Chiral N-Fmoc-β-amino alkyl isonitriles derived from amino acids: First synthesis and application in 1-substituted tetrazole synthesis

Article abstract of DOI:10.1021/jo801527d

(Chemical Equation Presented) A novel class of optically active N-Fmoc-protected amino isonitriles has been described for the first time. Conversion of the carboxyl group of Fmoc-β-amino acids into an isocyano group has resulted in a new class of N-uretha

Full text of DOI:10.1021/jo801527d

Chiral N-Fmoc-ꢀ-Amino Alkyl Isonitriles Derived from Amino
Acids: First Synthesis and Application in 1-Substituted Tetrazole
Synthesis
Vommina V. Sureshbabu,* N. Narendra, and G. Nagendra
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore
UniVersity, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
hariccb@rediffmail.com
ReceiVed July 11, 2008
A novel class of optically active N-Fmoc-protected amino isonitriles has been described for the first
time. Conversion of the carboxyl group of Fmoc-ꢀ-amino acids into an isocyano group has resulted in
a new class of N-urethane-protected amino isonitriles. All the isonitriles have been isolated as stable
solids, purified, and completely characterized. A synthetic application of the obtained isonitriles has also
been demonstrated through the synthesis of 1-substituted tetrazole analogues of amino acids via a 2 +
3 cycloaddition with trimethylsilyl azide.
Introduction
generated through metal-mediated coupling of isonitriles with
propargyl amine.11
Organic isonitriles are employed as key intermediates in a
wide range of reactions. The broad-spectrum reactivity of
isonitriles originates from their ability to react as both electro-
philes and nucleophiles as a result of the presence of a formally
divalent carbon in the isocyano group. Their important synthetic
utilities include conversion into isothiocyanates,1 formamidino
urea derivatives,2 R-keto and ꢀ-keto amides,3,4 and N,N′-dialkyl
carbodiimides.5 They are used in addition reactions to benzyne
species and pyridinium salts6 and in nitrile oxide reduction.7
1-Substitued tetrazoles and imidazoles are obtained through
isonitrile-azide cycloaddition8 and heterocoupling reaction
between two different isonitriles, respectively.9 Pyrrolles, in-
doles, oxazoles, and thiazoles are some of the other heterocycles
synthesized from isonitriles.10 N-Heterocyclic carbenes are
Isonitriles are used in Passerini three-component (Passerini
3CR) and Ugi four-component reactions (Ugi 4CR) to synthesize
a wide range of compounds.12 These include R-acyloxy amides,
R-epoxy and R-hydroxy amides, lactones, 2-hydroxy furans,
thiophenes and O-arylated phenols13 (via Passerini 3CR), R-acyl
amino amides, libraries for combinatorial synthesis, small
14
molecule macroarrays, macrocycles, natural products,
het-
erocycles,15 and several other classes of compounds16-18 (via
Ugi 4CR). The isocyano group is also present in many natural
(10) For synthesis of pyrroles, see: (a) van Leusen, A. M.; Siderius, H.;
Hoogenboom, B. E.; Daan van Leusen, Tetrahedron Lett. 1972, 13, 5337–5340.
For imidazoles, see: (b) Van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J.
Org. Chem. 1977, 42, 1153–1159. For indole, see: (c) Campo, J.; Garc´ıa-
Valverde, M.; Marcaccini, S.; Rojo, M. J.; Torroba, T. Org. Biomol. Chem. 2006,
4, 757–765. For oxazolines, see: (d) van Daan, L.; van Albert, L. M. Synthesis
1991, 1991, 531–532.
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modifications, see: (a) Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079–
4082. (b) Akritopoulou-Zanze, I.; Whitehead, A.; Waters, J. E.; Henry, R. F.;
Djuric, S. W. Org. Lett. 2007, 9, 1299–1302. (c) El Kaim, L.; Gizolme, M.;
Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019–4021. (d) Paulvannan, K. J. Org.
Chem. 2004, 69, 1207–1214.
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546–548. (b) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron
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Stefano, M.; Roberto, P.; Tomas, T. Synthesis 1993, 1993, 783–784. For
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Soc., Perkin Trans. 1 1996, 229–230. For O-aryl phenols, see: (g) El Kaim, L.;
Gizolme, M.; Grimaud, L. Org. Lett. 2006, 8, 5021–5023.
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10.1021/jo801527d CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 153–157 153

Sureshbabu et al.
peptide nucleic acids,27 peptides containing nonproteinogenic
amino acids, N-hydroxy peptides,28 selenocystine containing
peptide libraries,29 peptide ꢀ-turn mimetics,30 Weinreb amido
peptides,31 peptide heterocycles and peptide mimics, amino acid
derivatives such as R-methylated amino acids,32 fluorinated
amino acids,33 R-hydroxy ꢀ-amino amides,34 and thiazoles.35
Polyfunctionalized 1-isocyano-2-methylamino-alkenes derived
from simple R-isocyano esters have been used in diversity-
oriented organic synthesis.36 Solid-phase multicomponent reac-
tions using resin-bound isonitriles have also been described.37
The isocyano compounds (Figure 1) have played a vital role
in developing new MCR-based routes for peptide and peptide
derivatives. Their numerous synthetic applications in peptide
as well as peptidomimetic chemistry have been reported. They
have been synthesized through different methods and isolated
mostly as liquids or low melting solids. On the other hand,
contrary to R-isocyano esters/amides, insertion of the isocyano
group in place of the carboxylic group of amino acids can also
be accomplished to generate a new class of N-protected amino
isonitriles. With the expanding area of peptidomimetics and
increasing interest in new classes of molecules for combinatorial
synthesis, these novel isonitriles may form a useful set of
monomers to carry out several reactions leading to synthesis of
novel amino acid/peptide derivatives, construction of libraries
of new compounds, and obtaining MCR adducts with modified
structures. However, the synthesis of such type of N-protected
amino alkyl isonitriles starting from amino acids and their
synthetic applications still have to be demonstrated. In view of
this, we herein report the synthesis of optically active isonitriles
derived from N-Fmoc amino acids (Figure 2), which to the best
of our knowledge are hitherto unreported, and demonstrate one
FIGURE 1. R-Isocyano esters/amides.
products and biologically active molecules.19 The vast literature
on the preparation, properties, and reactions of the isonitriles
has been reviewed by various workers.20
In peptide chemistry, isonitriles of the type R-isocyano ester/
amide (Figure 1) that are obtained by converting the amino
group of amino acid ester into an isocyano group are well
known. Since the discovery of their use in peptide synthesis by
Ivar Ugi, these compounds are being explicitly employed in
the synthesis of amino acid and peptide derivatives. Peptide
synthesis via the Ugi four-component condensation of these
isonitriles with cleavable amine or aldehyde components has
been well described. Special cleavable isonitriles have also been
employed for MCR-based peptide synthesis.21 They are also
used to assemble di- and tripeptides containing tandem R,R-
diisopropyl and diphenyl glycyl residues,22 for macrocyclization
of oligopeptides,23 synthesis of ꢀ-lactams and other small and
medium ring sized lactams,24 glycopeptides,25 depsipeptides,26
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Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123–
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Lett. 2005, 7, 4455–4458. For macrocycles, see: (c) Beck, B.; Larbig, G.; Mejat,
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2003, 5, 1047–1050. (d) Rivera, D. G.; Wessjohann, L. A. J. Am. Chem. Soc.
2006, 128, 7122–7123. For natural product synthesis, see: (e) Fukuyama, T.;
Robins, B. D.; Sachleben, R. A. Tetrahedron Lett. 1981, 22, 4155–4158. (f) De
Laszlo, S. E.; Williard, P. G. J. Am. Chem. Soc. 1985, 107, 199–203. (g) Bauer,
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T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935–8939. (c) Ilyn, A. P.;
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(a) Umkehrer, M.; Kolb, J.; Burdack, C.; Ross, G.; Hiller, W. Tetrahedron Lett.
2004, 45, 6421–6424. With CO2, see: (b) Haslinger, E. Monatsh. Chem. 1978,
109, 749–750. With cyanate, see: (c) Short, K. M.; Ching, B. W.; Mjalli, A. M. M.
Tetrahedron Lett. 1996, 37, 7489–7492. With thiocyanate, see: (d) Ugi, I.;
Rosendalh, F. K.; Bodeshime, F. Liebigs Ann. Chem. 1963, 666, 54–61.
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2988–2989. (b) Ugi, I.; Betz, W.; Offermann, K. Chem. Ber. 1964, 97, 3008–
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condensation using isonitrile Fmoc-Gly-ψ[CH2NC] prepared starting from 1,2
diaminoethane, see: (a) Wang, W. H.; Zou, X. M.; Zhang, X.; Fu, Y. Q.; Xu, P.
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154 J. Org. Chem. Vol. 74, No. 1, 2009

Chiral N-Fmoc-ꢀ-Amino Alkyl Isonitriles
SCHEME 1. Synthesis of N-Fmoc-Protected Amino Alkyl
Isonitriles
FIGURE 2. N-Protected amino isonitriles from amino acids.
TABLE 1. List of Isonitriles and 1-Sustituted Tetrazoles Prepared
through Schemes 1 and 2, Respectively
yielda
yielda
R1
compound (%) compound (%)
H
CH3
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
80
78
75
81
73
75
80
83
70
80
75
73
76
72
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
90
88
87
90
88
86
89
90
86
86
88
84
87
85
CH(CH3)2
CH2C6H5
CH2CH(CH2)3
CH(CH3)CH2CH3
C6H5 (D-amino acid)
C6H5
-(CH2)3- (amino acid is proline)
(CH2)2SCH3
CH2COOCH2C6H5
(CH2)2COOCH2C6H5
CH2SCH2C6H5
SOCl2, and chlorothionoformates have been reported for
conversion of the formamides into isonitriles.40 Among them,
Burgess reagent41 displayed several advantageous features such
as mild and neutral reaction conditions, chemoselective dehy-
dration, and impressive yields that were ideally suited to carry
out the reactions of amino acid and peptide substrates without
loss of optical purity, cleavage of protecting groups, or
modification of the side chain functional groups. Burgess reagent
has been used for the conversion of a variety of formamides
including an N-formyl dipeptide ester, For-Val-Gly-OEt, into
isonitriles.42
In a typical experiment, the mixture of compound 2d and
Burgess reagent in dry CH2Cl2 was refluxed, and the reaction
was monitored through TLC and IR. Formation of isonitriles
could be easily detected by appearance of a strong stretching
frequency at 2158 cm-1 in the IR spectrum. Upon completion
of the reaction (which took 30 min), the desired isonitrile 3d
was isolated in 81% yield after purification through column
chromatography. Structure of 3d was confirmed by spectro-
scopic techniques. Other dehydrating agents were also screened
with the same substrate 2d. Phosgene and its surrogates
diphosgene and triphosgene were avoided because of their
toxicity. With POCl3 and pyridine the reaction was slower at
room temperature, and heating the reaction mixture resulted in
the cleavage of the Fmoc group. The isonitrile so formed was
also partially hydrolyzed to its formamide when the reaction
mixture was treated with aqueous Na2CO3 (required to remove
unreacted POCl3). Sluggishness in the reaction was noticed with
PPh3/CCl4 also. Thus, it was decided that Burgess reagent would
be preferred for further studies.
(CH2)4NH-Z
a Yield after purification by chromatography.
of their synthetic applications through the synthesis of novel
class of 1-substitued tetrazole analogues of Fmoc-amino acids.
Results and Discussion
Isonitriles are commonly prepared by dehydration of the
formamides. Accordingly, the synthesis of N-Fmoc alkyl
formamides as precursors of the title isonitriles was under-
taken.38 Formamides 2 can be synthesized by formylation of
the mono-N-Fmoc-protected alkyl vicinal diamines, which in
turn have to be prepared through a multistep protocol from
Fmoc-amino acids. Instead, we chose a more concise and
efficient route from using Fmoc ꢀ-amino acids as starting
materials and directly converted the -COOH group into formyl
amino group. Our group has reported for the first time a reaction
of this sort for the synthesis of N-Fmoc/Z,N′-formyl alkyl gem
diamines from amino acids via the Goldsmith-Wick coupling
of isocyanates derived from N-Fmoc/Z-amino acids with formic
acid.39 Adhering to this strategy, Fmoc ꢀ-amino acids 1 were
converted into acyl azides using the mixed anhydride method.
Heating the toluene solution of these azides for about 30 min
yielded the isocyanates, which were directly reacted without
isolation with 96% formic acid in presence of catalytic amount
of DMAP in dry CH2Cl2 solvent to obtain the desired forma-
mides. The crude products that precipitated out as solids from
the reaction mixture were isolated and purified through recrys-
tallization in about 80% yields. All of the formamides 2a-n
were characterized (see Supporting Information).
Employing Burgess reagent and maintaining the same condi-
tions, N-Fmoc-amino alkyl isonitriles 3a-i containing alkyl and
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Chem., Int. Ed. Engl. 1977, 16, 259–260. (b) Eckert, H.; Forster, B. Angew.
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Synthesis of Isonitriles. Fmoc-Aaa-ψ[CH2NC]. Synthesis
of the isonitriles from the formamides 2 was pursued using
compound 2d as specimen. Different dehydrating reagents such
as phosgene, di- and triphosgene, POCl3, PPh3/CCl4, PCl5, P2O5,
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J. Org. Chem. Vol. 74, No. 1, 2009 155

Sureshbabu et al.
aryl side chains were synthesized from the formamides 2a-i
in excellent yields. The procedure was repeated for five
examples of the formamides obtained from bifunctional amino
acids, Fmoc-Met-OH, Fmoc-Cys(Bzl)-OH, Fmoc-Asp(OBzl)-
OH, Fmoc-Glu(OBzl)-OH, and Fmoc-Lys(Z)-OH. In all cases,
the corresponding multifunctional isonitriles 3j-n were obtained
in good yields without the side chain protections being affected
(Scheme 1). The isocyano group was inserted into the side
chains of aspartic acid and glutamic acid also. Fmoc-Asp and
Fmoc-Glu were converted into 5-oxazolidinones and the free
ꢀ/γ-COOH of the latter was converted into the formyl-amino
group via the reported protocol.39 The resulting formamides
were then treated with Burgess reagent to yield the isonitriles
4a and 4b (Figure 3) in 68% and 65% yields, respectively.
and stabilizers of metallopeptides.43 5-Substituted tetrazoles have
been synthesized from 2 + 3 dipolar cycloaddition of azide with
nitriles obtained from N-urethane-protected amino acids,44 but
the isomeric 1-substituted tetrazole analogues of N-protected
amino acids are yet to be described. This class of tetrazoles is
accessed by the dipolar cycloaddition of azide with isonitriles.
These 1-substiutued tetrazoles are hydrophobic, with their
lipophilicity being comparable to aromatic heterocycles such
as pyrazoles, imidazoles, and even nitriles.45 N-Substituted
tetrazole moiety has been incorporated as pharmacophore en
route to development of potent bioactive compounds such as
apoptosis potentiator dimeric Smac peptide mimetics containing
a proline-derived tetrazole subunit, immunosuppressant clotri-
mazole analogue,45 and serotonin agonists.46 Synthesis of
1-substituted tetrazole derivatives of small organic molecules
and carbohydrates has also been reported.47
Isonitriles 3 were refluxed with trimethylsilyl azide in
presence of ZnBr2 as a catalyst in dry MeOH solvent for about
6 h, and the resulting tetrazoles were obtained in ∼90% yields.
The crude products were purified through column and were
completely characterized. Isonitriles 4a and 4b were also treated
with TMS azide under the same conditions to obtain new class
of unnatural amino acids 7a and 7b containing 1-substitued
tetrazoles in the side chains in nearly 80% yields. During the
reaction it was observed that the isonitriles were partially
hydrolyzed to formamides in the presence of a trace amount of
moisture in the reaction medium, resulting in decreased yields
of the tetrazoles. Hence, carrying out the reaction in completely
dry conditions and under nitrogen atmosphere significantly
improves the yield by minimizing hydrolysis.
FIGURE 3
Interestingly, unlike most of the organic isonitriles, including
R-isocyano esters, which are largely liquids or low melting
solids, isonitriles 3a-n were solids with high melting points.
They could be stored as stable solids at room temperature for
a long duration under anhydrous conditions. They were also
completely stable toward column chromatographic separation.
However their HPLC profiles contained the corresponding
formamide peaks to an extent of 15-20%, though the TLC of
the injected samples had a single peak. Appearance of the
formamide peak in HPLC could be due to partial hydrolysis of
the isonitriles during the analysis by standard 0.1% TFA
water-acetonitrile gradient.
SCHEME 2. Synthesis of N-Fmoc Amino Acid Derived
1-Substiututed Tetrazoles
Conclusion
A new class of optically pure N-Fmoc-protected isonitriles
has been efficiently synthesized. The synthesis has involved
direct conversion of the carboxyl group of several Fmoc-ꢀ-
amino acids containing alkyl, aryl, and functionalized side chains
Two examples of Fmoc-peptide isonitriles were also synthe-
sized and used as models to study the possibility of racemization
during the reaction. The dipeptide acids Fmoc-L-Phg-ꢀ-Ala-OH
and Fmoc-D-Phg-ꢀ-Ala-OH were converted into isonitriles 5a
and 5b following the similar protocol outlined in the Scheme
1. Their 1H NMR spectra contained the methyl group resonances
at δ 1.25 and 1.24 (for 5a) and at δ 1.18 and 1.17 (for 5b). The
appearance of a single doublet (corresponding to methyl group)
for each epimer sample revealed that the samples of 5a and 5b
were optically pure without a mixture of epimers. Also the
HPLC profiles of the samples of 5a and 5b had a single peak
corresponding to isonitrile at distinct tR values of 30.785 and
28.009 min, respectively, indicating the presence of only one
epimer in each sample. These studies confirmed the absence of
racemization during synthesis of the isonitriles.
(43) For isosters, see: (a) Wittenberger, S. J. Org. Prep. Proced. Int. 1994,
26, 499–531. For asymmetric catalysis, see: (b) Torii, H.; Nakadai, M.; Ishihara,
K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. Engl. 2004, 43, 1983–
1986. (c) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas,
C. F. Org. Lett. 2006, 8, 2839–2842. For pharmaceutical importance, see: (d)
Bavetsias, V.; Marriott, J. H.; Melin, C.; Kimbell, R.; Matusiak, Z. S.; Boyle,
F. T.; Jackman, A. L. J. Med. Chem. 2000, 43, 1910–1926. For metallopeptide
stabilization, see: (e) Lee, K.; Kim, Y.-J.; Baeck, K. K. J. Organomet. Chem.
2005, 690, 4319–4329.
(44) (a) Sureshbabu, V. V.; Venkataramanarao, R.; Naik, S. A.; Chenna-
krishnareddy, G. Tetrahedron Lett. 2007, 48, 7038. (b) Demko, Z. P.; Sharpless,
K. B. Org. Lett. 2002, 4, 2525–2527.
(45) Wulff, H.; Miller, M. J.; Hansel, W.; Grissmer, S.; Cahalan, M. D.;
Chandy, K. G. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 8151–8156.
(46) (a) For Smac peptide mimetics see: Harran, P. G.; Wang, X.; De
Brabander, K.; Li, L.; Thomas, M.; Suzuki, H. U. S. Patent Appl. 2005/0197403
A1, 2005. (b) For serotonin agonists, see: Street, L. J.; Baker, R.; Davey, W. B.;
Guiblin, A. R.; Jelley, R. A.; Reeve, A. J.; Routledge, H.; Sternfeld, F.; Watt,
A. P.; Beer, M. S.; Middlemiss, D. N.; Noble, A. J.; Stanton, J. A.; Scholey, K.;
Hargreaves, R. J.; Sohal, B.; Graham, M. I.; Matassat, V. G. J. Med. Chem.
1995, 38, 799–1810.
(47) (a) Potewar, T. M.; Siddiqui, S. A.; Lahoti, R. J.; Srinivasasn, K. V.
Tetrahedron Lett. 2007, 48, 1721–1724. For tetrazole derivatives of carbohy-
drates, see: (b) Couri, M. R.; Luduvico, I.; Santos, L.; Alves, R.; Prado, M. A.;
Gil, R. F. Carbohydr. Res. 2007, 342, 1096–1100.
Synthesis of 1-Substiututed Tetrazoles. As an example to
demonstrate the reactions of the isocyano group in case of the
newly prepared isonitriles, we proceeded with synthesis of the
1-substitued tetrazoles from compound 3. Amino acid derived
tetrazoles are being used as carboxylic acid isosteres, catalysts
in asymmetric organic synthesis, pharmaceutical compounds,
156 J. Org. Chem. Vol. 74, No. 1, 2009

Chiral N-Fmoc-ꢀ-Amino Alkyl Isonitriles
(S)-(9H-Fluoren-9-yl)methyl 1-Isocyano-6-(benzyl carbam-
ate)hexan-2-yl Carbamate, Fmoc-Lys(Cbz)-ψ[CH2-NC], 3n.
Yield 70%; Rf 0.40 (n-hexane/AcOEt 8:2); [R]23D ) -21.2 (c 1.0,
into a formyl amino group and dehydration of the formamide
with Burgess reagent under mild and neutral conditions. All of
the isonitriles have been isolated as solids, purified, and well
characterized. One application of the new isonitriles in organic
reactions has been demonstrated by their conversion into
5-substituted tetrazoles via cycloaddition with trimethylsilyl
azide. Further utility of these isonitriles in organic synthesis
including MCRs is anticipated.
CHCl3); mp ) 120-122 °C; IR (KBr) υmax ) 1705, 2158 cm-1
;
1H NMR (CDCl3, δ) 1.50 (m, 4H), 2.41 (m, 2H), 3.10 (m, 2H),
3.40 (m, 2H), 3.80 (br, 1H), 4.20 (t, 1H, J ) 8.0 Hz), 4.40 (d, 2H,
J ) 8.0 Hz), 4.97 (s, 2H), 5.02 (br, 1H), 7.20-7.8 (m, 13H); 13C
NMR (CDCl3, δ) 23.03, 30.04, 30.20, 46.22, 47.69, 49.94, 53.97,
54.81, 59.24, 67.24, 120.54, 125.49, 127.59, 128.28, 128.60, 129.02,
136.97, 141.82, 144.22, 156.36, 157.19, 158.65; HRMS calcd for
C30H31N3O4 m/z 520.2212 (M+ + Na), found 520.2216.
(S)-(9H-Fluoren-9-yl)methyl 3-Phenyl-1-(1H-tetrazol-1-yl)-
propan-2-yl Carbamate, Fmoc-Phe-ψ[CH2-CN4], 6d. Yield 90%;
Rf 0.37 (n-hexane/AcOEt 5:5); mp ) 170-172 °C; 1H NMR
(CDCl3, δ) 2.91 (m, 2H), 4.0-4.20 (m, 2H), 4.40-4.56 (m, 4H),
5.01 (br, 1H), 7.23-7.77 (m, 13H), 8.35 (s, 1H); 13C NMR (CDCl3,
δ) 37.50, 47.25, 49.59, 52.43, 66.44, 120.07, 124.81, 127.17, 127.31,
127.87, 128.98, 129.10, 135.87, 141.37, 143.35, 143.60, 158.46;
HRMS calcd for C25H23N5O2 m/z 448.1749 (M+ + Na), found
448.1746.
Experimental Section
General Procedure for the Synthesis of N-Fmoc-ꢀ-Amino
Alkyl Isonitriles 3. Burgess reagent (3.58 g, 15.0 mmol) was added
to a solution of N-Fmoc-ꢀ-amino formamide (10.0 mmol) in dry
CH2Cl2 (20 mL), and the resulting mixture was refluxed at 50 °C
till completion of the reaction (TLC). The reaction mixture was
then rapidly washed with water (2 × 10 mL), dried immediately
over anhydrous Na2SO4, and filtered. The filtrate was concentrated
in vacuo to obtain the crude product, which was purified by column
chromatography (20% EtOAc in hexane; 100-200 mesh size,
MERCK column chromatography silica gel) to yield the isonitrile
as a white solid. Alternatively, the reaction mixture was concen-
trated under reduced pressure and the crude compound was directly
column chromatographed to obtain pure isonitrile.
General Procedure for the Synthesis of 1-Substituted Tet-
razoles 6. To 10.0 mmol of the isonitrile 3 in 20.0 mL of dry
methanol were added 1.31 mL (12.0 mmol) of trimethylsilyl azide
and 450.0 mg (2.0 mmol) of ZnBr2, and the mixture was refluxed
with stirring until completion of the reaction as evident by TLC
and disappearance of the isonitrile peak at 2158 cm-1 in the IR
spectrum. Methanol was then evaporated under reduced pressure,
and the residue was dissolved in 30 mL of ethyl acetate. The organic
layer was washed with water (2 × 15 mL) and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to obtain the crude
product, which was purified over silica gel column (100-200 mesh
size, MERCK column chromatoraphy silica gel; 50% EtOAc in
hexane) to yield the pure tetrazole as white solid.
(S)-(9H-Fluoren-9-yl)methyl 4-(2-(1H-Tetrazol-1-yl)ethyl)-5-
oxazolidine-3-carboxylate, 7b. Yield 75%; Rf 0.40 (n-hexane/
1
AcOEt 5:5); mp ) 56-58 °C; [R]23 ) -3.2 (c 0.9, CHCl3); H
D
NMR (CDCl3, δ) 2.71-3.69 (br, 2H), 4.18 (t, 2H, J ) 7.5 Hz),
4.67 (br, 2H), 4.98 (br, 1H), 5.20 (s, 2H), 7.18-7.79 (m, 8H), 8.82
(s, 1H), 13C NMR (CDCl3, δ) 29.69, 47.19, 52.04, 55.38, 67.21,
70.33, 120.20, 124.43, 127.40, 128.10, 141.38, 143.08, 143.15,
152.74, 170.82; HRMS calcd for C21H19N5O4 m/z 428.1335 (M+
+ Na), found 428.1345.
Acknowledgment. The authors thank the Department of
Science and Technology, Government of India for the financial
support of this work (Grant No. SR/S1/OC-26/2008). They also
thank Prof. H. S. Suryaprakash Rao of Pondichery University
and Prof. S. Chandrasekar of Indian Institute of Chemical
Technology, Hyderabad for the help in recording NMR and
HRMS spectra respectively. The Department of Organic Chem-
istry and Department of Inorganic and Physical Chemistry of
Indian Institute of Science, Bangalore are also acknowledged
for their support in obtaining spectral data.
Spectral Characterization Data of Representative Com-
pounds. (S)-(9H-Fluoren-9-yl)methyl 1-Formamidopropan-2-
yl Carbamate, Fmoc-Ala-ψ[CH2-NHCHO], 2b. Yield 92%; Rf
Supporting Information Available: General experimental
procedures for formamides 2 and product characterization data
of all the compounds discussed along with copies of 1H NMR,
13C NMR, and HRMS spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
0.21 (n-hexane/AcOEt 5:5); mp ) 134-136 °C; IR (KBr) υmax
)
1
1712, 1662 cm-1; H NMR (CDCl3, δ) 1.09 (d, 3H, J ) 6.8 Hz),
3.24 (br, 2H), 3.74 (m, 1H), 4.10 (t, 1H, J ) 5.6 Hz), 4.34 (d, 2H,
J ) 6.0), 5.05 (s, 1H), 6.25 (s, 1H), 7.18-7.78 (m, 8H), 8.04 (s,
1H); 13C NMR (CDCl3, δ) 17.95, 39.62, 42.76, 46.76, 65.72, 119.45,
124.67, 126.60, 127.21, 140.73, 143.48, 155.98, 161.69; HRMS
calcd for C19H20N2O3 m/z 347.1372 (M+ + Na), found 347.1381.
JO801527D
J. Org. Chem. Vol. 74, No. 1, 2009 157