Ruthenium-catalyzed synthesis of 5-amino-1,2,3-triazole-4-carboxylates for triazole-based scaffolds: Beyond the Dimroth rearrangement

Article abstract of DOI:10.1021/jo502577e

The 5-amino-1,2,3-triazole-4-carboxylic acid is a suitable molecule for the preparation of collections of peptidomimetics or biologically active compounds based on the triazole scaffold. However, its chemistry may be influenced by the possibility of under

Full text of DOI:10.1021/jo502577e

Article
pubs.acs.org/joc
Ruthenium-Catalyzed Synthesis of 5‑Amino-1,2,3-triazole-4-
carboxylates for Triazole-Based Scaffolds: Beyond the Dimroth
Rearrangement
Serena Ferrini,† Jay ≠Zumbar Chandanshive,¶ Stefano Lena,¶ Mauro Comes Franchini,¶
Giuseppe Giannini,
Andrea Tafi,† and Maurizio Taddei*,†
†Dipartimento di Biotecnologie, Chimica e Farmacia, Universita
̀
di Siena, Via A. Moro 2, 53100 Siena, Italy
di Bologna, Viale Risogimento 4, 40136 Bologna, Italy
¶Dipartimento di Chimica Industriale “Toso Montanari”, Universita
̀
≠
R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy
S
* Supporting Information
ABSTRACT: The 5-amino-1,2,3-triazole-4-carboxylic acid is a suitable
molecule for the preparation of collections of peptidomimetics or
biologically active compounds based on the triazole scaffold. However,
its chemistry may be influenced by the possibility of undergoing the
Dimroth rearrangement. To overcome this problem, a protocol based
on the ruthenium-catalyzed cycloaddition of N-Boc ynamides with
azides has been developed to give a protected version of this triazole
amino acid. When aryl or alkyl azides are reacted with N-Boc-
aminopropiolates or arylynamides, the cycloaddition occurs with complete regiocontrol, while N-Boc-alkyl ynamides yield a
mixture of regioisomers. The prepared amino acids were employed for the preparation of triazole-containing dipeptides having
the structural motives typical of turn inducers. In addition, triazoles active as HSP90 inhibitors (as compound 41, IC50 = 29 nM)
were synthesized.
Scheme 1
INTRODUCTION
■
The development of compounds that mimic peptide secondary
structure is one of the most useful approaches for the design and
synthesis of new chemical entities interacting with biological
targets.1 Over the years, a big effort has been devoted to the
synthesis of constrained peptidomimetics in order to better
understand the bioactive conformations or to improve
bioavailability or generic metabolic stability.2 The incorporation
into a peptide chain of (hetero)cyclic scaffolds able to restrict
conformational freedom has been shown to be a valuable tool to
enhance some molecular properties such as stability to proteases,
potency, and receptor selectivity.3 Of particular interest is the use
of aromatic and heteroaromatic structures as dipeptide isosters
that have found interesting applications in the preparation of
active peptidomimetics.2a In the wake of the recent increase of
interest for triazoles, several examples of triazole-based amino
acids or peptide scaffolds have been described.4 1,2,3-Triazoles
have been demonstrated to be effective turn inducers for
conformationally constrained peptide analogues. In the first
papers, the triazole scaffold was produced by Cu-catalyzed
cycloaddition between α-azido acids (derived from α-amino
acids) and N- or C-propargyl derivatives.5 Afterward, the Ru-
catalyzed synthesis of a 1,5-disubstituted 1,2,3-triazole as a
proline mimic has been described.6 However, most of the
examples report 1,4- or 1,5-disubstituted triazoles carrying the
carboxyl and the amino groups on the carbon chain relatively far
from the triazole itself (Scheme 1 (i)).
A potentially useful alternative is the 5-amino-(1H)-1,2,3-
triazole-4-carboxylate scaffold (Scheme 1 (ii)), a triazole amino
Received: November 11, 2014
© XXXX American Chemical Society
A
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acid with three different points for substituent attachment. While
the amino and the carboxylic groups can be used to insert the
scaffold into a peptide chain using standard peptide couplings,
the substituent in position 1 may be used as a group that mimics
the side chain of the dipeptide involved in the turn. Alternatively,
with another functional group placed on the chain bonded in
position 1, the scaffold can be modeled according to the turn
required and/or the reagents employed. Nevertheless, although
known since the beginning of the 20th century,7 the 5-amino-
1,2,3-triazole 4 carboxylates have found relatively few applica-
tions.8
(ii)). This compound was produced by the Dimroth rearrange-
ment,10 which proceeds through the ring opening at the bond
between N1−N2 with formation of a diazo intermediate (A,
Scheme 2 (ii)) where rotation is now possible. A further
cyclization may occur on the less substituted nitrogen with
formation of a new 1-NH-triazole 6b (and its tautomer 6b′). The
Dimroth rearrangement is known to be accelerated by the
presence of electron-withdrawing substituents in position 4 of
the triazole and by strong acid or basic media. After purification,
the two 5-aminotriazoles 5a and 5b were submitted to standard
peptide bond formation with N-CbzAlaOH in the presence of
different coupling agents (e.g., DCC, EDC, HATU, DMTMM).
Unfortunately, acylation occurred with low yields, and the
rearranged compound always contaminated the products.
Since this approach seemed not suitable for an easily
functionalization of the 5-amino-1,2,3-triazole-4-carboxylate
(as, for example, its introduction in a peptide chain), we decided
to explore the possibility to carry out a [3 + 2] cycloaddition
between an alky or aryl azide and a N-protected ynamide in order
to control the introduction of nitrogen in position 5. This
reaction has been described using terminal ynamides carrying a
tosyl or an oxazolidinone group on the ynamide nitrogen. The
reaction was carried out thermally11 or under Cu12 or Ru
catalysis,13 giving simple 4-amido or 5-amido-1,2,3-triazoles,
structures on which removal of the substituent on the nitrogen
was not easy.
RESULTS AND DISCUSSION
Intrigued by the possibility of using structures as 5a or 5b
(Scheme 2) for the preparation of triazole-based peptide
■
Scheme 2
With the idea to exploit the Ru-catalyzed Huisgen cyclo-
addition for the synthesis of a stable and synthetically versatile
analogue of 5-amino-1,2,3-triazole-4-carboxylate, we decided to
investigate the cycloaddition of alkyl or aryl azides with methyl
N-Boc-aminopropiolates 10 and 11 (Scheme 3). These are new
Scheme 3. Preparation of N-Boc-ynamides
highly functionalized ynamides equipped with a protected amino
group and a carboxylate ester, both moieties suitable for easy tag
introduction after the cycloaddition has taken place. Compounds
10 and 11 were prepared by Ullmann-type condensation of N-
Boc-aniline or N-Boc-benzylamine, respectively, with
(triisopropylsilyl)bromoacetylene14 in the presence of catalytic
amount of the complex phenanthroline/CuI. The silyl protection
was then removed and compounds 8 and 9 were acylated
through lithiation with LHMDS followed by reaction with
methylchloroformate to give 10 and 11 in 85−86% overall yield
(Scheme 3).
scaffolds, we decided to investigate the synthesis and the
reactivity of these aminotriazoles toward standard peptide
chemistry. Compounds 5a and 5b were prepared following the
approach described in the literature9 reacting phenyl and benzyl
azide (1a and 1b, respectively) with ethyl cyanomalonate 2 in the
presence of EtONa (Scheme 2 (i)). The malonate anion attacks
the terminal nitrogen of the azide, and the more nucleophilic part
of the azide reacts with the nitrile to give an imino triazole
intermediate (4a or 4b) that immediately tautomerizes to the
aromatic ethyl 5-amino-1,2,3-triazole-4-carboxylate (5a or 5b).
While aryl azide 1a, after 6 h in refluxing ethanol, produced
exclusively compound 5a (65% isolated yield), the benzyl azide
2b gave a 2:1 mixture of the expected 5-amino-1-benzyl triazole
5b together with the 5-benzylamino derivative 6b (Scheme 2
When 10 was submitted to cycloaddition with azide 1a in
DMF at rt for 2 h in the presence of [Cp*RuCl]4 as the catalyst,
the corresponding N-Boc-5-aminotriazole 12 was isolated in
good yield. The cycloaddition produced a single diastereomer as
1
revealed by H and 13C NMR analysis. Analogously, cyclo-
addition of ynamide 10 with azide 1b gave triazole 13 in good
yield. Following the same synthetic scheme, different azides (1c−
h, see Table 1) were cyclized to give the corresponding N-Boc-5-
amino-1,2,3-triazole-4-carboxylates 16−21 in good yields. Also
ynamide 11, in the cycloaddition with azides 1a,b, gave triazoles
14 and 15, respectively (Table 1) .
B
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Table 1. Ruthenium Cycloaddition between Methyl N-Boc-aminopropiolates 10 and 11 and Azides
a
Yield of isolated products.
The reaction worked well with aromatic and aliphatic azides
and even with α-azido amino acids giving the triazole amino acids
20 and 21 (entries 9 and 10, Table 1) always in good yield and
with complete regiocontrol. The regiochemistry presenting the
carboxylate in position 4 and the nitrogen in position 5 was
postulated on the basis of the orientation proposed in analogous
reactions with aryl-substituted ynamides11 or phenylpropiolate
(see below).15
C
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Table 2. Ru-Mediated Cycloaddition of Different Ynamides
a
b
c
Prepared as described for compound 10. Yield of isolated compound. Yield relative to the regioisomer mixture.
As the regiochemical control in the cycloaddition was
Scheme 4. Proposed Intermediates for the Different
Regiochemical Outcomes
a
complete and due to the potential applications of the reaction
for the synthesis of diverse 5-amino-1,2,3-triazoles, the influence
on the regiochemistry of the ynamide C-substituent was
investigated (Table 2).
To our surprise, while the regiocontrol was complete also with
the phenylethyny derivative 22 (entries 1 and 2 in Table 2), in
the presence of an alkyl chain (not too large, as for ynamides 23
and 24) a mixture of regioisomers was obtained, even though the
5 amino-substituted triazole prevailed (entries 3−5 in Table 2).
This last quite unexpected result16 suggests that probably the
high regiocontrol observed with ynamides 10, 11, and 22 may be
explained by a possible additional interaction between the Ru
atom and the full nonbonding orbitals of the carboxymethyl
group (for 10 and 11) or the π aromatic orbitals of the phenyl in
compound 22 (Scheme 4).11 In the absence of these effects, the
interaction of Ru with the N-Boc-aminoaryl substituent drives
the orientation toward the opposite regioisomers (as 27b−29b
in Table 2).
To explore the synthetic potential and the scope of the
reaction, a general functionalization around the triazole ring was
explored. The carboxymethyl group in position 4 of triazole 12
was directly transformed into amide by displacement with a
primary amine such as allylamine or benzylamine giving
compounds 30 and 31 in 75 and 69% yield, respectively.
Alternatively, the hydrolysis of the ester in position 4 of 12 or 14
a
Parts i and ii justify the selectivity toward the 5-amino-substituted
triazole; iii justifies the formation of the 4-amino-substituted triazole in
the reaction with alkyl N-Boc-ynamides.
produced the carboxylic acids that were further transformed into
the corresponding acyl chlorides (Scheme 5).
D
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ester gave the triazole-containing dipeptide 37 in 36% yield
(Scheme 7).
Scheme 5. Functionalization at Position 4
The enantiomeric integrity of products 20, 21, 32, 33, and 36
was determined by HPLC analysis on a chiral column in
comparison with the chromatograms recorded with the coupling
products obtained from the racemic amino acids.
Finally, the carboxylic group of the α-azido acids inserted in
position 1 of the triazole (compound 20) was reacted with L-
alanine tert-butyl or methyl esters in the presence of DMTMM18
as the coupling agent to generate the triazole-containing peptides
38 and 39 (Scheme 8).
Scheme 8. Preparation of Triazole-Based Dipeptide
The further coupling with (S)-alanine methyl ester mediated
by DIPEA and DMAP in DMF gave triazole dipeptides 32 and
33, respectively, in 52 and 58% isolated yield.17
The functionalization in position 5 of triazole passed through
the removal of Boc that was accomplished with TFA (Scheme 6).
Scheme 6. Functionalization at Position 5
Elongation of the peptide could be possible by methyl ester
hydrolysis of 38 followed by EDC-mediated coupling with (S)-
alanine methyl ester. Final treatment with HCl in MeOH
removed the Boc and the tert-butyl protections to yield the
triazole containing (inverted) peptide 40. In all of the cases
described above, formation of products derived from the
Dimroth rearrangement was never observed. This is a remarkable
result especially regarding products having an alkyl group in
position 1 that, coupled with an electron-withdrawing group in
position 4, is known to promote this rearrangement.19
Compound 39 crystallized on standing in H2O to give crystals
that were submitted to X-ray analysis, confirming the stereo-
chemistry outcome of the cycloaddition (Supporting Informa-
tion).
Unfortunately, the aniline-type NH in position 4 of the
product derived from 12 was a poor nucleophile as it reacted
exclusively with acetic anhydride or benzoyl chloride to yield
compounds 34 and 35 in acceptable yields.
The reaction between the deprotected 5-aminotriazoles and
different carboxylic acids using the most common peptide-
coupling agents (DCC, EDC HATU, PyBOP) was also
attempted. Starting from the N-benzyl derivative 14 and
subsequent TFA-mediated Boc removal, EDC coupling with
N-Boc-protected alanine methyl ester gave product 36 in
moderate yield (Scheme 7).
Analogously, starting from compound 33, removal of the Boc
and further EDC-mediated coupling with (S)- alanine methyl
To investigate the suitability of aminotriazole scaffold to mimic
peptides, with particular reference to reverse turns, comparison
of derivative 39 with this structural element was made in detail.
Our molecular prototype was subjected to thorough computa-
tional analysis of its conformational properties by molecular
mechanics (MM), quantum mechanics (QM), and molecular
dynamics (MD). The conformational analysis showed that 39
has some populated conformers satisfying reverse turn require-
ments. In particular, two geometries have a β value much smaller
than 90° and a dα < 7 Å. Moreover, one of the two most stable
conformers shows the CO−HN H-bond typical of β turns. In
addition, a trial-and-error type approach to classify β-turn type
was attempted, based on the atom-by-atom superposition of the
two conformers onto a built-on-purpose template. This method
suggested a type I′ β-turn reference frame for one conformer and
a V′ β-turn reference for the other. The superposition of both
Scheme 7. Preparation of Triazole-Based Peptides
E
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lowest energy conformers of 39 onto, respectively, standard type
I′ and standard type V′ β-turns, are shown in Figure 1 and 2,
Scheme 9. Preparation of a Triazole-Based HSP90 Inhibitor
Figure 1. Conformer of 39 colored by atom types (crossed stereoview),
superimposed with standard type-I′ β-turn (yellow structure with
omitted hydrogen atoms).
Figure 2. Conformer of 39 colored by atom types (crossed stereoview),
superimposed with a standard type-V′ β-turn (yellow structure with
omitted hydrogen atoms).
control the regiochemistry of the addition based on the
substrate/catalyst structure. This procedure avoids the event of
the Dimroth rearrangement that may give different (and
sometimes unpredictable) substituted triazoles. The N-Boc-5-
aminotriazoles were transformed into the trifluoroacetates after
deprotection and reacted as their free amine during the coupling.
The reaction products can be used as stereodefined scaffolds for
the preparation of triazole-containing peptidomimetics or as
generic scaffolds for the preparation of diverse trisubstituted
amino triazoles. The procedure can be also applied to the
preparation of triazoles containing a substituent arrangement
suitable for producing antitumor compounds based on HSP90
inhibition.
confirming, as outlined by the X-ray data, that compound 39 can
be considered as a good candidate to mimic a reverse turn. A
more detailed explanation of the molecular modeling study is
reported in the Supporting Information.
The 5-amino-1,2,3-triazole carboxylates can also find interest-
ing applications as scaffolds for the preparation of bioactive
compounds in medicinal chemistry. Based on a recent report that
points out how substituted amidoisoxazole or -triazole
carboxylates can be employed in HSP90 binding,20 we prepared
5-amido-4-carboxytriazole 41 through Ru-mediated cycloaddi-
tion of the cumenediol azide 4320b and the ynamido propiolate
42.
This product was prepared by Ullmann-type reaction of amide
44 with TIPS-bromoacetylene 7 followed by deprotection and
carboxylation with LiHMDS and methyl chloroformate (Scheme
9). Ru-mediated cycloaddition between 42 and 43 gave the
triazole carboxylate that was transformed into amide by reaction
with ethylamine and further deprotected first using H2 on
Pd(OH)2/C to remove the benzyl groups and then with DDQ in
DCM/H2O to remove the p-methoxybenzoyl protecting group
to give amidotriazole 41 in 26% yield. Compound 41 was
submitted to a binding text with HSP90 determined by a
fluorescence polarization assay (FP Assay) to give an IC50 of 29
4 nM (mean value with n = 4). Cytotoxicity on NCI-H460 non-
small cell lung carcinoma cells confirmed a promising IC50 value
of 96 2 nM (n = 4).
EXPERIMENTAL SECTION
■
General Methods. All reagents were used as purchased from
commercial suppliers without further purification. The reactions were
carried out in oven-dried or -flamed vessels and performed under
nitrogen. Solvents were dried and purified by conventional methods
prior use. Flash column chromatography was performed with silica gel
60, 0.040−0.063 mm (230−400 mesh). Aluminum-backed plates
precoated with silica gel 60 (UV254) were used for thin-layer
chromatography and were visualized by staining with KMnO4. NMR
spectra were recorded under conditions that are specified for each
spectrum (temperature 25 °C unless specified). Splitting patterns are
designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. Chemical shifts (δ) are given in ppm relative to the resonance of
their respective residual solvent peak, CHCl3 (7.27 ppm, 1H; 77.16
ppm, the middle peak, 13C). High- and low-resolution mass spectros-
copy analyses were recorded at 70 eV by electrospray ionization using a
triple quadrupole mass spectrometer. Melting points were determined
in open capillary tubes and are uncorrected. Specific rotations were
measured with a 10 cm cell with a Na 589 nm filter: values are given in
10−1 deg·cm3·g−1.
CONCLUSION
■
In conclusion, we have developed a regiocontrolled synthesis of
5-amino-trisubstitued triazoles via Ru mediated cycloaddition of
ynamides and azides. The regiocontrol of the reaction was
possible only if a group able to interact with the Ru catalyst were
present on the other side of the triple bond with respect to the
ynamide moiety. This is an efficient example of the possibility to
L-Phenyl-4-carbethoxy-5-amino-l,2,3-triazole (5a). Compound
5a was prepared following the general procedure previously described.9a
The product was isolated by crystallization from petroleum ether 40−60
°C: mp 125−127 °C (lit.21 mp 125−126 °C); H NMR (400 MHz,
1
CDCl3) δ 7.81−7.31 (m, 5H), 6.50 (bs, 2H), 4.15 (m, 2H), 1.30 (m,
F
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3H); 13C NMR (100 MHz, CDCl3) δ 15.3, 60.0, 114.7, 122.9, 127.5,
128.7, 128.7, 137.1, 147.2, 159.6.
(2C), 82.3, 52.4, 51.7, 27.5 (3C); HRMS (ESI) m/z calcd for
C22H24N4O4Na+ 431.1695, found 431.1690.
1-Benzyl-4-carbethoxy-5-amino-l,2,3-triazole (5b). Com-
pound 5b was prepared following the general procedure described for
5a. The product was isolated by crystallization from petroleum ether
Methyl 1-Benzyl-5-(N-benzyl-tert-butoxycarbonylamino)-
1H-1,2,3-triazole-4-carboxylate 15. Column chromatography
(petroleum ether 40−60/EtOAc 65:45) gave compound 15 (380 mg,
90%) as a waxy material. An analytical sample was crystallized from
EtOH/H2O: mp 127−129 °C; 1H NMR (400 MHz, CDCl3) δ 7.40−
6.83 (m, 10H), 4.99 (m 2H), 4.40 (m, 2H), 3.82 (s, 3H), 1.09 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 160.0, 152.8, 139.4, 135.4, 133.1, 132.2,
40−60 °C: mp 153−153 °C (lit.9a mp 152−154 °C); H NMR (400
1
MHz, CDCl3) δ 7.54−6.95 (m, 5H), 6.38 (bs, 2H), 5.24−4.78 (m, 2H),
4.15 (m, 2H), 1.30 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 16.3, 51.9,
61.0, 112.8, 125.6, 128.7, 129.2, 129.4, 135.4, 148.7, 165.6.
Methyl N-Phenyl-N-Boc-3-aminopropiolate (10). Compound 8
(434 mg, 2 mmol, prepared as described in ref 14) was dissolved in dry
THF (10 mL) under nitrogen; the solution was cooled to −78 °C, and
LiHMDS (3.5 μL of a solution 1 M in THF, 3.5 mmol) was added. The
mixture was slowly warmed to −40 °C and maintained at this
temperature for 1 h. The solution was transferred via cannula to a flask
containing methyl chloroformate (620 mg μL, 6.5 mmol) in THF (6
mL) at −40 °C, and the solution was warmed to room temperature.
Saturated aqueous NH4Cl (10 mL) and EtOAc (10 mL) were added,
and the organic phase was extracted (3 × 15 mL EtOAc) and dried over
Na2SO4. The title compound was obtained after purification by column
chromatography (petroleum ether 40−60/EtOAc from 80:20 to 75:25)
129.1 (2C), 128.4 (2C), 128.3 (2C), 128.0 (3C), 127.6, 81.9, 52.8, 51.6,
50.4, 27.2 (3C); ESI/MS (M + Na)+ 445. Anal. Calcd for C23H26N4O4
C, 65.39; H, 6.20; N, 13.26; O, 15.15. Found: C, 65.34; H, 6.22; N,
13.24.
Methyl 1-p-Chlorophenyl-5-(N-phenyl-tert-butoxycarbony-
lamino)-1H-1,2,3-triazole-4-carboxylate 16. Column chromatog-
raphy (petroleum ether 40−60/EtOAc 65:45) gave compound 16 (346
mg, 81%) as a waxy material. An analytical sample was crystallized from
EtOH/H2O: mp 117−119 °C; 1H NMR (300 MHz, CDCl3) δ 7.69 (m
2H), 7.45 (m, 4H), 7.33−7.10 (m, 2H), 7.03−6.96 (m, 1H), 3.31 (s,
3H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 160.1, 151.9, 139.7,
138.7, 136.6 (2C), 134.1, 133.4 (2C), 131.4 (2C), 129.2 (2C), 126.7,
125.8, 125.4, 83.8, 50.8, 28.1 (3C); ESI/MS (M + Na)+. 451 Anal. Calcd
for C21H21ClN4O4: C, 58.81; H, 4.94; N, 13.06; O, 14.92; Cl, 8.27.
Found: C, 58.77; H, 4.97; N, 13.04.
Methyl 1-p-Methoxyphenyl-5-(N-phenyl-tert-butoxycarbo-
nylamino)-1H-1,2,3-triazole-4-carboxylate 17. Column chroma-
tography (petroleum ether 40−60/EtOAc 65:45) gave compound 17
(334 mg, 79%) as a dense oil: 1H NMR (300 MHz, CDCl3) δ 7.41−6.67
(m, 9H), 3.80 (s 3H), 3.30 (s, 3H), 1.45−1.20 (m, 9H); 13C NMR (75
MHz, CDCl3) δ 161.1, 160.2, 148.7, 139.7, 139.6, 133.8, 129.4 (2C),
129.1 (2C), 126.8 (2C), 126.1, 125.4, 114.9 (2C), 83.4, 55.9, 53.3, 28.2
(3C); HRMS (ESI) m/z calcd for C22H24N4O5Na+ 447.1645, found
447.1643.
1
(467 mg, 85%): H NMR (400 MHz, CDCl3) δ 7.48−7.12 (m, 5H),
3.71 (s, 3H), 1.50 (s, 9H); 13CNMR (101 MHz, CDCl3) δ 154.4, 151.5,
137.4, 128.7 (2C), 127.2 (2C), 124.5, 84.6, 82.5, 65.3, 51.86, 27.3 (3);
HRMS (ESI) m/z calcd for C15H17NO4Na+ 298.1055, found 298.1050.
Methyl N-Phenyl-N-Boc-3-aminopropiolate (11). Column
chromatography (petroleum ether 40−60/EtOAc from 80:20 to
1
75:25) gave compound 11 (497 mg, 86%) as an oil: H NMR (400
MHz, CDCl3) δ 7.53−7.18 (m, 5H), 4.24 (s, 2H), 3.71 (s, 3H), 1.51 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 154.4, 151.5, 137.4, 128.8 (2C),
127.3 (2C), 124.5, 84.6, 82.6, 65.3, 60.8, 51.8, 27.3 (3C); HRMS (ESI)
m/z calcd for C16H19NO4Na+ 312.1212, found 312.1206.
Methyl 1-Phenyl-5-(N-phenyl-tert-butoxycarbonylamino)-
1H-1,2,3-triazole-4-carboxylate 12, General Procedure. To
phenyl azide 1a (120 mg, 1 mmol) dissolved in dry DMF (2.5 mL) at
rt was added compound 10 (275 mg, 1 mmol). The flask was subjected
to three vacuum−nitrogen cycles, then (Cp*RuCl)4 (49 mg, 0.045
mmol) was added followed other three vacuum−nitrogen cycles. The
reaction was stirred at room temperature until completion (monitored
by TLC, 2 h). EtOAc (10 mL) and water (5 mL) were then added. The
organic phase was extracted four times with EtOAc (5 mL each), washed
with water (2 mL, three times) and brine (5 mL, one time), and dried
over Na2SO4; the solvent was removed, and the mixture was purified by
column chromatography (petroleum ether 40−60/EtOAc 60:40). The
title compound was obtained as a purple oil with a tendency to solidify
on standing (339 mg, 86%). An analytical sample was crystallized two
times from EtOH/H2O: mp 123−126 °C; 1H NMR (400 MHz, CDCl3)
δ 7.52−6.99 (m, 8H), 6.90 (dm, 2H), 3.87 (s, 3H), 1.29 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 159.8, 138.9, 134.3, 132.9, 129.9 (2C),
129.18 (2C), 128.4 (2C), 126.3 (2C), 124.8 (2C), 123.9, 122.5, 82.9,
51.7, 27.4 (3C); ESI/MS (M + Na)+ 417. Anal. Calcd for C21H22N4O4:
C, 63.95; H, 5.62; N, 14.20; O, 16.23. Found: C, 63.89; H, 5.65; N,
14.17.
Methyl 1-p-Benzyloxyphenyl-5-(N-phenyl-tert-butoxycarbo-
nylamino)-1H-1,2,3-triazole-4-carboxylate 18. Column chroma-
tography (petroleum ether 40−60/EtOAc 65:45) gave compound 18
(465 mg, 93%) as a red waxy material. An analytical sample was
crystallized from EtOH/H2O: mp 105−107 °C; 1H NMR (400 MHz,
CDCl3) δ 7.45−6.69 (m, 14H), 4.75 (d, J = 14.3 Hz, 1H), 4.48 (d, J =
14.3 Hz, 1H), 3.89 (s, 3H), 1.38−1.07 (m, 9H); 13C NMR (101 MHz,
DMSO-d) δ 160.3, 151.7, 149.2, 134.7, 133.1, 129.3 (4C), 129.1 (4C),
128.9 (3C), 128.7 (4C), 124.8 (2C), 83.9, 52.1, 50.5, 28.0 (3C); ESI/
MS (M + Na). Anal. Calcd for C28H28N4O5: C, 67.19; H, 5.64; N, 11.19;
O, 15.98. Found: C, 67.14; H, 5.61; N, 11.16.
Methyl 1-Phenethyl-5-(N-phenyl-tert-butoxycarbonylami-
no)-1H-1,2,3-triazole-4-carboxylate 19. Column chromatography
(petroleum ether 40−60/EtOAc 65:45) gave compound 19 (371 mg,
1
88%) as a dense oil: H NMR (300 MHz, CDCl3) δ 7.37−6.93 (m,
10H), 4.33−4.17 (m, 4H), 3.29 (s, 3H), 1.41 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 160.3, 152.0, 139.3, 136.7, 134.0, 129.6 (2C), 129.1
(2C), 129.0 (2C), 128.1, 128.0, 127.0, 126.6, 125.3, 83.5, 61.5, 50.5,
34.5, 28.1 (3C); HRMS (ESI) m/z calcd for C23H26N4O4Na+ 445.1852,
found 445.1849.
(S)-2-(5-(tert-Butoxycarbonyl(phenyl)amino)-4-(methoxycar-
bonyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoic Acid 20. Col-
umn chromatography (petroleum ether 40−60/EtOAc from 15:85 to
0:100) gave compound 20 (400 mg, 86%) as a dense oil. An analytical
sample was obtained by crystallization of the dimethylamine salt in
acetone: [α]21D (of dimethylamine salt) = −9.96 (c = 0.67 in MeOH/
H2O 1/1); 1H NMR (400 MHz, CDCl3) δ 8.43 (bs, 1H), 7.54−6.83 (m,
10H), 4.86 (bs, 1H), 3.88 (s, 3H), 2.41 (m, 1H), 2.02−1.84 (m, 1H),
1.33 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 170.2, 164.0, 160.4, 160.3,
160.0, 151.7, 151.7, 138.9, 138.7, 128.2 (2C), 128.1 (2C), 126.8 (2C),
126.6 (2C), 124.8, 82.7, 51.0, 36.6, 27.5 (3C); ESI/MS (M − H)− 449.
Anal. Calcd for C26H33N5O6 (dimethylamine salt): C, 61.04; H, 6.50; N,
13.69; O, 18.77. Found: C, 60.99; H, 6.53; N, 13.73.
Methyl 1-Benzyl-5-(N-phenyl-tert-butoxycarbonylamino)-
1H-1,2,3-triazole-4-carboxylate 13. Column chromatography
(petroleum ether 40−60/EtOAc 60:40) gave compound 13 (359 mg,
88%) as a waxy material. An analytical sample was crystallized from i-
PrOH: mp 113−115 °C; 1H NMR (400 MHz, CDCl3) δ 7.45−6.89 (m,
10H), 5.44 (bs, 1H), 4.88 (bs, 1H), 3.87 (s, 3H), 1.18 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ = 167.6, 159.9, 150.8, 138.7, 138.1, 133.9, 133.0,
128.7 (2C), 128.4 (2C), 127.2 (2C), 126.1, 124.3 (2C), 82.7, 51.7, 51.3,
27.2 (3C); ESI/MS (M + Na)+ 431. Anal. Calcd for C22H24N4O4 C,
64.69; H, 5.92; N, 13.72; O, 15.67. Found: C, 64.62; H. 5.94; N, 13.70.
Methyl 1-Phenyl-5-(N-benzyl-tert-butoxycarbonylamino)-
1H-1,2,3-triazole-4-carboxylate 14. Column chromatography
(petroleum ether 40−60/EtOAc 50:50) gave compound 14 (331 mg,
1
81%) as a dense oil: H NMR (400 MHz, CDCl3) δ 7.62−6.57 (m,
(S)-2-(5-(tert-Butoxycarbonyl(phenyl)amino)-4-(methoxycar-
bonyl)-1H-1,2,3-triazol-1-yl)-4-methylpentanoic Acid 21. Col-
umn chromatography (petroleum ether 40−60/EtOAc from 15:85 to
0:100) gave compound 21 (358 mg, 83%) as a dense oil. An analytical
10H), 4.75 (d, J = 14.2 Hz, 1H), 4.48 (d, J = 14.3 Hz, 1H), 3.89 (s, 3H),
1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 159.9, 152.5, 134.3, 129.3
(2C), 129.0 (2C), 128.8 (2C), 128.0 (2C), 127.7 (2C), 124.4, 123.6
G
DOI: 10.1021/jo502577e
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The Journal of Organic Chemistry
Article
sample was obtained by crystallization of the dimethylamine salt in
The solvent and the excess of the amine were removed under reduced
pressure and the residue was crystallized from MeOH/H2O to give
compound 30 (83 mg, 80%): mp 186−187 °C; H NMR (400 MHz,
acetone: [α]21D (of dimethylamine salt) = −13.66 (c = 0.86 in MeOH/
1
1
H2O 1/1); H NMR (400 MHz,CDCl3) δ 7.73 (t, J = 7.6 Hz, 2H),
7.50−7.12 (m, 3H), 4.64 (m, 1H), 3.95 (s, 3H), 2.40 (m 1H), 2.34−2.06
(m, 2H), 1.58 (s, 9H), 0.95 (d, J = 5.6 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 160.7, 150.7, 139.1, 138.4, 133.0, 128.5, 128.4 (2C), 127.9,
127.7, 127.2 (2C), 83.3, 62.5, 56.2, 51.2, 39.8, 25.2 (3C), 18.5; ESI/MS
(M − H) 431. Anal. Calcd for C23H35N5O6 (dimethylamine salt): C,
57.85; H, 7.39; N, 14.67; O, 0.10. Found: C, 57.80; H, 7.42; N, 14.71.
tert-Butyl (1,4-Diphenyl-1H-1,2,3-triazol-5-yl)-
phenylcarbamate 25. Column chromatography (petroleum ether
40−60/EtOAc 70:30) gave compound 24 (297 mg, 72%) as a dense oil
with a tendency to solidify on standing. An analytical sample was
CDCl3) δ 7.69−6.90 (m, 11H), 6.06−5.77 (m, 1H), 5.35−5.07 (m, 2H),
4.07 (d, J = 14.0 Hz, 2H), 1.34 (s, 9H); 13C NMR (101 MHz CDCl3) δ
158.6 (2C), 134.5, 133.5, 129.9, 129.8 (2C), 129.3, 129.3 (2C), 129.1,
128.4, 128.4, 128.3, 126.4, 125.5, 124.1, 116.2, 82.7, 40.87 27.5 (3C);
ESI/MS (M + Na) 442. Anal. Calcd for C23H25N5O3: C, 65.85; H, 6.01;
N, 16.70; O, 11.44. Found: C, 65.81; H, 6.04; N, 16.68.
tert-Butyl [4-[(Benzylamino)carbonyl]-1-phenyl-1H-1,2,3-tri-
azol-5-yl]phenylcarbamate 31. Starting from 14 and following the
same procedure described for 30, compound 31 was crystallized from
1
MeOH/H2O (95 mg, 81%): mp 202 °C (dec); H NMR (400 MHz,
1
CDCl3) δ 7.90 (m, 2H), 7.64−7.10 (m, 13H), 5.48 (d, J = 15.2 Hz, 1H),
4.78 (d, J = 15.3 Hz, 1H), 0.93 (s, 10H); 13C NMR (101 MHz, CDCl3) δ
150.8, 141.7, 138.6, 133.8, 132.5, 129.8, 129.2, 128.9 (2C), 128.5, 128.4,
128.3, 128.0, 127.9, 127.8, 127.2, 125.4, 125.0 (2C), 122.9, 122.8, 82.4,
51.2, 51.2, 26.9 (3C); ESI/MS (M + Na) 492. Anal. Calcd for
C27H27N5O3: C, 69.07; H, 5.80; N, 14.92; O, 10.22. Found: C, 69.01; H,
5.83; N, 14.90.
obtained by crystallization from i-PrOH: mp 154−156 °C (dec); H
NMR (400 MHz, CDCl3) δ 7.90 (m, 3H), 7.64−6.76 (m, 12H), 1.23 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 151.6, 140.9, 139.2, 134.9, 133.7,
129.3, 129.0, 128.4 (2C), 128.1 (2C), 125.5 (6C), 125.4 (2C), 123.9
(2C), 123.2 (2C), 82.8, 27.3; ESI/MS (M + Na)+ 435. Anal. Calcd for
C25H24N4O2: C, 72.80; H, 5.86; N, 13.58; O, 7.76. Found: C, 72.77; H,
5.88; N, 13.56.
Methyl N-([5-[(tert-Butoxycarbonyl)(phenyl)amino]-1-phe-
nyl-1H-1,2,3-triazol-4-yl]carbonyl)-L-alaninate 32, General Pro-
cedure. Compound 12 (100 mg, 0.25 mmol) was dissolved in MeOH
(0.5 mL) and the solution added to 2 mL of a 1 M solution of NaOH at
rt. The solution was stirred for 2 h, then cooled to 0 °C, and 3 mL of a 1
M solution of HCl was added. EtOAc (10 mL) was then added, and the
organic phase was separated and dried over anhydrous Na2SO4. The
solvent was evaporated, the residue taken in dry toluene (5 mL), and the
solvent evaporated under reduced pressure in order to dry the product.
Oxalyl chloride (2 mL) was added and the solution stirred at rt for 3 h.
The liquid phase was removed under vacuum (10 mmHg) and the
residue dissolved in dry CH2Cl2 (0.5 mL). This solution was added to a
solution containing H-AlaOMe (41 mg, 0.4 mmol), DIPEA (0.39 mL,
2.5 mmol), and DMAP (5 mg) in dry CH2Cl2 (1 mL). The solution was
stirred at rt for 6 h, then CH2Cl2 (10 mL) was added, and the organic
phase was washed with a solution of HCl 1 M, (2 × 4 mL), NaHCO3 1
M (2 × 25 mL), water (2 mL), and brine (15 mL). The organic phase
was separated and dried over anhydrous Na2SO4 and the solvent
evaporated. Column chromatography (petroleum ether 40−60/EtOAc
tert-Butyl (1-Benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)-
phenylcarbamate 26. Column chromatography (petroleum ether
40−60/EtOAc 70:30) gave compound 26 (349 mg, 82%) as a dense oil
with a tendency to solidify on standing. An analytical sample was
obtained by crystallyzation from i-PrOH: mp 168 °C (dec); 1H NMR
(400 MHz CDCl3) δ 8.20−6.83 (m, 15H), 5.47 (d, J = 10.2 Hz, 1H),
4.77 (d, J = 10.2 Hz, 1H), 0.94 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
150.8, 141.7, 138.6, 133.7, 129.1, 128.8 (2C), 128.5 (2C), 128.3 (2C),
128.0, 127.9 (2C), 127.2 (2C), 125.4, 125.0 (2C), 122.8 (2C), 82.4 51.2,
26.9 (3C); ESI/MS (M + Na) 449. Anal. Calcd for C26H26N4O2: C,
73.22; H, 6.14; N, 13.14; O, 7.50. Found: C, 73.18; H, 6.17; N, 13.12.
tert-Butyl (4-Butyl-1-phenyl-1H-1,2,3-triazol-5-yl)-phenylcar-
bamate 27a. Column chromatography (petroleum ether 40−60/
EtOAc 70:30) gave compound 27 (298 mg, 76%) as a mixture of
1
isomers. The ratio was determined by H NMR. A second column
chromatography with petroleum ether 40−60/EtOAc from 100:0 to
1
80:20 allowed the isolation of pure 27a as a dense oil: H NMR (400
MHz CDCl3) δ 7.60−6.90 (m, 10H), 2.62−2.49 (m, 1H), 2.49−2.34
(m, 1H), 1.39−1.25 (m, 3H), 1.17 (s, 10 H), 0.83 (t, J = 7.3 Hz, 3H); 13C
NMR (101 MHz CDCl3) δ 153.2, 143.7, 141.1, 136.3, 132.7, 129.3,
129.1, 128.3 (2C), 125.7 (2C), 125.5 (2C), 124.9 (2C), 81.4, 28.9, 27.7
(3C), 22.2, 21.9, 13.0; HRMS (ESI) m/z calcd for C23H28N4O2Na+
415.2110, found 415.2116.
from 40:60 to 0:100) gave compound 32 (60 mg, 52%) as a waxy
1
material: [α]21 = −15.36 (c = 0.5 in CDCl3); H NMR (400 MHz,
D
CDCl3) δ 7.51−7.33 (m, 6H), 7.23−7.04 (m, 4H), 6.63 (d, J = 7.9 Hz,
1H), 4.76 (m, 1H), 3.74 (s, 3H), 1.53 (d, J = 7.1 Hz, 3H), 1.34 (s, 9H);
13C NMR (101 MHz CDCl3) δ 172.5, 161.7, 141.3, 139.2, 135.7, 134.5,
tert-Butyl (4-Butyl-1-benzyl-1H-1,2,3-triazol-5-yl)-
phenylcarbamate 28a. Column chromatography (petroleum ether
40−60/EtOAc 70:30) gave compound 28 (320 mg, 79%) as a mixture of
129.8, 129.2, 128.4 (4C), 126.4, 126.3, 125.5, 124.1, 123.4, 122.7, 120.1,
120.1, 82.6, 52.1, 47.3, 27.56 (3C), 17.9; HRMS (ESI): m/z calcd for
C24H27N5O5Na+ 488.1910, found 488.1906
1
isomers. The ratio was determined by H NMR. A second column
chromatography with petroleum ether 40−60/EtOAc from 100:0 to
Methyl N-([5-[(tert-Butoxycarbonyl)(phenyl)amino]-1-ben-
zyl-1H-1,2,3-triazol-4-yl]carbonyl)-L-alaninate 33. Starting from
14 and following the same procedure described for 32, column
chromatography (petroleum ether 40−60/EtOAc from 40:60 to 0:100)
gave compound 33 (67 mg, 58%) as a waxy material: [α]21D = −17.67 (c
= 0.5 in CDCl3); 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.83−
6.92 (m, 10H), 5.16 (s, 2H), 4.75 (q, J = 6.7 Hz, 1H), 3.77 (s, 3H), 1.44
(s and d, 12H); 13C NMR (101 MHz, CDCl3) δ 169.8, 158.0, 149.1,
144.3, 137.6, 135.1, 129.2, 128.5, 128.3 (2C), 127.9 (2C), 127.8 (2C),
127.3 (2C), 119.8, 81.2, 52.1, 50.7, 49.9, 27.8 (3), 19.8; HRMS (ESI) m/
z calcd for C25H29N5O5Na+ 502.2067, found 502.2064
Methyl 5-[Acetyl(phenyl)amino]-1-phenyl-1H-1,2,3-triazole-
4-carboxylate 34. Trifluoaroacetic acid (0.16 mL, 2 mmol) was added
to a solution of 12 (120 mg, 0.3 mmol) in CH2Cl2 (2 mL) at 0 °C. The
solution was stirred at this temperature for 20 min and then warmed to
room temperature and stirred for 4 h. The TFA was removed under
vacuum, and to the residue were added acetic anhydride (1 mL) and
AcONa (0.1 g), and the solution was stirred at rt overnight. The reaction
was quenched with 3 mL of a 1 M solution of HCl and extracted with
CH2Cl2 (10 mL × 3). The organic solution was then dried over
anhydrous Na2SO4 and concentrated under vacuum. The residue was
purified by flash column chromatography on (petroleum ether 40−60/
EtOAc 80:20) to give compound 34 (74 mg, 73%). An analytical sample
1
80:20 allowed the isolation of pure 28a as a dense oil: H NMR (400
MHz, CDCl3) δ 7.67−6.67 (m, 10H), 5.33 (d, J = 15.2 Hz, 1H), 4.94 (d,
J = 15.2 Hz, 1H), 2.49 (m, 2H), 1.78−1.52 (m, 2H), 1.41−1.17 (m,
11H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 151.3,
143.0, 139.2, 133.9, 132.2, 128.4 (3C), 128.3, 127.8 (2C), 127.3, 125.3
(2C), 123.5, 82.3, 51.2, 29.8, 27.3 (2C), 24.0, 22.2, 13.3; HRMS (ESI)
m/z calcd for C24H30N4O2Na+ 429.2267, found 429.2263.
tert-Butyl (4-Ethyl-1-phenyl-1H-1,2,3-triazol-5-yl)-
phenylcarbamate 29a. Column chromatography (petroleum ether
40−60/EtOAc 70:30) gave compound 29 (266 mg, 73%) as a mixture of
1
isomers. The ratio was determined by H NMR. A second column
chromatography with petroleum ether 40−60/EtOAc from 100:0 to
1
80:20 allowed the isolation of pure 29a as a dense oil: H NMR (400
MHz, CDCl3) δ 7.43−7.36 (m, 7H), 7.17−7.13 (m, 3H), 2.86−2.73 (t-
like, 2H), 1.38 (s, 9H), 0.93 (t, J = 7.7 Hz, 3H); 13C NMR (101 MHz,) δ
154.6, 143.0, 140.6, 135.6, 129.2, 128.5 (2C), 127.9 (2C), 127.8 (2C),
125.3 (2C), 124.7 (2C), 81.1, 30.3, 28.0(3C), 11.9; HRMS (ESI) m/z
calcd for C21H24N4O2Na+ 387.1797, found 387.1793.
tert-Butyl [4-[(Allylamino)carbonyl]-1-phenyl-1H-1,2,3-tria-
zol-5-yl]phenylcarbamate 30. Allylamine (142 mg, 2.5 mmol) was
added to compound 12 (100 mg, 0.25 mmol) dissolved in dry MeOH
(0.5 mL), and the mixture was heated for 6 h at 80 °C in a sealed tube.
H
DOI: 10.1021/jo502577e
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The Journal of Organic Chemistry
Article
1
was crystallized from EtOH/H2O: mp 123−124 °C; H NMR (400
MHz, CDCl3) δ 7.61−6.98 (m, 8H), 6.81 (d, J = 7.4 Hz, 2H), 3.96 (s,
3H), 1.99 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.8, 160.3, 139.5,
134.0, 130.3, 130.3, 129.8(2C), 129.2(2C), 129.0(2C), 128.6, 127.1,
124.9, 115.9, 53.8, 51.8; ESI/MS (M + Na) 359. Anal. Calcd for
C18H16N4O3: C, 64.28; H, 4.79; N, 16.66; O, 14.27. Found: C, 64.24; H,
4.81; N, 16.64.
Dipetide 39. Column chromatography (petroleum ether 40−60/
EtOAc 40:60 to EtOAc/MeOH 98:2) gave compound 39 (41 mg, 74%)
as a waxy material: 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.87−
7.57 (m, 2H), 7.53−7.03 (m, 7H), 6.61 (t, J = 7.1 Hz, 1H), 5.23−4.98
(m, 1H), 4.08−3.78 (m, 4H), 3.79−3.57 (m, 4H), 3.57−3.42 (m, 1H),
1.72 (s, 9H), 1.29 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
170.2, 164.0, 160.4, 160.3, 160.0, 151.7, 151.7, 138.8, 138.7, 128.2 (2C),
128.1 (2C), 126.7 (2C), 126.6 (2C), 124.7, 82.7, 54.9, 51.0, 42.8, 37.9,
36.6, 27.5 (3C), 20.2; HRMS (ESI) m/z calcd for C28H33N5O7Na+
574.2278, found 574.2280.
Methyl 5-[Benzoyl(phenyl)amino]-1-phenyl-1H-1,2,3-tria-
zole-4-carboxylate 35. The Boc was removed as described for 34,
the residue was dissolved in dry DMF (1 mL), and the solution cooled to
0 °C. Pyridine (0.5 mL) was added followed by DMAP (20 mg) and
benzoyl chloride (140 mg, 1 mmol). The solution stirred at rt for 12 h.
The same workup of 34 gave product 35 (91 mg, 76%). An analytical
sample was crystallized from i-PrOH: mp 164−167 °C; 1H NMR (400
MHz, CDCl3) δ 7.49−6.92 (m, 15H), 3.87 (s, 3H); 13C NMR (101
MHz CDCl3) δ 164.3, 157.5, 147.3, 136.6, 135.9, 129.5, 129.0, 128.5
(2C), 128.4 (2C), 128.0 (3C), 127.8 (2C), 127.5 (2C), 127.2 (2C),
122.0 (2C), 51.9; ESI/MS (M + Na) 421. Anal. Calcd for C23H18N4O3
C, 69.34; H, 4.55; N, 14.06; O, 12.05. Found: C, 69.30; H, 4.57; N,
14.02.
Methyl 5-[[N-(tert-Butoxycarbonyl)-L-alanyl](phenyl)amino]-
1-benzyl-1H-1,2,3-triazole-4-carboxylate 36, General Proce-
dure. Compound 14 (48 mg, 0.1 mmol) was deprotected from Boc
as previously described. The residue was dissolved in dry DMF (1 mL),
and this solution was added to a solution containing N-Boc-AlaOH (96
mg, 0.5 mmol), DIPEA (0.39 mL, 2.5 mmol), and DMAP (5 mg) in dry
DMF (1 mL) cooled to 0 °C. The mixture was gently warmed to 50 °C
(water bath) and stirred at this temperature for 12. Then CHCl3 (10
mL) was added, and the organic phase was washed with a solution of
HCl 1 M (2 × 4 mL), NaHCO3 1 M (2 × 25 mL), water (2 mL), and
brine (15 mL). The organic phase was separated and dried over
anhydrous Na2SO4, and the solvent evaporated. Column chromatog-
raphy (petroleum ether 40−60/EtOAc from 40:60 to 0:100) gave
compound 36 (103 mg, 43%) as a waxy material: 1H NMR (400 MHz,
CDCl3) δ 7.51- 6.52 (m, 11H), 4.75 (d, J = 14.3 Hz, 1H), 4.48 (d, J =
14.3 Hz, 1H), 3.89 (s, 3H), 3.78−3.61 (m, 1H), 1.38−1.16 (m, 12H);
13C NMR (101 MHz, CDCl3) δ 170.4, 160.37, 152.7, 139.0, 134.4,
Peptide 40. Compound 38 (40 mg, 0.072 mmol) was dissolved in
MeOH (0.5 mL) and the solution added to 0.5 mL of a 1 M solution of
NaOH at rt. The solution was stirred for 2 h and then cooled to 0 °C, and
0.6 mL of a 0.1 M solution of HCl was added. EtOAc (5 mL) was added
and the organic phase rapidly separated and dried over anhydrous
Na2SO4. The solvent was evaporated, the residue taken in dry toluene (5
mL), and the solvent evaporated under reduced pressure in order to dry
the product. Oxalyl chloride (1 mL) was added and the solution stirred
at rt for 3 h. The liquid phase was removed under vacuum (10 mmHg)
and the residue dissolved in dry DMF (0.5 mL). This solution was added
to a solution containing H-AlaOMe (20 mg, 0.2 mmol), EDC (77 mg,
0.5 mmol), DIPEA (0.2 mL, 1.3 mmol), and DMAP (5 mg) in dry
CH2Cl2 (1 mL). The solution was stirred at rt for 6 h, then CH2Cl2 (10
mL) was added, and the organic phase was washed with a 10 aqueous
solution of citric acid (2 × 4 mL), NaHCO3 1 M (2 × 25 mL), water (2
mL), and brine (15 mL). The organic phase was separated and dried
over anhydrous Na2SO4 and the solvent evaporated. A solution prepared
by dissolving Me3SiCl (0.127 mL, 1 mmol) in dry MeOH (0.5 mL) was
added and the mixture stirred at rt for 2 h. The solvent was evaporated
and the residue dissolved in MeOH and passed through a LC-SCX
cartridge for weak acids. First elution was done with MeOH, then H2O
and NH4OH 2% in MeOH. The product was removed with 2% formic
acid in MeOH. The solvent was evaporated to give compound 40 (20
mg, 56%): 1H NMR (400 MHz, CDCl3) δ 11.06 (bs, 1H), 9.02−8.66
(m, 3H), 8.05−7.85 (m, 2H), 7.54−7.01 (m, 7H), 6.74−6.46 (m, 1H),
5.15−4.94 (m, 1H), 4.86−4.62 (m, 1H), 4.53 (m, 1H), 4.13−3.89 (m,
1H), 3.90−3.67 (m, 4H), 1.55−1.22 (m, 6H); 13C NMR (101 MHz,
CDCl3d) δ 170.2, 168.1, 164.8, 160.3, 139.3, 137.6, 136.1, 130.3 (2C),
129.2 (2C), 128.6, 127.0 (2C), 124.9 (2C), 124.9, 119.9, 64.1, 54.5, 53.8,
51.9, 36.8, 22.7, 21.9; HRMS (ESI) m/z calcd for C25H28N6O6Na+
531.1968, found 531.1962.
134.2, 129.4, 129.1, 128.9, 128.3 (2C), 128.0 (2C), 127.7, 127.3, 125.9,
124.3, 123.6, 82.3, 52.4, 51.7, 27.5 (3), 19.1; HRMS (ESI) m/z calcd for
C25H29N5O5Na+ 502.2067, found 502.2063.
Methyl N-([1-Benzyl-5-[[N-(tert-butoxycarbonyl)-L-alanyl]-
(phenyl)amino]-1H-1,2,3-triazol-4-yl]carbonyl)-L-alaninate 37.
Starting from 33 and following the same procedure described for 36,
column chromatography (petroleum ether 40−60/EtOAc 40:60 to
EtOAc/MeOH 98:2) gave compound 37 (20 mg, 36%) as a waxy
material: 1H NMR (400 MHz, CDCl3) δ 8.16−6.86 (m, 12H), 5.66−
5.45 (m, 2H), 4.73 (d, J = 7.8 Hz, 1H), 4.66−4.55 (m, 1H), 3.88−3.53
(s, 3H), 1.49−1.31 (m, 12H), 1.23 (d, J = 6.0 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 173.5, 168.1, 152.7, 151.0, 140.3, 138.20, 138.1, 136.0,
134.3, 126.3 (2C), 125.9 (2C), 125.6 (2C), 125.2, 124.8, 121.3, 82.5,
55.8, 54.4, 53.1, 51.3, 27.8, 26.6 (3C), 18.5; HRMS (ESI) m/z calcd for
C28H34N6O6Na+ 573.2438, found 573.2434.
Methyl p-[(Methoxyphenyl)methyl](p-anisoyl)-
aminopropiolate 42. Amide 44 (1.03 g, 3.8 mmol) was dissolved in
toluene (8 mL), and to this solution were added CuI (0.224 g, 1.17 mol),
1,10-phenanthroline (0.252 g, 1.4 mmol), and KHMDS (10 mL of a 0.5
M solution in toluene, 5 mmol) under nitrogen. After 30 min of stirring
at rt, silane 7 (1.04 g, 4 mmol) was added and the flask sealed and heated
at 90 °C for 6 h under stirring. After cooling, the solid was filtered away
and the toluene evaporated and substituted with dry THF (10 mL). The
solution was cooled to 0 °C, TBAF (0.954 g, 3.02 mmol) was added, and
the solution was stirred at this temperature for 4 h. The solution was
diluted with EtOAc (25 mL) and washed with a saturated solution of
NH4Cl and water. The organic layer was separated and dried over
Na2SO4 and the solvent evaporated. A passage on a short column of
silica gel gave the desilylated product practically pure for the next step
(MS/ESI 296 [M + 1]+). This product (0.950 g) was dissolved in dry
THF (20 mL) and cooled to −78 °C. LHMDS (5.58 mL of a 1 M
solution in THF, 5.58 mmol) was slowly added and the mixture stirred
for 30 min at −78 °C and 1 h at −40 °C. At this temperature, methyl
chloroformiate (0.404 g, 4.28 mmol) in dry THF (4 mL) was slowly
added and the solution gently warmed to rt and stirred for 2 h. Standard
aqueous workup followed by flash chromatography on silica gel
(petroleum ether 40−60/EtOAc from 100:0 to 90:10) gave compound
42 (0.788 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.1 Hz,
2H), 7.10 (d, J = 7.1 Hz, 2H), 6.94 (d, J = 6.7 Hz, 2H), 6.79 (d, J = 7.3
Hz, 2H), 4.81 (s, 2H), 3.95 (s, 3H), 3.74 (d, J = 30.9 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 169.6, 161.6, 159.0, 130.6, 130.0, 127.9, 125.4,
113.4, 112.5, 99.1, 71.3, 54.9, 54.8, 52.2; ES/MS 376 [M + Na]+. Anal.
Calcd for C20H19NO5 C, 67.98; H, 5.42; N, 3.96. Found: C, 67.99; H,
5.39; N, 3.98.
Dipeptide 38, General Procedure. Compound 20 (46 mg, 0.1
mmol) was dissolved in DMF (1 mL) followed by H-Ala(O-t-Bu) (73
mg, 0.5 mmol) and NMM (100 mg, 1 mmol). To this solution was
added DMTMM-Cl (138 mg, 0.5 mmol) and the mixture stirred at rt for
6 h. Then CHCl3 (5 mL) was added and the organic phase washed with a
solution of HCl 1 M, (2 × 2 mL), NaHCO3 1 M (4 × 2 mL), water (2
mL) and brine (2 mL). The organic phase was separated and dried over
anhydrous Na2SO4 and the solvent evaporated. Column chromatog-
raphy (petroleum ether 40−60/EtOAc 40:60 to EtOAc/MeOH 98:2)
1
gave compound 38 (42 mg, 71%) as a waxy material: H NMR (400
MHz, CDCl3) δ 7.55−7.13 (m, 10H), 6.67−6.52 (m, 1H), 5.10 (d, J =
7.8 Hz, 1H), 4.40 (d, J = 6.9 Hz, 1H), 3.95 (s, 4H), 3.80−3.62 (m, 1H),
1.59−1.32 (m, 18H), 1.31 (d, J = 6.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 173.3, 164.9, 159.1, 152.8, 150.5, 139.4, 138.8, 129.3, 128.9,
128.5, 127.9, 127.8, 122.0, 80.2, 78.8, 65.0, 55.9, 52.0, 51.1, 32.1, 25.4,
25.4, 25.3, 25.1 (3C), 25.0 (3C), 25.05, 18.94; HRMS (ESI) m/z calcd
for C31H39N5O7Na+ 616.2748, found 616.2744.
I
DOI: 10.1021/jo502577e
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Article
Triazole Amide 45. To aryl azide 43 (186 mg, 0.5 mmol) dissolved
in dry DMF (2.5 mL) at rt was added compound 42 (160 mg, 0.45
mmol). The flask was subjected to three vacuum−nitrogen cycles, then
(Cp*RuCl)4 (24 mg, 0.022 mmol) was added followed by three other
vacuum−nitrogen cycles. The reaction was stirred at room temperature
until completion (monitored by TLC, 2 h). EtOAc and water were then
added. The organic phase was extracted four times with EtOAc, washed
with water (three times) and brine (one time), and dried over Na2SO4;
the solvent was removed, and the mixture was purified by passage on a
shorth path of silica. The crude was dissolved in EtNH2 (2.0 mL of a
solution 2 M in MeOH), and the mixture was heated for 24 h at 80 °C in
a sealed tube. The solvent and the excess of amine were removed under
reduced pressure, and the residue was submitted to column
chromatography (petroleum ether 40−60/EtOAc 60:40). Compound
45 was obtained as a purple oil with a tendency to solidify on standing
(175 mg, 55%). An analytical sample was obtained by crystallization
from MeOH/water: mp 96−98 °C; 1H NMR (400 MHz, CDCl3) δ 8.92
(dd, J = 20.7, 5.1 Hz, 1H), 8.44−8.17 (m, 2H), 7.51 (dd, J = 21.6, 7.3 Hz,
7H), 7.40−7.05 (m, 10H), 7.01 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.7 Hz,
2H), 6.29 (s, 1H), 5.53 (s, 2H), 5.15−4.91 (m, 4H), 3.93 (s, 3H), 3.78
(s, 3H), 3.51 (q, J = 7.2 Hz, 2H), 3.35 (d, J = 6.9 Hz, 1H), 1.32−1.01 (m,
9H); 13C NMR (101 MHz, CDCl3) δ 162.4, 160.0, 138.7, 138.2, 133.9,
133.0, 128.8, 128.4, 128.1, 127.2, 126.2, 124.4, 82.7, 65.7, 61.5, 58.7,
51.7, 51.4, 34.5, 27.2; MS-ESI 764 [M + MeOH + Na]+. Anal. Calcd for
C43H43N5O5: C, 72.76; H, 6.11; N, 9.87. Found: C, 72.79; H, 6.09; N,
9.86.
Amidotriazolylamide 41. Compound 45 (150 mg, 0.211 mmol)
was dissolved in EtOH (5 mL), and Pd(OH)2/C (10 mg of a 10%
dispersion on C, 0.01 mmol) was added. The mixture was stirred under
an atmosphere of hydrogen (balloon) for 5 h while the reaction progress
was monitored by TLC. The catalyst was filtered off through Celite, and
the ethanol was removed under reduced pressure. The residue was
dissolved in a mixture of DCM/water 3/1 (2 mL), DDQ (95 mg, 0.42
mmol) was added, and the mixture was stirred for 3 h at rt. The solvent
was evaporated and the residue submitted to flash chromatography
(DCM/MeOH, 90/10) to give 41 as a waxy material (24 mg, 26%
yield): 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 8.8 Hz, 2H), 7.10 (s,
1H), 6.95 (d, J = 8.8 Hz, 2H), 6.46 (s, 1H), 3.82 (s, 3H), 3.40 (d, J = 7.3
Hz, 2H), 3.24−3.06 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.13 (d, J = 6.8 Hz,
6H); 13C NMR (100 MHz, CD3OD) δ 162.9, 156.7, 152.2, 149.8, 145.2,
133.8, 129.2, 126.6, 125.9, 124.5, 124.2, 113.8, 113.1, 102.1, 54.2, 33.2,
25.7, 21.2, 13.2; HRMS (ESI) m/z calcd for C22H25N5O5Na+ 462.1754,
found 462.1751.
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ASSOCIATED CONTENT
* Supporting Information
■
S
General description of modeling studies, HPLC conditions for
control of stereochemical integrity of compounds 20, 21, 32, 33,
and 36, ORTEP diagram of 39, and spectra of compounds 10−
21, 25−42, and 45. This material is available free of charge via the
Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*Tel: +300577234275. Fax: +390577234333. E-mail: maurizio.
taddei@unisi.it.
■
(12) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007, 2420−
2422. (b) Zhang, X.; Li, H.; You, L.; Tang, H.; Hsung, R. P. Adv. Synth.
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Notes
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2008, 130, 8923−8930. (c) Oppilliart, S.; Mousseau, G.; Zhang, L.; Jia,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
G.; Thuery, P.; Rousseau, B.; Cintrata, J. C. Tetrahedron 2007, 63,
8094−8098.
We thank Dr. Loredana Vesci and Dr. Massimo Castorina
(Sigma-tau Italia, Pomezia) for the biological data and Dr. Gilles
Pain (Sigma-tau Italia, Pomezia) for critical revision of the
manuscript. This work was supported by grants from Sigma-Tau
Research Switzerland S.A. (Dr. Alessandro Noseda). Financial
support from MIUR (Rome, PRIN project 2009RMW3Z5_006)
is also acknowledged.
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triazole carrying the nitrogen substituent in position 4.
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from the racemic amino acids.
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substituent on the nitrogen linked to position 5.
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K
DOI: 10.1021/jo502577e
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