Hydrazinopeptide motifs synthesized via the Ugi reaction: An insight into the secondary structure

Article abstract of DOI:10.1055/s-0029-1219274

A number of N^α-alkyl,N^β-acylhydrazines have been synthesized via the Ugi reaction of N-acylhydrazones with an isocyanide and trifluoroacetic acid. The trifluoroacetic acid acted as a silent partner and becomes removed upon basic workup of the reaction. These compounds have been efficiently modified further via reductive alkylation to produce N^α,N^α-dialkyl,N^β- acylhydrazines. The two groups of novel hydrazinopeptide motifs have been shown by simple ¹H NMR spectroscopic experiments to display two different secondary structure patterns. These observations were confirmed by X-ray crystallographic analysis. Combining the hydrazone and carboxylic acid moieties in one reaction precursor offers the opportunity for an intramolecular hydrazino-Ugi reaction, which was also demonstrated. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1219274

PAPER
933
Hydrazinopeptide Motifs Synthesized via the Ugi Reaction: An Insight into the
Secondary Structure
H
ydrazinopeptide Mot
iifs via
t
he
U
gi Reac
h
tion ail Krasavin,*a Ekaterina Bushkova,a Vladislav Parchinsky,b Alexei Shumskyb
a
Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, Yaroslavl 150000, Russian Federation
Fax +7(495)6269780; E-mail: myk@chemdiv.com
b
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Region 141400, Russian Federation
Received 26 October 2009
carboxylic acid partner in the reaction of hydrazones 1
with isocyanides 2. The initially formed ‘hydrazino-Ugi’
products 3 contain a labile trifluoroacetyl group that is
easily removed by mild basic hydrolysis of the isolated
Abstract: A number of Na-alkyl,Nb-acylhydrazines have been syn-
thesized via the Ugi reaction of N-acylhydrazones with an isocya-
nide and trifluoroacetic acid. The trifluoroacetic acid acted as a
‘silent partner’ and becomes removed upon basic workup of the re-
action. These compounds have been efficiently modified further via products 3 or in situ. The resulting Na-alkyl,Nb-acylhydra-
reductive alkylation to produce Na,Na-dialkyl,Nb-acylhydrazines.
The two groups of novel hydrazinopeptide motifs have been shown
by simple 1H NMR spectroscopic experiments to display two differ-
ent secondary structure patterns. These observations were con-
firmed by X-ray crystallographic analysis. Combining the
hydrazone and carboxylic acid moieties in one reaction precursor
offers the opportunity for an ‘intramolecular’ hydrazino-Ugi reac-
tion, which was also demonstrated.
zines 4 represent hydrazinopeptide-like8 structures and
also contain a reactive a-nitrogen atom that can be used
for further derivatization of the newly formed hydrazi-
nopeptide backbone, e.g. through a second Ugi reaction
(Scheme 1).9 Hydrazinopeptides represent a less-studied
class of peptidomimetics useful in preparing more pro-
teolytically stable10 analogues of natural bioactive pep-
tides with preserved biological activity.11 In addition,
these motifs are quite appealing as they are known12 to
adopt a unique secondary structure, a ‘hydrazino turn’,
owing to the bifurcated hydrogen bond involving the sp3-
hydridized a-nitrogen atom (Figure 1), in a similar man-
ner to the natural peptide b-turn.
Key words: multicomponent reactions, hydrazones, substituent ef-
fects, peptidomimetics, secondary structures
The four-component reaction of an amine, a carbonyl
compound, a carboxylic acid, and an isocyanide, known
as the Ugi reaction,1 delivers medicinally relevant2 dipep-
toid compounds in a remarkably efficient, atom-economic
manner, the only byproduct being water from the conden-
sation reaction forming the initial imine.
O
CF3
O
R3NC (2), TFA
O
N
R2
N
O
R2
R1
N
R1
N
H
dioxane
r.t., 16–20 h
H
R3
N
H
The reaction has gone a long evolutionary path since its
discovery in 1959. A common theme in the development
of novel isocyanide-based multicomponent reactions has
been the replacement of one or more reaction partners in
the ‘Ugi foursome’ with various surrogates. The most-
developed strategy to date is the use of noncarboxylate
nucleophiles to intercept the isocyanide interacting with
the iminium species.3 However, finding workable surro-
gates for the iminium component, the formation of which
from the amine and carbonyl compounds under acidic
catalysis triggers the Ugi reaction, appears more challeng-
ing as one finds only a handful of examples of this
approach in the literature. Among the examples reported
are the successful uses of various hydrazones4 and
oximes,5 and more recently published methodologies in-
volving N-acylazinium6 and N-fluoropyridinium7 salts as
less obvious substitutes for the iminium reaction partner
for an isocyanide.
1
3
1) R3NC (2)
TFA
dioxane
r.t., 16–20 h
2) 10% aq K2CO3
r.t., 3 h
10% aq
K2CO3
r.t., 3 h
O
α
N
H
R2
R1
N
H
β
R3
O
N
H
4
second Ugi reaction
R5
O
N
NH
H
R1
N
R4
H
O
N
R2
R3
We have recently modified the early methodology by Ugi
and Bodesheim4b and employed trifluoroacetic acid as the
O
Scheme 1 Synthesis of Na-alkyl,Nb-acylhydrazines 4 for use as star-
ting materials in a second Ugi reaction
SYNTHESIS 2010, No. 6, pp 0933–0942
x
x
.
x
x
.2
0
1
0
Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1219274; Art ID: P15009SS
© Georg Thieme Verlag Stuttgart · New York

934
M. Krasavin et al.
PAPER
butoxycarbonyl-protected hydrazine analogues of valine
amides.13
i–1
O
i+1
R
O
R
H
N
N
H
N
H
It should be noted that (trifluoroacetyl)hydrazines 3 are, in
principle, stable to isolation, as demonstrated by the isola-
tion and characterization of a representative compound,
derivative 3i (en route to 4i).
Ri
O
α
β
H
H
R
N
N
O
natural peptide
O
H
N
The choice of dioxane as the medium for the hydrazino-
Ugi reaction is important; the same reaction carried out in
methanol, often the solvent of choice for a number of Ugi
reactions,14 leads to a more-complex mixture of products
as shown for the two reactions presented in Scheme 2.
Without the basic workup, the reaction mixtures were an-
alyzed by LC-MS to reveal the presence of equal amounts
of the expected hydrazino-Ugi product 3 and de-trifluoro-
acetylated product 4. In addition, substantial amounts of
methyl esters 5 were present; these latter byproducts were
isolated chromatographically in the yields indicated and
characterized. The formation of products 4 and 5 in meth-
anol can be rationalized by possible interference of the nu-
cleophilic solvent molecule during the course of the
reaction, as indicated in Scheme 3.
'hydrazino turn'
i–1
O
i
R
R
O
H
H
N
N
N
H
N
H
i+1
O
R
hydrazinopeptide
Figure 1 Hydrazinopeptides and their hydrazino turn conformation
Herein, we report on the synthesis of an extended set of
hydrazinopeptide units 4 and their modification at the a-
nitrogen atom via reductive alkylation. The propensity of
such structures to yield intriguing secondary structure pat-
terns also prompted us to investigate the latter modified
products using NMR spectroscopy and X-ray crystallog-
raphy to reveal marked regularity that we disclose in this
paper.
If two reaction partners for the Ugi process are combined
within the structure of a single reactant, a ring-forming
process can occur, as has been shown using various oxo-
and formyl-substituted acids as substrates for a four-
center, three-component Ugi reaction.15 We designed a
precursor, compound 6, containing both the hydrazone
and carboxylic acid moieties which was synthesized in
four straightforward chemical operations and involved
one purification. Analogous to the previously reported
preparation of aza-b-lactams from a-hydrazino acids via
the Ugi reaction,16 compound 6 produced N-monoalkylat-
ed tetrahydropyridazine-3,6-dione 7 in good yield upon an
Thirteen hydrazinopeptide motifs 4a–m were synthesized
according to the above one-pot procedure, with the mild
basic workup of the reaction mixture leading to the clean
and complete removal of the trifluoroacetyl group
(Scheme 1). The isolated yields were moderate to good
(Table 1) and the identities of the compounds were con-
sistent with their characterization data. Interestingly,
compounds 4j and 4k are essentially the racemic tert-
Table 1 Synthesis of Na-Alkyl,Nb-acylhydrazines 4a
Compound
R1
R2
R3
Isolated yield (%) LC-MS (m/z) [M + H+]
4a
4b
4c
4d
4e
4f
pyridin-4-yl
4-MeC6H4CH2
pyrazin-2-yl
pyridin-4-yl
pyridin-4-yl
pyrazin-2-yl
pyridin-4-yl
4-MeC6H4CH2
4-MeOC6H4OCH2
t-BuO
c-Hex
c-Hex
c-Hex
Pr
MeOCH2CH2
MeOCH2CH2
MeOCH2CH2
MeOCH2CH2
Bn
52
68
54
58
44
44
48
78
64
84
84
77
59
335
362
336
295
327
368
367
332
366
288
352
334
334
Pr
c-Hex
c-Hex
Et
Bn
4g
4h
4i
Bn
c-Hex
i-Bu
i-Pr
t-Bu
4j
t-Bu
4k
4l
t-BuO
i-Pr
4-MeOC6H4CH2
2-MeOC6H4CH2
MeOCH2CH2
Me
c-Hex
c-Hex
4m
Ph
a See Scheme 1 for the corresponding reaction conditions and structures.
Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York

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Hydrazinopeptide Motifs via the Ugi Reaction
935
MeO
O
CF3
NC
O
O
O
O
TFA
MeOH, r.t., 20 h
H
N
H
N
R2
N
R2
R2
R2
+
N
+
R1
N
H
R1
N
H
R1
N
R1
N
H
H
OMe
OMe
1
O
N
H
O
N
H
O
OMe
3
4
5c, 13%
5d, 24%
N
1,3–5c, R1
1, 3–5d, R1
=
=
R2
R2
=
=
N
N
Scheme 2 Hydrazino-Ugi reaction in methanol
H+
O
O
O
H
H
N
R2
a
R2
N
N
R2
R1
N
R1
N
R1
N
a
O
H
H
H
OMe
H
O
R3
R3
HO
H
C–
N
O
N
O
b
CF3
H
O
H+
N+
Me
H+
R3
Me
O
b
O
CF3
CF3
– R3NH2
O
O
O
O
H
H
R3
N
N
R1
N
OMe
R1
N
N
H
H
H
R2
R2
4
5
Scheme 3 Possible mechanistic rationale for the formation of byproducts 4 and 5 during the hydrazino-Ugi reaction in methanol
O
NH2
O
O
O
4 M HCl
dioxane
O
N
H
H
EtO
N
O
EtO
EtO
NH2
N
H
Cl
N
H
⋅HCl
O
O
CH2Cl2, Et3N, r.t.
O
O
O
CHO
O
NaOH
MeOH, Et3N
r.t.
EtO
N
HO
N
N
N
H
aq MeOH, r.t.
O
H
O
O
6
+
N
C –
NH
O
N
i-PrOH, 50 °C
72%
N
H
O
7
Scheme 4 Preparation of hydrazone 6 and its intramolecular hydrazino-Ugi reaction
‘intramolecular’ Ugi reaction with tert-butyl isocyanide methanol, which is more nucleophilic than isopropyl alco-
in isopropyl alcohol (Scheme 4). Notably, when the same hol, during the course of the intramolecular Ugi reaction
reaction was performed in methanol, methyl ester 8 was (Scheme 5).
identified by LC-MS as the main reaction product, though
we failed to isolate it from the reaction mixture. Its forma-
tion can be rationalized, again, by the interference of
ther diverse functionalities off the hydrazine moiety, as
The a-nitrogen atom of compounds 4 is a potential reac-
tive center and it can be used for the introduction of fur-
Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York

936
M. Krasavin et al.
PAPER
NH
+
N
C–
O
O
O
NH
HO
O
N
HN
MeOH, 50 °C
N
H
O
6
OMe
8
b
Me
H
O
H+
O
O
N+
b
O
N
C–
O
NH
N
O
a
a
X
–O
O
N+
O
N
HN
H
NH
H
N
H
7
O
Scheme 5 Mechanistic rationale for the formation of methyl ester 8 upon reaction of hydrazone 6 with tert-butyl isocyanide in methanol
was demonstrated by its participation in the Ugi reaction Having prepared two sets of hydrazinopeptide fragments,
(Scheme 1).9 Therefore, we explored its reactivity in re- compounds 4 and 9, we proceeded to study their second-
1
ductive alkylation reactions. Although we found reductive ary structures. We compared changes in the H NMR
alkylation was not feasible with aromatic or heteroaro-
matic aldehydes, using a range of solvents and tempera-
tures and with various reductants, Na,Na-dialkyl,Nb-
acylhydrazines 9a–k were successfully prepared in good
to excellent yields using isovaleraldehyde and butyralde-
hyde (Scheme 6 and Table 2).
R4
O
O
α
H
N
α
β
N
H1
β
N
H1
R2
N
R2
R1
R1
R3
R3
O
N
H2
O
N
H2
4
9
R4
O
O
α
O
α
H
N
R2
R4CHO
R2
N
O
R2
R1
N
R1
N
β
NH2
β
R1
N
H
H
R3
R3
NaBH(OAc)3
CH2Cl2, r.t., 18 h
R3
H1
N
H
O
N
H2
O
N
H
4
9
4 = i-Bu, n-Pr
10
11
R
Scheme 6 Synthesis of Na,Na-dialkyl,Nb-acylhydrazines 9 via re-
ductive alkylation
Figure 2 Structures of units 4 and 9 and the reference fragments for
the 1H NMR spectroscopic study
Table 2 Synthesis of Na,Na-Dialkyl,Nb-acylhydrazines 9a
Compound R1
R2
R3
R4
Isolated yield (%) LC-MS (m/z) [M + H+]
9a
9b
9c
9d
9e
9f
pyridin-4-yl
c-Hex
c-Hex
c-Hex
Pr
MeOCH2CH2
i-Bu
i-Bu
Pr
62
85
58
64
62
74
72
74
68
80
59
405
432
392
365
351
438
424
438
423
397
383
4-MeC6H4CH2
pyrazin-2-yl
pyridin-4-yl
pyridin-4-yl
pyrazin-2-yl
pyrazin-2-yl
pyrazin-4-yl
pyridin-4-yl
pyridin-4-yl
pyridin-4-yl
MeOCH2CH2
MeOCH2CH2
MeOCH2CH2
i-Bu
Pr
Pr
MeOCH2CH2
c-Hex
c-Hex
c-Hex
c-Hex
Pr
Bn
Bn
Bn
Bn
Bn
Bn
i-Bu
Pr
9g
9h
9i
i-Bu
Pr
9j
i-Bu
Pr
9k
Pr
a See Scheme 6 for the corresponding reaction conditions and structures.
Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York

PAPER
Hydrazinopeptide Motifs via the Ugi Reaction
937
spectroscopic chemical shifts of the protons in 4 and 9 spectively (Figure 2).19 Roughly the same downfield shift
suspected of participation in intramolecular hydrogen of the 1H NMR spectroscopic signals was observed for the
bonding with the same changes in reference fragments 10 Nb-H1 protons of compounds 4 compared to those of 10,
and 11 (Figure 2),17 in which no such bonding is possible. but this was not the case for the terminal amide protons
Upon solvent change from deuterated dimethylsulfoxide H2, which were significantly less sensitive to the solvent
(DMSO-d6) to chloroform-d (CDCl3), one can pinpoint change than the corresponding H2 protons in 11. This can
those protons that are indeed involved in the intramolecu- be explained only by the involvement of H2 in the terminal
lar hydrogen bond.18
amide of compounds 4 in an intramolecular hydrogen
bond. The situation reverses for compounds 9, and this
observation prompted us to conclude that the introduction
of the second alkyl group at the a-nitrogen makes an alter-
native hydrogen bonding pattern, involving H1 not H2 this
Indeed, as can be seen from Table 3, using DMSO-d6 as a
solvent capable of accepting a hydrogen bond from the
solute causes the downfield shift of the acidic, amide-type
protons H1 and H2 in reference fragments 10 and 11, re-
Table 3 Changes in the 1H NMR Spectroscopic Chemical Shift Values of the Amide Nitrogen-Bound Protons of Hydrazinopeptide Units 4
and 9 Compared with Those of Reference Fragments 10 and 11 upon Solvent Changea,b
Compound
Dd (DMSO-d6 → CDCl3) for H1
Dd (DMSO-d6 → CDCl3) for H2
4(9)
2.43
2.21
1.56
2.40
1.77
0.87
2.17
2.53
1.08
2.09
2.12
1.65
1.50
0.24
0.89
0.05
0.42
0.40
0.28
0.10
–0.02
0.08
0.24
0.54
10
Difference [Dd10 – Dd4(9)
]
4(9)
0.73
0.95
0.49
0.74
0.99
0.88
0.99
1.02
0.50
0.51
0.71
0.71
0.58
2.48
1.98
1.82
1.81
1.73
2.28
2.29
2.39
2.38
2.17
1.89
11
Difference [Dd11 – Dd4(9)]
4a
4b
4c
4d
4e
4f
2.47
2.39
1.29
2.47
2.47
1.29
2.47
2.39
1.49
1.79
1.79
1.51
2.09
2.47
2.39
1.29
2.47
2.47
1.29
1.29
2.47
2.47
2.47
2.47
0.04
0.18
–0.27
0.07
0.70
0.42
0.30
–0.14
0.41
–0.30
–0.33
–0.14
0.59
2.23
1.50
1.24
2.05
2.07
1.01
1.19
2.49
2.39
2.23
1.93
2.00
2.00
2.00
2.00
2.49
2.69
2.69
2.09
1.99
2.04
2.30
2.09
2.00
2.00
2.00
2.00
2.00
2.00
2.69
2.69
2.69
2.69
2.49
2.49
1.27
1.05
1.51
1.26
1.50
1.81
1.70
1.07
1.49
1.53
1.59
1.38
1.42
–0.48
0.02
0.18
0.19
0.27
0.41
0.40
0.30
0.31
0.32
0.60
4g
4h
4i
4j
4k
4l
4m
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
a The 1H NMR spectra of samples containing compounds 4, 9, 10, or 11 (15 mmol) in the solvent (0.6 mL) were recorded at a temperature of
273 K.
b See Figure 2 and Tables 1 and 2 for the corresponding structures.
Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York

938
M. Krasavin et al.
PAPER
Figure 3 Markedly different secondary structure patterns observed for compounds 4i and 9h confirmed by X-ray crystallographic analysis
phy system equipped with Shimadzu SPD-10A UV-vis (254 nm)
and Sedex 75 ELSD detectors. Elemental analyses were obtained at
the Research Institute for Chemical Crop Protection, Moscow, us-
ing a Carlo Erba Strumentazione 1106 analyzer. All solvents and re-
agents were obtained from commercial sources and were used
without purification.
time, more favorable. To our delight, the above conclu-
sions were fully confirmed by the single-crystal X-ray
analysis20 of compounds 4i and 9h, representative of each
set of the hydrazinopeptide units studied. Indeed, com-
pound 4i adopted the typical hydrazino turn secondary
structure, while for the Na,Na-dialkyl derivative 9h this
structural bias was not observed (Figure 3).21 These ob-
servations are expected to be of importance in the selec-
tion of appropriate hydrazinopeptide inserts for natural
peptide analogue design.
2-Cyclohexyl-2-(2-isonicotinoylhydrazino)-N-(2-methoxyeth-
yl)acetamide (4a); Typical Procedure
N¢-(Cyclohexylmethylene)isonicotinohydrazide (600 mg, 2.6
mmol) was dissolved in anhyd dioxane (10 mL) and then 2-methoxy-
ethyl isocyanide (320 mL, 3.9 mmol) was added, followed by TFA
(193 mL, 2.6 mmol). The mixture was stirred at r.t. overnight and
then was diluted with 10% aq K2CO3 (25 mL) and stirred for 3 h.
The solution was extracted with CHCl3 (3 × 50 mL), and the ex-
tracts were dried (anhyd MgSO4), filtered, and concentrated under
reduced pressure. Chromatography on silica gel (10–65% EtOAc in
hexanes) provided 4a as a white solid. Yield: 450 mg (52%); mp
132–134 °C.
1H NMR (DMSO-d6, 300 K): d = 0.98–1.34 (m, 5 H), 1.50–1.85 (m,
6 H), 2.93 (d, J = 2.8 Hz, 1 H), 3.14–3.43 (m, 7 H), 5.24 (br s, 1 H),
7.62 (m, 3 H), 8.66 (d, J = 1.8 Hz, 2 H), 9.77 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 25.8, 28.6, 28.9, 38.1, 38.6, 57.8,
68.6, 70.5, 121.1, 140.2, 150.1, 163.5, 171.4.
In conclusion, we have reported on the application of the
Ugi reaction of hydrazones toward the simple and effi-
cient preparation of racemic hydrazinopeptide units 4. An
intramolecular version of the same reaction was devel-
oped using hydrazone 6 containing a carboxylic acid side
chain. The modification of units 4 at the a-nitrogen via re-
ductive alkylation with aliphatic aldehydes produced
compounds 9. As demonstrated by simple 1H NMR spec-
troscopic experiments in solvents with different hydrogen
bond accepting abilities and confirmed by X-ray crystal-
lographic analysis, compounds 4 and 9 consistently dis-
played two different secondary structure patterns.
Anal. Calcd for C17H26N4O3: C, 61.06; H, 7.84; N, 16.75. Found: C,
61.16; H, 7.92; N, 16.77.
All reactions were run in oven-dried glassware under an atmosphere
of nitrogen. Melting points were measured with a Buchi B-520
melting point apparatus and are uncorrected. Analytical TLC was
carried out on EM Separations Technology F254 silica gel plates;
2-Cyclohexyl-N-(2-methoxyethyl)-2-{2-[2-(4-tolyl)acetyl]hy-
drazino}acetamide (4b)
White solid; mp 108–110 °C.
1H NMR (DMSO-d6, 300 K): d = 0.99–1.19 (m, 5 H), 1.48–1.71 (m,
6 H), 2.25 (s, 3 H), 3.03 (d, J = 2.9 Hz, 1 H), 3.10–3.27 (m, 9 H),
4.98 (br s, 1 H), 7.08 (m, 4 H), 7.86 (br s, 1 H), 9.33 (br s, 1 H).
1
compounds were visualized with short-wavelength UV light. H
and 13C NMR spectra were recorded on Bruker DPX-300 spectrom-
eters in DMSO-d6 using TMS as an internal standard. LC-MS anal-
yses were obtained on a PE SCIEX API 150EX mass spectrometer
following separation on a Shimadzu LC-10AD liquid chromatogra-
Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York

PAPER
Hydrazinopeptide Motifs via the Ugi Reaction
939
13C NMR (DMSO-d6, 300 K): d = 20.5, 25.8, 28.4, 28.9, 38.0, 39.3,
57.8, 69.0, 70.4, 128.7, 132.9, 135.3, 169.2, 171.4.
13C NMR (DMSO-d6, 300 K): d = 25.7, 27.4, 28.9, 29.1, 41.9, 68.6,
121.1, 126.6, 127.1, 128.0, 139.4, 140.0, 150.1, 163.3, 171.5.
Anal. Calcd for C20H31N3O3: C, 66.45; H, 8.64; N, 11.62. Found: C,
66.51; H, 8.67; N, 11.77.
Anal. Calcd for C21H26N4O2: C, 68.83; H, 7.15; N, 15.29. Found: C,
68.80; H, 7.25; N, 15.38.
2-Cyclohexyl-N-(2-methoxyethyl)-2-[2-(pyrazin-2-ylcarbon-
yl)hydrazino]acetamide (4c)
White solid; mp 108–110 °C.
N-Cyclohexyl-2-{2-[2-(4-tolyl)acetyl]hydrazino}butanamide
(4h)
White solid; mp 150–152 °C.
1H NMR (DMSO-d6, 300 K): d = 1.06–1.30 (m, 5 H), 1.53–1.85 (m,
6 H), 3.21 (s, 3 H), 3.22–3.40 (m, 5 H), 5.23 (br s, 1 H), 7.73 (br s,
1 H), 8.61 (br s, 1 H), 8.81 (br s, 1 H), 9.12 (br s, 1 H), 9.67 (br s, 1
H).
13C NMR (DMSO-d6, 300 K): d = 25.9, 28.5, 29.0, 38.0, 38.7, 57.8,
68.0, 70.5, 143.3, 143.4, 144.4, 147.5, 161.1, 171.6.
1H NMR (DMSO-d6, 300 K): d = 0.83 (t, J = 7.5 Hz, 3 H), 0.89–1.28
(m, 5 H), 1.44–1.70 (m, 7 H), 2.25 (s, 3 H), 3.13 (m, 1 H), 3.35 (s,
2 H), 3.44 (m, 1 H), 5.00 (br s, 1 H), 7.06 (d, J = 8.2 Hz, 2 H), 7.10
(d, J = 8.2 Hz, 2 H), 7.76 (d, J = 8.0 Hz, 1 H), 9.34 (d, J = 3.3 Hz, 1
H).
13C NMR (DMSO-d6, 300 K): d = 9.8, 20.5, 23.9, 24.4, 25.2, 32.0,
32.3, 47.2, 65.0, 128.6, 128.7, 132.8, 135.3, 169.4, 170.7.
Anal. Calcd for C16H25N5O3: C, 57.30; H, 7.51; N, 20.88. Found: C,
57.39; H, 7.64; N, 21.06.
Anal. Calcd for C19H29N3O2: C, 68.85; H, 8.82; N, 12.68. Found: C,
68.95; H, 8.91; N, 12.74.
2-(2-Isonicotinoylhydrazino)-N-(2-methoxyethyl)pentanamide
(4d)
White solid; mp 123–125 °C.
N-(tert-Butyl)-2-{2-[2-(4-methoxyphenoxy)acetyl]hydrazino}-
4-methylpentanamide (4i)
White solid; mp 173 °C (dec.).
1H NMR (DMSO-d6, 300 K): d = 0.90 (t, J = 2.3 Hz, 3 H), 1.40 (m,
2 H), 1.58 (m, 2 H), 2.98 (br s, 1 H), 3.18–3.49 (m, 7 H), 5.46 (br s,
1 H), 7.65 (d, J = 1.8 Hz, 2 H), 7.78 (br s, 1 H), 8.68 (d, J = 1.8 Hz,
2 H), 9.83 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 13.9, 18.4, 33.1, 26.4, 57.8, 63.3,
70.5, 121.2, 140.4, 149.9, 163.7, 172.2.
1H NMR (DMSO-d6, 300 K): d = 0.90 (d, J = 5.9 Hz, 6 H), 1.28 (s,
9 H), 1.40 (m, 2 H), 1.80 (m, 1 H), 3.30 (t, J = 6.4 Hz, 1 H), 3.72 (s,
3 H), 4.44 (br s, 2 H), 4.85 (br s, 1 H), 6.86 (d, J = 9.3 Hz, 2 H), 6.90
(d, J = 9.3 Hz, 2 H), 7.32 (br s, 1 H), 9.02 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 22.3, 23.0, 24.2, 28.4, 40.5, 49.6,
55.9, 62.9, 67.2, 114.5, 115.7, 151.6, 153.9, 166.7, 172.1.
Anal. Calcd for C14H22N4O3: C, 57.13; H, 7.53; N, 19.03. Found: C,
57.33; H, 7.50; N, 18.96.
Anal. Calcd for C19H31N3O4: C, 62.44; H, 8.55; N, 11.50. Found: C,
62.49; H, 8.64; N, 11.30.
N-Benzyl-2-(2-isonicotinoylhydrazino)pentanamide (4e)
Beige solid; mp 147–149 °C.
N-(tert-Butyl)-2-{2-[2-(4-methoxyphenoxy)acetyl]-1-(2,2,2-tri-
fluoroacetyl)hydrazino}-4-methylpentanamide (3i)
The compound was prepared according to the same procedure as for
de-trifluoroacetylated product 4i, but the basic workup was omitted.
1H NMR (DMSO-d6, 300 K): d = 0.91 (t, J = 6.7 Hz, 3 H), 1.42 (m,
2 H), 1.63 (m, 2 H), 3.52 (t, J = 3.5 Hz, 1 H), 4.32 (ddd, J1 = 13.9
Hz, J2 = 5.2 Hz, J3 = 4.0 Hz, 2 H), 5.23 (br s, 1 H), 7.15–7.30 (m, 5
H), 7.63 (d, J = 3.4 Hz, 2 H), 8.15 (br s, 1 H), 8.68 (d, J = 3.4 Hz, 2
H), 9.89 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 13.9, 18.5, 33.9, 14.9, 63.3,
121.0, 126.6, 127.0, 128.1, 139.3, 140.0, 150.0, 163.7, 172.2.
Off-white solid; mp 148 °C (dec.).
1H NMR (DMSO-d6, 363 K): d = 0.88 (d, J = 6.4 Hz, 6 H), 1.27 (s,
9 H), 1.47–1.74 (m, 3 H), 3.72 (s, 3 H), 4.48 (t, J = 7.1 Hz, 1 H),
4.64 (s, 2 H), 6.87 (d, J = 9.2 Hz, 2 H), 6.94 (d, J = 9.2 Hz, 2 H),
7.75 (br s, 1 H), 10.4 (br s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 22.1, 22.3, 24.2, 28.2, 37.1, 50.4,
55.8, 62.1, 67.0, 115.0, 115.5 (J = 288.5 Hz), 116.2, 152.0, 154.5,
157.4 (J = 35.8 Hz), 167.8, 169.0.
Anal. Calcd for C18H22N4O2: C, 66.24; H, 6.79; N, 17.16. Found: C,
66.07; H, 6.88; N, 17.27.
N-Benzyl-2-cyclohexyl-2-[2-(pyrazin-2-ylcarbonyl)hydrazi-
no]acetamide (4f)
Gray solid; mp 163–166 °C.
1H NMR (DMSO-d6, 300 K): d = 1.03–1.33 (m, 5 H), 1.55–1.88 (m,
6 H), 3.41 (d, J = 5.1 Hz, 1 H), 4.32 (ddd, J1 = 18.7 Hz, J2 = 6.0 Hz,
J3 = 5.2 Hz, 2 H), 5.29 (br s, 1 H), 7.12–7.28 (m, 5 H), 8.19 (br s, 1
H), 8.65 (d, J = 1.8 Hz, 1 H), 8.82 (d, J = 1.8 Hz, 1 H), 9.10 (s, 1 H),
9.79 (br s, 1 H).
Anal. Calcd for C21H30F3N3O5: C, 54.66; H, 6.55; N, 9.11. Found C,
54.60; H, 6.43; N, 8.97.
tert-Butyl 2-[1-(tert-Butylcarbamoyl)-2-methylpropyl]hydra-
zine-1-carboxylate (4j)
White solid; mp 172–174 °C.
1H NMR (DMSO-d6, 300 K): d = 0.84 (d, J = 7.0 Hz, 3 H), 0.91 (d,
J = 7.0 Hz, 3 H), 1.25 (s, 9 H), 1.39 (s, 9 H), 1.86 (m, 1 H), 2.92 (d,
J = 3.8 Hz, 1 H), 4.73 (s, 1 H), 7.63 (br s, 1 H), 8.20 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 25.8, 25.9, 28.6, 29.1, 41.9, 68.0,
126.5, 127.1, 127.9, 139.4, 143.2, 143.3, 144.3, 147.5, 160.9, 171.7.
Anal. Calcd for C20H25N5O2: C, 65.37; H, 6.86; N, 19.06. Found: C,
65.33; H, 6.91; N, 18.92.
13C NMR (DMSO-d6, 300 K): d = 18.2, 18.9, 28.2, 28.3, 29.5, 49.6,
70.1, 78.3, 156.2, 170.8.
Anal. Calcd for C14H29N3O3: C, 58.51; H, 10.17; N, 14.62. Found:
C, 58.43; H, 10.07; N, 14.77.
N-Benzyl-2-cyclohexyl-2-(2-isonicotinoylhydrazino)acetamide
(4g)
Gray solid; mp 115–116 °C.
tert-Butyl 2-{1-[(4-Methoxybenzyl)carbamoyl]-2-methylpro-
pyl}hydrazine-1-carboxylate (4k)
White solid; mp 180 °C (dec.).
1H NMR (DMSO-d6, 300 K): d = 0.92 (d, J = 6.8 Hz, 3 H), 0.94 (d,
J = 6.8 Hz, 3 H), 1.40 (s, 9 H), 1.95 (m, 1 H), 3.14 (br s, 1 H), 3.75
(s, 3 H), 4.25 (ddd, J1 = 36.5 Hz, J2 = 5.0 Hz, J3 = 5.3 Hz, 2 H), 4.50
1H NMR (DMSO-d6, 300 K): d = 1.09–1.30 (m, 5 H), 1.55–1.87 (m,
6 H), 3.34 (d, J = 3.9 Hz, 1 H), 4.32 (ddd, J1 = 22.1 Hz, J2 = 6.6 Hz,
J3 = 5.8 Hz, 2 H), 5.30 (br s, 1 H), 7.24 (m, 5 H), 7.62 (d, J = 2.6 Hz,
2 H), 8.10 (br s, 1 H), 8.67 (d, J = 2.6 Hz, 2 H), 9.84 (br s, 1 H).
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M. Krasavin et al.
PAPER
(s, 1 H), 6.86 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 8.2 Hz, 2 H), 8.11 (br
s, 1 H), 8.22 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 18.3, 18.9, 28.2, 29.7, 41.7, 55.2,
69.8, 78.7, 113.9, 128.5, 131.6, 156.2, 158.4, 171.6.
4-[2-(Cyclohexylmethylene)hydrazino]-4-oxobutanoic Acid (6)
tert-Butyl carbazate (1320 mg, 10 mmol) was dissolved in CH2Cl2
(50 mL) and the solution was cooled to 5 °C. Ethyl 4-chloro-4-oxo-
butanoate (2.15 g, 13 mmol) was added dropwise to maintain the
temperature of the mixture below 10 °C. The mixture was warmed
to r.t. and stirred for 1 h. Then, the mixture was washed with 10%
aq Na2CO3 (100 mL) and H2O (100 mL), dried (anhyd MgSO4), and
concentrated in vacuo. The residue was dissolved in dioxane (10
mL) and treated with 4 M HCl in dioxane (10 mL). The mixture was
stirred at r.t. overnight and the resulting precipitate was collected by
filtration and dissolved in MeOH (20 mL). Cyclohexanecarbalde-
hyde (1.2 mL, 10 mmol) and Et3N (1.4 mL, 10 mmol) were added
and the resulting mixture was stirred at r.t. for 2 h. Then, the solvent
was removed in vacuo, the residue was dispersed in H2O and col-
lected by filtration, and the filter cake was washed with hexane
(3 × 50 mL). The solid product was dissolved in MeOH (10 mL),
and NaOH (400 mg, 10 mmol) in H2O (5 mL) was added. The re-
sulting mixture was stirred at r.t. for 3 h and the solvent was re-
moved under reduced pressure. The residue was dissolved in H2O
(30 mL), the mixture was filtered, and the filtrate was carefully neu-
tralized with 5% aq HCl (ca. 15 mL). The resulting precipitate was
collected by filtration. Additional crystallization (MeOH) provided
6 as an amber solid. Yield: 720 mg (32%); mp 147–149 °C.
Anal. Calcd for C18H29N3O4: C, 61.52; H, 8.32; N, 11.96. Found C,
61.57; H, 8.02; N, 12.13.
2-(2-Acetylhydrazino)-2-cyclohexyl-N-(2-methoxybenzyl)acet-
amide (4l)
White solid; mp 166–168 °C.
1H NMR (DMSO-d6, 300 K): d = 1.03–1.29 (m, 5 H), 1.53–1.92 (m,
9 H), 3.14 (d, J = 1.6 Hz, 1 H), 3.81 (s, 3 H), 4.30 (m, 2 H), 4.87 (s,
1 H), 6.88 (t, J = 6.4 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1 H), 7.20 (m, 2
H), 7.89 (br s, 1 H), 8.93 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 20.6, 25.9, 26.0, 28.8, 29.2, 37.4,
55.6, 69.5, 111.0, 120.2, 127.2, 128.0, 128.3, 157.1, 168.2, 171.7.
Anal. Calcd for C18H27N3O3: C, 64.84; H, 8.16; N, 12.60. Found: C,
64.86; H, 8.26; N, 12.80.
2-(2-Benzoylhydrazino)-2-cyclohexyl-N-(2-methoxyethyl)acet-
amide (4m)
Yellowish solid; mp 144–145 °C.
1H NMR (DMSO-d6, 300 K): d = 1.07–1.30 (m, 5 H), 1.56–1.84 (m,
6 H), 2.97–3.45 (m, 8 H), 5.20 (br s, 1 H), 7.38–7.54 (m, 3 H), 7.69
(br s, 1 H), 7.77 (d, J = 7.0 Hz, 2 H), 9.53 (br s, 1 H).
1H NMR (DMSO-d6, 363 K): d = 1.19–1.42 (m, 5 H), 1.59–1.85 (m,
5 H), 2.21 (m, 1 H), 2.41–2.76 (m, 4 H), 5.17 (br s, 1 H), 7.31 (br s,
1 H), 10.28 (br s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 24.8, 25.5, 28.3, 28.9, 39.7,
151.3, 172.1, 173.4.
13C NMR (DMSO-d6, 300 K): d = 25.9, 28.9, 29.2, 38.3, 39.7, 57.8,
69.2, 70.8, 127.1, 128.2, 131.1, 133.6, 165.8, 171.6.
N-tert-Butyl-2-cyclohexyl-2-(3,6-dioxotetrahydropyridazin-1-
yl)acetamide (7)
Anal. Calcd for C18H27N3O3: C, 64.84; H, 8.16; N, 12.60. Found: C,
64.84; H, 8.10; N, 12.46.
Compound 6 (340 mg, 1.5 mmol) was dissolved in i-PrOH (5 mL),
and t-BuNC (200 mL, 2.1 mmol) was added. The mixture was
stirred at 50 °C overnight. Then, the solvent was removed under re-
duced pressure and the product was purified by column chromatog-
raphy on silica gel (0–2.5% MeOH in CHCl3) to provide 7 as a
white solid. Yield: 334 mg (72%); mp 129–131 °C.
1H NMR (DMSO-d6, 300 K): d = 1.08–1.32 (m, 14 H), 1.59–1.79
(m, 6 H), 2.53–2.66 (m, 4 H), 3.16 (d, J = 7.2 Hz, 1 H), 5.46 (d, J =
1.5 Hz, 1 H), 7.58 (s, 1 H).
Methyl 2-Cyclohexyl-2-[2-(pyrazin-2-ylcarbonyl)hydra-
zino]acetate (5c)
The compound was prepared using the same procedure as for com-
pound 4c except MeOH (10 mL) was used as the solvent. The title
compound was isolated from the mixture by column chromatogra-
phy on silica gel (35–70% EtOAc in hexanes) as a sticky colorless
solid. Yield: 0.21 g (13%).
1H NMR (DMSO-d6, 300 K): d = 1.06–1.32 (m, 5 H), 1.57–1.82 (m,
5 H), 1.84 (m, 1 H), 3.26 (br s, 1 H), 3.51 (d, J = 6.2 Hz, 1 H), 3.66
(s, 3 H), 8.66 (s, 1 H), 8.80 (s, 1 H), 9.11 (s, 1 H), 9.85 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 25.8, 26.1, 28.2, 28.4, 28.9, 39.6,
49.8, 67.1, 95.5, 164.2, 170.0, 175.3.
13C NMR (DMSO-d6, 300 K): d = 25.5, 25.8, 28.9, 38.7, 51.4, 67.3,
LC-MS: m/z = 310 [M + H+].
143.2, 143.4, 144.3, 147.5, 160.6, 172.8.
Anal. Calcd for C16H27N3O3: C, 56.44; H, 8.35; N, 11.52. Found: C,
56.11; H, 8.27; N, 11.48.
LC-MS: m/z = 293 [M + H+].
Anal. Calcd for C14H20N4O3: C, 57.52; H, 6.90; N, 19.16. Found: C,
57.68; H, 7.04; N, 19.36.
2-Cyclohexyl-2-[2-isonicotinoyl-1-(3-methylbutyl)hydrazino]-
N-(2-methoxyethyl)acetamide (9a); Typical Procedure
Compound 4a (335 mg, 1 mmol) was dissolved in CH2Cl2 (5 mL).
Isovaleraldehyde (165 mL, 1.5 mmol) was added, followed by
NaBH(OAc)3 (380 mg, 2 mmol). The resulting mixture was stirred
at r.t. overnight and then was diluted with CH2Cl2 (25 mL), washed
with H2O (3 × 25 mL), dried (anhyd MgSO4), filtered, and concen-
trated in vacuo to provide the crude product. The compound was pu-
rified by column chromatography on silica gel (0–5% MeOH in
CHCl3) to provide 9a as a white solid. Yield: 250 mg (62%); mp 99–
101 °C.
1H NMR (DMSO-d6, 363 K): d = 0.88 (d, J = 6.6 Hz, 6 H), 0.96–
1.20 (m, 5 H), 1.38 (m, 2 H), 1.46–1.82 (m, 6 H), 2.20 (m, 1 H), 2.73
(m, 2 H), 3.18 (d, J = 9.5 Hz, 1 H), 3.27 (s, 3 H), 3.33 (t, J = 5.2 Hz,
2 H), 3.41 (t, J = 5.2 Hz, 2 H), 7.60 (d, J = 5.4 Hz, 2 H), 8.10 (br s,
1 H), 8.71 (d, J = 5.4 Hz, 2 H), 9.40 (br s, 1 H).
Methyl 2-(2-Isonicotinoylhydrazino)pentanoate (5d)
The compound was prepared using the same procedure as for com-
pound 4d except MeOH (10 mL) was used as the solvent. The title
compound was isolated from the mixture by column chromatogra-
phy on silica gel (35–50% EtOAc in hexanes) as a sticky colorless
solid. Yield: 0.33 g (24%).
1H NMR (DMSO-d6, 300 K): d = 0.91 (t, J = 7.3 Hz, 3 H), 1.40 (m,
2 H), 1.66 (q, J = 7.3 Hz, 2 H), 3.63 (t, J = 7.1 Hz, 1 H), 3.66 (s, 3
H), 4.95 (br s, 1 H), 7.70 (d, J = 4.9 Hz, 2 H), 8.70 (d, J = 4.9 Hz, 2
H), 10.00 (br s, 1 H).
13C NMR (DMSO-d6, 300 K): d = 13.6, 18.3, 32.3, 51.6, 62.0,
121.6, 141.1, 149.0, 163.3, 172.8.
LC-MS: m/z = 252 [M + H+].
13C NMR (DMSO-d6, 363 K): d = 22.3, 25.4, 26.1, 29.0, 29.9, 35.6,
37.2, 38.1, 54.3, 57.8, 70.6, 70.7, 120.6, 141.4, 150.3, 162.8, 172.3.
Anal. Calcd for C12H17N3O3: C, 57.36; H, 6.82; N, 16.72. Found: C,
57.50; H, 6.94; N, 16.67.
Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York

PAPER
Hydrazinopeptide Motifs via the Ugi Reaction
941
Anal. Calcd for C22H36N4O3: C, 65.32; H, 8.97; N, 13.85. Found: C,
65.40; H, 9.04; N, 13.90.
13C NMR (DMSO-d6, 363 K): d = 22.4, 25.3, 26.1, 29.2, 29.6, 35.6,
36.8, 41.8, 54.9, 69.6, 126.9, 127.4, 128.2, 139.0, 143.4, 143.4,
144.4, 147.7, 160.0, 172.5.
2-Cyclohexyl-N-(2-methoxyethyl)-2-{1-(3-methylbutyl)-2-[2-(4-
tolyl)acetyl]hydrazino}acetamide (9b)
White solid; mp 126–128 °C.
Anal. Calcd for C25H35N5O2: C, 68.62; H, 8.06; N, 16.00. Found: C,
68.70; H, 8.18; N, 15.77.
1H NMR (DMSO-d6, 363 K): d = 0.68–0.91 (m, 8 H), 0.93–1.69 (m,
11 H), 2.04 (m, 1 H), 2.25 (s, 3 H), 2.56 (m, 2 H), 2.94 (d, J = 9.5
Hz, 1 H), 3.17–3.41 (m, 9 H), 7.08 (d, J = 8.2 Hz, 2 H), 7.14 (d, J =
8.2 Hz, 2 H), 8.18 (br s, 1 H), 8.50 (s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 20.6, 22.4, 25.2, 26.2, 28.8, 29.8,
35.5, 36.6, 37.8, 41.1, 54.1, 57.8, 70.5, 71.0, 128.7, 128.8, 133.1,
135.4, 168.5, 172.1.
N-Benzyl-2-[1-butyl-2-(pyrazin-2-ylcarbonyl)hydrazino]-2-cy-
clohexylacetamide (9g)
Gray solid; mp 129–131 °C.
1H NMR (DMSO-d6, 363 K): d = 0.86 (t, J = 7.0 Hz, 3 H), 0.93–1.20
(m, 5 H), 1.28–1.72 (m, 9 H), 2.24 (m, 1 H), 2.75 (m, 2 H), 3.23 (d,
J = 9.1 Hz, 1 H), 4.40 (ddd, J1 = 9.6 Hz, J2 = 4.8 Hz, J3 = 4.8 Hz, 2
H), 7.18–7.37 (m, 5 H), 8.54 (br s, 1 H), 8.68 (s, 1 H), 8.83 (s, 1 H),
9.16 (s, 1 H), 10.15 (s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 13.7, 19.6, 25.2, 26.0, 28.8, 36.8,
41.8, 56.3, 69.7, 126.9, 127.4, 128.3, 139.0, 143.4, 144.4, 147.7,
160.0, 172.5.
Anal. Calcd for C25H41N3O2: C, 69.57; H, 9.57; N, 9.74. Found: C,
69.66; H, 9.61; N, 9.88.
2-[1-Butyl-2-(pyrazin-2-ylcarbonyl)hydrazino]-2-cyclohexyl-
N-(2-methoxyethyl)acetamide (9c)
Gray solid; mp 137–139 °C.
Anal. Calcd for C24H33N5O2: C, 68.06; H, 7.85; N, 16.53. Found: C,
68.01; H, 7.73; N, 16.64.
1H NMR (DMSO-d6, 363 K): d = 0.88 (t, J = 6.6 Hz, 3 H), 0.94–1.18
(m, 5 H), 1.33–1.71 (m, 9 H), 2.25 (m, 1 H), 2.73 (m, 2 H), 3.18 (d,
J = 9.5 Hz, 1 H), 3.27 (s, 3 H), 3.33 (t, J = 5.2 Hz, 2 H), 3.41 (t, J =
5.2 Hz, 2 H), 8.05 (br s, 1 H), 8.68 (s, 1 H), 8.82 (s, 1 H), 9.17 (s, 1
H), 10.14 (br s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 13.7, 19.6, 25.2, 26.1, 28.8, 29.6,
36.7, 37.9, 56.2, 57.8, 69.7 70.6, 143.3, 143.4, 144.4, 147.7, 160.0,
172.6.
N-Benzyl-2-cyclohexyl-2-[1-(3-methylbutyl)-2-(pyrazin-2-yl-
carbonyl)hydrazino]acetamide (9h)
White solid; mp 154–156 °C.
1H NMR (DMSO-d6, 363 K): d = 0.86 (dd, J1 = 6.9 Hz, J2 = 2.7 Hz,
6 H), 0.94–1.19 (m, 5 H), 1.27–1.78 (m, 8 H), 2.24 (m, 1 H), 2.78
(m, 2 H), 3.24 (d, J = 9.9 Hz, 1 H), 4.37 (ddd, J1 = 19.2 Hz, J2 = 5.6
Hz, J3 = 5.6 Hz, 2 H), 7.20–7.35 (m, 5 H), 8.58 (br s, 1 H), 8.68 (s,
1 H), 8.83 (d, J = 1.9 Hz, 1 H), 9.17 (s, 1 H), 10.18 (s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 22.4, 25.3, 26.1, 29.2, 29.6, 35.6,
36.8, 41.8, 54.9, 69.6, 126.9, 127.4, 128.2, 139.0, 143.4, 143.4,
144.4, 147.7, 160.0, 172.5.
Anal. Calcd for C20H33N5O3: C, 61.36; H, 8.50; N, 17.89. Found: C,
61.43; H, 8.60; N, 17.95.
2-[2-Isonicotinoyl-1-(3-methylbutyl)hydrazino]-N-(2-methoxy-
ethyl)pentanamide (9d)
Beige solid; mp 148 °C (dec.).
Anal. Calcd for C25H35N5O2: C, 68.62; H, 8.06; N, 16.00. Found: C,
68.71; H, 8.11; N, 15.93.
1H NMR (DMSO-d6, 363 K): d = 0.86 (m, 9 H), 1.25–1.47 (m, 4 H),
1.50–1.79 (m, 3 H), 2.81 (m, 2 H), 3.26 (s, 3 H), 3.29 (m, 2 H), 3.35–
3.47 (m, 3 H), 7.62 (d, J = 3.7 Hz, 2 H), 8.00 (br s, 1 H), 8.70 (d,
J = 3.7 Hz, 2 H), 9.30 (br s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 13.7, 18.8, 22.3, 25.3, 31.7, 36.0,
38.2, 39.2, 53.3, 57.7, 66.8, 70.6, 120.9, 141.2, 150.2, 163.9, 172.8.
N-Benzyl-2-(1-butyl-2-isonicotinoylhydrazino)-2-cyclohexyl-
acetamide (9i)
White solid; mp 157 °C (dec.).
1H NMR (DMSO-d6, 363 K): d = 0.87 (t, J = 7.0 Hz, 3 H), 0.96–1.22
(m, 5 H), 1.34–1.76 (m, 9 H), 2.20 (m, 1 H), 2.80 (m, 2 H), 3.24 (d,
J = 9.2 Hz, 1 H), 4.40 (ddd, J1 = 7.0 Hz, J2 = 5.5 Hz, J3 = 5.5 Hz, 2
H), 7.20–7.34 (m, 5 H), 7.63 (d, J = 7.3 Hz, 2 H), 8.50 (br s, 1 H),
8.73 (d, J = 4.8 Hz, 2 H), 9.40 (br s, 1 H).
Anal. Calcd for C19H32N4O3: C, 62.61; H, 8.85; N, 15.37. Found: C,
62.55; H, 8.92; N, 15.38.
13C NMR (DMSO-d6, 363 K): d = 13.5, 19.5, 25.3, 26.0, 29.0, 29.9,
37.4, 42.2, 55.7, 70.8, 120.8, 126.8, 127.5, 128.1, 138.9, 141.8,
149.9, 162.8, 172.2.
2-(1-Butyl-2-isonicotinoylhydrazino)-N-(2-methoxyethyl)pen-
tanamide (9e)
Yellow solid; mp 128–130 °C.
Anal. Calcd for C25H34N4O2: C, 71.06; H, 8.11; N, 13.26. Found: C,
70.99; H, 8.03; N, 13.34.
1H NMR (DMSO-d6, 363 K): d = 0.86 (m, 6 H), 1.30–1.50 (m, 6 H),
1.60 (m, 2 H), 2.80 (m, 2 H), 3.21–3.24 (m, 5 H), 3.35–3.47 (m, 3
H), 7.63 (d, J = 3.8 Hz, 2 H), 7.97 (br s, 1 H), 8.71 (d, J = 3.8 Hz, 2
H), 9.30 (br s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 13.5, 13.6, 18.8, 19.6, 29.1, 31.7,
38.2, 54.7, 57.8, 66.9, 70.6, 120.9, 141.2, 150.1, 163.9, 172.8.
N-Benzyl-2-[2-isonicotinoyl-1-(3-methylbutyl)hydrazino]pen-
tanamide (9j)
Beige solid; mp 133–134 °C.
1H NMR (DMSO-d6, 363 K): d = 0.81–0.91 (m, 9 H), 1.29–1.49 (m,
4 H), 1.54–1.74 (m, 3 H), 2.85 (m, 2 H), 3.51 (t, J = 6.0 Hz, 1 H),
4.34 (ddd, J1 = 5.5 Hz, J2 = 4.1 Hz, J3 = 4.8 Hz, 2 H), 7.19–7.23 (m,
5 H), 7.64 (d, J = 5.8 Hz, 2 H), 8.45 (br s, 1 H), 8.72 (d, J = 5.8 Hz,
2 H), 9.34 (br s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 13.6, 18.8, 22.3, 25.3, 31.7, 36.0,
42.2, 53.4, 66.8, 121.1, 126.7, 127.3, 128.1, 139.1, 141.5, 149.8,
163.8, 172.8.
Anal. Calcd for C18H30N4O3: C, 61.69; H, 8.63; N, 15.99. Found: C,
61.56; H, 8.71; N, 16.07.
N-Benzyl-2-cyclohexyl-2-[1-(3-methylbutyl)-2-(pyrazin-2-yl-
carbonyl)hydrazino]acetamide (9f)
Colorless foam; mp 118–120 °C.
1H NMR (DMSO-d6, 363 K): d = 0.86 (dd, J1 = 6.9 Hz, J2 = 2.7 Hz,
6 H), 0.94–1.19 (m, 5 H), 1.27–1.78 (m, 8 H), 2.24 (m, 1 H), 2.78
(m, 2 H), 3.24 (d, J = 9.9 Hz, 1 H), 4.37 (ddd, J1 = 19.2 Hz, J2 = 5.6
Hz, J3 = 5.6 Hz, 2 H), 7.20–7.35 (m, 5 H), 8.58 (br s, 1 H), 8.68 (s,
1 H), 8.83 (d, J = 1.9 Hz, 1 H), 9.17 (s, 1 H), 10.18 (s, 1 H).
Anal. Calcd for C23H32N4O2: C, 69.67; H, 8.13; N, 14.13. Found: C,
69.55; H, 8.07; N, 14.19.
Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York

942
M. Krasavin et al.
PAPER
N-Benzyl-2-(1-butyl-2-isonicotinoylhydrazino)pentanamide
(9k)
Yellowish solid; mp 150 °C (dec.).
(9) Bushkova, E.; Parchinsky, V.; Krasavin, M. Mol. Diversity
2010, in press; DOI: 10.1007/s11030-009-9200-6.
(10) Lelais, G.; Seebach, D. Helv. Chim. Acta 2003, 86, 4152.
(11) Guy, L.; Vidal, J.; Collet, A. J. Med. Chem. 1998, 41, 4833.
(12) Aubury, A.; Mangeot, J.-P.; Vidal, J.; Collet, A.; Zerkout, S.;
Marraud, M. Int. J. Pept. Protein Res. 1994, 43, 305.
(13) Efforts are currently underway in our laboratories to realize
a strategy of stereochemistry relay from nonracemic partners
in the hydrazino-Ugi reaction and, thus, prepare short
nonracemic hydrazinopeptide compounds via
1H NMR (DMSO-d6, 363 K): d = 0.87 (m, 6 H), 1.28–1.51 (m, 6 H),
1.65 (m, 2 H), 2.82 (m, 2 H), 3.50 (t, J = 6.3 Hz, 1 H), 4.35 (d, J =
5.8 Hz, 2 H), 7.17–7.33 (m, 5 H), 7.63 (d, J = 4.4 Hz, 2 H), 8.43 (br
s, 1 H), 8.70 (d, J = 4.4 Hz, 2 H), 9.34 (br s, 1 H).
13C NMR (DMSO-d6, 363 K): d = 13.5, 13.6, 18.8, 19.6, 29.1, 31.7,
42.2, 54.8, 66.8, 121.0, 126.7, 127.3, 128.1, 139.1, 141.4, 150.0,
164.0, 172.3.
diastereomeric resolution.
(14) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(15) (a) Marcaccini, S.; Miguel, D.; Torroba, T.; Garcia-
Valverde, M. J. Org. Chem. 2003, 68, 3315.
Anal. Calcd for C22H30N4O2: C, 69.08; H, 7.91; N, 14.65. Found: C,
68.93; H, 8.00; N, 14.52.
(b) Marcaccini, S.; Pepino, R.; Torroba, T.; Miguel, D.;
Garcia-Valverde, M. Tetrahedron Lett. 2002, 43, 8591.
(c) Ilyin, A. P.; Trifilenkov, A.; Kurashvili, I.; Krasavin, M.;
Ivachtchenko, A. V. J. Comb. Chem. 2005, 7, 360.
(d) Ilyin, A. P.; Loseva, M. V.; Vvedensky, V. Y.; Putsykina,
E. B.; Tkachenko, S. E.; Kravchenko, D. V.; Khvat, A. V.;
Krasavin, M.; Ivachtchenko, A. V. J. Org. Chem. 2006, 71,
2811.
Acknowledgment
This research was supported by the Federal Agency for Science and
Innovation
(Russian
Federation
Government
Contract
02.740.11.0092). Dr. Alexander Manaev of the Chemical Diversity
Research Institute is acknowledged for his help in obtaining X-ray
crystallographic data. Dr. Yan Ivanenkov of the Chemical Diversity
Research Institute is thanked for performing molecular mechanics
calculations.
(16) Naskar, D.; Roy, A.; Seibel, W. L.; West, L.; Portlock, D. E.
Tetrahedron Lett. 2003, 44, 6297.
(17) The 1H NMR spectroscopic chemical shifts showed the a-
nitrogen proton in 4 as well as the analogous proton in 10 to
be negligibly sensitive to the solvent change, most likely
because the protons are less acidic.
References
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(19) All reference fragments 10 and 11 used in this work are
known and commercially available compounds.
(20) Crystallographic data (excluding structure factors) for
structures 4i and 9h have been deposited with the Cambridge
Crystallographic Data Centre (CCDC) as supplementary
publications CCDC 743067 (4i) and CCDC 752329 (9h),
respectively. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 (1223)336033, e-mail:
deposit@ccdc.cam.ac.uk].
(21) Molecular mechanics (MM2) calculations performed using
ChemBio3D (Ultra) v11.0 demonstrated that the observed
conformations for compounds 4i and 9h displayed
minimized energies of 6.48 and 7.62 kcal/mol, respectively.
Alternative hydrogen-bonded conformations displayed
significantly higher minimized energies (14.1 and 14.0 kcal/
mol, respectively).
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Synthesis 2010, No. 6, 933–942 © Thieme Stuttgart · New York