Benzotriazol-1-yl-sulfonyl azide for diazotransfer and preparation of azidoacylbenzotriazoles

Article abstract of DOI:10.1021/jo101296s

Benzotriazol-1-yl-sulfonyl azide, a new crystalline, stable, and easily available diazotransfer reagent provides N-(α-azidoacyl)benzotriazoles convenient for N-, O-, C- and S-acylations. The efficient syntheses of various amides, azido protected peptides, esters, ketones and thioesters is reported together with a wide range of azides (including α-azido acids from α- amino acids in partially aqueous conditions) and diazo compounds.

Full text of DOI:10.1021/jo101296s

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Benzotriazol-1-yl-sulfonyl Azide for Diazotransfer and Preparation of
Azidoacylbenzotriazoles
Alan R. Katritzky,*,‡ Mirna El Khatib,‡ Oleg Bol’shakov,‡ Levan Khelashvili,‡ and
Peter J. Steel§
‡Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville,
Florida 32611-7200, and §Chemistry Department, University of Canterbury, Christchurch, New Zealand
katritzky@chem.ufl.edu
Received July 1, 2010
Benzotriazol-1-yl-sulfonyl azide, a new crystalline, stable, and easily available diazotransfer reagent
provides N-(R-azidoacyl)benzotriazoles convenient for N-, O-, C- and S-acylations. The efficient
syntheses of various amides, azido protected peptides, esters, ketones and thioesters is reported
together with a wide range of azides (including R-azido acids from R- amino acids in partially aqueous
conditions) and diazo compounds.
Introduction
depends on the degree of activation and the nature of the
selectivity required together with convenience in preparation
and use. We now report that N-(R-azidoacyl)benzotriazoles
are efficient agents for N-, O-, S-, and C- acylations that
introduce azide as a masked amino group.1,2a
The choice of an appropriate amino protecting group
depends on its stability and the conditions that can be
tolerated for its removal. Activation of the carboxyl group
Organic azides2b,3a have been utilized (i) as building
blocks,3 exemplified by the synthesis of natural products,4
(ii) in photoaffinity labeling,5 (iii) as drugs, such as anti-HIV
medication (AZT),6 and (iv) as masked amines such as in the
synthesis of oseltamivir phosphate Tamiflu.3a,7
(1) Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1996, 35,
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side antibiotics,3 glycosoaminoglycans,8 and peptidonucleic
acids (PNA)9 and in solid-phase peptide synthesis.10
Azides can be prepared by (i) classical nucleophilic displace-
ment with azide anion;11 however such reactions at the sp3
carbon may cause inversion, epimerization,12 or concurrent
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C. A.; Piantadosi, S; Modest, E. J. J. Med. Chem. 1991, 34, 1408–1414.
gate Chem. 2003, 14, 554–562. (b) Radominska, A.; Drake, R. R. Methods
Enzymol. 1994, 230, 330–339. (c) Buchmueller, K. L.; Hill, B. T.; Platz, M. S.;
Weeks, K. M. J. Am. Chem. Soc. 2003, 125, 10850–10861. (d) Pinney, K. G.;
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6532 J. Org. Chem. 2010, 75, 6532–6539
Published on Web 09/08/2010
DOI: 10.1021/jo101296s
r
2010 American Chemical Society

Katritzky et al.
JOCArticle
elimination and when performed in solvents such as DMF
and DMSO can hinder isolation of the azide product; (ii)
reactions of aryldiazonium salts with inorganic azides;13 (iii)
catalyzed displacement by sodium azide with aryl and vinyl
boronic acids,14 or (iv) catalyzed displacement by sodium
azide with aryl halides.15
SCHEME 1. Synthesis of Benzotriazol-1-sulfonyl Azide 1
The alternative preparation of azides from amines by
diazo transfer16a avoids epimerization, inversion, and elim-
ination. An ideal diazotransfer reagent should be crystalline
(for ease of purification, handling16b and stability), non-
explosive, easily prepared, and of general applicability for
diazotransfer. p-Tosyl azide, the classical diazotransfer re-
agent, melts at 21-22 °C,17a and requires relatively harsh
conditions that limit its use.17b Suggested replacements include
(i) mesyl azide,18 an oil needing distillation at 56 °C (0.5 mm.
Choice of activation for an R-azido acid is important: (i)
acyl halides tend to be over-activated26,27 and require base
for neutralizing the hydrogen halide formed;2a (ii) acid
anhydrides easily form imides with ammonia and primary
amines; (iii) esters are frequently under-activated and
require basic catalysts and/or high pressure,26,27 By contrast
N-acylbenzotriazoles are efficient neutral acylating agents
and form amide bonds at ambient temperatures with un-
protected amino acids in aqueous/organic solvents resisting
side reactions in the preparation of N-terminal protected
peptides.23,28 Thus N-(protected-R-aminoacyl)benzotriazoles
have enabled fast preparations of biologically relevant pep-
tides and peptide conjugates in high yields and purity, under
mild reaction conditions, with full retention of the original
chirality.29
Hg); (ii) polystyrene-supported benzenesulfonyl azide,19
a
safe-to-handle but insoluble resin; (iii) oligomer-bound ben-
zenesulfonyl azide,20 which is insoluble in most organic
solvents, lacks long-term stability, and needs to be utilized
within 1-2 weeks; (iv) imidazole-1-sulfonyl azide,16 a color-
less oil used as crystalline hydrochloride salt; and (v) the
most commonly used “diazo-transfer reagent” of amines to
azides, trifluoromethanesulfonyl azide (TfN3),7,16,17b,21 pre-
pared from sodium azide and trifluoromethanesulfonic an-
hydride, which has a poor shelf life and must be used in situ as
a solution because of its explosive nature. Thus, the synthesis
of an improved diazotransfer reagent is of considerable
interest. We have prepared benzotriazol-1-sulfonyl azide,
1, convenient for converting R-amino acids into R-azido
acids (see later).
In R-azido acyl groups the azide both masks the amine
functionality and strongly activates the carboxyl moiety,22
thus facilitating the formation of peptide bonds.23 The small
size of the azide unit in comparison to, e.g., Boc or Fmoc may
assist in hindered coupling. The azide group is stable under
both acidic and basic conditions and toward osmium-3a,24
and ruthenium-catalyzed dihydroxylation or alkylation.3a,25
Results and Discussion
Preparation and Characterization of Benzotriazol-1-yl-sul-
fonyl Azide 1. We react chlorosulfonyl azide, prepared in situ
from sodium azide and sulfuryl chloride, with benzotriazole
(2 equiv) and pyridine (1 equiv) in MeCN to give benzotria-
zol-1-yl-sulfonyl azide 1 (70%, obtained after aqueous
workup) as a white crystalline solid (mp 85.3-88.3 °C)
requiring no further purification (Scheme 1). The reagent 1
as a dry solid has a long shelf life at room temperature and
could be utilized 6 weeks after its preparation. (Caution:
appropriate safety measures must always be taken at all
times because azides are high energy compounds). Reagent 1
is soluble in many organic solvents as well as in partially
aqueous conditions (e.g., MeCN, CH2Cl2, MeOH, EtOAc,
MeCN/H2O (1:1)).
(12) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
Chem. Soc. 1990, 112, 4011–4030.
The detailed molecular structure of benzotriazol-1-yl-
sulfonyl azide 1 was established by X-ray diffraction analysis
(see Supporting Information).
(13) Das, J.; Patil, S. N.; Awasthi, R.; Narasimhulu, C. P.; Trehan, S.
Synthesis 2005, 1801–1806.
(14) Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X. Tetra-
hedron Lett. 2007, 48, 3525–3529.
Thermogravimetric analysis (TGA) shows that 64 wt % of
1 is lost around 112 °C. Differential scanning calorimetry
(DSC) shows that 1 is stable below 95 °C melting and
resolidifying (see Figure 1, which shows 2 cycles of heating
to 95 °C and cooling to -100 °C). The heats of fusion (166.7
J/g for cycle 1 and 163.8 J/g for cycle 2) and heats of freezing
(114.1 J/g for cycle 1 and 101.4 J/g for cycle 2) show that there
is negligible material loss (see Supporting Information).
Preparation of Azides by the Reaction of Benzotriazole-1-
sulfonyl Azide 1 with Primary Amines. Benzotriazol-1-yl-sulfonyl
azide 1converted amine compounds 2a-finto the corresponding
azides 3a-f (in 47-85% yields, average 64%), without requiring
a base. In a typical reaction, benzotriazol-1-yl-sulfonyl azide 1
(15) Zhu, W.; Ma, D. Chem. Commun. 2004, 888–889.
(16) (a) For a proposal of the diazotransfer mechanism see: Nyffler, P. T.;
Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J. Am. Chem. Soc. 2002, 124,
10773–10778. and references therein. (b) Goddard-Borger, E. D.; Stick,
R. V. Org. Lett. 2007, 9, 3797–3800.
(17) (a) Curphey, T. J. Org. Prep. Proced. Int. 1981, 13, 112–115. (b) Liu,
Q.; Tor, Y. Org. Lett. 2003, 5, 2571–2572. (c) Somnath, G.; Indira, D. Synth.
Commun. 1991, 21, 191–200. (d) Doyle, K. J.; Moody, C. J. Tetrahedron.
1994, 50, 3761–3772.
(18) (a) Boyer, J. H.; Mack, C. H.; Goebel, N.; Morgan, L. R., Jr. J. Org.
Chem. 1958, 23, 1051–1052. (b) Taber, D. F.; Ruckle, R. E., Jr.; Hennessy,
M. J. J. Org. Chem. 1986, 51, 4077–4078.
(19) Green, G. M.; Peet, N. P.; Metz, W. A. J. Org. Chem. 2001, 66, 2509–
2511.
(20) Harned, A. M.; Sherrill, W. M; Flynn, D. L.; Hanson, P. R. Tetra-
hedron 2005, 61, 12093–12099.
(21) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 37,
6029–6032.
(22) Rijkers, D. T. S.; Ricardo van Vugt, H. H.; Jacobs, H. J. F.; Liskamp,
R. M. J. Tetrahedron Lett. 2002, 43, 3657–3660.
(23) Katritzky, A. R.; Angrish, P.; Suzuki, K. Synthesis 2005, 411–424.
(24) Ainai, T.; Wang, Y.-G.; Tokoro, Y.; Kobayashi, Y. J. Org. Chem.
2004, 69, 655–659.
(25) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353–3356.
(26) March, J. Advanced Organic Chemistry, 4th ed.; John Wiley & Sons:
New York, 1992; pp 416-425.
(27) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65,
8210–8213.
(28) (a) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis 2004, 2645–
2652. (b) Katritzky, A. R.; Angrish, P.; Todadze, E. Synlett 2009, 2392–2411.
(c) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synthesis 2005, 1656–1665.
(29) Katritzky, A. R.; Khelashvili, L.; Munawar, M. A. J. Org. Chem.
2008, 73, 9171–9173.
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JOCArticle
FIGURE 1. Differential scanning calorimetry of 1 (heats of fusion and freezing are recorded in Supporting Information).
TABLE 1. Synthesis of Azides from Primary Aromatic Amines Utilizing 1
REt3N (1 equiv) was required.
reacted with an amine in methanol at room temperature in the
presence of copper(II) sulfate (Table 1). The reaction of benzo-
triazol-1-yl-sulfonyl azide 1with 4-methoxyphenylamine 2a with-
out catalyst gave 4-methoxyphenyl azide 3a (57%) after 24 h.
Preparation of r-Azido Acids by the Reaction of Benzo-
triazole-1-sulfonyl Azide 1 with Amino Acids. Benzotriazol-1-
yl-sulfonyl azide 1 reacted with free amino acids 4a-e, (4a þ
4a0) at 20 °C in aqueous CH3CN in the presence of Et3N and
copper(II) sulfate to give corresponding R-azido acids 5a-e,
(5a þ 5a0) in good yield (60-87%, average 70%) (Table 2).
HPLC analysis [chirobiotic T column (250 mm ꢀ 4.6 mm),
detection at 254 nm, flow rate 0.5 mL/min, MeOH] on 5a
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SCHEME 2. Proposed Mechanism for the Formation of Diazo Compounds 12
TABLE 2. Synthesis of R-Azido Acids from R-Amino Acids Utilizing 1
TABLE 3. Synthesis of N-(R-Azidoacyl)benzotriazoles 6 from R-Azido
Acids
entry
substrate
L-Phe, 4a
product
5a
5b
time (h)
yield (%)
R-azido acids, 5
product
6a
6b
yield (%)
mp (°C)
1
2
3
4
5
6
12
12
12
12
12
12
65
65
60
65
87
77
N3-L-Phe, 5a
N3-L-Leu, 5d
98
96
65
98
72
66.1-68.3
47.3-49.0
77.0-77.9
oil
L-Leu, 4b
L-Ala, 4c
5c
DL-Phe, (4a þ 4a0)
(5a þ 5a0)
N3-L-Ala, 5c
N3-DL-Phe, (5a þ 5a0)
6c
(6a þ 6a0)
L-Val, 4d
(L-Cys)2, 4e
5d
5e
N3-L-Val, 5d
6d
oil
(single peak, retention time 7.2 min) and (5a þ 5a0) (two
equal peaks, retention times 6.7 and 7.2 min) confirmed that
product 5a is enantiomerically pure.
The details of the interconversion of an amine into an
azide are not well established. The mechanism for diazo-
transfer has been proposed involving a tetrazene intermedi-
ate. The mechanism incorporates a divalent metal ion that
complexes with the amine. The amine in this complex is then
thought to attack the electrophilic azide.16a
case ligation occurs spontaneously providing the N-acylated
dipeptides containing free thiol in the absence of base.
O-, S-, and C-Acylation. Similarly, the reactivity of
N-(R-azidoacyl)benzotriazoles 6a-c, (6a þ 6a0) was tested
against a variety of O-, S-, and C- nucleophiles (Table 5). As
expected, azide as a protecting group is well tolerated, and
N-(R-azidoacyl)benzotriazoles 6 could be used in the acy-
lation of phenols, alcohols (including sterols), thiols, and
stabilized enolates (Table 5).
Preparation of Diazo Compounds by the Reaction of Ben-
zotriazole-1-sulfonyl Azide 1 with Activated Methylene Sub-
strates. Diazo compounds are versatile synthetic building
blocks31 with rich transition-metal-catalyzed chemistry.32
Thus, carbene insertion into C-H bonds has increased in
importance since its discovery by Meerwein and Werner.33
We utilized benzotriazol-1-yl-sulfonyl azide 1 in the prepara-
tion of diazo compounds 12a,b containing activated methy-
lene groups, and the results are summarized in Table 6. In
general, yields and reaction times compare favorably with
those reported in the literature using the most recent diazo-
transfer reagent, imidazole-1-sulfonyl azide hydrochloride.16
We believe that the formation of diazo compounds from
activated CH2 groups via diazotransfer occurs through a nucleo-
philic attack of an intermediate enolate 13 onto benzotriazol-1-yl-
sulfonyl azide 1, followed by proton transfer to give intermediate
14. In the presence of base, intermediate 15 is formed, which is
converted to the desired diazo product 12 (Scheme 2).
Preparation of N-(r-Azidoacyl)benzotriazoles. N-(R-Azi-
doacyl)benzotriazoles 6a-d, (6a þ 6a0) were prepared in
good yields (65-98%) by the treatment of the corresponding
R-azido acids 5a-d, (5a þ 5a0) with 1.2 equiv of thionyl
chloride and 2 equiv of benzotriazole in methylene chloride
(Table 3).
N-Acylation. The reliability of N-(R-azidoacyl)benzotriazoles
as acylating agents was tested on a variety of N-nucleophiles to
provide amides 8a-k in 62-87% yields (Table 4). The azide
demonstrated its functional group tolerance as a protecting
group in N-acylation of aromatic, aliphatic amines and free
amino acids (including free cysteine), nucleobases, nucleosides,
and sulfonamides. HPLC analysis [chiracel OD-H column (250
mm ꢀ 4.6 mm), detection at 254 nm, flow rate 0.5 mL/min,
hexane/isopropyl alcohol (90:10)] on 8a (single peak, retention
time 50.8 min) and 8g (two equal peaks, retention times 47.6 and
51.4 min) confirmed that product 8a is enantiomerically pure
(Figure 2) (this was also confirmed with a co-injection).
Entries 9 and 10 (Table 4) were performed without added base
with the objective of forming S-acylated products according to a
reported literature method by our group where S-acylation was
performed on aryl N-acylbenzotriazoles.30 It is expected that
S-acylation occurs first giving the thioester product, followed by
S- to N-shift to provide the amide linkage. Interestingly, in this
Conclusions
Benzotriazol-1-yl-sulfonyl azide 1 is a new, stable, and safe
to handle crystalline diazotransfer reagent with a long shelf
(31) Maas, G. Angew. Chem., Int. Ed. 2009, 48, 8186–8195.
(32) (a) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137–1156.
(b) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2903.
(c) Davies, H. M. L.; Antoulinakis, E. G. J. Organomet. Chem. 2001,
617-618, 47–55.
(30) Katritzky, A. R.; Tala, S. R.; Abo-Dya, N. E.; Gyanda, K.;
El-Gendy, B. E. M.; Abdel-Samii, Z. K.; Steel, P. J. J. Org. Chem. 2009,
74, 7165–7167.
(33) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160.
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TABLE 4. Synthesis of Amides from N-(R-Azidoacyl)benzotriazoles 6
life and high solubility in organic and aqueous solvents,
which allows convenient and efficient synthesis of a wide
range of azides and diazo compounds, including N-(R-azidoacyl)-
benzotriazoles, which are efficient N-, S-, C-, and O-acylating
agents and enable facile preparation of azido-peptides.
0.15 mol) was dissolved in pyridine (6.46 mL, 0.08 mol) and
acetonitrile (10 mL), and the solution was added to the suspen-
sion at 0 °C. The resulting suspension was stirred for 10 h at
room temperature. The unreacted solid was filtered, and the
yellow-orange filtrate was evaporated and then diluted with
ethyl acetate. The organic layer was then washed with a satu-
rated solution of sodium carbonate to remove the excess of benzo-
triazole, dried over anhydrous MgSO4, and filtered. The filtrate
was dried under vacuum to give a light brown solid that was later
used directly. Recrystallization using hexane/EtOAc 7:3 gave a
white crystalline solid (12.5 g, 70%): mp 85.3-88.3 °C; 1H NMR
(300 MHz, CDCl3) δ 8.17 (d, J = 8.4, 1H), 7.91 (d, J = 8.4 Hz,
1H), 7.72 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 145.3, 131.6, 126.9, 121.3, 112.1. Anal.
Calcd for C6H4N6O2S: C, 32.14; H, 1.80; N, 37.48. Found: C,
Experimental Section
Melting points were determined on a capillary point appara-
tus equipped with a digital thermometer and are uncorrected.
The NMR spectra were recorded in CDCl3, DMSO-d6 with
TMS for 1H (300 MHz) and 13C (75 MHz) as an internal
reference. Silica was used as the stationary phase for column
chromatography.
Benzotriazol-1-yl-sulfonyl Azide (1). Sulfuryl chloride (6.23
mL, 0.08 mol) was added portion-wise to a suspension of NaN3
(5 g, 0.08 mol) in MeCN (25 mL) at 0 °C, and the mixture was
stirred overnight at room temperature. Benzotriazole (18.35 g,
1
32.18; H, 1.74; N, 37.27. NOTE: H NMR on reagent 1 was
performed after it had been stored in a closed clear glass vial at
room temperature for a period of 6 weeks, showing its longevity.
6536 J. Org. Chem. Vol. 75, No. 19, 2010

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FIGURE 2. HPLC analysis for compounds 8a and 8g.
A moderate exothermic decomposition was noted when the
hammer test was performed on 1. [Caution: Although no
trouble was noted when utilizing sodium azide, the in situ
generated chlorosulfonyl azide, or any of the synthesized orga-
nic azides, appropriate safety measures must always be taken at
chromatography (hexane/EtOAc, 9.8:0.2)] to give 1-azido-3-
nitrobenzene 3c3 as a yellow solid (209 mg, 57%): mp
1
53.1-54.5 °C; H NMR (300 MHz, CDCl3) δ 8.01-7.98 (m,
1H), 7.89 (t, J = 2.1 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.35 (dd,
J = 1.8, 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 141.9, 130.6,
124.9, 119.7, 114.1.
all times because azides are high energy compounds.3a,7,34
]
General Procedure for the Preparation of Azides, 3a-f. Ben-
zotriazol-1-yl-sulfonyl azide 1 (0.50 g, 2.23 mmol) was added to
the amine (2.23 mmol) in MeOH (20 mL). CuSO4 5H2O (2.5
mg, 10 μmol) was then added, and the mixture was stirred at
room temperature for the specified time (Table 1). The mixture was
concentrated, diluted with water (20 mL), and extracted with ethyl
acetate. The organic layer was dried over anhydrous MgSO4,
filtered, and concentrated. Purification was performed via flash
column chromatography to give the corresponding azide.
3-Azidopyridine (3d). Pyridin-3-amine (210 mg, 2.23 mmol)
was treated according to the above procedure [flash chroma-
tography (hexane)] to give 3-azidopyridine 3d4 as a pale yellow
oil (126 mg, 47%): 1H NMR (300 MHz, CDCl3) δ 8.41-8.35 (m,
2H), 7.38-7.27 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 145.8,
141.1, 137.0, 125.8, 124.0.
3
(2-Azidoethyl)benzene (3e). 2-Phenylethanamine (270 mg,
2.23 mmol) was treated according to the above procedure [chro-
matography (hexane)] to give (2-azidoethyl)benzene 3e5 as color-
less oil (279 mg, 85%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.23
1-Azido-4-methoxybenzene (3a). 4-Methoxyaniline (275 mg,
2.23 mmol) was treated according to the above procedure [flash
chromatography (hexane/EtOAc, 9:1)] to give 1-azido-4-meth-
(m, 5H), 3.52 (t, J = 7.4 Hz, 2H), 2.92 (t, J = 7.2 Hz, 2H); 13
C
NMR (75 MHz, CDCl3) δ 137.9, 128.6, 128.5, 126.7, 52.4, 35.3.
(1S,2S,3S,5R)-3-(Azidomethyl)-2,6,6-trimethylbicyclo[3.1.1]-
heptanes (3f). (þ)-3-Pinanemethylamine hydrochloride (454 mg,
2.23 mmol) and triethyl amine (1 equiv) were treated according
to the above procedure [flash chromatography (hexane)] to
give (1S,2S,3S,5R)-3-(azidomethyl)-2,6,6-trimethylbicyclo-
1
oxybenzene 3a1 as a pale yellow oil (233 mg, 70%): H NMR
(300 MHz, CDCl3) δ 6.98-6.87 (m, 4H), 3.80 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 156.9, 132.3, 120.0, 115.1, 55.6.
1-Azido-4-bromobenzene (3b). 4-Bromoaniline (384 mg, 2.23
mmol) was treated according to the above procedure [flash
chromatography (hexane)] to give 1-azido-4-bromobenzene
20
[3.1.1]heptanes 3f as a yellow oil (220 mg, 51%): [R]D þ6.9 (c
1
3b2 as a pale yellow oil (332 mg, 75%): H NMR (300 MHz,
1.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.32 (dd, J = 5.7,
11.7 Hz, 1H), 3.18 (dd, J = 7.5, 11.7 Hz, 1H), 2.35-2.26 (m,
1H), 2.22-2.12 (m, 1H), 2.04-1.89 (m, 2H), 1.81-1.68 (m, 2H),
1.59-1.51 (m, 1H), 1.20 (s, 3H), 1.07 (dd, J = 1.5, 7.2 Hz, 3H),
1.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 59.6, 47.7, 41.3, 40.5,
38.8, 36.5, 33.5, 32.2, 27.9, 22.9, 21.6; HRMS m/z for C11H20N
[M - N2 þ H]þ calcd 166.1590, found 166.1593.
CDCl3) δ 7.47-7.44 (m, 2H), 6.92-6.88 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 139.2, 132.7, 120.6, 117.7.
1-Azido-3-nitrobenzene (3c). 3-Nitroaniline (308 mg, 2.23
mmol) was treated according to the above procedure [flash
(34) Griffiths, J. J. Chem. Soc. C 1971, 19, 3191–3195.
J. Org. Chem. Vol. 75, No. 19, 2010 6537

Katritzky et al.
JOCArticle
TABLE 5. O-, S-, and C-Acylations Utilizing N-(R-Azidoacyl)benzotriazoles 6
TABLE 6. Synthesis of Diazo Compounds Utilizing 1
was added to the solution followed by CuSO4 5H2O (2.5 mg, 10
3
μmol), and the mixture stirred at room temperature for 12 h. The
mixture was then acidified with 6 N HCl, concentrated, and then
diluted with ethyl acetate. This was washed with 6 N HCl to
remove benzotriazole. The organic layer was collected, dried
over anhydrous MgSO4, filtered, and concentrated to give the
corresponding R-azido acid 5.
(2S)-2-Azido-3-phenylpropanoic Acid (5a). L-Phenylalanine
(736 mg, 4.46 mmol) was treated according to the above
procedure to give (2S)-2-azido-3-phenylpropanoic acid 5a6 as
a pale yellow oil (278 mg, 65%): 1H NMR (300 MHz, CDCl3) δ
9.90 (s, 1H), 7.38-7.27 (m, 5H), 4.15 (dd, J = 4.8, 9.0 Hz, 1H),
3.22 (d, J = 5.1 Hz, 1H), 3.08-3.03 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 175.7, 135.6, 129.2, 128.8, 127.4, 63.1, 37.5.
(S)-2-Azido-4-methylpentanoic Acid (5b). L-Leucine (586 mg,
4.46 mmol) was treated according to the above procedure to give
(S)-2-azido-4-methylpentanoic acid 5b7 as a pale yellow oil
product
R
R0
time [lit.]a (h)
yield [lit.]a (%)
12a
12b
CN
SO2Ph
CO2Et
CO2Et
12 [9]
14 [48]
65 [61]
56 [-]b
aReaction with imidazole-1-sulfonyl azide. bNo reaction was observed
using imidazole-1-sulfonyl azide hydrochloride.16
General Procedure for the Preparation of r-Azido Acids, 5a-e
(5a þ 5a0). The amino acid (4.46 mmol, 2 equiv) was dissolved in
MeCN/H2O (1:1, 20 mL) and triethyl amine (0.78 mL, 5.58
mmol). Benzotriazol-1-yl-sulfonyl azide 1 (0.50 g, 2.23 mmol)
6538 J. Org. Chem. Vol. 75, No. 19, 2010

Katritzky et al.
JOCArticle
(228 mg, 65%): 1H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 3.88
(dd, J = 5.7, 9.0 Hz, 1H), 1.89-1.77 (m, 1H), 1.76-1.64 (m,
2H), 1.00-0.96 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 177.0,
60.0, 39.8, 25.0, 22.7, 21.4.
(S)-2-Azidopropanoic Acid (5c). L-Alanine (396 mg, 4.46
mmol) was treated according to the above procedure to give
(S)-2-azidopropanoic acid 5c8 as a yellow oil (154 mg, 60%): 1H
NMR (300 MHz, CDCl3) δ 4.56 (s, 1H), 4.03 (q, J = 7.1 Hz,
1H), 1.54 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
177.0, 57.0, 16.6.
2-Azido-3-phenylpropanoic Acid (5a þ 5a0). D,L-Phenylala-
nine (736 mg, 4.46 mmol) was treated according to the above
procedure to give 2-azido-3-phenylpropanoic acid (5a þ a0)7
as a pale yellow oil (278 mg, 65%): 1H NMR (300 MHz,
CDCl3) δ 7.38-7.25 (m, 5H), 4.17 (dd, J = 5.0, 8.9 Hz, 1H),
3.25 (dd, J = 5.0, 14.0 Hz, 1H), 3.05 (dd, J = 8.9, 14.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 175.6, 135.5 129.2, 128.8,
127.4, 63.0, 37.5.
(277 mg, 87%): 1H NMR (300 MHz, CDCl3) δ 11.8 (s, 1H), 3.76
(d, J = 5.7 Hz, 1H), 2.27-2.17 (m, 1H), 1.02 (dd, J = 6.9, 15 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 176.5, 67.8, 30.8, 19.3, 17.6.
2-Azido-3-(((R)-2-azido-2-carboxyethyl)disulfanyl)propanoic
Acid (5e). L-Cystine (268 mg, 1.12 mmol) was treated according
to the above procedure to give 2-azido-3-(((R)-2-azido-2-
carboxyethyl)disulfanyl)propanoic acid 5e as an orange-brown
oil (252 mg, 77%); [R]D20 -37.7 (c 1.3, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.59 (bs, 2H), 4.43 (dd, J = 5.0, 7.1 Hz, 2H),
3.32 (dd, J = 5.0, 14.0 Hz, 2H), 3.03 (dd, J = 7.2, 13.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 174.4, 60.8, 39.9; HRMS m/z for
C6H8O4N6S2Na [M þ Na]þ calcd 314.9941, found 314.9940.
Acknowledgment. We thank Dr. C. D. Hall for helpful
discussions.
Supporting Information Available: X-ray analysis and
thermo analytical measurements for 1, experimental details,
and 1H and 13C NMR for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(S)-2-Azido-3-methylbutanoic Acid (5d). L-Valine (523 mg,
4.46 mmol) was treated according to the above procedure
to give (S)-2-azido-3-methylbutanoic acid 5d7 as a yellow oil
J. Org. Chem. Vol. 75, No. 19, 2010 6539