Highly efficient synthesis of α-amino amidines from ynamides by the Cu-catalyzed three-component coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2008.01.073

Using ynamides as one of the reacting components, the Cu-catalyzed three-component reaction of sulfonyl or phosphoryl azides and amines affords α-amino amidines in high yields under mild conditions. Synthetic utility of the produced compounds was demonstr

Full text of DOI:10.1016/j.tetlet.2008.01.073

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1745–1749
Highly efficient synthesis of a-amino amidines from ynamides
by the Cu-catalyzed three-component coupling reactions
Ji Young Kim, Seok Hwan Kim, Sukbok Chang *
Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and School of Molecular Science (BK21), Korea
Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
Received 16 December 2007; revised 13 January 2008; accepted 17 January 2008
Available online 20 January 2008
Abstract
Using ynamides as one of the reacting components, the Cu-catalyzed three-component reaction of sulfonyl or phosphoryl azides and
amines affords a-amino amidines in high yields under mild conditions. Synthetic utility of the produced compounds was demonstrated in
the diastereoselective alkylation of a-amino amidines bearing a chiral oxazolidinone moiety. It was also shown that a-amino imidates
could be readily prepared by employing alcohols instead of amines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: a-Amino amidines; Ynamides; Three-component reactions; Copper catalysis
a-Amino amidines are widely found in natural pro-
ducts,1 and used as important synthetic building units in
the synthesis of iminopeptides2 and antitumor or antibiotic
compounds.3 However, only a few synthetic methods for
the a-amino amidine compounds have been developed.4
For instance, Keung et al. presented a novel procedure
for the synthesis of a-amino amidine via Sc-mediated Ugi
condensation reactions.4c We recently developed the
three-component synthesis of N-sulfonylamidines by the
copper-catalyzed coupling reaction of alkynes, sulfonyl
azides, and amines.5 Imidates and amides were also pre-
pared under the similar conditions with the use of alcohols6
or water7 instead of amines. More recently, phosphoryl
azides were also found to be a facile reacting partner in
the catalytic three-component reactions.8
lyzed [3+2] cycloaddition reactions between ynamides and
alkyl- or aryl azides producing 4-amino-1,2,3-triazoles.9
However, no example of utilizing ynamides in the catalytic
three-component coupling reactions has been shown to
afford a-amino amidines, which will be described herein
(Scheme 1).
Since ynamides or ynamines bearing electron-deficient
substituents have been shown to be highly useful synthetic
precursors,10–12 several preparative routes are reported.
For instance, Witulski paved the way for the synthesis of
electronically tunable 1-alkynylamides using iodonium tri-
flate salts in reaction with electron-deficient amines.13
Hsung demonstrated that N-alkynylation of oxazolidinon-
es and lactams with alkynyl halides can be catalyzed by
CuCN.14 Danheiser developed a modified procedure of
N-alkynylation of carbamates, ureas, and sulfonamides
Along with this line, we envisioned that a-amino
amidines could be readily prepared by the Cu-catalyzed
three-component coupling reactions when ynamides are
employed as a source of terminal triple bonds. Hsung and
Cintrat independently reported the highly efficient Cu-cata-
R4
R1
H
N
cat. CuI
R1
N
R3 N3
N
N
R5
R4
R5
R2
R2
NR3
(R3: sulfonyl
phosphoryl)
*
Corresponding author. Tel.: +82 42 869 2841; fax: +82 42 869 2810.
Scheme 1.
E-mail address: sbchang@kaist.ac.kr (S. Chang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.073

1746
J. Y. Kim et al. / Tetrahedron Letters 49 (2008) 1745–1749
using stoichiometric amounts of KHMDS and CuI.15
Urabe and Sato reported a route to N-(1-alkynyl)sulfon-
amides based on the Cu catalysis.16 Hsung’s approach for
the cross-coupling of amides with alkynyl bromides using
catalytic amounts of CuSO4 and 1,10-phenanthroline
significantly broadened the availability of ynamides.17
Tam subsequently developed a method for the facile syn-
thesis of acyclic ynamides by the slow addition of KHMDS
to CuI catalytic systems.18
Table 1
Optimization of the a-amino amidine synthesisa
Ph
Boc
N(iPr)2
Boc
Ph
catalyst
N
Ts N3
(iPr)2NH
N
solvent
25 oC, 6 h
N
(1)
Ts
Entry
Catalyst
CuCl
Solvent
Yieldb (%)
1
2
3
THF
35
<1
78
80
53
59
<1
66
82
66
43
71
62
74
CuBrꢀSMe2
THF
THF
CuI
Following Tam’s procedure with a slight modification,
we were able to prepare a variety of ynamides in high yields
substituted with several functional groups such as oxazo-
lidinones, acyclic carbamates, and sulfonamides. A repre-
sentative example is shown in Scheme 2. Cross-coupling
of N-Boc-aniline and bromo(triisopropylsilyl)acetylene,
which can be obtained by bromination of TIPS-acetylene
with NBS,19 was successfully achieved by the action
of CuI and 1,10-phenanthroline catalysts under the slow
addition conditions.20 Subsequent desilylation was readily-
carried out with tributylammonium fluoride, thus leading
to the desired N-ethynyl-N-phenyl-(tert-butyl) carbamate
(1) in 80% overall yield. Other substrates of ynamide deriva-
tives could be readily prepared in similar yields using the
same procedure.
4
5
6
7
8
9
10
11
12
13
14c
a
CuCN
Cu(acac)2
Cu(OAc)2
Cu(OTf)2
CuI
CuI
CuCN
CuI
THF
THF
THF
THF
CH2Cl2
CHCl3
CHCl3
DMF
CH3CN
CuI
CuI
CuI
1,4-Dioxane
CHCl3
A mixture of p-toluenesulfonyl azide (0.6 mmol), 1 (0.5 mmol), diiso-
propylamine (0.6 mmol), and Cu catalyst (10 mol %) in solvent (1.0 mL)
was stirred at 25 °C for 6 h.
b
H NMR yield (internal standard: 1,3-benzodioxole).
20 Mol % of tris(benzyltriazolylmethyl)amine was added.
c
With ynamides in our hands, we tried to optimize
the reaction conditions for the synthesis of a-amino
amidines using the Cu-catalyzed three-component reaction
(Table 1). Initially, catalytic activity of various Cu species
was examined in THF to reveal that CuI and CuCN were
especially effective for the three-component reaction, lead-
ing to the desired product with high yields (entries 3 and 4,
respectively). However, copper(II) complexes displayed
reduced catalytic activities (entries 5–7). Among several
solvents screened, chloroform turned out to be the best
one with CuI catalyst (entry 9) while polar media were less
effective (entries 11–13). Interestingly, no significant effects
of external ligands were observed (entry 14).21,22
Under the optimized conditions, a wide range of
ynamides, azides, and amines were smoothly reacted to
afford the corresponding a-amino amidine products in
good yields (Table 2).23 In addition to acyclic N-ethynyl
carbamate (entry 1), cyclic analogs such as ynamides of
oxazolidinone could also be readily employed as a viable
type of substrates (entries 2–5). Interestingly, steric varia-
tion on the cyclic skeleton in these substrates does not alter
efficiency of the coupling reactions. For instance, reactions
with substrates bearing various substituents such as benzyl,
isopropyl, or tert-butyl group on the 4-position of oxazo-
lidinone provided the corresponding products with high
yields in all cases (entries 3–5, respectively). N-Sulfonamido
acetylene was also employed as a substrate to afford a-
sulfonamido amidine in a moderate yield (entry 6).
It was revealed that, like arenesulfonyl azides,
alkylsulfonyl azides were also smoothly reacted leading to
N-alkylsulfonyl amidines in high yields as demonstrated
in entry 7. We were pleased to observe that phosphoryl
azides displayed similar reactivity with ynamides to afford
the corresponding a-amino-N-phosphoryl amidines in
excellent yields (entries 8 and 9). It should be mentioned
that the scope of amine species was very broad. Aniline
derivatives as well as aliphatic amines were shown to be
efficiently coupled in the presence of triethylamine (entry
10). Primary amines and amino esters were also readily
employed in this coupling (entries 11 and 12, respectively).
The produced a-amino amidine compounds can be
regarded as a-amino acid isosteres. For further synthetic
applications, asymmetric alkylation of optically active
a-amino amidines was next investigated (Table 3). It was
especially interesting to see any steric influence of 4-substi-
tuents of the oxazolidinone skeleton on the diastereoselec-
tivity during the alkylation process.24 After examining
various reaction conditions, it was found that deprotona-
tion of the chiral a-amino amidines with LHMDS (in
THF) followed by alkylation with electrophiles provided
monoalkylated products in moderate to good chemical
yields.
Ph
Boc
Ph
Boc
H
Br
N
N
a
b
c
95%
90%
94%
Si(iPr)3
Si(iPr)3
Si(iPr)3
H
(1)
Scheme 2. Reagents and conditions: (a) N-Bromosuccinimide (1.2 equiv),
AgNO3 (0.1 equiv), acetone, 25 °C, 2 h; (b) N-Boc-aniline (0.8 equiv), CuI
(0.25 equiv), 1,10-phenanthroline (0.3 equiv), KHMDS (1.1 equiv), tolu-
ene, 90 °C, 12 h; (c) TBAF (2.0 equiv), THF, 0 °C, 1 h.
Not surprisingly, the observed diastereoselectivity
turned out to be dependent on the steric environment on
the oxazolidinone moiety despite the fact that the extent

J. Y. Kim et al. / Tetrahedron Letters 49 (2008) 1745–1749
1747
Table 2
Cu-catalyzed three-component coupling reactions for the synthesis of a-amino amidinesa
R4
N
R1
R1
H
cat. CuI
CHCl3, 25 oC, 6 h
R3 N3
R5
N
N
N
R4
R5
R2
R2
N
R3
Entry
1
Ynamide
Azide
Amine
Yieldb (%)
82
O
Boc
N
S
N3
Me
(i-Pr)2NH
3
Ph
O
1
2
O
2
2
3
83
O
N
O
(R: Bn)
(R: i-Pr)
(R: t-Bu)
3
4
5
2
2
2
3
3
3
89
78
85
O
N
R
Ts
N
Et
6
7
2
3
3
65
90
O
1
1
Me
S
N3
O
O
8
9
3
3
90
86
P
N3
PhO
PhO
O
N3
1
P
O
O
10c
11
1
1
2
2
PhNHMe
i-PrNH2
87
75
CO2Me
NH2 / HCl
12c
1
2
74
a
Ynamide (0.5 mmol), azide (0.6 mmol), amine (0.6 mmol), and CuI (10 mol %) in CHCl3 (1.0 mL) at 25 °C for 6 h.
Isolated yield after column chromatography.
Et3N (1.2 equiv to alkyne) was added.
b
c
of stereoselectivity was not significantly changed. A moder-
LHMDS, are chelated to lithium metal to form a seven-
membered transition state during the a-alkylation process
(Fig. 1).25 Accordingly, the major diastereomer product is
predicted to form by the alkylation from the less congested
face of the proposed transition state.26
In addition to the synthesis of a-amino amidines, we
used ynamides as a coupling partner in the imidate-forming
reactions by employing alcohols instead of amines. We
were pleased to observe that imidates were readily pro-
duced under the similar conditions except that triethyl-
amine is required to complete the conversion. For
example, the Cu-catalyzed reaction of ynamide 1 with
ate diastereomeric ratio (2.7:1) was obtained from the
methylation reaction of a chiral a-amino amidine bearing
4-isopropyloxazolidinone moiety (entry 1). When the iso-
propyl group was replaced by a benzyl substituent, the cor-
responding diastereoselectivity was increased to 4.0:1 under
the identical conditions. This ratio was not further signifi-
cantly improved upon the introduction of tert-butyl substi-
tuent on the oxazolidinone (entry 3).
It is postulated that a carbonyl oxygen of oxazolidinone
ring and a nitrogen of sulfonenamido species, which is
generated upon deprotonation of a-amino amidine with

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J. Y. Kim et al. / Tetrahedron Letters 49 (2008) 1745–1749
Table 3
References and notes
a-Methylation of chiral a-amino amidine derivatives
1. Goto, T.; Isobe, M.; Coviello, D. A.; Kishi, Y.; Inoue, S. Tetrahedron
1973, 29, 2035.
Me
O
O
i) LHMDS (1.2 equiv)
THF, 25 oC, 2 h
N(iPr)2
N(iPr)2
Ts
N
N
2. For selected synthetic applications of a-amino amidines, see: (a)
Yamada, T.; Suegane, K.; Kuwata, S.; Watanabe, H. Bull. Chem.
Soc. Jpn. 1977, 50, 1088; (b) Yamada, T.; Takashima, K.; Miyazawa,
T.; Kuwata, S.; Watanabe, H. Bull. Chem. Soc. Jpn. 1978, 51,
878.
O
O
N
N
ii) MeI (8 equiv), 12 h
Ts
R
R
Entry
R
Yielda (%)
d.r.b
1
2
3
a
CH(CH3)2
CH2Ph
C(CH3)3
57
51
68
2.7:1
4.0:1
4.1:1
3. Umezawa, H.; Takita, T.; Sugiura, Y.; Otsuka, M.; Kobayashi, S.;
Ohno, M. Tetrahedron 1984, 40, 501.
4. For notable examples, see: (a) McFarland, J. W. J. Org. Chem. 1963,
28, 2179; (b) Tunge, J. A.; Czerwinski, C. J.; Gately, D. A.; Norton,
J. R. Organometallics 2001, 20, 254; (c) Keung, W.; Bakir, F.; Patron,
A. P.; Rogers, D.; Priest, C. D.; Darmohusodo, V. Tetrahedron Lett.
2004, 45, 733.
Isolated yield.
Diastereomeric ratio was determined by HPLC.
b
E+
5. (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038; (b)
Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S. K.
J. Am. Chem. Soc. 2006, 128, 12366.
6. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8,
1347.
7. (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005,
127, 16046; (b) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46,
1897.
8. Kim, S. H.; Jung, D. Y.; Chang, S. J. Org. Chem. 2007, 72,
9769.
E
O
N(iPr)2
N
major
O
O
N
N
N(iPr)2
LHMDS
O
Ts
R
N
O
O
N
R
N
Li
N
Ts
R
N(iPr)2
Ts
E
O
N(iPr)2
Ts
N
minor
O
E+
R
9. (a) Ijsselstijn, M.; Cintrat, J.-C. Tetrahedron 2006, 62, 3837; (b)
Zhang, X.; Hsung, R. P.; You, L. Org. Biomol. Chem. 2006, 4,
2679; (c) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007,
2420.
Fig. 1. Proposed transition state of the asymmetric a-alkylation.
p-toluenesulfonyl azide and methanol resulted in the corres-
ponding a-amino imidate in 60% yield (Eq. 1).
10. For recent reviews on ynamines and ynamides, see: (a) Zificsak, C. A.;
Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetra-
hedron 2001, 57, 7575; (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung,
R. P. Synlett 2003, 1379.
11. For a special issue on chemistry of electron-deficient ynamines and
ynamides, see: Tetrahedron 2006, 62, 3771–3938.
12. For recent reports on ynamides, see: (a) Couty, S.; Meyer, C.; Cossy,
J. Angew. Chem., Int. Ed. 2006, 45, 6726; (b) Dunetz, J. R.; Danheiser,
R. L. J. Am. Chem. Soc. 2005, 127, 5776; (c) Zhang, Y. Tetrahedron
Lett. 2005, 46, 6483.
13. Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489.
14. Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang,
J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003,
125, 2368.
Ph
Boc
Boc
Ph
CuI (10 mol %)
Et3N (1.2 equiv)
O
N
N
Me
Ts N3
MeOH
ð1Þ
N
(1.2 equiv)
(1.2 equiv)
Ts
CHCl3, 25 o
C
60%
(1)
In summary, we have demonstrated that ynamides can
be utilized as a new type of reacting partner in the Cu-cata-
lyzed three-component coupling reactions for the prepara-
tion of a-amino amidines and imidates. The substrate
scope is very broad including a wide range of ynamides,
sulfonyl or phosphoryl azides, and amines or alcohols.
Synthetic applicability of the produced a-amino amidines
was demonstrated by the diastereoselective a-alkylation.
15. Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
16. Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6,
727.
17. Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L.
Org. Lett. 2004, 6, 1151.
18. Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681.
19. For preparation of TIPS alkynyl bromides, see: Hofmeister, H.;
Annen, K.; Laurent, H.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1984, 23, 727.
Acknowledgments
This research was supported by the KOSEF grant (R01-
2007-000-10618-0), and KAIST through the URP (under-
graduate research program) and CMDS. The authors
thank Dr. Doo Young Jung for the initial experiments.
We also acknowledge the Korea basic science institute
(KBSI) for the mass analysis.
20. See the Supplementary data for details.
21. (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev.
2000, 100, 2159; (b) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev.
2000, 100, 3553.
22. (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853; (b) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed.
2006, 45, 3157.
23. General procedure for the synthesis of a-amino amidines: To a stirred
mixture of azide (0.6 mmol), ynamide (0.5 mmol), and CuI
(0.05 mmol) in CHCl3 (1 mL) was slowly added amine nucleophile
(0.6 mmol) at room temperature under an N2 atmosphere. Triethyl-
amine (0.6 mmol) was added after the addition of amine, if necessary
(entries 10 and 12 of Table 2). After 6 h, the reaction mixture was
diluted by adding CH2Cl2 (3 mL) and aqueous NH4Cl solution
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.01.073.

J. Y. Kim et al. / Tetrahedron Letters 49 (2008) 1745–1749
1749
(3 mL). The mixture was stirred for an additional 30 min and two
layers were separated. The aqueous layer was extracted with CH2Cl2
(3 mL ꢁ 3). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude residue was purified by
flash column chromatograph with an appropriate eluting solvent
system. Spectroscopic data for representative compound: N1,N1-
diisopropyl-N2-(diphenylphosphoryl)-2-[N-(1,1-dimethylethoxy)car-
bonyl-N-phenyl]amino acetamidine (Table 2, entry 8): light orange
liquid; isolated yield 90%; 1H NMR (400 MHz, CDCl3) d 7.31–7.23
(m, 4H), 7.21–7.13 (m, 5H), 7.05–6.99 (m, 6H), 5.10 (s, 2H), 4.32 (m,
1H), 3.34 (m, 1H), 1.35 (s, 9H), 1.16 (d, J = 6.5 Hz, 6H), 0.95 (d,
J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 163.5, 163.4, 154.1,
151.7, 151.6, 139.8, 129.1, 128.5, 127.4, 126.7, 123.8, 120.5, 81.1, 50.1,
49.7, 47.6, 28.0, 20.5, 19.2; IR (NaCl) m 2972, 1692, 1579, 1491, 1251,
1203, 1058, 921, 692 cmꢂ1; HRMS (FAB) m/z calcd for C31H41N3O5P
[M+H]+: 566.2784, found: 566.2781.
24. (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737; (b) Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.;
Mandel, G. J. Am. Chem. Soc. 1984, 106, 1154.
25. Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238.
26. For selected examples of cycloaddition reactions via 7-membered
chelating transition states, see: (a) Walters, M. A.; Arcand, H. R.
J. Org. Chem. 1996, 61, 1478; (b) MaGee, D. I.; Godineau, E.;
Thornton, P. D.; Walters, M. A.; Sponholtz, D. J. Eur. J. Org. Chem.
2006, 3667.