Silver-Catalyzed Three-Component 1,1-Aminoacylation of Homopropargylamines: α-Additions for Both Terminal Alkynes and Isocyanides

Article abstract of DOI:10.1002/anie.201704727

The reaction of secondary homopropargylamines, isocyanides, and water in the presence of a catalytic amount of silver acetate and subsequent purification by chromatography on silica gel afforded substituted proline amides in good to excellent yields. Primary homopropargylamines underwent a cyclizative Ugi–Joullié three-component reaction with isocyanides and carboxylic acids to afford functionalized N-acyl proline amides. High diastereoselectivity was observed in the synthesis of 4-alkoxy and 4,5-disubstituted proline derivatives. This work represents the first examples of a three-component cyclizative 1,1-aminoacylation of terminal alkynes.

Full text of DOI:10.1002/anie.201704727

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Silver-Catalyzed Three-Component 1,1-Aminoacylation of
Homopropargylamines: Dual -Additions between Terminal
Alkynes and Isocyanides
Authors: Shuo Tong, Cyril Piemontesi, Qian Wang, Mei-Xiang Wang,
and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704727
Angew. Chem. 10.1002/ange.201704727
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10.1002/anie.201704727
Angewandte Chemie International Edition
COMMUNICATION
Silver-Catalyzed Three-Component 1,1-Aminoacylation of
a
Homopropargylamines: Dual -Additions between Terminal
Alkynes and Isocyanides
Shuo Tong,+ Cyril Piemontesi,+ Qian Wang, Mei-Xiang Wang and Jieping Zhu*
Abstract:
Reaction
of
secondary
homopropargylamines,
and are key structural units of a number of pharmaceuticals.[9]
isocyanides and water in the presence of a catalytic amount of silver
acetate followed by silica gel chromatography purification afforded
substituted proline amides in good to excellent yields. Primary
homopropargylamines underwent cyclizative Ugi-Joullié three-
component reaction with isocyanides and carboxylic acids to afford
functionalized N-acyl proline amides. High diastereoselectivity was
observed in the synthesis of 4-alkoxy and 4,5-disubstituted proline
derivatives. This represented the first examples of three-component
cyclizative 1,1-aminoacylation of terminal alkynes.
Odom and co-workers: Iminoamination of alkynes
R1
Ti(NMe2)2(dpma)
(0.1 equiv)
R2NH2
H
R2N
R1
eq 1
+
C
toluene, 100 °C
RNC
NHR
1
Fukumoto and co-workers: Silylimination of alkynes
R1
Rh4(CO)12
(0.015 equiv)
HSiR2
3
RN
H
R1
eq 2
+
SiR2
H
THF, 70 °C
3
RNC
2
This work: 1,1-Aminoacylation of alkynes
R2
O
RNC
AgOAc (0.1 equiv)
toluene, 40 °C
NHR2
N
Both terminal alkynes and isocyanides are popular substrates in
the development of novel multicomponent reactions (MCR).[1] It
is therefore interesting to note that combination of these two
building blocks has rarely been exploited.[2] Odom and co-
workers reported a titanium-catalyzed three-component reaction
of terminal alkynes, isocyanides and amines for the synthesis of
a,b-unsaturated b-iminoamines 1 (Scheme 1, eq 1),[3] while
Fukumoto and co-workers developed a Rh-catalyzed three-
component coupling of alkynes, isocyanides and silanes for the
synthesis of 4-silyl-1-azadienes 2 (eq 2).[4] In both cases,
isocyanide and another nucleophile added across the triple bond
affording 1,2-difunctionalized products.
4
R1
+
+
eq 3
eq 4
NHR
R1
H2O
then FCC on SiO2
5 R = 4-silyloxy, d.r. > 19:1
3
6
R3
O
RNC
R2
R1
O
NH2
AgOAc (0.1 equiv)
toluene, 40 °C
N
R2
4
NHR
R3COOH
R1
8 major diastereoisomer
7
N
Ag+
H2O (RCOOH)
NR
We report herein a silver acetate-catalyzed four-center
three-component reaction of secondary homopropargyl amines
3, isocyanides 4 and water for the synthesis of functionalized N-
aryl(alkyl)-proline amides 5 (eq 3). Under slightly modified
conditions, primary homopropargyl amines 6 underwent Ugi-
Scheme 1. Reaction of terminal alkynes with isocyanides: 1,2- vs 1,1-
difunctionalization of alkynes. Abbrev. FCC = Flash Column Chromatography
Homopropargyl amine 3a (R1 = R2 = Ph, R3 = H) and tert-
butylisocyanide (4a) were chosen as test substrates (Scheme 2).
To channel the reaction towards the planned pathway,
competitive insertion of isocyanide 4a to the N-H bond of 3a
leading to amidine has to be avoided.[10] While many transition
metals promote this transformation efficiently,[11] we have
recently shown that silver salt, due to its high alkynophilicity,
preferred to coordinate to triple bond of the propargylamine
inhibiting therefore the N-H insertion process.[12] To our delight,
reaction of 3a and 4a in toluene in the presence of AgOTf
afforded indeed the proline amide 5a (16%) resulting from a
formal 1,1-gem difunctionalization of the terminal alkyne.
Systematic survey of reaction conditions varying the silver salt,
the solvent, the temperature allowed us to obtain 5a in 82% yield
(d.r. 1/1) under following optimized conditions: AgOAc (0.1
equiv), toluene, 40 °C, then FCC on SiO2 (See SI for details).
Joullié multicomponent reaction[5] with isocyanides
4 and
carboxylic acids 7 to afford N-acyl proline derivatives 8 in
excellent yields and diastereoselectivities (eq 4). In this process
of 100% atom efficiency, alkyne and isocyanide underwent
unprecedented dual a-additions at their terminal carbons with
concurrent formation of two C-N, one C-C and one C-O bonds
(eq 4). Although oxidative functionalization of terminal alkynes
via metal vinylidene intermediates is well developed,[6] the
transformation involving cyclizative 1,1-aminoacylation of
terminal alkyne (eq 3, 4) is, to the best of our knowledge,[7]
unknown. Proline derivatives 5/8 are useful building blocks for
the synthesis of conformationally constrained peptidomimetics[8]
[*]
Dr. S. Tong,+ C. Piemontesi,+ Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
These authors contributed equally to this work
Prof. Dr. M.-X. Wang
Laboratory of Bioorganic Phosphorous Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084 (China)
This novel cyclizative 1,1-difunctionalization of terminal
alkynes was applicable to a wide range of substrates (Scheme
2). The reaction was insensitive to the electronic nature of the
aromatic ring attached to the Ca position of the propargylamines
(5a-5e). Carboxamide (5k) and alkyl groups (5l, 5m) were also
tolerated at this position. Both N-aryl (5f-5i) and N-alkyl (5j, 5r)
substituted secondary amines participated in the reaction. In
addition to tert-butylisocyanide (4a), secondary isocyanide (5n)
and arylisocyanides (5o-5q) were equally effective reaction
[+]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201704727
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COMMUNICATION
partners. Tri- and tetra-substituted proline amides (5r, 5s) as
well as tricyclic compound 5t were accessible. Finally,
performing the reaction of 3a (1.2 g) with 4a in gram scale
provided 5a in a slightly higher yield (85%). The stereochemistry
Interestingly, the reaction of 1-(arylamino)but-3-yn-2-ol with
4a afforded 4-alkoxy proline amides (5u-5y) with excellent
diastereoselectivity (d.r. > 19:1, Scheme 3). While low yield was
obtained with free alcohol 5u, the 4-silyloxy proline amides (5v-
5y) were isolated in very good yields. The Ugi’s[14] and
Linderman’s[15] convertible isocyanides participated in the
reaction to afford 5z and 5aa, respectively, in excellent yields
of cis-5d was determined by X-ray structure analysis.[13] The H
NMR spectra of cis- and trans-5d were significantly different.
Since this difference was preserved in all this series of
compounds, their stereochemistry was assigned accordingly.
1
and diastereoselectivities (d.r.
>
19:1). The 2,4-cis-
stereochemistry was determined by X-ray structure analysis of
5ac obtained by the TBAF-mediated desilylation of 5x.[13] The
hydroxyl group was key to the observed high cis-selectivity since
cyclization of 1-(phenylamino)-2-methyl-but-3-yne afforded
trans-4-methyl proline amide 5ab as a major product (d.r. 2.5:1).
Compounds 5z and 5aa were converted to esters 5ad and 5ae,
respectively, increasing therefore the versatility of the present
reaction. Finally, the N-(4-methoxy)phenyl group of 5w was
removed to provide 5af in 98% yield, while the tert-butyl amide
can also be converted to primary amide (5ag) in excellent yield.
R2
R1 NHR2
a
]
a
Conditions[
N
R1
R3
R3
R3
CONHR
+
+
H2O
b
RNC
H
R3
H
3
4
5
R2
N
Ph
N
R1
Ph
CONHtBu
CONHtBu
5f R2 = 4-MeOC6H4, 48%
5g R2 = 4-ClC6H4, 93%
5h R2 = 3-ClC6H4, 86%
5i R2 = 2-MeC6H4, 55% cis only
5j R2 = Bn, 42%
5a R1 = Ph, 82%
5b R1 = 4-ClC6H4, 84%
5c R1 = 4-MeOC6H4, 77%
5d R1 = 2-BrC6H4, 88%, cis/trans = 1:2.4
5e R1 = 3-BrC6H4, 90%, cis/trans = 1:1.5
R3
O
Ph
Ph
N
Ph
O
N
R2
NH2
R
a
]
Conditions[
N
N
PhHNOC
CONHtBu
R2
CONHtBu
Ph
CONHR
R3COOH
+
+
R
R
RNC
N
R1
H
5n R = c-hexyl, 80%
5o R = 4-MeOC6H4, 72%
5p R = 2,4,6-(Me)3C6H2, 72%
5q R = 2,6-(Me)2C6H3, 72%
R1
b
5l R = H, 47%[
6
]
4
7
8
5k 69%, cis/trans = 2.2:1
c
5m R = Me, 65%[
]
R
R2
N
O
O
R
R1
N
CONHtBu
Ph
CONHtBu
N
Ph
CONHtBu
Me
Me
N
CONHtBu
R1
8d, R = CF3, R1 = CH3, 86%, d.r. 4:1
8e, R = CF3, R1 = iPr, 98%, d.r. 4:1
8f, R = CH3, R1 = iPr, 99%, d.r. 10:1
8g, R = Ph, R1 = iPr, 99%, d.r. 10:1
8a, R = CF3, 97%, d.r. 1:1
8b, R = CH3, 94%, d.r. 1:1
8c, R = Ph, 98%, d.r. 1:1
5r R1 = H, R2 = Bn, 78%[
5s R1 = R2 = Ph, 72%
c
]
5t 78%
O
O
Scheme 2. [a] Conditions: 3 (0.2 mmol), 4 (0.4 mmol), AgOAc (0.1 equiv),
toluene (2.0 mL, c 0.1 M), 40 °C, 30 h, then FCC on SiO2, d.r. 1:1 unless
otherwise specified. [b] 50 °C for 96 h. [c] 50 °C for 48 h.
O
N
Ph
O
N
H
Bn
Bn
N
Ph
N
H
COOMe
8h, 95%, d.r. 7:1
8i, 94%, d.r. 10:1
R2
N
O
NHR2
O
O
NHBoc
NHBoc
Conditions[a]
O
N
+
R
RNC
+
H2O
Ph
CONHtBu
Bn
N
H
N
R1O
Bn
OMe
Ph
N
H
R1O
3
4
5
8j, 91%, d.r. 5:1
O
R2
5u, R1= H, R2 = Ph, 34%
8k, 90%, d.r. 10:1
5v, R1 = TBS, R2 = Ph, 80%
N
CONHtBu
O
O
5w, R1 = TBS, R2 = 4-MeOC6H4, 62%
5x, R1 = TBS, R2 = 4-ClC6H4, 90%
5y, R1 = TIPS, R2 = Ph, 71%
R2
O
O
N
R1O
Ph
N
Ph
N
H
O
N
H
R2
Ph
OEt
O
O
O
OEt
N
N
N
CONHtBu
O
TBSO
N
H
N
H
O
8l, 92%, d.r. 5:1
8m, 95%, d.r. 3:1
TBSO
TBSO
Me
OTBS
5z, R2 = 4-ClC6H4, 80% 5aa, R2 = 4-ClC6H4, 85%
5ab, 62%[b]
Scheme 4. [a] Conditions: 6 (0.2 mmol), AgOAc (0.1 equiv), toluene (2.0 mL, c
0.1 M), 40 °C, 12 h then 4 (0.24 mmol), 7 (0.24 mmol), RT.
HO
TBSO
TBSO
N
Cl
N
Cl
N
Cl
CONHtBu
5ac 99%[c]
COOEt
5ad 72%[d]
O
O
We
next
turned
our
attention
to
primary
homopropargylamines 6.[16]
The Ugi-Joullié type three-
HO
TBSO
5ae 50%[e]
NH2
N
Cl
N
H
component reaction of 1-phenylbut-3-yn-1-amine (6a, R1 = H, R2
= Ph), tert-butylisocyanide (4a) and trifluoroacetic acid (7a)
under the above defined conditions did not produce the desired
proline derivatives. Competitive reactions such as protonation
and/or acylation of amine,[12b] the Lewis acid-catalyzed
condensation of 4a with 7a,[17] etc, could indeed hamper the
occurrence of the desired reaction pathway. A series of control
experiments (See SI) have been performed. The results clearly
indicated that the protonation of amine by carboxylic acid was
responsible for the failure of the reaction. Therefore, the addition
CONH2
5ag 98%[g]
CONHtBu
5af 98%[f]
Scheme 3. [a] Conditions: 3 (0.2 mmol), 4 (0.4 mmol), AgOAc (0.1 equiv),
toluene (2.0 mL, c 0.1 M), 40 °C then FCC on SiO2, d.r. > 19:1 unless
otherwise specified. [b] d.r. 2.5:1. [c] 5x, TBAF in THF, RT. [d] 5z, KOtBu, THF,
RT. [e] 5aa, HCl in MeOH, RT. [f] 5w, CAN, MeCN/H2O (4:1), RT. [g] 5ac,
BF3•Et2O, ClCH2CH2Cl, reflux.
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order was readjusted. Gratefully, simply heating a toluene
solution of 6a with AgOAc (0.1 equiv) at 40 °C for 12 h followed
by addition of 4a and 7a at room temperature afforded the three-
component adduct 8a in 97% isolated yield. The protocol was
applicable to a wide range of substrates (Scheme 4). Enantio-
enriched primary homopropargylamines (ee 99%), easily
n(NºC)coord - n(NºC)free = 61 cm-1].[17] However, no insertion of
isocyano group to NH bond was observed in accordance with
the high alkynophilicity of the silver complex. The pre-
synthesized (tBuNC)AgOAc (10) has exactly the same catalytic
activity as AgOAc.
On the basis of the aforementioned experimental results, a
possible reaction pathway is presented in Scheme 6. In situ
formation of silver complex (tBuNC)AgOAc (10) followed by its
chemoselective coordination to the triple bond of 3 would
produce A. A 5-endo-dig cyclization would then generate a
vinylsilver species B[21] that would be in equilibrium with iminium
salt C. Removal of silver from the latter would produce
dihydropyrrole 9 with concurrent regeneration of catalyst 10. The
reaction stopped evolving in the flask but once the crude
reaction mixture was submitted to FCC on silica gel, the reaction
between 9 and isocyanide occurred via iminium intermediate D.
Thus, nucleophilic addition of isocyanide 4 to D would produce
the nitrilium intermediate E, which upon trapping by water and
tautomerization would produce the observed proline amide 5.
We note that in the case of the primary homopropargyl amines,
the sequence of cyclization/Ugi-Joullié three-component reaction
took place in the same flask.
accessible by
a
proline-catalyzed Mannich reaction,[18]
participated in the reaction to afford the proline amides without
erosion of the enantiopurity (8d-8m). In addition to simple
tertiary (8a-8g, 8j) and primary isocyanides (8h), isocyanides
derived from amino acids (8i, 8k) as well as convertible
isocyanides (8l, 8m) took part in the reaction to afford the
corresponding N-acyl 4,5-disubstituted proline derivatives in
excellent yields with good to high diastereoselectivities. Besides
simple acids (R = CF3, CH3, Ph), N-protected amino acids
participated equally well to afford dipeptide 8j and tripeptide 8k
in excellent yields and diastereoselectivities (d.r. 10:1).
Monitoring the reaction of secondary propargylamine 3a and
4a under standard conditions by TLC indicated a clean formation
of one major product, which has later been identified as proline
amide 5a. However, the same reaction afforded, after
conventional aqueous work-up, a complex mixture containing
only a trace amount of 5a based on both TLC and NMR analysis.
On the other hand, loading the reaction mixture directly on a
silica gel column without evaporation of solvent afforded, after
FCC (eluent: petroleum ether/EtOAc), compound 5a in 82%
isolated yield. To understand this unusual phenomenon, the
AgOAc-catalyzed reaction of homopropargylamine 3a with
mesitylisocyanide (4b) in deuterated toluene was monitored by
1H NMR spectroscopy. The result, together with those of other
control experiments (see SI), allowed us to conclude that the
formation of 5p went through two phases: a AgOAc-catalyzed 5-
endo-dig cyclization of homopropargyl amine 3a in the reaction
flask and an on-column truncated Ugi reaction of dihydropyrrole
9a with isocyanide and water (Scheme 5).
NHR2
3
AgOAc
(RNC)AgOAc
RNC
+
R1
4
10
Ag(CNR)OAc
R2
A
R2
R2
AcO–
Ag(CNR)OAc
H
AcO–
N
N
N
10
R1
R1
R1
Ag(CNR)
Ag(CNR)
B
C
9
In the flask
FCC on SiO2
R2
O
N
R2
N
X-
R2
N
H2O
NR
RNC
4
NHR
R1
Ph
R1
R1
Ph
N
Ph
N
5
E
D
a
b
NHPh
+
Mesityl-NC
Ph
Ph
CONHMesityl
5p
3a
4b
Scheme 6. Pathway leading to 1,1-difunctionalization of terminal alkynes.
9a
Scheme 5. NMR monitoring of reaction pathway. [a] AgOAc (0.1 equiv),
R2
toluene-d8, 40 °C. [b] FCC on SiO2 (petroleum ether/EtOAc = 8:1).
R2
R2
N
N
CONHR
R1O
N
OR1
G
R1O
Silica gels from different sources worked well for this
purpose (See SI). However, FCC of the reaction mixture on Et3N
pretreated silica gel failed to provide proline amide 5a, indicating
the importance of the acidity of SiO2 in promoting the on-column
Ugi reaction. The temporary separation of enamine 9a and its
iminium form during FCC on silica gel might avoid the
dimerization/oligomerization of enamine 9a,[19] providing
therefore high yield of proline amide 5a. The use of columns
packed with silica gel supported reagent/catalyst have been
developed into a useful synthetic technology.[20] However, on-
column multicomponent reaction is, to the best of our knowledge,
unprecedented.
CNR
F
5
Scheme 7. Rational for the highly diastereostereoselective synthesis of 4-
alkoxy proline amides.
Following
this
mechanistic
hypothesis,
the
high
diastereoselectivity observed with the 1-(arylamino)but-3-yn-2-ol
could be accounted for by invoking the preferred conformation of
iminium intermediate G in which the alkoxy group adopted a
pseudoaxial position.[22] Inside attack of nucleophile would then
afford 2,4-cis proline derivatives (Scheme 7).[23] On the other
hand, addition of isocyanide to the iminium derived from
enamine 9a (cf Scheme 5) is known to be non-stereoselective.[5c]
Several isocyanide-ligated silver salts were synthesized and
spectroscopically characterized (See SI). For (tBuNC)AgOAc
(10), the shortened bond length of NºC, hence the increased
electrophilicity of the isocyano group, is evident from its higher
While Ag-catalyzed 5-endo-dig cyclization of N-Ts
propargylamine leading to dihydropyrrole has been reported,[24]
cyclization of N-arylated counterparts needed in general a
NºC vibrational frequency [2195 cm-1 vs 2134 cm-1, ∆nNC
=
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10.1002/anie.201704727
Angewandte Chemie International Edition
COMMUNICATION
2013, 42, 4867; d) T. Vlaar, E. Ruijter, B. U. W. Maes, R. V. A. Orru,
Angew. Chem. 2013, 125, 7222; Angew. Chem. Int. Ed. 2013, 52, 7084.
[12] a) S. Tong, Q. Wang, M.-X. Wang, J. Zhu, Angew. Chem. 2015, 127,
1309; Angew. Chem. Int. Ed. 2015, 54, 1293; b) S. Tong, Q. Wang, M.-
X. Wang, J. Zhu, Chem. Eur. J. 2016, 22, 8332; c) For related
transformation catalyzed by Brønsted acid, see: O. Ghashghaei, M.
Revés, N. Kielland, R. Lavilla, Eur. J. Org. Chem. 2015, 4383.
[13] CCDC 1059103 (cis-5d) and 1546339 (5ac) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
stoichiometric amount of silver salt to afford directly N-arylated
pyrrole due to the in situ oxidation of the dihydropyrrole to
pyrrole.[25-27] However, this was not happening in our case. We
assumed that the presence of isocyanide in the reaction mixture
has effectively bypassed this undesired side reaction leading
efficiently to N-arylated dihydropyrrole.
In summary, we developed
a AgOAc-catalyzed three-
component reaction of homopropargylamines, isocyanides and
water or carboxylic acids for the synthesis of substituted proline
amides. The 1,1-gem aminoacylation of terminal alkyne was
accomplished by way of an unprecedented dual a-additions
between the terminal alkyne and the isocyano carbon. That an
alkyne function can act as a surrogate of a carbonyl group would
without doubt increase further the application scope of the
Passerini and Ugi type multicomponent reactions.[28]
[14] T. Lindhorst, H. Bock, I. Ugi, Tetrahedron 1999, 55, 7411.
[15] R. J. Linderman, S. Binet, S. R. Petrich, J. Org. Chem. 1999, 64, 336.
[16] Silver-salt catalyzed terminal homopropargyl amines is to be the best of
our knowledge unknown. For internal alkynes, see: B. C. J. van
Esseveldt, P. W. H. Vervoort, E. L. van Delft, F. P. J. T. Rutjes, J. Org.
Chem. 2005, 70, 1791.
[17] Y. Odabachian, S. Tong, Q. Wang, M.-X. Wang, J. Zhu, Angew. Chem.
2013, 125, 11078; Angew. Chem. Int. Ed. 2013, 52, 10878.
Acknowledgements
[18] J. W. Yang, M. Stadler, B. List, Nat. Protocol 2007, 2, 1937.
[19] a) J. M. Matsen, J. W. Harding, E. M. Magee, J. Phy. Chem. 1965, 69,
522; b) A compound resulting from the dimerization of dihydropyrrole
6a followed by truncated Ugi reaction was isolated in some of these
control experiments (cf Supporting information)
Financial supports from EPFL (Switzerland), Swiss State
Secretariat for Education and Research (SER), the Swiss
National Science Foundation (SNSF) and National Natural
Science Foundation of China (21320102002, 21502202) are
gratefully acknowledged. We thank Dr. F.-T. Farzaneh and Dr.
R. Scopelliti for X-ray crystallographic analysis of cis-5d, 5ac.
[20] For examples of on-column reactions promoted by silica gel-supported
Brønsted acid, see: a) Y. Shimoda, H. Yamamoto, Tetrahedron Lett.
2015, 56, 3090; b) silica gel-supported H5IO6 for the cleavage of diols,
S. C. Dakdouki, D. Villemin, N. Bar, Eur. J. Org. Chem. 2012, 780.
[21] For a comprehensive review on the cyclization of alkynes, see: K.
Gilmore, I. V. Alabugin, Chem. Rev. 2011, 111, 6513.
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10.1002/anie.201704727
Angewandte Chemie International Edition
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Synthetic Method
O
BocHN
Ph
BocHN
COOH
NH2
O
OMe
Bn
Shuo Tong,+ Cyril Piemontesi,+ Qian
Wang, Mei-Xiang Wang and Jieping
Zhu*__________ Page – Page
AgOAc (0.1 equiv)
Toluene, 40 °C
HN
N
O
Ph
+
Bn
CN
Bn
O
OMe
Bn
90%, d.r. 10:1
Silver-Catalyzed Three-Component 1,1-
Aminoacylation of
Homopropargylamines: Dual -
a
Additions between Terminal Alkynes
and Isocyanides
No Atom Lost. Reaction of homopropargylamines with isocyanides and carboxylic acids or water in the
presence of a catalytic amount of silver acetate afforded substituted proline amides in good to excellent
yields.
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