Synthesis of guanidines from azides: A general and straightforward methodology in carbohydrate chemistry

Article abstract of DOI:10.1021/jo100876r

(Figure presented) The ability of the guanidinylating reagent N′,N′′-diBoc-N-triflyl-guanidine (GN-Tf) to react with in situ formed free amines from azides in carbohydrate scaffolds was explored. This reaction proved to be an efficient method to prepare guanidine derivatives in a one-pot manner with good to excellent yields, either with primary or secondary azides with different substitution patterns. Labile protecting groups such as benzyl ethers are not removed under these hydrogenolytic conditions.

Full text of DOI:10.1021/jo100876r

pubs.acs.org/joc
Synthesis of Guanidines From Azides: A General and
Straightforward Methodology In Carbohydrate
Chemistry
ꢀ
Andres G. Santana, Cosme G. Francisco, Ernesto Suarez,
ꢀ
ꢀ
and Concepcion C. Gonzalez*
ꢀ
FIGURE 1. (A) Marine hepatotoxin cylindrospermopsin, (B) influ-
enza neuraminidase inhibitor zanamivir, and (C) asymmetric nitroal-
dol organocatalyst.
´
Instituto de Productos Naturales y Agrobiologıa del C.S.I.C.,
´
ꢀ
Avenida Astrofısico Francisco Sanchez, 3,
38206 La Laguna Tenerife, Spain
give and accept H-bonds make them very interesting targets
to achieve chemical recognition and/or catalysis (Figure 1C).5
The most commonly used methods to synthesize the gua-
nidine moiety are multistep processes, such as the treatment
of thioureas,6 carbodiimides,7 or cyanamides8 with a protec-
ted primary amine (or ammonia). More recently, with the
successful development of efficient guanidinylating reagents
by Goodman and co-workers,9 an alternative route has emerged.
However, in some cases, the preparation of a free amine is not
possible due to the presence of other reactive groups, such as
esters, acetals, or aldehydes. In spite of the growing interest
in guanidinylated products, there are still few general and
direct methodologies to access these compounds.10
ccgm@ipna.csic.es
Received May 10, 2010
On the other hand, carbohydrates are the most abundant
class of organic compounds in nature, being involved in almost
every essential process to sustain life.11 They have attracted
The ability of the guanidinylating reagent N0,N00-diBoc-N-
triflyl-guanidine (GN-Tf) to react with in situ formed free
amines from azides in carbohydrate scaffolds was explored.
This reaction proved to be an efficient method to prepare
guanidine derivatives in a one-pot manner with good to
excellent yields, either with primary or secondary azides with
different substitution patterns. Labile protecting groups
such as benzyl ethers are not removed under these hydro-
genolytic conditions.
(6) (a) Chen, C.-Y.; Lin, H.-C.; Huang, Y.-Y.; Chen, K.-L.; Huang, J.-J.;
Yeh, M.-Y.; Wong, F. F. Tetrahedron 2010, 66, 1892–1897. (b) Wang, Y.;
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DOI: 10.1021/jo100876r
r
Published on Web 06/28/2010
J. Org. Chem. 2010, 75, 5371–5374 5371
2010 American Chemical Society

Santana et al.
JOCNote
SCHEME 1. Two-Step vs One-Pot Synthesis of Guanidine 2a
TABLE 1. Guanidinylation of Primary Azidesa
aReagents and conditions: (a) (i) H2, 10% Pd/C, AcOEt; (ii) GN-Tf, TEA,
DCM, 85%. (b) H2, 10% Pd/C, GN-Tf, DIPEA, AcOEt, overnight, 100%.
the attention of synthetic organic chemists because of their
potential usefulness as easily available chiral substrates with
a well-defined stereochemistry and a highly functionalized
nature. These reasons make them suitable starting materials
to translate their structural features into intermediates for
the synthesis of more complex bioactive compounds.12 As
part of our ongoing research directed to the development of
new methodologies leading to functionalized heterocycles,13
we were interested in a rapid installation of the guanidine
moiety in carbohydrate scaffolds. Herein we report on a
mild and convenient method to prepare protected guanidines
from azides.
As our first approach to this kind of guanidinylated sugar
derivatives, we decided to prepare the azide 1, readily avail-
able from D-ribose,14a which was reduced and subsequently
treated, with no further purification than filtration and eva-
poration, with the guanidinylating reagent N0,N00-diBoc-
N-triflyl-guanidine (GN-Tf, 1.0 equiv) and TEA (1.0 equiv)
in DCM (0.1 M), at room temperature. The desired guanidine-
derivative 2 was isolated after column chromatography in a
satisfactory 85% yield (Scheme 1a).
To improve this methodology and to simplify the pro-
cedure, we tested the possibility of carrying out the two
steps in a one-pot fashion, since the introduction of other N-
protecting groups, such as Boc,15 can be performed in this way.
We were pleased to find that the hydrogenation of the
same ribo-azide with 10% Pd/C in AcOEt in the presence of
N0,N00-diBoc-N-triflyl-guanidine and diisopropylethylamine
(DIPEA) gave the corresponding guanidine derivative in
quantitative yield (Scheme 1b). This material was identical
aReaction conditions: azide (1.0 mmol), 10% Pd/C (20% w/w), GN-Tf
(1.0 mmol), DIPEA (1.5 mmol), AcOEt (15 mL/mmol) under H2 atmos-
phere (balloon), overnight. bIsolated yield.
(12) Hanessian, S. Total Synthesis of Natural Products. The Chiron
Approach; Pergamon Press: Oxford, UK, 1983.
ꢀ
(13) (a) Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Leon, E. I.; Riesco-
Fagundo, C.; Suarez, E. J. Org. Chem. 2001, 66, 1861–1866. (b) Francisco,
ꢀ
ꢀ
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C. G.; Freire, R.; Gonzalez, C. C.; Suarez, E. Tetrahedron: Asymmetry 1997,
ꢀ
with that afforded upon sequential hydrogenation of the
azide and guanidinylation of the intermediate free amine; it
showed in its 1H NMR the appearance of two singlets at 1.50
and 1.53 ppm, belonging to the tert-butyls of the Boc groups,
as well as two broad singlets for the NH and NHBoc at 8.49
and 11.21 ppm, respectively. The 13C NMR spectrum also
featured peaks at 153.0, 156.4, and 163.5 ppm, correspond-
ing to the three quaternary carbons of the diBoc-guanidine
moiety.
This encouraging result prompted us to extend the scope of
this protocol to other saccharidic primary azides.13a,14b-f
The results are illustrated in Table 1, where the yields repre-
sent isolated pure products. Several groups that are labile to
other alternative reductive methods were still stable under these
conditions. Esters (benzoates: entries 1, 2, and 3; acetate: entry 6)
ꢀ
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Lett. 1996, 37, 1687–1690.
(14) (a) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am.
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Chem. 2005, 48, 1941–1947. (c) Martinez, M. B.; Mata, F. Z.; Donoso,
M. T. U.; Perez, J. A. G. Carbohydr. Res. 1992, 230, 191–196. (d) Yoshimura,
J.; Asano, K.; Umemura, K.; Horito, S.; Hashimoto, H. Carbohydr. Res.
1983, 121, 187–204. (e) Francisco, C. G.; Herrera, A. J.; Martin, A.; Perez-
Martin, I.; Suarez, E. Tetrahedron Lett. 2007, 48, 6384–6388. (f) Mitchell,
D. A.; Jones, N. A.; Hunter, S. J.; Cook, J. M. D.; Jenkinson, S. F.; Wormald,
M. R.; Dwek, R. A.; Fleet, G. W. J. Tetrahedron: Asymmetry 2007, 18, 1502–
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5372 J. Org. Chem. Vol. 75, No. 15, 2010

Santana et al.
JOCNote
TABLE 2. Guanidinylation of Secondary Azidesa
its importance in carbohydrate chemistry and in organic syn-
thesis in general, that the benzylidene protecting group also
can be employed under these conditions. In the guanidinyla-
tion of compound 21 (entry 3), concomitant formation of
methyl 2,3-anhydro-4,6-benzylidene-R-D-mannopyranoside
was detected,17 showing that the installation of the bulky
diBoc-guanidine group in position 3 of benzylidene-tethered
pyranoses was strongly hindered. To avoid this side reaction,
the free alcohol was protected as its MOM-ether. The guani-
dinylation of this new compound afforded the corresponding
guanidine in a better yield, though it was still modest (entry 4).
Finally, the reaction of compound 31 gave the desired
guanidine 32 (entry 8) in poor yield, probably due to the
proximity of the also bulky TBDMS-ether.18
This reaction was proven to tolerate a wide diversity of
substitution patterns, as well as a variety of the most common
protecting groups in organic synthesis. It is also noteworthy
that this guanidinylation is metal-free and that it is not neces-
sary to add any other coreagent than a neutral base in order
to scavenge the residual proton.
In conclusion, we have demonstrated the ability of the
guanidinylating reagent N0,N00-diBoc-N-triflyl-guanidine to
react with in situ formed free amines from azides in carbo-
hydrate scaffolds. We believe that the application of this
protocol to the synthesis of other more general guanidine
derivatives will be of interest and that this method could
also be applicable to nonsaccharidic azides. Further investi-
gation of the synthetic potential of these compounds is
currently under development in our laboratory, and will be
reported soon.
Experimental Section
Representative Procedure for the Hydrogenation-Guanidinylation
of the Azides. A stirred solution of the corresponding azide (1.0
mmol) in ethyl acetate (15 mL) was treated with N0,N00-diBoc-N-
triflyl-guanidine (1.0 mmol), 10% Pd/C (20% w/w), and diethyl-
isopropylamine (DIPEA) (1.5 mmol). Three vacuum/hydrogen
cycles were performed, and the mixture was further stirred under
a H2 atmosphere (balloon) overnight. The reaction mixture was
then filtered over a Celite pad, which was washed twice with ethyl
acetate, and the combined filtrates were evaporated. Column
chromatography of the residue (hexanes/EtOAc mixtures) aff-
orded the required guanidinylated compounds.
aReaction conditions: azide (1.0 mmol), 10% Pd/C (20% w/w), GN-Tf
(1.0 mmol), DIPEA (1.5 mmol), AcOEt (15 mL/mmol) under H2 atmos-
phere (balloon), overnight. Isolated yield. Methyl 2,3-anhydro-4,6-ben-
b
c
1-O-Benzoyl-5-[(N0,N00-di-tert-butoxycarbonyl)guanidino]-
5-deoxy-2,3-O-isopropylidene-β-D-ribofuranose (2) (Table 1, entry 1):
oil; [R]D þ0.45 (c 0.44); IR 3431, 1724, 1640, 1620, 1418, 1328,
zylidene-R-D-mannopyranoside was isolated in a ca. 20% yield.
1
1139 cm-1; H NMR (500 MHz, 70 °C) δH 1.36 (3H, s), 1.45
and hemiacetals (entry 8) are tolerated well, as are benzyl
ethers (entry 6), which are not removed under the hydrogeno-
lytic conditions.16 In all the cases the yield of the combined
method was almost quantitative, excepting the C-glycosidic
azide 13 (entry 7), and the branched compound 15 (entry 8),
where the anomeric alcohol was unprotected.
With the aim of further extending the scope of this metho-
dology, we embarked on the study of this approach with a
battery of secondary azides,13a,14g-j thus covering every
position in the sugar ring, both in the furanose and the pyra-
nose form. These results are summarized in Table 2.
(3H, s), 1.50 (9H, s), 1.53 (9H, s), 3.38 (1H, ddd, J=3.1, 9.1, 13.2
Hz), 3.95 (1H, ddd, J=6.3, 6.3, 13.2 Hz), 4.52 (1H, dd, J=6.3,
9.1 Hz), 4.78 (1H, d, J=5.7 Hz), 4.89 (1H, d, J=5.7 Hz), 6.51
(1H, s), 7.40-7.43 (2H, m), 7.53-7.56 (1H, m), 7.98-8.00 (2H,
m), 8.49 (1H, br s), 11.21 (1H, br s); 13C NMR (125.7 MHz, 70 °C)
δC 25.2 (CH3), 26.6 (CH3), 28.1 (3 ꢀ CH3), 28.4 (3 ꢀ CH3), 43.7
(CH2), 79.2 (C), 82.4 (CH), 83.2 (C), 85.7 (CH), 85.9 (CH), 103.6
(CH), 113.4 (C), 128.4 (2 ꢀ CH), 129.8 (2 ꢀ CH), 129.9 (C),
133.2 (CH), 153.0 (C), 156.4 (C), 163.5 (C), 164.8 (C); MS (ESI)þ
m/z (rel intensity) 536 (Mþ þ H, 100). HRMS (ESI)þ Calcd
for C26H38N3O9 536.2608, found 536.2626. Anal. Calcd for
As can be seen from the results shown, most of the gua-
nidine derivatives were successfully synthesized in ca. 90%
yield (entries 1, 2, 5, 6, and 7). It is worth mentioning, due to
(17) For a similar result, see: (a) White, R. D.; Wood, J. L. Org. Lett.
2001, 3, 1825–1827. (b) Back, T. G.; Baron, D. L.; Yang, K. J. Org. Chem.
1993, 58, 2407–2413.
(18) Theuse of protected thioureaswiththe Mukaiyama reagent seems to be
superior for guanidinylation of sterically hindered and less reactive amines; see:
Organic Syntheses; Wiley: New York, 2004; Collect. Vol. X, p 266.
(16) For selective inhibition of benzyl ether hydrogenolysis, see: Sajiki,
H. Tetrahedron Lett. 1995, 36, 3465–3468.
J. Org. Chem. Vol. 75, No. 15, 2010 5373

Santana et al.
JOCNote
C26H37N3O9: C, 58.31; H, 6.96; N, 7.85. Found: C, 58.47; H,
6.96; N, 7.92.
Europeo de Desarrollo Regional (FEDER). A.G.S. thanks the
I3P-CSIC Program for a fellowship.
Supporting Information Available: Experimental proce-
dures, characterization, and copies of NMR (1H and 13C)
spectra for all pure compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the inves-
tigation program no. CTQ2007-67492/BQU of the Ministe-
ꢀ
rio de Educacion y Ciencia (Spain) cofinanced with the Fondo
5374 J. Org. Chem. Vol. 75, No. 15, 2010