RuCl3-promoted amide formation from azides and thioacids

Article abstract of DOI:10.1016/j.tetlet.2003.10.054

Described here is the Ru(III)-promoted amide formation from azides and thioacids, which were shown not to form amides at room temperature in the absence of ruthenium. We belive that a complex formed by Ru(III) increases the reactivity of thiocarbonyl species and therefore reaction with azides occurs at room temperature, even when less reactive (electron rich and/or sterically hindered) azides are employed.

Full text of DOI:10.1016/j.tetlet.2003.10.054

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9083–9085
RuCl3-promoted amide formation from azides and thioacids
Fabio Fazio and Chi-Huey Wong*
Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 28 August 2003; revised 8 October 2003; accepted 13 October 2003
Abstract—Described here is the Ru(III)-promoted amide formation from azides and thioacids, which were shown not to form
amides at room temperature in the absence of ruthenium. We believe that a complex formed by Ru(III) increases the reactivity
of the thiocarbonyl species and therefore reaction with azides occurs at room temperature, even when less reactive (electron rich
and/or sterically hindered) azides are employed.
© 2003 Published by Elsevier Ltd.
The amide bond formation is one of the most studied
reactions in organic chemistry: an activated carboxylic
acid reacts with an amine to form the highly stable
peptide bond. In 1988, a new method for the formation
of amide bond was reported.1 Azides were directly
converted into amides by reaction with thioacids. The
authors assumed that this reaction was initiated by
traces of H2S contained in thioacids, which might have
reduced azides to amines. Recently, a revised mecha-
nism has been proposed for this reaction.2 A thiatriazo-
line intermediate, first formed from the azide and the
thiocarboxylate, gives the corresponding amide
together with nitrogen and sulfur as byproducts (Fig.
1). The authors have also excluded the formation of
amines as reactive intermediates and have found that
bases such as 2,6-lutidine accelerate this reaction. These
new conditions work well in different solvents and
yields are generally good to quantitative. One limitation
of this method, however, is the use of relatively harsh
reaction conditions (60°C, 36 h), especially when less
reactive azides were employed. We have recently
applied this reaction to carbohydrate conjugation as a
part of our effort to develop carbohydrate arrays.
However, the use of high temperature and long reaction
times can not be sustained by sensitive complex
oligosaccharides for high-throughput generation of
libraries in micro/nano-molar quantities (e.g. reaction
in microtiter plates). We had employed the copper(I)-
catalyzed 1,3-diplar cycloaddition3 between alkynes and
azides for the assembly of oligosaccharide microarrays
in microtiter plates with very high yield.4 This method
is capable of high-throughput synthesis in aqueous
solution at room temperature without protecting group
manipulation, and the reaction product can be used for
screening without isolation. The idea of microscale
synthesis and screening in situ was also demonstrated in
our previous work on amide formation from amines
and acids.5 We intend to develop another amide forma-
tion from thioacids and azides so that it can be carried
out at room temperature for screening in situ. From the
published results it was evident that electron-poor
azides are more reactive to form amides, suggesting
that the LUMO orbitals of the dipole are involved in
the formation of the thiatriazoline intermediate. Two
mechanisms are possible, either a concerted inverse-
electron demand 1,3-diploar cycloaddition (IED 1,3-
DC) or a two-step ‘diazotransfer like’ cyclization. It is
known that both types of reactions can be accelerated
by metals.6 Indeed, we have found that ruthenium(III)
promotes the amide formation from azides and
thioacids. In this work, we only selected examples
which do not (or poorly) form amides at room temper-
Figure 1. Mechanism of amide formation from azides and
thioacids.
Keywords: ruthenium trichloride; amide formation; thioacids; azides.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.10.054

9084
F. Fazio, C.-H. Wong / Tetrahedron Letters 44 (2003) 9083–9085
ature under the reaction conditions reported before2
and as a thioacid model we chose thiolacetic acid.
1-Azido-1-deoxy-b-D-glucose (Table 1, entry 1) was
nism, ruthenium might form a complex with the thio-
carbonyl species8 and increase the electron density of
the HOMOdipolarophile orbitals (Fig. 2).
taken as first model study. This compound was con-
verted, as reported, to the corresponding acetamide in
80% yield when heated in water at 60°C for 36 h.
However, when this reaction was run at room tempera-
ture, a very slow conversion was observed, and after 18
h, no product could be isolated. We tested different
concentrations of RuCl3, and found that the optimal
amount is 0.5 equivalents (Table 1, entry 1). Reactions
were run both in water and methanol with comparable
yields. Other examples of azides with poor reactivity
without RuCl3 are reported in Table 1 (entries 2–6).
Examples for both protected and free sugar-azides are
shown and in all cases, after 18 h at room temperature,
high yields of the corresponding acetamides were iso-
lated.7 A few key experiments were then run to under-
stand the pathway of this promoted reaction. When
azides were reacted with RuCl3/base, in the absence of
thioacids, only starting material was recovered and no
traces of the reduced amine were detected by NMR.
Moreover, amines did not form the corresponding
amide products under the same reaction conditions.
These two additional experiments confirmed the revised
mechanism for this amide formation. In Figure 2, a
mechanism is proposed. Either in the concerted (IED
1,3-DC, path a) or diazotransfer like (path b) mecha-
This Ru(III)-promoted amide bond formation allows
synthesis of amides from azides and thioacids at room
temperature and the reaction is applicable to those with
less reactive azides. This reaction is complimentary to
the traditional amide forming reaction and should be
useful for synthesis of amides without protecting group
manipulation.
Figure 2. Ru(III)-promoted amide formation from thioacids
and azide.
Table 1. Conversion of azides to acetamides at room temperaturea
a Azide (0.2 M), thiolacetic acid (2.5 equiv.), 2,6-lutidine (2.5 equiv.), 18 h.

F. Fazio, C.-H. Wong / Tetrahedron Letters 44 (2003) 9083–9085
9085
References
l 171.05, 170.58, 170.36, 169.82, 169.55, 78.15, 73.46,
72.63, 70.53, 68.05, 61.57, 23.34, 20.53. HR-MALDI-
FTMS: calcd for C16H23NO10Na [M+Na]+, 412.1214;
1. Rosen, T.; Lico, I. M.; Chu, D. T. W. J. Org. Chem. 1988,
53, 1580.
2. Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams,
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found, 412.1214. (2-Acetamido-ethyl)-b-D-glucopyranoside
1
(3): FC: AcOEt/MeOH (4:1“1:1). Yield 85% (23 mg). H
NMR (CD3OD): l 4.26 (d, 1H, J=7.70 Hz), 3.90 (m, 1H),
3.86 (dd, 1H, J=12.10 Hz, J=1.46 Hz), 3.65 (m, 2H), 3.44
(m, 1H), 3.34 (m, 2H), 3.26 (m, 2H), 3.18 (dd, 2H, J=9.16
Hz, J=7.70 Hz), 1.94 (s, 3H). 13C NMR (CD3OD): l
173.43, 104.49, 77.97, 77.94, 75.09, 71.58, 69.59, 62.66,
40.71, 22.55. HR-MALDI-FTMS: calcd for C10H19NO7Na
[M+Na]+, 288.1054; found, 288.1056. (2-Acetamido-ethyl)-
4. Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong,
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2,3,4,6-tetraacetyl-b-D-glucopyranoside (4): FC: AcOEt/n-
hexane (1:1)“AcOEt. Yield 80% (35 mg). 1H NMR
(CDCl3): l 5.94 (m, 1H), 5.18 (t, 1H, J=9.68 Hz), 5.04 (t,
1H, J=9.68 Hz), 4.96 (dd, 1H, J=9.68 Hz, J=7.92 Hz),
4.48 (d, 1H, J=7.92 Hz), 4.23 (dd, 1H, J=12.32 Hz,
J=4.98 Hz), 4.13 (dd, 1H, J=12.32 Hz, J=2.34 Hz), 3.81
(m, 1H), 3.69 (m, 2H), 3.42 (m, 2H), 2.06 (s, 3H), 2.03 (s,
3H), 2.00 (s, 3H), 1.98 (s, 3H), 1.96 (s, 3H). 13C NMR
(CDCl3): l 170.64, 170.26, 170.16, 169.60, 169.43, 100.94,
72.52, 71.93, 71.29, 69.35, 68.20, 61.75, 39.23, 23.16, 20.72,
20.58. HR-MALDI-FTMS: calcd for C18H27NO11Na [M+
Na]+, 456.1476; found, 456.1469. 1,2-Dicetamido-1,2-
6. For a review on catalyzed 1,3-DC reactions, see: Gothelf,
K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863. For
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7. General procedure for the RuCl3-promoted amide forma-
tion: The starting azide (0.1 mmol) was dissolved in 500
mL of the suitable solvent (MeOH or H2O, see Table 1).
To this solution were added 2,6-lutidine (2.5 equiv.), thio-
lacetic acid (2.5 equiv.) and RuCl3 (0.5 equiv.). The mix-
ture was stirred at room temperature in a capped vial for
18 h, the catalyst was then removed by filtration and the
crude product purified by flash chromatography on silica
dideoxy-b-D-glucose (5): FC: AcOEt/MeOH (2:1). Yield
1
85% (22 mg). H NMR (CD3OD): l 4.95 (d, 1H, J=9.98
Hz), 3.83 (dd, 1H, J=11.74 Hz, J=1.76 Hz), 3.73 (t, 1H,
J=9.98 Hz), 3.65 (m, 1H), 3.47 (m, 1H), 3.33 (m, 2H),
1.96 (s, 3H), 1.92 (s, 3H). 13C NMR (CD3OD): l 174.38,
173.89, 80.30, 79.66, 76.26, 71.81, 62.64, 56.12, 22.84,
22.77. HR-MALDI-FTMS: calcd for C10H18N2O6Na [M+
Na]+, 285.1057; found 285.1057. 1,2-Dicetamido-1,2-
gel. 1-Acetamido-1-deoxy-b-D-glucose (1): FC: AcOEt/
MeOH (4:1“1:1). Yield 91% (20 mg). 1H NMR
(CD3OD): l 3.81 (dd, 1H, J=12.10 Hz, J=2.20 Hz), 3.63
(dd, 1H, J=12.10 Hz, J=5.50 Hz), 3.38 (t, 1H, J=9.16
Hz), 3.33–3.27 (complex, 3H), 3.22 (t, 1H, J=9.16 Hz),
1.98 (s, 3H). 13C NMR (CD3OD): l 174.44, 81.02, 79.59,
78.89, 73.88, 71.40, 62.69, 22.87. HR-MALDI-FTMS:
calcd for C8H15NO6Na [M+Na]+, 244.0792; found,
dideoxy-3,4,6-triacetyl-b-D-glucose (6): FC: AcOEt/MeOH
1
(95:5). Yield 78% (30 mg). H NMR (CDCl3): l 7.01 (d,
1NH, J=8.44 Hz), 6.21 (d, 1NH, J=8.44 Hz), 5.06 (m,
3H), 4.26 (dd, 1H, J=12.83 Hz, J=4.40 Hz), 4.11 (m,
1H), 4.05 (dd, 1H, J=12.47 Hz, J=2.20 Hz), 3.75 (m,
1H), 2.05 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H),
1.93 (s, 3H). 13C NMR (CDCl3): l 172.00, 171.84, 170.96,
170.71, 169.29, 80.18, 73.39, 72.91, 67.70, 61.73, 53.28,
23.36, 23.07, 20.73, 20.69, 20.57. HR-MALDI-FTMS:
calcd for C16H25N2O9 [M+H]+, 389.1554; found 389.1562.
8. Schenk, W. A. J. Organomet. Chem. 2002, 661, 129.
244.0794.
1-Acetamido-1-deoxy-2,3,4,6-tetraacetyl-b-D-
glucose (2): FC: AcOEt/n-hexane (1:1)“AcOEt. Yield
80% (31 mg). 1H NMR (CDCl3): l 6.29 (d, 1H, J=9.39
Hz), 5.27 (t, 1H, J=9.68 Hz), 5.21 (t, 1H, J=9.39 Hz),
5.02 (t, 1H, J=9.68 Hz), 4.88 (t, 1H, J=9.68 Hz), 4.28
(dd, 1H, J=12.61 Hz, J=4.40 Hz), 4.05 (dd, 1H, J=12.61
Hz, J=2.34 Hz), 3.79 (m, 1H), 2.04 (s, 3H), 2.02 (s, 3H),
2.00 (s, 3H), 1.98 (s, 3H), 1.96 (s, 3H). 13C NMR (CDCl3):