Azidation of β-carbonyl lactones and lactams

Article abstract of DOI:10.1016/j.tetlet.2009.07.039

The direct azidation of various heterocyclic β-ketoesters, lactones, and lactams is reported. By using tosylazide and an organic base such as l-proline or TBD, the direct α-insertion of azide into these substrates was achieved in moderate to good yields,

Full text of DOI:10.1016/j.tetlet.2009.07.039

Tetrahedron Letters 50 (2009) 5379–5381
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Azidation of b-carbonyl lactones and lactams
*
*
Dhurke Kashinath, Ghyslain Budin, Rachid Baati, Stéphane Meunier , Alain Wagner
Laboratory of Functional Chemo-Systems, UMR 7199, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, BP24, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct azidation of various heterocyclic b-ketoesters, lactones, and lactams is reported. By using tosy-
Received 19 May 2009
Revised 6 July 2009
Accepted 7 July 2009
Available online 25 July 2009
lazide and an organic base such as
was achieved in moderate to good yields, without competitive deacylating diazo transfer. This procedure
represents an interesting alternative to the usual two-step approach of
displacement with azide ion.
L-proline or TBD, the direct a-insertion of azide into these substrates
a-halogenation and subsequent
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Azidation
Proline
TBD
Dicarbonyl
TsN3
The high versatility of organic azides made them very useful in
organic synthesis. They are reported to react with electrophiles,
nucleophiles, and radical species and to yield reactive nitrenes un-
der thermal and photochemical conditions.1 Azides are easily con-
verted into amines by the Staudinger reaction,2 and are useful for
the preparation of various types of heterocycles.3 Furthermore,
they act as 1,3-dipoles in cycloaddition reactions and have been
extensively used in the highly robust Huisgen azide–alkyne 1,3-
dipolar cycloaddition under thermal activation or under Cu(I)
catalysis.4
transformation only when extended cyclic or hindered substrates
are engaged (Fig. 1).6a,c
Given our synthetic constraints, we sought a direct azidation
reaction, instead of a two-step procedure through a-halogenation
and subsequent displacement of halide with azide ion.7 Consider-
ing the above-mentioned literature data, we anticipated that the
study of the reactivity of sulfonyl azides toward a collection of het-
erocyclic b-ketoesters (Scheme 1, X = O, NH) would be of interest to
the synthetic community.
In preliminary experiments, our model substrate 2-acetyl-c-
In the course of our synthetic work we envisioned direct azida-
tion of heterocyclic b-ketoesters (Scheme 1, X = O) by using sulfo-
nyl azides. Heterocyclic b-ketoesters have been extensively studied
in synthetic chemistry,5 that is, in various C-alkylation reactions,5a
electrophilic amination,5b,c halogenations,5d or for addition to Mi-
chael acceptors.5e–g Surprisingly, studies devoted to their direct
azidation have not been reported in the literature thus far (Scheme
1, path b). The closest related works have mentioned the reactivity
of sulfonyl azides with carbocyclic b-ketoesters (Scheme 1,
X = CH2).6 These studies revealed two-competitive reactions: the
usually major deacylating diazo transfer (Scheme 1, pathway a)
and the minor azido group transfer reaction (Scheme 1, pathway
b).6 The ratio between these two possible pathways depends on
the nature of the sulfonyl azide reagent and on the nature of the
substrate; the azido group transfer reaction being the dominant
butyrolactone 1a was treated under two reported conditions: by
O
O
O
CO2CH3
N3
CO2C2H5
CO2C2H5
N3
N3
O
Figure 1. Examples of reported azidocarbocyclic b-ketoesters.
O
N2
Y
a
( )n
ArO2SHN
X
O
O
O
X
ArSO2N3
+
Y
( )n
O
X
O
X = CH2, O, NH
Y = CH3, OAlk
n = 1, 2, 3
b
Y
N3
( )n
* Corresponding authors. Tel.: +33 3 90 24 42 95; fax: +33 3 90 24 43 06 (S.M.),
tel.: +33 3 90 24 42 97; fax: +33 3 90 24 43 06 (A.W.).
E-mail addresses: meunier@bioorga.u-strasbg.fr (S. Meunier), wagner@bioorga.
u-strasbg.fr (A. Wagner).
Scheme 1. Reactivity of sulfonyl azides toward heterocyclic and carbocyclic
b-ketoesters.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.039

5380
D. Kashinath et al. / Tetrahedron Letters 50 (2009) 5379–5381
generating triflic azide in situ,8 and by using a combination of trim-
ethylsilylazide and iodosobenzene.9 Both these conditions gave the
desired azido transfer product 2a in poor yield (32% and 5%, respec-
tively, Scheme 2).
Table 2
Azidation of selected heterocyclic b-ketoestersa
Entry Substrate
Base Solvent Product
Yieldb
(%)
We then focused on the use of commercially available tosylaz-
ide (TsN3) with organic bases. First, we followed the conditions
used for the preparation of examples shown in Figure 1. However,
in the presence of 1 equiv of TsN3 and 1 equiv of TEA (triethyl-
amine) or DBU (1,8-diaza-bicyclo[5,4,0]undec-7-ene) no reaction
was observed after 72 h in DCM (Table 1, entries 1 and 2). Changing
the base to TBD (1,5,7-triazabicyclo[4.4.0]dec-1-ene), previously
studied by our group for its high reactivity,10 afforded the expected
azido product 2a in moderate to good yields in DCM, toluene, and
O
O
O
O
1
2
L
L
-Pro DMSO
-Pro DMSO
38
30
2b
2c
1b
1c
O
O
OEt
OEt
N3
O
O
O
O
HN
O
HN
O
OEt
OEt
N3
THF (Table 1, entries 3–5). We then turned our attention to
line, known to be a good activator of 1,3-dicarbonyl compounds.11
Treating 1a with 1 equiv of TsN3 and 1 equiv of -proline in DMF for
L-pro-
O
O
O
O
3
4
5
L
-Pro DMSO
12
66
52
L
HN
OEt
HN
OEt
1d
1e
2d
2e
72 h at room temperature afforded 2a in 52% of yield (Table 1, en-
try 6). The best azidation result was obtained by changing the sol-
vent to DMSO, affording in this case, the desired azidation product
2a in 62% yield along with the recovery of 15% of the starting mate-
rial (Table 1, entry 7). The use of both reagents in excess did not
change the efficiency of the reaction. Importantly, in none of these
reactions were the products of the competitive deacylating diazo
transfer reaction detected (Scheme 1).
TBD DCM
DBU DCM
N3
O
O
O
O
O
O
6
7
8
L
-Pro DMSO
0
HN
OEt
HN
OEt
TBD DCM
DBU DCM
78c
83c
N3
a
b
c
Having successfully synthesized the azido derivative of 2-acet-
yl-c-butyrolactone 1a, we moved our attention toward demon-
strating the generality of the strategy starting from various
heterocyclic b-ketoesters, lactones, and lactams. Compounds 1b–
d were prepared following the literature procedures,12 whereas
compound 1e is commercially available. When treated under the
TsN3 (1 equiv), base (1 equiv), 72 h at rt.
Yields are reported for pure products.
48 h at rt.
was very low, only 2d could be obtained in 12% yield (Table 2, en-
tries 3 and 6). Surprisingly, in the case of 1d–e, the use of TBD or
DBU improved the formation of the azidation products 2d–e to a
large extent (Table 2, entries 4–5 and 7–8). All the resulting azides
were characterized from spectral data.13 It is noteworthy to men-
tion that in none of these reactions the deacylating diazo transfer
adduct (Scheme 1, pathway a) was formed in an isolable amount.
Instead, the unreacted starting material could be recovered almost
quantitatively.
optimized conditions in the presence of L-proline, five-membered
lactone 1b and five-membered lactam 1c afforded the desired azi-
do compounds 2b and 2c in moderate yields (Table 2, entries 1 and
2). Lower yields (<20%) were obtained using TBD, DBU, or TEA as
base (in DCM) instead of
L-proline. For six-membered lactams
1d–e, -proline failed to afford the desired azidation products in
L
acceptable yields. In both cases, the starting material conversion
Considering the above-mentioned results, it appears that the
azidation reaction is highly sensitive to the substrate’s structure
and this preliminary study did not allow us to draw any general
conclusions. Yields were found to be reproducible, but depending
on the base used, the outcome of the reaction is not easily
predictable.
Finally, compound 2e was used in further transformations to as-
say the azide moiety reactivity. Under classical Staudinger reaction
conditions the azido compound 2e could be converted into the
amino product 3, in a moderate but non-optimized yield (Scheme
3).14 Moreover, as an example of click reaction, 2e was engaged in a
Huisgen azide–alkyne 1,3-dipolar cycloaddition catalyzed by Cu(I),
O
O
O
O
(i) or (ii)
O
O
N3
1a
2a
(i) NaN3, F3CSO2Cl, Et3N, dry DMF, RT, 32%
(ii) Me3SiN3, (PhIO)n, dry THF, <5%
Scheme 2. Azidation of 2-acetyl-
c
-butyrolactone 1a using literature methods.
Table 1
Azidation of 2-acetyl-
c
-butyrolactone 1a
O
O
O
O
TsN3 (1 equiv)
Base (1 equiv)
O
O
O
O
O
O
PPh (1 equiv)
3
HN
OEt
N3
HN
OEt
2
N
RT, 72 h
3
NH
Toluene:HCl (5%)
RT, 12 h
1a
Base
2a
2e
3
Entry
Solvent
Yielda (%)
51 %
Ph
(1 equiv)
tBuOH/H O, RT
2
1
2
3
4
5
6
7
TEA
DBU
TBD
TBD
TBD
DCM
DCM
DCM
0
0
CuSO (10 mol%)
Sodium ascobate
4
overnight
45 %
O
42
38
56
52b
62b
O
Toluene
THF
HN
OEt
N
L
-Pro
-Pro
DMF
DMSO
L
N
N
4
a
Yields are reported for pure products.
Racemic compound.
b
Scheme 3. Reactivity of azido compound 2e.

D. Kashinath et al. / Tetrahedron Letters 50 (2009) 5379–5381
5381
10. (a) Sabot, C.; Kumar, K. A.; Antheaume, C.; Mioskowski, C. J. Org. Chem. 2007, 72,
5001–5004; (b) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron
Lett. 2007, 78, 3863–3866; (c) Ghobril, C.; Sabot, C.; Mioskowski, C.; Baati, R.
Eur. J. Org. Chem. 2008, 4104–4108.
11. Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693–4695.
12. Hamashima, Y.; Ishikura, K.; Kubota, T.; Minami, K. US Patent 4,578,378, 1986.
with phenylacetylene affording compound 4, in a medium but non-
optimized yield (Scheme 3).15
In conclusion, direct azidation of heterocyclic b-ketoesters using
TsN3 and organic bases was studied. Each selected substrate could
be converted into the azido derivative in moderate to good yields.
It appears that base plays a critical role in the outcome of the reac-
13. General procedure for the azidation reaction: To a solution of
(100 mg, 0.7 mmol) in dry DMSO (5 mL) was added TsN3 (153 mg, 0.7 mmol)
followed by -proline (89 mg, 0.7 mmol) and the mixture was allowed to stir at
c-butyrolactone 1a
L
tion. Results showed that L-proline should be preferred for the azi-
rt for 72 h. The reaction mixture was diluted with water (10 mL) and extracted
with CH2Cl2 (2 Â 10 mL). The organic layers were dried over Na2SO4 and
concentrated under reduced pressure to give the crude product, which was
purified by silica gel column chromatography. Elution of the column with
ethylacetate:cyclohexane (2:8) gave the desired azidation product 2a as a
colorless liquid (81 mg, 62%). Spectral data for azidation product 2a: 1H NMR
(300 MHz, CDCl3): d 2.27–2.36 (m, 1H), 2.43 (s, 3H), 2.71–2.79 (m, 1H), 4.33–
4.47 (s, 2H); 13C NMR (75 MHz, CDCl3): d 26.3, 32.4, 66.4, 72.8, 170.7, 200.4.; IR
(Neat): 2107, 1765, 1722, 1359, 1219, 1191, 1166, 1019 cmÀ1.; LC–MS (CI):
170.1 (M+1); 2b: (1H NMR (300 MHz, CDCl3): d 1.34 (t, J = 4.56 Hz, 3H), 2.28
(quintet, J = 4.58 Hz, 1H), 2.76 (quintet, J = 3.74 Hz, 1H), 4.34 (q, J = 4.8 Hz, 2H),
4.39–4.47 (m, 2H); 13C NMR (75 MHz, CDCl3): d 14.3, 14.4, 33.7, 64.0, 66.9,
167.1, 171.1; IR (Neat): 2117, 1776, 1746, 1242, 1214, 1172, 1117, 1020, 909,
729 cmÀ1; LC–MS (CI): 200.1 (M+1); 2c: 1H NMR (300 MHz, CDCl3): d 1.37 (t,
J = 5.2 Hz, 3H), 2.68 (d, J = 18.4 Hz, 1H), 3.1 (d, J = 18.0 Hz, 1H), 4.40 (q,
J = 7.1 Hz, 2H), 8.69 (br s, 1H).; 13C NMR (75 MHz, CDCl3): d 14.3, 41.0, 64.5,
67.4, 166.6, 172.0, 173.1; IR (Neat): 3268, 2986, 2120, 1715, 1368, 1267, 1234,
1182, 1051, 732, 696 cmÀ1; LC–MS (CI): 213 (M+1); 2d: 1H NMR (300 MHz,
CDCl3): d 1.31 (t, J = 3 Hz, 3H), 2.01–2.08 (m, 1H), 2.40–2.48 (m, 1H), 2.64–2.76
(m, 2H), 4.32–4.39 (q, J = 3 Hz, 2H), 8.50 (br s, 1H); 13C NMR (75 MHz, CDCl3): d
14.3, 27.5, 28.2, 64.0, 67.3, 167.2, 167.3, 171.1; IR (Neat): 3242, 3106, 2985,
2117, 1702, 1354, 1232, 1187, 1095, 1048, 729 cmÀ1; LC–MS (CI): 227 (M+1);
2e: 1H NMR (300 MHz, CDCl3): d 1.36 (t, J = 6 Hz, 3H), 1.87–2.00 (m, 3H), 2.16–
2.29 (m 1H), 3.37–3.45 (m, 2H), 4.27–4.43 (m, 2H), 7.02 (br s, 1H); 13C NMR
(75 MHz, CDCl3): d 13.7, 17.9, 30.6, 41.7, 62.3, 67.5, 166.2, 168.7; IR (Neat):
dation of five-membered rings and TBD or DBU are more
appropriate for the conversion of six-membered rings. Thus, it ap-
pears that direct azidation of heterocyclic b-ketoesters is a potent
alternative to the standard two-step procedure (halogenation and
displacement with azide ion).
Acknowledgments
We thank the CNRS, the Agence nationale de la recherche (ANR)
for financial support.
References and notes
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130.6, 147.4, 164.8, 167.9; IR (Neat): 3249, 2930, 2122, 1747, 1678, 1254, 1200,
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