=7.6 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.06 (d, J=8.0 Hz,
2H), 6.76 (br s, 1H), 6.74 (d, J=8.4 Hz, 2H), 5.41 (br s, 1H),
4.46 (br s, 1H), 3.04 (t, J=7.2 Hz, 2H), 1.43 (s, 9H); 13C-
NMR (101 MHz, CDCl3): d (ppm) 170.0, 156.0, 155.1, 137.2,
130.4, 128.9, 128.1, 124.6, 120.2, 115.7, 60.5, 37.7, 28.3, 14.2;
HRMS (ESI): m/z [M+H]+ calcd for C20H25N2O4: 357.1809;
found 357.1816.
Na-(tert-Butoxycarbonyl)-N-phenyl-l-tryptophanamide (l-
3r)[32] Prepared from N-tert-butyl-S,N’-diphenylisothiourea
(1a) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-(l)-Trp-OH (l-
2r) (109 mg, 0.36 mmol, 1.2 equiv.) according to the general
procedure A with 72 hours reaction time. The residue was
purified by column chromatography on silica gel with
heptane/EtOAc=1:1 to 1:2 as eluent. Na-(tert-Butoxycarbon-
yl)-N-phenyl-l-tryptophanamide was obtained in 92% yield
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
1
(105 mg). White solid, m.p.: 151–1538C (lit.:[32] 48–498C), H
NMR (400 MHz, DMSO-d6): d (ppm) 10.81 (s, 1H), 10.01 (s,
1H), 7.67 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.32
(dd, J=14.8, 7.6 Hz, 3H), 7.19 (s, 1H), 7.04 (dd, J=14.4,
7.6 Hz, 2H), 6.99 (t, J=7.6 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H),
4.42 (d, J=5.6 Hz, 1H), 3.16 (dd, J=14.4, 5.2 Hz, 1H), 3.03
(dd, J=14.4, 5.2 Hz, 1H), 1.35 (s, 9H); 13C NMR (101 MHz,
DMSO-d6): d (ppm) 171.1, 155.3, 139.0, 136.0, 128.6, 127.3,
123.8, 123.3, 120.9, 119.4, 118.6, 118.2, 111.3, 109.9, 78.1, 55.8,
28.2, 27.8; HRMS (ESI): m/z [M+H]+ calcd for C22H26N3O3:
380.1974; found 380.1982.
Na-(tert-Butoxycarbonyl)-N-phenyl-d-tyrosinam
(d-3p)[30]
Prepared from N-tert-butyl-S,N’-diphenylisothiourea (1a)
(85 mg, 0.30 mmol, 1.0 equiv.), Boc-(d)-Tyr-OH (d-2p)
(101 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3 (5.3 mg,
5 mol%) according to the general procedure A with 72 hours
reaction time. The residue was purified by column chroma-
tography on silica gel with heptane/EtOAc=1:3 as eluent.
Na-(tert-butoxycarbonyl)-N-phenyl-d-tyrosinam was ob-
tained in 94% yield (101 mg). White solid, m.p.: 117–1208C,
1H NMR (400 MHz, CDCl3): d (ppm) 8.45 (br s, 1H), 7.41
(br s, 1H), 7.35 (d, J=7.6 Hz, 2H), 7.22–7.12 (m, 2H), 7.02 (d,
J=8.0 Hz, 3H), 6.72 (d, J=8.2 Hz, 2H), 5.56 (br s, 1H), 4.51
(br s, 1H), 3.07–2.94 (m, 2H), 1.39 (s, 9H); 13C NMR
(101 MHz, CDCl3): d (ppm) 170.2, 156.0, 155.2, 137.2, 130.4
128.8, 124.6, 120.3, 115.7, 80.8, 59.1, 41.9, 37.8, 28.3; HRMS
(ESI): m/z [M+H]+ calcd for C20H25N2O4: 357.1809; found
357.1816.
Na-(tert-Butoxycarbonyl)-N-phenyl-d-tryptophanamide (d-
3r)[33] Prepared from N-tert-butyl-S,N’-diphenylisothiourea
(1a) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-(d)-Trp-OH (d-
2r) (109 mg, 0.36 mmol, 1.2 equiv.) according to the general
procedure A with 72 hours reaction time. The residue was
purified by column chromatography on silica gel with
heptane/EtOAc=1:1 to 1:2 as eluent. Na-(tert-Butoxycarbon-
yl)-N-phenyl-d-tryptophanamide was obtained in 93% yield
1
(106 mg). White solid, m.p.: 151–1538C, H NMR (400 MHz,
tert-Butyl-(1S)-(2-oxo-1-phenyl-2-(phenylamino)ethyl)
DMSO-d6): d (ppm) 10.80 (s, 1H), 10.01 (s, 1H), 7.66 (d, J=
7.6 Hz, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.32 (dd, J=15.6,
8.0 Hz, 3H), 7.18 (s, 1H), 7.06 (dd, J=14.4, 7.2 Hz, 2H), 6.98
(t, J=7.6 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 4.42 (d, J=
5.2 Hz, 1H), 3.16 (dd, J=14.4, 4.4 Hz, 1H), 3.03 (dd, J=14.4,
4.4 Hz, 1H), 1.34 (s, 9H); 13C NMR (101 MHz, DMSO-d6): d
(ppm) 171.2, 155.4, 139.0, 136.1, 128.7, 127.3, 123.9, 123.3,
120.9, 119.4, 118.7, 118.2, 111.3, 110.0, 78.1, 55.8, 28.2, 27.8;
HRMS (ESI): m/z [M+H]+ calcd for C22H26N3O3: 380.1974;
found 380.1980.
carbamate (l-3q)[31a] Prepared from N-tert-butyl-S,N’-diphe-
nylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.), Boc-(l)-
Phg-OH (l-2q) (90 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:1 as
eluent.
tert-Butyl-(1S)-(2-oxo-1-phenyl-2-(phenylamino)
ethyl)carbamate was obtained in 90% yield (88 mg). White
solid, m.p.: 116–1198C, 1H NMR (400 MHz, CDCl3): d (ppm)
8.68 (br s, 1H), 7.50 (d, J=6.3 Hz, 2H), 7.41 (d, J=7.8 Hz,
2H), 7.36–7.27 (m, 3H), 7.18 (t, J=7.5 Hz, 2H), 7.02 (t, J=
46 7.0 Hz, 1H), 6.06 (d, J=4.8 Hz, 1H), 5.57 (br s, 1H), 1.43 (s,
47
Na-(tert-Butoxycarbonyl)-N-phenyl-l-histidinamide (l-3s)[34]
Prepared from N-t-butyl-S,N’-diphenylisothiourea (1d)
(85 mg, 0.30 mmol, 1.0 equiv.), Boc-(l)-His-OH (l-2s)
(92 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3 (10.6 mg,
10 mol%) according to the general procedure A with 72
hours reaction time. The residue was purified by column
chromatography on silica gel with EtOAc as eluent. Na-(tert-
Butoxycarbonyl)-N-phenyl-l-histidinamide was obtained in
9H); 13C NMR (101 MHz, CDCl3): d (ppm) 169.0, 155.7,
137.6, 137.4, 128.9, 128.7, 128.4, 127.3, 124.2, 119.9, 80.5, 59.2,
28.3; HRMS (ESI): m/z [M+H]+ calcd for C19H23N2O3:
327.1703; found 327.1712.
48
49
50
51
52
tert-Butyl-(1R)-(2-oxo-1-phenyl-2-(phenylamino)ethyl)
carbamate (d-3q)[31b] Prepared from N-tert-butyl-S,N’-diphe-
53 nylisothiourea (1d) (85 mg, 0.30 mmol, 1.0 equiv.), Boc-(d)-
1
88% yield (88 mg). White solid, m.p.: 118–1208C, H NMR
Phg-OH (d-2q) (90 mg, 0.36 mmol, 1.2 equiv.) according to
the general procedure A. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:1 as
54
55
56
57
(400 MHz, CDCl3): d (ppm) 9.54 (br s, 1H), 9.00 (br s, 1H),
7.52 (s, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.26 (t, J=8.0 Hz, 2H),
7.07 (t, J=7.6 Hz, 1H), 6.77 (s, 1H), 6.15 (br s, 1H), 4.61 (br
eluent.
tert-Butyl-(1R)-(2-oxo-1-phenyl-2-(phenylamino)
Adv. Synth. Catal. 2017, 359, 1–19
11
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
s, 1H), 3.10 (d, J=5.2 Hz, 2H), 1.42 (s, 9H); 13C NMR
(101 MHz, CDCl3): d (ppm) 171.2, 170.5, 156.0, 137.7, 134.8,
128.8, 124.4, 120.2, 80.4, 60.4, 29.8, 29.2, 28.3; HRMS (ESI):
m/z [M+H]+ calcd for C17H23N4O3: 331.1765; found
331.1767.
tert-Butyl 4-(phenylcarbamoyl)piperidine-1-carboxylate was
obtained in 99% yield (90 mg). White solid, m.p.: 156–1588C
1
2
3
4
5
6
7
8
9
1
(lit.:[36] 155–1588C), H NMR (400 MHz, CDCl3): d (ppm)
8.33 (d, J=6.4 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.27 (t, J=
7.6 Hz, 2H), 7.07 (t, J=7.6 Hz, 1H), 4.13 (d, J=11.6 Hz, 2H),
2.70 (m, 2H), 2.36–2.43 (m, 1H), 1.82 (d, J=2.4 Hz, 1H), 1.80
(s, 1H), 1.69–1.76 (dt, J=12.0, 4.0 Hz, 2H), 1.46 (s, 9H); 13C
NMR (101 MHz, CDCl3): d (ppm) 173.2, 154.6, 137.9, 128.7,
124.1, 120.1, 79.7, 43.7, 42.9, 28.4, 28.3; HRMS (ESI): m/z
[M+H]+ calcd for C17H25N2O3: 305.1865; found: 305.1864.
Na-(tert-Butoxycarbonyl)-N-phenyl-d-histidinamide (d-3s)
Prepared from N-tert-butyl-S,N’-diphenylisothiourea (1a)
(85 mg, 0.30 mmol, 1.0 equiv.), Boc-(d)-His-OH (d-2s)
(92 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3 (10.6 mg,
10 mol%) according to the general procedure A with 72
hours reaction time. The residue was purified by column
chromatography on silica gel with EtOAc as eluent. Na-(tert-
Butoxycarbonyl)-N-phenyl-d-histidinamide was obtained in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
Na-(tert-Butoxycarbonyl)glycylglycyl-N-phenylglycinamide
(3aa) Prepared from N-tert-butyl-S,N’-diphenylisothiourea
(1a) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-Gly-Gly-Gly-
OH (2w) (104 mg, 0.36 mmol, 1.2 equiv.) according to the
general procedure A. The residue was purified by recrystal-
ization with MeOH. Na-(tert-Butoxycarbonyl)glycylglycyl-N-
phenylglycinamide was obtained in 83% yield (91 mg). White
solid, m.p.: 193–1958C, 1H NMR (400 MHz, DMSO-d6): d
(ppm) 9.78 (s, 1H), 8.16–8.23 (m, 2H), 7.61 (d, J=7.6 Hz,
2H), 7.30 (t, J=8.0 Hz, 2H), 6.99–7.07 (m, 2H), 3.89 (d, J=
6.0 Hz, 2H), 3.77 (d, J=5.6 Hz, 2H), 3.61 (d, J=6.0 Hz, 2H),
1.38 (s, 9H); 13C NMR (101 MHz, DMSO-d6): d (ppm) 170.1,
169.2, 167.5, 155.8, 138.7, 128.6, 123.3, 119.2, 78.1, 42.2, 40.1,
39.9, 28.1; HRMS (ESI): m/z [M+H]+ calcd for C17H25N4O5:
365.1825.
1
88% yield (87.6 mg). White solid, m.p.: 118–1208C, H NMR
(400 MHz, CDCl3): d (ppm) 10.44 (br s, 1H), 9.46 (br s, 1H),
7.59 (s, 1H), 7.48 (d, J=7.6 Hz, 2H), 7.26 (t, J=8.0 Hz, 2H),
7.07 (t, J=7.6 Hz, 1H), 6.78 (s, 1H), 6.08 (br s, 1H), 4.60 (br
s, 1H), 3.10 (d, J=6.0 Hz, 2H), 1.40 (s, 9H); 13C NMR
(101 MHz, CDCl3): d (ppm) 176.5, 170.4, 156.0, 137.7, 134.6,
128.9, 124.4, 120.2, 80.4, 53.8, 29.7, 29.2, 28.2; HRMS (ESI):
m/z [M+H]+ calcd for C17H23N4O3: 331.1765; found
331.1767.
Benzyl
[2-methyl-1-oxo-1-(phenylamino)propan-2-yl]
carbamate (3t)[35] Prepared from N-tert-butyl-S,N’-diphenyli-
sothiourea (1a) (85 mg, 0.30 mmol, 1.0 equiv.) and Z-2-
methylalanine (2t) (85 mg, 0.36 mmol, 1.2 equiv.) according
to the general procedure A. The residue was purified by
column chromatography on silica gel with heptane/EtOAc=
1:2 as eluent. Benzyl [2-methyl-1-oxo-1-(phenylamino)prop-
an-2-yl]carbamate was obtained in 91% yield (85 mg). White
solid, m.p.: 162–1648C (lit.:[35] 142–1448C), 1H-NMR
(400 MHz, DMSO-d6): d (ppm) 9.41 (s, 1H), 7.60 (d, J=
7.6 Hz, 2H), 7.34–7.39 (m, 4H), 7.29 (t, J=7.6 Hz, 3H), 7.03
(t, J=7.2 Hz, 1H), 5.02 (s, 2H), 1.44 (s, 6H); 13C NMR
(101 MHz, DMSO-d6): d (ppm) 172.9, 154.8, 139.2, 137.0,
128.3, 128.2, 127.6, 127.5, 123.0, 120.0, 65.2, 56.6, 25.0; HRMS
(ESI): m/z [M+H]+ calcd for C18H21N2O3: 313.1547; found
313.1553.
Na-(tert-Butoxycarbonyl)-N-phenyl-d-histidinamide
(3ab)
Prepared from N-t-butyl-N’-(4-(t-butyl)phenyl)-S-phenyliso-
thiourea (1y) (102 mg, 0.30 mmol, 1.0 equiv.), Boc-Gly-Gly-
Gly-OH (2w) (104 mg, 0.36 mmol, 1.2 equiv.) and Fe(acac)3
(2.65 mg, 2.5 mol%) according to the general procedure A.
The residue was purified by recrystalization with MeOH. Na-
(tert-Butoxycarbonyl)-N-phenyl-d-histidinamide was ob-
tained in 87% yield (110 mg). White solid, m.p.: 202–2048C,
1H NMR (400 MHz, DMSO-d6): d (ppm) 9.83 (s, 1H), 8.31 (s,
1H), 8.26 (s, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz,
2H), 7.01 (s, 1H), 3.88 (d, J=5.2 Hz, 2H), 3.76 (d, J=4.4 Hz,
2H), 3.63 (d, J=4.8 Hz, 2H), 1.37 (s, 9H), 1.25 (s, 9H); 13C
NMR (101 MHz, DMSO-d6): d (ppm) 170.2, 169.2, 167.3,
155.8, 145.5, 136.2, 125.1, 119.0, 78.1, 43.4, 42.6, 42.3, 33.9,
31.1, 28.1; HRMS (ESI): m/z [M+H]+ calcd for C21H33N4O5:
421.2445; found: 421.2449.
tert-Butyl [3-oxo-3-(phenylamino)propyl]carbamate (3u)[35]
Prepared from N-t-butyl-S,N’-diphenylisothiourea (1a)
(85 mg, 0.30 mmol, 1.0 equiv.) and Boc-b-Ala-OH (2u)
(68 mg, 0.36 mmol, 1.2 equiv.) according to the general
procedure A. The residue was purified by column chroma-
tography on silica gel with heptane/EtOAc=1:1 as eluent.
tert-Butyl [3-oxo-3-(phenylamino)propyl] carbamate was ob-
tained in 92% yield (73 mg). White solid, m.p.: 164–1668C
Na-(tert-Butoxycarbonyl)glycylglycyl-N-(4-bromophenyl)gly-
cinamide (3ac) Prepared from N-tert-butyl-N’-(4-bromo-
phenyl)-S-phenylisothiourea (1m) (109 mg, 0.30 mmol,
1.0 equiv.) and Boc-Gly-Gly-Gly-OH (2w) (104 mg,
0.36 mmol, 1.2 equiv.) according to the general procedure A.
The residue was purified by recrystalization with MeOH. Na-
(tert-Butoxycarbonyl)glycylglycyl-N-(4-bromophenyl)glyci-
namide was obtained in 79% yield (105 mg). White solid,
1
(lit.:[35] 162–1648C), H NMR (400 MHz, CDCl3): d (ppm)
46 7.97 (br s, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.33 (t, J=7.6 Hz,
2H), 7.12 (t, J=7.2 Hz, 1H), 5.24 (br s, 1H), 3.50 (d, J=
4.4 Hz, 2H), 2.61 (s, 2H), 1.45 (s, 9H); 13C NMR (101 MHz,
CDCl3): d (ppm) 169.7, 156.6, 137.9, 128.9, 124.3, 119.9, 79.6,
37.6, 36.6, 28.4; HRMS (ESI): m/z [M+H]+ calcd for C14H21
N2O3: 265.1552; found 265.1546.
47
48
49
50
51
52
1
m.p.: 239–2418C, H NMR (400 MHz, DMSO-d6): d (ppm)
10.14 (s, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.65 (d, J=8.4 Hz,
2H), 7.46 (d, J=8.4 Hz, 2H), 7.01 (s, 1H), 3.90 (d, J=5.2 Hz,
2H), 3.77 (d, J=5.2 Hz, 2H), 3.63 (d, J=5.2 Hz, 2H), 1.36 (s,
9H); 13C NMR (101 MHz, DMSO-d6): d (ppm) 170.2, 169.3,
167.8, 155.8, 138.2, 131.4, 121.4, 114.8, 78.1, 43.3, 42.7, 42.2,
28.1; HRMS (ESI): m/z [M+H]+ calcd for C17H24BrN4O5:
443.0925; found: 443.0924.
tert-Butyl
4-(phenylcarbamoyl)piperidine-1-carboxylate
53 (3v)[36] Prepared from N-tert-butyl-S,N’-diphenylisothiourea
(1a) (85 mg, 0.30 mmol, 1.0 equiv.) and Boc-Inp-OH (2v)
(83 mg, 0.36 mmol, 1.2 equiv.) according to the general
procedure A. The residue was purified by column chroma-
tography on silica gel with heptane/EtOAc=1:1 as eluent.
54
55
56
57
tert-Butyl 2-((3-methyl-1-oxo-1-(2-(phenylcarbamoyl)pyrroli-
din-1-yl)butan-2-yl)carbamoyl)pyrrolidine-1-carboxylate
Adv. Synth. Catal. 2017, 359, 1–19
12
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
(3ad) Prepared from N-tert-butyl-S,N’-diphenylisothiourea
(1a) (85 mg, 0.30 mmol, 1.0 equiv.), N-Boc-l-pro-l-val-l-pro-
OH (2x) (148 mg, 0.36 mmol, 1.2 equiv.) according to the
general procedure A. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:3 as
eluent. tert-Butyl 2-((3-methyl-1-oxo-1-(2-(phenylcarbamoyl)
pyrrolidin-1-yl)butan-2-yl)carbamoyl)pyrrolidine-1-carboxy-
late was obtained in 69% yield (101 mg). White solid, m.p.:
tained in 95% yield (83 mg). Yellow solid, m.p.: 129–1318C,
1H NMR (400 MHz, CDCl3): d (ppm) 7.88 (br s, 1H), 6.98–
7.04 (m, 3H), 5.38 (d, J=6.4 Hz, 1H), 4.38 (br s, 1H), 2.14 (s,
6H), 1.43–1.45 (m, 12H); 13C NMR (101 MHz, CDCl3): d
(ppm) 171.5, 155.7, 135.3, 133.4, 127.9, 127.0, 79.9, 50.2, 28.2,
18.3, 18.0; HRMS (ESI): m/z [M+H]+ calcd for C16H25N2O3:
292.1787; found 293.1876.
1
2
3
4
5
6
7
8
9
tert-Butyl-(2S)-(1-((2,6-dimethylphenyl)amino)-1-oxopro-
pan-2-yl)carbamate (l-3w) Prepared from N-tert-butyl-N’-
1
80–828C, H NMR (400 MHz, CDCl3): d (ppm) 9.47 (br s,
1H), 7.66 (br, s, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.25 (t, J=
6.8 Hz, 2H), 7.03 (t, J=6.8 Hz, 1H), 4.78 (d, J=6.4 Hz, 1H),
4.55 (s, 1H), 4.37 (s, 1H), 3.81 (q, J=8.0 Hz, 1H), 3.63 (s,
1H), 3.46 (s, 1H), 3.37 (s, 1H), 2.49 (s, 1H), 2.29 (s, 1H), 2.17
(2,6-dimethylphenyl)-S-phenylisothiourea
(1v)
(94 mg,
10
11
12
0.30 mmol, 1.0 equiv.) and Boc-(l)-Ala-OH (l-2c) (68 mg,
0.36 mmol, 1.2 equiv.) according to the general procedure A
in 2-butanol at 988C. The residue was purified by column
chromatography on silica gel with heptane/EtOAc=1:1 as
eluent. tert-Butyl-(2S)-(1-((2,6-dimethylphenyl)amino)-1-ox-
opropan-2-yl)carbamate was obtained in 91% yield (80 mg).
13 (s, br, 2H), 2.03–2.08 (m, 2H), 1.90 (s, br, 3H), 1.47 (s, 9H),
0.93 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H); 13C NMR
14
(101 MHz, CDCl3): d (ppm) 172.4, 172.2, 169.0, 138.2, 128.7,
123.8, 119.6, 80.3, 60.6, 59.6, 55.7, 47.7, 46.9, 31.3, 28.3, 26.4,
25.1, 19.2, 17.6; HRMS (ESI): m/z [M+H]+ calcd for C26H39
N4O5: 487.2915; found 487.2919.
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
Yellow solid, m.p.: 129–1318C, H NMR (400 MHz, CDCl3):
d (ppm) 7.88 (br s, 1H), 6.98–7.04 (m, 3H), 5.38 (d, J=
6.4 Hz, 1H), 4.38 (br s, 1H), 2.14 (s, 6H), 1.43–1.45 (m, 12H);
13C NMR (101 MHz, CDCl3): d (ppm) 171.5, 155.7, 135.3,
133.4, 127.9, 127.0, 79.9, 50.2, 28.2, 18.3, 18.0; HRMS (ESI):
m/z [M+H]+ calcd for C16H25N2O3: 292.1787; found
293.1876.
N-(tert-butoxycarbonyl)-l-tryptophyl-l-glutaminyl-N-
phenyl-l-alaninamide (3ae) Prepared from N-tert-butyl-S,N’-
diphenylisothiourea (1a) (42.4 mg, 0.15 mmol, 1.0 equiv.), N-
Boc-l-Trp-l-Gln-l-Ala-OH
(2y)
(90 mg,
0.18 mmol,
1.2 equiv.) according to the general procedure A with 48
hours reaction time. The residue was purified twice by an
automated flash chromatography system using a C18-silica
cartridge and H2O/CH3CN (from 100% H2O to 40% CH3CN
in 40 minutes, 25 mL/min) as eluent. N-(tert-butoxycarbon-
yl)-l-tryptophyl-l-glutaminyl-N-phenyl-l-alaninamide was
obtained in 77% yield (66 mg). White solid, m.p.: 206–2078C,
1H NMR (400 MHz, DMSO-d6, 808C): d (ppm) 10.57 (br s,
1H), 9.60 (br s, 1H), 8.21 (s, 1H), 7.88 (t, J=7.7 Hz, 2H),
7.61–7.56 (m, 2H), 7.32–7.27 (m, 3H), 7.13 (s, 1H), 7.13–6.99
(br s, 2H), 6.97 (t, J=7.7 Hz, 2H), 6.43 (br s, 1H), 4.46–4.26
(m, 4H), 2.18–2.15 (t, J=7.5 Hz, 1H), 2.04–1.83 (m, 1H), 3.37
(s, 1H), 2.49 (s, 1H), 2.29 (s, 1H), 2.17 (s, br, 2H), 2.03–2.08
(m, 2H), 1.35–1.33 (m, 12H); 13C NMR (101 MHz, DMSO-d6,
808C): d (ppm) 173.5, 171.7, 170.5, 170.5, 154.8, 138.5, 135.9,
128.1, 123.0, 120.4, 119.3, 117.9, 117.8, 110.8, 109.9, 78.7, 78.0,
55.3, 52.2, 48.8, 31.0, 27.7, 27.5, 17.5; HRMS (ESI): m/z [M+
H]+ calcd for C30H39N6O6: 579.2926; found 579.2925.
N-(2,6-dimethylphenyl)-d-alaninamide (d-3x)[37] A 50 mL
round-bottom flask was charged with tert-Butyl-(2R)-(1-
((2,6-dimethylphenyl)amino)-1-oxopropan-2-yl)carbamate
(d-3w) (292 mg, 1.0 mmol, 1.0 equiv.), and EtOAc (5 mL).
Then hydrochloric acid in dioxane (4 M, 2 mL) was added
dropwise to the mixture. The reaction mixture was stirred at
258C for 24 hours. The solvent was removed under reduced
pressure, and EtOAc (30 mL) was added. The organic phase
was washed three times with NaOH (10% in H2O, 20 mL)
and dried over anhydrous MgSO4 and subsequently concen-
trated under reduced pressure. The residue was purified by
column chromatography on silica gel with heptane/EtOAc=
1:3 as eluent. N-(2,6-Dimethylphenyl)-d-alaninamide was
obtained in 89% yield (171 mg). White solid, m.p.: 246–
1
2668C (lit.:[37] 242–2468C), H NMR (400 MHz, CDCl3): d
(ppm) 8.88 (br s, 1H), 6.96–6.99 (m, 3H), 3.74 (q, J=6.4 Hz,
1H), 3.20 (br s, 2H), 2.14 (s, 6H), 1.41 (d, J=6.8 Hz, 3H); 13C
NMR (101 MHz, CDCl3): d (ppm) 173.6, 134.9, 133.7, 127.9,
126.8, 50.8, 21.4, 18.2; HRMS (ESI): m/z [M+H]+ calcd for
C11H17N2O: 193.1263; found 193.1339.
tert-Butyl-(2R)-(1-((2,6-dimethylphenyl)amino)-1-oxopro-
pan-2-yl)carbamate (d-3w) Method 1: Prepared from N-tert-
butyl-N’-(2,6-dimethylphenyl)-S-phenylisothiourea
(1v)
N-(tert-Butylcarbamoyl)-N-phenylbenzamide (7) A 100 mL
round-bottom flask was charged with N-tert-butyl-N’-phenyl-
urea (4) (576 mg, 3.0 mmol, 1.0 equiv.) and pyridine
(3.0 mL). The reaction mixture was cooled to 08C and stirred
for 30 minutes. Then, benzoyl chloride (504 mg, 3.6 mmol,
1.2 equiv.) was dropwise added to the above reaction mixture
under 08C. The mixture was stirred for 1 h at 08C. The
mixture was extracted with EtOAc (30 mL) and washed with
HCl (1 M, 20 mL) for three times. The organic phase was
dried with anhydrous MgSO4. The filtrate was concentrated
and dried under vacuum. The residue was purified by column
chromatography on silica gel heptane/EtOAc=1:1 as eluent.
N-(tert-Butylcarbamoyl)-N-phenylbenzamide was obtained
in 74% yield (657 mg).
(94 mg, 0.30 mmol, 1.0 equiv.) and Boc-(d)-Ala-OH (d-2c)
(68 mg, 0.36 mmol, 1.2 equiv.) according to the general
procedure A in 2-butanol at 988C. The residue was purified
by column chromatography on silica gel with heptane/
EtOAc=1:1 as eluent. tert-Butyl-(2R)-(1-((2,6-dimethyl-
phenyl)amino)-1-oxopropan-2-yl)carbamate was obtained in
93% yield (81 mg).
Method 2: Prepared from N-tert-butyl-N’-(2,6-dimethylphen-
yl)-S-phenylisothiourea (1v) (94 mg, 0.3 mmol, 1.0 equiv.),
Boc-(d)-Ala-OH ((d)-2c) (68 mg, 0.36 mmol, 1.2 equiv.) and
Fe(acac)3 (11 mg, 10 mol%) according to the general proce-
dure A in isopropanol at 838C for 72 hours. The residue was
purified by column chromatography on silica gel with
heptane/EtOAc=1:1 as eluent. tert-Butyl-(2R)-(1-((2,6-di-
methylphenyl)amino)-1-oxopropan-2-yl)carbamate was ob-
1
White solid, m.p.: 82–848C, H NMR (400 MHz, CDCl3): d
(ppm) 9.10 (s, 1H), 7.10–7.24 (m, 10H), 1.45 (s, 9H); 13C
Adv. Synth. Catal. 2017, 359, 1–19
13
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
NMR (101 MHz, CDCl3): d (ppm) 173.7, 152.8, 139.0, 136.3,
130.1, 130.0, 128.5, 128.4, 127.8, 127.7, 51.4, 28.8; HRMS
(ESI): m/z [M+H]+ calcd for C18H21N2O2: 297.1598; found
297.1603.
147.6, 146.0, 136.1, 130.1, 129.6, 129.5, 129.2, 127.6, 122.4,
53.7, 50.7, 31.3, 30.9, 28.8, 18.6; HRMS (ESI): m/z [M+H]+
calcd for C23H33N2S: 369.2359; found: 369.2361.
1
2
3
4
5
6
7
8
9
N-(tert-Butyl)-N’-(ethyl)-S-phenylisothiourea (12) To a sus-
pension of N-tert-butyl-N-ethyl carbodiimide (129 mg,
1.0 mmol, 1.0 equiv.) in DCM (10 mL, dry) was added
benzenethiol (121 mg, 1.1 mmol, 1.1 equiv.) at room temper-
ature under Ar atmosphere. The reaction mixture was stirred
for 12 hours at room temperature. The mixture was
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel with
Heptane/EtOAc=10:1 as eluent. N-(tert-Butyl)-N’-ethyl -S-
phenylisothiourea was obtained in 90% yield (212 mg).
N-Pentyl-N’-(2,6-dimethylphenyl)-S-phenylisothiourea
Prepared from 2,6-dimethylaniline (206 mg, 1.7 mmol,
1.7 equiv.), S-phenyl benzenethiosulfonate (250 mg,
(9)
1.0 mmol, 1.0 equiv.) and 1-isocyanopentane (242.5 mg,
2.5 mmol, 2.5 equiv.) according to our previous reported
procedure.[17] The residue was purified by column chromatog-
raphy on silica gel with Heptane/EtOAc=100:1 to 10:1 as
eluent. N-Pentyl-N’-(2,6-dimethylphenyl)-S-phenylisothiour-
ea was obtained in 99% yield (323 mg). White solid, m.p.:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
1
1
72–748C, H NMR (400 MHz, CDCl3): d (ppm) 7.56 (d, J=
Colorless oil, H NMR (400 MHz, CDCl3): d (ppm) 7.43 (d,
7.2 Hz, 2H), 7.40–7.45 (m, 3H), 7.07 (d, J=7.2 Hz, 2H), 6.93
(t, J=7.2 Hz, 1H), 4.02 (s, 1H), 3.40 (q, J=6.4 Hz, 2H), 2.26
(s, 6H), 1.54 (t, J=7.2 Hz, 2H), 1.30–1.34 (m, 2H), 1.21–1.28
(m, 2H), 0.91 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d (ppm) 149.5, 147.1, 135.9, 129.7, 129.6, 129.59,
127.6, 122.7, 43.0, 28.9, 28.8, 22.3, 18.3, 13.9 (1C missed).
HRMS (ESI): m/z [M+H]+ calcd for C20H27N2S: 327.1889;
found: 327.1887.
J=6.8 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.28 (d, J=
6.8 Hz,1H), 3.68 (s, 1H), 3.41 (q, J=7.2 Hz, 2H), 1.24 (s, 9H),
1.15 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
(ppm) 143.5, 133.1, 132.3, 129.3, 127.9, 52.4, 45.9, 28.6, 16.8;
HRMS (ESI): m/z [M+H]+ calcd for C13H21N2S: 237.1420;
found: 237.1422.
N-(tert-Butyl)benzamide (13)[39] Method 1: Prepared from N-
tert-butyl-N’-ethyl-S-phenylisothiourea
(12)
(85 mg,
N-(2,6-Dimethylphenyl)benzamide (10)[38] Method 1: Pre-
pared from N-2,6-dimethylphenyl-N’-pentyl-S-phenyliso-
thiourea (9) (85 mg, 0.30 mmol, 1.0 equiv.), and benzoic acid
(5a) (44 mg, 0.36 mmol, 1.2 equiv.) in o-xylene at 1308C for
24 hours according to the general procedure A. The residue
was purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 as eluent. N-(2,6-dimethylphenyl)ben-
zamide (10) was obtained in 91% yield (61 mg).
0.30 mmol, 1.0 equiv.) and benzoic acid (5a) (44 mg,
0.36 mmol, 1.2 equiv.) in o-xylene at 1308C for 24 hours
according to the general procedure A. The residue was
purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 to 1:1 as eluent. N-(tert-Butyl)benza-
mide (13) was obtained in 14% yield (7 mg) together with N-
ethylbenzamide (14).
Method 2: Prepared from N-tert-butyl-N’-ethylglycinyl-S-
phenylisothiourea (15) (88 mg, 0.30 mmol, 1.0 equiv.) and
benzoic acid (5a) (43.9 mg, 0.36 mmol, 1.2 equiv.) in o-xylene
at 1308C according to the general procedure A. The residue
was purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 to 1:1 as eluent. N-(tert-butyl)benza-
mide (13) was obtained in 33% yield (17.5 mg) together with
N-ethyl benzoylglycinate (16).
Method 2: Prepared from N-(2,4,4-trimethylpent-2-yl)-N’-
(2,6-dimethylphenyl)-S-phenylisothiourea (11) (110 mg,
0.3 mmol, 1.0 equiv.) and benzoic acid (5a) (44 mg,
0.36 mmol, 1.2 equiv.) in o-xylene at 1308C for 24 hours
according to the general procedure A. The residue was
purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 as eluent. N-(2,6-dimethylphenyl)ben-
zamide (10) was obtained in 93% yield (63 mg). Yellow solid,
m.p.: 154–1568C (lit.:[8] 157–1588C), 1H NMR (400 MHz,
CDCl3): d (ppm) 7.91 (d, J=7.2 Hz, 2H), 7.77 (s, 1H), 7.56 (t,
J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.10–7.16 (m, 3H),
2.28 (s, 6H); 13C NMR (101 MHz, CDCl3): d (ppm) 165.9,
135.6, 134.4, 134.0, 131.6, 128.6, 128.1, 127.3, 127.2, 18.3;
HRMS (ESI): m/z [M+H]+ calcd for C15H15NO: 226.1226;
found 226.1224.
Method 3: Prepared from N-tert-butyl-N’-2,2,2-trifluoroethyl-
S-phenylisothiourea (17) (87 mg, 0.30 mmol, 1.0 equiv.) and
benzoic acid (5a) (44 mg, 0.36 mmol, 1.2 equiv.) in o-xylene
at 1308C for 24 hours according to the general procedure A.
The residue was purified by column chromatography on
silica gel with Heptane/EtOAc=3:1 to 1:1 as eluent. N-(tert-
Butyl)benzamide (13) was obtained in 82% yield (44 mg).
White solid, m.p.: 136–1388C (lit.:[39] 1368C), 1H NMR
(400 MHz, CDCl3): d (ppm) 7.72 (d, J=7.2 Hz, 2H), 7.45 (t,
J=7.2 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H), 6.03 (br s, 1H), 1.47
(s, 9H); 13C NMR (101 MHz, CDCl3): d (ppm) 166.8, 135.9,
130.9, 128.3, 126.6, 51.5, 28.8; HRMS (ESI): m/z [M+H]+
calcd for C11H16NO: 178.1232; found: 178.1235.
N-(2,4,4-Trimethylpentan-2-yl)-N’-(2,6-dimethylphenyl)-S-
phenylisothiourea (11) Prepared from 2,6-dimethylaniline
(206 mg, 1.7 mmol, 1.7 equiv.), S-phenyl benzenethiosulfo-
nate (250 mg, 1.0 mmol, 1.0 equiv.) and 2-isocyano-2,4,4-
trimethylpentane (348 mg, 2.5 mmol, 2.5 equiv.) according to
our previous reported procedure.[17] The residue was purified
by column chromatography on silica gel with Heptane/
EtOAc=100:1 to 10:1 as eluent. N-(2,4,4-Trimethylpentan-2-
yl)-N’-(2,6-dimethylphenyl)-S-phenylisothiourea was ob-
N-Ethylbenzamide (14)[40] This compound was obtained in
84% yield (38 mg) together with N-(tert-butyl)benzamide
(13) when N-tert-butyl-N’-ethyl-S-phenylisothiourea (12) was
used as reactant. White solid, m.p.: 64–668C (lit.:[40] 608C),
1H NMR (400 MHz, CDCl3): d (ppm) 7.78 (d, J=7.2 Hz,
2H), 7.47 (t, J=7.2 Hz, 1H), 7.40 (t, J=7.6 Hz, 2H), 6.45 (br
s, 1H), 3.45–3.52 (m, 2H), 1.24 (t, J=7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3): d (ppm) 167.5, 134.8, 131.2, 128.4, 126.8,
53 tained in 65% yield (239 mg). Yellow solid, m.p.: 65–688C,
1H NMR (400 MHz, CDCl3): d (ppm) 7.46 (d, J=7.2 Hz,
54
2H), 7.34 (br t, 3H), 7.01 (d, J=7.6 Hz, 2H), 6.88 (d, J=
7.2 Hz, 1H), 3.84 (s, 1H), 2.25 (s, 6H), 1.79 (s, 2H), 1.38 (s,
6H), 0.89 (s, 9H); 13C NMR (101 MHz, CDCl3): d (ppm)
55
56
57
Adv. Synth. Catal. 2017, 359, 1–19
14
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
34.8, 14.8; HRMS (ESI): m/z [M+H]+ calcd for C9H12NO:
150.0913; found 150.0915.
(ESI): m/z [M+H]+ calcd for C16H15NOF3: 294.1106; found
294.1108.
1
2
3
4
5
6
7
8
9
N-(tert-Butyl)-N’-(ethyl glycinyl)-S-phenylisothiourea (15)
To a suspension of ethyl 2-azidoacetate (129 mg, 1.0 mmol,
1.0 equiv.) in DCM (10 mL, dry) was added triphenylphos-
phine (262 mg, 1.0 mmol, 1.0 equiv.) at room temperature
under Ar atmosphere. The reaction mixture was stirred for 2
hours at room temperature. Then tert-butyl isocyanate
(99 mg, 1.0 mmol, 1.0 equiv.) was added to the above mixture
at 08C. Subsequently, benzenethiol (121 mg, 1.1 mmol,
1.0 equiv.) was added. The reaction mixture was stirred at
room temperature for 12 hours. The reaction mixture was
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel with
Heptane/EtOAc=100:1 to 10:1 as eluent. N-(tert-Butyl)-N’-
(ethylglycinyl)-S-phenylisothiourea was obtained in 61%
2,2-Diphenyl-N-(2,2,2-trifluoroethyl)propanamide (21) Pre-
pared from N-tert-butyl-N’-(2,2,2-trifluoroethyl)-S-phenyliso-
thiourea (17) (87 mg, 0.30 mmol, 1.0 equiv.) and 2,2-diphe-
nylpropanoic acid (5c) (81 mg, 0.36 mmol, 1.2 equiv.) in o-
xylene at 1308C according to the general procedure A. The
residue was purified by column chromatography on silica gel
with Heptane/EtOAc=3:1 to 1:1 as eluent. 2,2-Diphenyl-N-
(2,2,2-trifluoroethyl)propanamide (21) was obtained in 71%
yield (65 mg) together with N-(tert-butyl)-2,2-diphenylpropa-
namide (20). White solid, m.p.: 101–1038C, 1H NMR
(400 MHz, CDCl3): d (ppm) 7.33 (t, J=7.2 Hz, 4H), 7.28 (d,
J=6.8 Hz, 2H), 7.23 (d, J=7.2 Hz, 4H), 5.73 (br s, 1H), 3.89
(dq, J=9.2, 6.8 Hz, 2H), 2.00 (s, 3H); 13C NMR (101 MHz,
CDCl3): d (ppm) 175.4, 144.1, 128.6, 128.0, 127.2, 124.0 (q,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
1
yield (179 mg). Colorless oil, H NMR (400 MHz, CDCl3): d
J
C-F =278.7 Hz), 57.1, 40.9 (q, JC-F =34.6 Hz), 27.1; 19F-NMR
(ppm) 7.43 (d, J=6.8 Hz, 2H), 7.35 (d, J=7.6 Hz, 1H), 7.33
(t, J=7.6 Hz, 2H), 4.24 (s, 2H), 4.17 (q, J=7.2 Hz, 2H), 4.02
(s, 1H), 1.29 (s, 9H), 1.27 (t, J=7.2 Hz, 3H); 13C-NMR
(100 MHz, CDCl3): d (ppm) 171.8, 135.3, 132.8, 131.7, 129.5,
128.2, 60.4, 52.9, 28.8, 28.5, 14.2; HRMS (ESI): m/z [M+H]+
calcd for C15H23N2O2S: 295.1475; found: 295.1470.
(376 MHz, CDCl3): d (ppm) ꢀ72.371; HRMS (ESI): m/z
[M+H]+ calcd for C17H17NOF3: 308.1262; found 308.1272.
2,2,2-Triphenyl-N-(2,2,2-trifluoroethyl)acetamide (22) Pre-
pared from N-tert-butyl-N’-(2,2,2-trifluoroethyl)-S-phenyliso-
thiourea (17) (87 mg, 0.30 mmol, 1.0 equiv.) and 2,2,2-
triphenylacetic acid (5d) (104 mg, 0.36 mmol, 1.2 equiv.) in
o-xylene at 1308C according to the general procedure A. The
residue was purified by column chromatography on silica gel
with Heptane/EtOAc=3:1 to 1:1 as eluent. 2,2,2-Triphenyl-
N-(2,2,2-trifluoroethyl)acetamide (22) was obtained in 83%
yield (92 mg). White solid, m.p.: 157–1598C, 1H NMR
(400 MHz, CDCl3): d (ppm) 7.30 (d, J=7.2 Hz, 3H), 7.27 (d,
J=7.6 Hz, 6H), 7.25 (t, J=8.0 Hz, 6H), 6.04 (br s, 1H), 3.93
(dq, J=9.2, 6.8 Hz, 2H); 13C NMR (101 MHz, CDCl3): d
Ethyl N-benzoylglycinate (16)[41] This compound was ob-
tained in 45% yield (28 mg) together with N-(tert-butyl)
benzamide (13) when N-tert-butyl-N’-(ethylglycinyl)-S-phe-
nylisothiourea (15) was used as reagent. White solid, m.p.:
61–638C (lit.:[41] 618C), 1H NMR (400 MHz, CDCl3): d (ppm)
7.82 (d, J=7.2 Hz, 2H), 7.49 (d, J=7.2 Hz, 1H), 7.43 (t, J=
7.6 Hz, 2H), 6.83 (br s, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.23 (s,
2H), 1.30 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): d
(ppm) 170.1, 167.5, 133.7, 131.7, 128.5, 127.0, 61.6, 41.8, 14.1;
HRMS (ESI): m/z [M+H]+ calcd for C11H14NO3: 208.0974;
found 208.0968.
(ppm) 173.6, 142.7, 130.4, 128.1, 127.3, 124.0 (q, JC-F
=
278.8 Hz), 67.8, 41.0 (q, JC-F =34.6 Hz); HRMS (ESI): m/z
[M+H]+ calcd for C22H19NOF3: 370.1419; found 370.1414.
N-(tert-Butyl)-2,2-diphenylacetamide (18)[42] Prepared from
N-tert-butyl-N’-(2,2,2-trifluoroethyl)-S-phenylisothiourea
(17) (87 mg, 0.30 mmol, 1.0 equiv.) and 2,2-diphenylacetic
acid (5b) (76 mg, 0.36 mmol, 1.2 equiv.) in o-xylene at 1308C
according to the general procedure A. The residue was
purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 to 1:1 as eluent. 2,2-N-(tert-butyl)-2,2-
diphenylacetamide (18) was obtained in 12% yield (10 mg)
together with 2,2-diphenyl-N-(2,2,2-trifluoroethyl)acetamide
(19). White solid, m.p.: 200–2038C (lit.:[42] 201–2028C), 1H
NMR (400 MHz, CDCl3): d (ppm) 7.31 (t, J=7.2 Hz, 4H),
7.26 (d, J=7.2 Hz, 4H), 7.24 (t, J=7.2 Hz, 2H), 5.39 (br s,
1H), 4.81 (s, 1H), 1.32 (s, 9H); 13C NMR (101 MHz, CDCl3):
General procedure B for the synthesis of N-alkylamides: A
10 mL pressure vial was charged with N,N’-dialkyldicarbodii-
mide (23) (0.30 mmol, 1.0 equiv.), 2,2,2-triphenylacetic acid
(5d) (0.36 mmol, 1.2 equiv.) and o-xylene (2.0 mL). The vial
was sealed and the reaction mixture was stirred at 1308C for
24 h under air atmosphere. The mixture was cooled down to
room temperature, concentrated under reduced pressure and
dried under vacuum. The residue was purified by flash
column chromatography on silica gel to yield the correspond-
ing N-alkylamide.
N-Cyclohexyl-2,2,2-triphenylacetamide (24a)[43] Prepared
from 1,3-dicyclohexylcarbodiimide (23a) (62 mg, 0.30 mmol,
1.0 equiv.) according to general procedure B. The residue
was purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 to 1:1 as eluent. N-Cyclohexyl-2,2,2-
triphenylacetamide (24a) was obtained in 68% yield
(75 mg). White solid, m.p.: 116–1198C (lit.:[43] 144–1458C), 1H
NMR (400 MHz, CDCl3): d (ppm) 7.26 (m, 15H), 5.62 (d, J=
4.0 Hz, 1H), 3.92 (t, J=4.0 Hz, 1H), 1.85 (d, J=9.2 Hz, 2H),
1.53 (d, J=5.2 Hz, 2H), 1.33 (q, J=10.8 Hz, 2H), 1.13 (t, J=
10.8 Hz, 2H), 1.05 (hex, J=10.8 Hz, 2H); 13C NMR
(101 MHz, CDCl3): d (ppm) 172.0, 143.5, 130.4, 127.7, 126.8,
67.5, 48.5, 32.5, 25.4, 24.4; HRMS (ESI): m/z [M+H]+ calcd
for C26H28NO: 370.2171; found 370.2181.
46 d (ppm) 171.0, 139.9, 128.8, 128.7, 127.1, 59.9, 51.5, 28.7;
47
HRMS (ESI): m/z [M+H]+ calcd for C18H22NO: 268.1701;
found 268.1707.
48
49
50
51
52
2,2-Diphenyl-N-(2,2,2-trifluoroethyl)acetamide (19) This
compound was obtained in 63% yield (55 mg) together with
N-(tert-butyl)-2,2-diphenylacetamide (18). White solid, m.p.:
144–1478C, 1H NMR (400 MHz, CDCl3): d (ppm) 7.33 (t, J=
53 7.6 Hz, 4H), 7.27 (d, J=6.8 Hz, 2H), 7.22 (d, J=7.6 Hz, 4H),
6.11 (br s, 1H), 4.95 (s, 1H), 3.85 (dq, J=9.6, 3.2 Hz, 2H); 13
C
54
55
56
57
NMR (101 MHz, CDCl3): d (ppm) 172.3, 138.7, 128.9, 128.8,
127.5, 124.0 (q, JC-F =278.6 Hz), 58.8, 40.8 (q, JC-F = 34.6 Hz);
19F-NMR (376 MHz, CDCl3): d (ppm) ꢀ72.371; HRMS
Adv. Synth. Catal. 2017, 359, 1–19
15
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
N-Isopropyl-2,2,2-triphenylacetamide (24b) Prepared from
N,N’-diisopropylcarbodiimide (23b) (38 mg, 0.30 mmol,
1.0 equiv.) according to general procedure B. The residue
was purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 to 1:1 as eluent. N-Isopropyl-2,2,2-
triphenylacetamide (24b) was obtained in 73% yield
mixture. After stirring the mixture at room temperature
overnight, THF was evaporated and the residue was taken
up in EtOAc (40 mL) and cooled in the refrigerator. Then
N,N’-dicyclohexylurea (DCU) was filtered off, the filtrate
washed with saturated Na2CO3 (33 10 mL), HCl (1 N, 33
10 mL), brine (33 10 mL) and dried over MgSO4. The
solvent was evaporated to give the crude product which was
purified by flash column chromatography on silica gel.
1
2
3
4
5
6
7
8
9
1
(72 mg). White solid, m.p.: 113–1168C, H NMR (400 MHz,
CDCl3): d (ppm) 7.26 (m, 15H), 5.52 (s, 1H), 4.18 (hex, J=
6.8 Hz, 1H), 1.07 (d, J=6.8 Hz, 6H); 13C-NMR (101 MHz,
CDCl3): d (ppm) 172.0, 143.5, 130.5, 127.8, 126.8, 67.5, 42.0,
22.3; HRMS (ESI): m/z [M+H]+ calcd for C23H24NO:
330.1858; found 330.1859.
Method 2 (for compounds 24a–24e):[47] A 25 mL round
bottomed flask was charged with 2,2,2-triphenylacetic acid
(5d, 1.05 mmol, 1.05 equiv.) and DCM (5 mL) and cooled to
08C, then 1,3-dicyclohexylcarbodiimide (DCC, 1.08 mmol,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
N-(tert-Butyl)-2,2,2-triphenylacetamide (24c)[44] Prepared
from di-tert-butylcarbodiimide (23c) (46 mg, 0.30 mmol,
1.0 equiv.) according to general procedure B. The residue
was purified by column chromatography on silica gel with
Heptane/EtOAc=3:1 to 1:1 as eluent. N-(tert-Butyl)-2,2,2-
triphenylacetamide (24c) was obtained in 71% yield (73 mg).
White solid, m.p.: 106–1098C (lit.:[44] 125.8–127.18C), 1H
NMR (400 MHz, CDCl3): d (ppm) 7.26 (m, 15H), 5.51 (s,
1H), 1.29 (s, 9H); 13C NMR (101 MHz, CDCl3): d (ppm)
172.0, 143.7, 130.5, 127.7, 126.8, 68.1, 51.6, 28.4; HRMS
(ESI): m/z [M+H]+ calcd for C24H26NO: 344.2014; found
344.2002.
1.08 equiv.)
and
4-dimethylaminopyridine
(DMAP,
0.25 mmol, 25 mol%) were dissolved in DCM (5 mL) and
added dropwise to the above mixture. The reaction mixture
was subsequently stirred at 08C for 30 minutes, then an
amine (1.0 mmol, 1.0 equiv.) was added and the reaction
mixture was stirred for 24 h at room temperature. The
mixture was filtered through filter paper, the solid was
thoroughly washed with EtOAc, and the combined filtrates
concentrated and dried in vacuo. The residue was purified by
flash column chromatography on silica gel.
Acknowledgements
N-(Adamantan-1-yl)-2,2,2-triphenylacetamide (24d)[45] Pre-
pared from di-(1-adamantanyl)carbodiimide (23d) (93 mg,
0.30 mmol, 1.0 equiv) according to general procedure B. The
residue was purified by column chromatography on silica gel
with Heptane/EtOAc=3:1 to 1:1 as eluent. N-(Adamantan-
1-yl)-2,2,2-triphenylacetamide (24d) was obtained in 62%
yield (78 mg). White solid, m.p.: 221–2248C, 1H NMR
(400 MHz, CDCl3): d (ppm) 7.24–7.27 (m, 15H), 5.38 (s, 1H),
2.03 (br, s, 3H) 1.95 (s, 6H), 1.64 (s, 6H); 13C NMR
(101 MHz, CDCl3): d (ppm) 171.8, 143.7, 130.5, 127.7, 126.7,
68.1, 41.2, 36.3, 29.3; HRMS (ESI): m/z [M+H]+ calcd for
C30H32NO: 422.2484; found 422.2495.
This work has been supported by the European Union’s
Horizon 2020 research and innovation programme under the
Marie Skłodowska-Curie grant agreement 657883 (scholar-
ship for Y.-P. Z.), the Research Foundation-Flanders (FWO)
(scholarship for P.M., Research Project and Scientific
Research Network (WOG)), UAntwerpen (BOF), and the
Hercules Foundation. The research leading to these results has
also received funding from the Innovative Medicines Initiative
(www.imi.europa.eu) Joint Undertaking project CHEM21
under grant agreement 115360, resources of which are
composed of financial contribution from the European
Union’s Seventh Framework Programme and EFPIA compa-
nies’ in kind contribution. The authors would like to thank
Philippe Franck for LC analysis, and Karlijn Hollanders and
Victor Terrier for providing the tripeptides.
N-(2,6-Diisopropylphenyl)-2,2,2-triphenylacetamide
(24e)
Prepared from bis(2,6-diisopropylphenyl)carbodiimide (23e)
(109 mg, 0.30 mmol, 1.0 equiv.) according to general proce-
dure B. The residue was purified by column chromatography
on silica gel with Heptane/EtOAc=3:1 to 1:1 as eluent. N-
(2,6-Diisopropylphenyl)-2,2,2-triphenylacetamide (24e) was
obtained in 72% yield (97 mg). White solid, m.p.: 97–1008C,
1H NMR (400 MHz, CDCl3): d (ppm) 7.50 (d, J=7.6 Hz,
6H), 7.31 (t, J=7.2 Hz, 6H), 7.25 (d, J=7.2 Hz, 3H), 7.21 (d,
J=8.4 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=7.6 Hz, 2H), 2.87
(hept, J=6.8 Hz, 2H), 1.09 (d, J=6.8 Hz, 12H); 13C NMR
References
[1] a) V. R. Pattabiraman, J. W. Bode, Nature 2011, 480,
471–479; b) E. Valeur, M. Bradley, Chem. Soc. Rev.
2009, 38, 606–631; c) A. Ojeda-Porras, D. Gamba-
Sꢂnchez, J. Org. Chem. 2016, 81, 11548–11555; d) R. M.
de Figueiredo, J.-S. Suppo, J.-M. Campagne, Chem. Rev.
2016, 116, 12029–12122.
[2] a) H. Lundberg, F. Tinnis, N. Selander, H. Adolfsson,
Chem. Soc. Rev. 2014, 43, 2714–2742; b) A. K. Ghose,
V. N. Viswanadhan, J. J. Wendoloski, J. Comb. Chem.
1999, 1, 55–68; c) J. S. Carey, D. Laffan, C. Thomson,
M. T. Williams, Org. Biomol. Chem. 2006, 4, 2337–2347.
[3] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54,
3451–3479.
46 (101 MHz, CDCl3): d (ppm) 171.8, 145.9, 143.4, 131.2, 130.4,
128.0, 127.0, 123.3, 68.6, 28.4, 23.6 (1c missing); HRMS
(ESI): m/z [M+H]+ calcd for C32H34NO: 448.2640; found
448.2640.
47
48
49
50
51
52
General procedures for amide synthesis via DCC coupling:
Method 1 (for compounds l-3j, l-3l, l-3s):[46] A solution of
carboxylic acid 2 (1.0 mmol, 1.0 equiv.) and 1-hydroxybenzo-
53 triazole hydrate (1.1 mmol, 1.1 equiv.) in THF (5 mL, anhy-
drous) was cooled to 08C. Subsequently, a solution of 1,3-
dicyclohexylcarbodiimide (1.1 mmol, 1.1 equiv.) (DCC) in
THF (1 mL, anhydrous) was added. After 20 minutes an
amine (1.1 mmol, 1.1 equiv.) was added to the reaction
54
55
56
57
[4] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R.
Humphrey, J. J. L. Leazer, R. J. Linderman, K. Lorenz,
Adv. Synth. Catal. 2017, 359, 1–19
16
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
J. Manley, B. A. Pearlman, A. Wells, A. Zaks, T. Y.
Zhang, Green Chem. 2007, 9, 411–420.
2012, 51, 12036–12040. b) A. D. Kosal, E. E. Wilson,
B. L. Ashfeld, Chem. Eur. J. 2012, 18, 14444–14453.
[16] a) Y.-P. Zhu, S. Sergeyev, P. Franck, R. V. A. Orru,
B. U. W. Maes, Org. Lett. 2016, 18, 4602–4605, b) P.
Debnath, M. Baeten, N. Lefꢄvre, S. V. Daele, B. U. W.
Maes, Adv. Synth. Catal. 2015, 357, 197–209.
[17] P. Mampuys, Y. Zhu, T. Vlaar, E. Ruijter, R. V. A. Orru,
B. U. W. Maes, Angew. Chem. 2014, 126, 13063–13068;
Angew. Chem. Int. Ed. 2014, 53, 12849–12854.
[18] Pharmaceutical Substances: Syntheses, Patents, Applica-
tions of the most relevant APIs. (Eds.: A. Kleemann, J.
Engel, B. Kutscher, D. Reichert), Thieme, Stuttgart,
2008.
1
2
3
4
5
6
7
8
9
[5] a) T. Xu, F. Sha, H. Alper, J. Am. Chem. Soc. 2016, 138,
6629–6635; b) X. Fang, H. Li, R. Jackstell, M. Beller, J.
Am. Soc. Chem. 2014, 136, 16039–16043; c) X. Fang, R.
Jackstell, M. Beller, Angew. Chem. 2013, 125, 14339–
14343; Angew. Chem. Int. Ed. 2013, 52, 14089–14093;
d) T. Fujihara, Y. Katafuchi, T. Iwai, J. Terao, Y. Tsuji, J.
Am. Chem. Soc. 2010, 132, 2094–2098.
[6] a) T. Wang, S. J. Danishefsky, Proc. Natl. Acad. Sci.
USA. 2013, 110, 11708–11713; b) R. V. Kolakowski, N.
Shangguan, R. R. Sauers, L. J. Williams, J. Am. Chem.
Soc. 2006, 128, 5695–5702; c) T. Wang, S. J. Danishefsky,
J. Am. Chem. Soc. 2012, 134, 13244–13247.
[7] a) F.-L. Zhang, Y.-F. Wang, G. H. Lonca, X. Zhu, S.
Chiba, Angew. Chem. 2014, 126, 4479–4483; Angew.
Chem. Int. Ed. 2014, 53, 4390–4394; b) C. Tang, N. Jiao,
Angew. Chem. 2014, 126, 6646–6650, Angew. Chem. Int.
Ed. 2014, 53, 6528–6532.
[8] a) C. Gunanathan, D. Milstein, Science 2013, 341, 249–
260; b) S. L. Zultanski, J. Zhao, S. S. Stahl, J. Am. Chem.
Soc. 2016, 138, 6416–6419; c) K. Yamaguchi, H. Kobaya-
shi, T. Oishi, N. Mizuno, Angew. Chem. Int. Ed. 2012,
51, 544–547; d) B. Kang, Z. Fu, S. H. Hong, J. Am.
Chem. Soc. 2013, 135, 11704–11707.
[9] a) B. Shen, D. M. Makley, J. N. Johnston, Nature 2010,
465, 1027–1032; b) K. E. Schwieter, B. Shen, J. P.
Shackleford, M. W. Leighty, J. N. Johnston, Org. Lett.
2014, 16, 4714–4717; c) K. E. Schwieter, J. N. Johnston,
Chem. Sci. 2015, 6, 2590–2595.
[10] a) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan, A.
Lei, Angew. Chem. 2014, 126, 512–516; Angew. Chem.
Int. Ed. 2014, 53, 502–506; b) Z. Liu, J. Zhang, S. Chen,
E. Shi, Y. Xu, X. Wan, Angew. Chem. 2012, 124, 3285–
3289; Angew. Chem. Int. Ed. 2012, 51, 3231–3235.
[11] a) G. Schꢃfer, C. Matthey, J. W. Bode, Angew. Chem.
2012, 124, 9307–9310; Angew. Chem. Int. Ed. 2012, 51,
9173–9175. b) G. Schꢃfer, J. W. Bode, Org. Lett. 2014,
16, 1526–1529.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
[19] S. Okumura, Y. Takeda, K. Kiyokawa, S. Minakata,
Chem. Commun. 2013, 49, 9266–9268.
[20] a) A. F. Hegarty, M. T. McCormack, G. Ferguson, P. J.
Roberts, J. Am. Chem. Soc. 1977, 99, 2015–2016.
b) J. S. P. Schwarz, J. Org. Chem. 1972, 37, 2906–2908.
c) N. Chꢅron, R. Ramozzi, L. E. Kaꢆm, L. Grimaud, P.
Fleurat-Lessard, J. Org. Chem. 2012, 77, 1361–1366.
d) E. R. van Rijssel, T. P. M. Goumans, G. Lodder, H. S.
Overkleeft, G. A. Van der Marel, J. D. C. Codꢅe, Org.
Lett. 2013, 15, 3026–3029.
[21] a) Peptide Synthesis and Applications. (Eds.: K. J. Jen-
sen, S. P. Tofteng, S. L. Pedersen), Springer, Heidelberg,
2013; b) H. G. Khorana, J. Chem. Soc. 1952, 2081–2088.
[22] a) WꢀX. Zhang, L. Xu, Z. Xi, Chem. Commun. 2015,
51, 254–265, b) M. Lazar, R. J. Angelici, J. Am. Chem.
Soc. 2006, 128, 10613–10620, c) TꢀH. Zhu, SꢀY. Wang,
YꢀQ. Tao, SꢀJ. Ji, Org. Lett. 2015, 17, 1974–1977.
[23] K. Thalluri, K. C. Nadimpally, M. P. Chakravarty, A.
Paul, B. Mandal, Adv. Synth. Catal. 2013, 355, 448–462.
[24] F. Chen, S. Huang, H. Zhang, F. Liu, Y. Peng,
Tetrahedron 2008, 64, 9585–9591.
[25] P. Pelagatti, M. Carcelli, F. Calbiani, C. Cassi, L. Elviri,
C. Pelizzi, U. Rizzotti, D. Rogolino, Organometallics
2005, 24, 5836–5844.
[26] K. N. Gavrilov, A. A. Shiryaev, S. V. Zheglov, O. V.
Potapova, I. V. Chuchelkin, I. M. Novikov, E. A. Rastor-
guev, V. A. Davankov, Tetrahedron Asymmetry 2013,
24, 409–417.
38 [12] a) J. R. Dunetz, J. Magano, G. A. Weisenburger, Org.
Process. Res. Dev. 2016, 20, 140–177. b) S. J. Aspin, S.
Taillemaud, P. Cyr, A. B. Charette, Angew. Chem. 2016,
128,14037–14041; Angew. Chem. Int. Ed. 2016, 55,
13833–13837. c) T. Krause, S. Baader, B. Erb, L. J.
Goossen, Nat. Commun. 2016, 7, doi:10.1038/
ncomms11732. d) L. Hu, S. Xu, Z. Zhao, Y. Yang, Z.
Peng, M. Yang, C. Wang, J. Zhao, J. Am. Chem. Soc.
2016, 138, 13135–13138. e) R. M. Al-Zoubi, O. Marion,
D. G. Hall, Angew. Chem. 2008, 120, 2918–2921; Angew.
Chem. Int. Ed. 2008, 47, 2876–2879; f) H. Lundberg, H.
Adolfsson, ACS Catalysis 2015, 5, 3271–3277; g) C. L.
Allen, A. R. Chhatwal, J. M. J. Williams, Chem. Com-
mun. 2012, 48, 666–668.
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[27] T. Kanemitsu, A. Umehara, R. Haneji, K. Nagata, T.
Itoh, Tetrahedron, 2012, 68, 3893–3898.
[28] I. M. Bell, S. N. Gallicchio, M. Abrams, D. C. Beshore,
C. A. Buser, J. C. Culberson, J. Davide, M. Ellis-
Hutchings, C. Fernandes, J. B. Gibbs, S. L. Graham,
G. D. Hartman, D. C. Heimbrook, C. F. Homnick, J. R.
Huff, K. Kassahun, K. S. Koblan, N. E. Kohl, R. B.
Lobell, J. J. Lynch, P. A. Miller, C. A. Omer, A. D.
Rodrigues, E. S. Walsh, T. M. Williams, J. Med. Chem.
2001, 44, 2933–2949.
[29] Y. Fujita, Y. Tsuda, T. Li, T. Motoyama, M. Takahashi,
Y. Shimizu, T. Yokoi, Y. Sasaki, A. Ambo, A. Kita, Y.
Jinsmaa, S. D. Bryant, L. H. Lazarus, Y. Okada, J. Med.
Chem. 2004, 47, 3591–3599.
[13] X. Li, Y. Yuan, C. Kan, S. J. Danishefsky, J. Am. Chem.
Soc. 2008, 130, 13225–13227.
[30] Y. Zhang, J. Feng, C. Liu, H. Fang, W. Xu, Bioorg. Med.
[14] J.-S. Suppo, G. Subra, M. Bergꢄs, R. Marcia de Figueir-
edo, J.-M. Campagne, Angew. Chem. 2014, 126, 5493–
5497; Angew. Chem. Int. Ed. 2014, 53, 5389–5393.
[15] a) A. D. Kosal, E. E. Wilson, B. L. Ashfeld, Angew.
Chem. 2012, 124, 12202–12206; Angew. Chem. Int. Ed.
Chem. 2011, 19, 4437–4444.
[31] a) K. N. Gavrilov, A. A. Shiryaev, S. V. Zheglov, O. V.
Potapova, I. V. Chuchelkin, I. M. Novikov, E. A. Rastor-
guev, V. A. Davankov, Tetrahedron: Asymmetry, 2013,
24, 409–417. b) A. E. Sheshenev, E. V. Boltukhina,
Adv. Synth. Catal. 2017, 359, 1–19
17
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
A. J. P. White, K. K. Hii, Angew. Chem. 2013, 125,
[39] T. Ueda, H. Konishi, K. Manabe, Org. Lett. 2012, 14,
5370–5373.
[40] R. Chinchilla, D. J. Dodsworth, C. Nꢂjera, J. M. Soriano,
Tetrahedron Lett. 2003, 44, 463–466.
[41] T. Ueda, H. Konishi, K. Manabe, Org. Lett. 2012, 14,
5370–5373.
[42] J. J. Ritter, F. X. Murphy, J. Am. Chem. Soc. 1952, 74,
763–765.
[43] D. T. McQuade, S. L. McKay, D. R. Powell, S. H. Gell-
man, J. Am. Chem. Soc. 1997, 119, 8528–8532.
[44] M. E. Due-Hansen, S. K. Pandey, E. Christiansen, R.
Andersen, S. V. F. Hansen, T. Ulven, Org. Biomol.
Chem. 2016, 14, 430–433.
1
2
3
4
5
6
7
8
9
7126–7129; Angew. Chem. Int. Ed. 2013, 52, 6988–6991
[32] Y. Shinya, M. Hironori, H. Yoji, Eur. Pat. Appl.
2457655, 2012.
[33] Y. Huang, Y. Liu, Y. Liu, H. Song, Q. Wang, Bioorg.
Med. Chem, 2016, 24, 462–473.
[34] A. Ottavio, F. Mauro, S. Isaac Thomas, T. Greg R., PCT
Int. Appl. 2013116663, 2013.
[35] A. El-Fahm, M. Abdul-Ghani, Org. Prep. Proc. Int.
2003, 35, 369–374.
10
11
12
[36] S. Hu, Q. Gu, Z. Wang, Z. Weng, Y. Cai, X. Dong, Y.
Hu, T. Liu, X. Xie, Eur. J. Med. Chem. 2014, 71, 259–
266.
13 [37] F. Corbo, C. Franchini, G. Lentini, M. Muraglia, C.
[45] R. S. Dothager, K. S. Putt, B. J. Allen, B. J. Leslie, V.
Nesterenko, P. J. Hergenrother, J. Am. Chem. Soc. 2005,
127, 8686–8696.
[46] Y. Zhang, J. Feng, C. Liu, H. Fang, W. Xu, Bioorg. Med.
Chem. 2011, 19, 4437–4444.
Ghelardini, R. Matucci, N. Galeotti, E. Vivoli, V.
Tortorella, J. Med. Chem. 2007, 50, 1907–1915.
[38] I. Vazzana, R. Budriesi, E. Terranova, P. Ioan, M. P.
Ugenti, B. Tasso, A. Chiarini, F. Sparatore, J. Med.
Chem. 2007, 50, 334–343
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[47] X. Ju, Z. Liu, Chinese Patent CN101701016A, 2011.
Adv. Synth. Catal. 2017, 359, 1–19
18
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

1
2
UPDATES
Amine Activation: N-Arylamino Acid Amide Synthesis
3
4
from Isothioureas and Amino Acids
5
6
7
Adv. Synth. Catal. 2017, 359, 1–19
8
9
Y.-P. Zhu, P. Mampuys, S. Sergeyev, S. Ballet, B. U. W.
Maes*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57