Practical azidation of 1,3-dicarbonyls

Article abstract of DOI:10.1002/chem.201102680

An operationally simple, direct azidation of 1,3-dicarbonyl compounds has been developed. The reaction proceeds readily under ambient conditions using sodium azide and an iodine-based oxidant such as I₂ or 2-iodoxybenzoic acid (IBX)-SO₃K/NaI. In particular, the latter method, as a new and well-balanced oxidizing agent, shows excellent functional group tolerance and substrate scope and thus allows access to a variety of tertiary 2-azido and 2,2-bisazido 1,3-dicarbonyl compounds that would be more difficult to access by using traditional methods. Because the azide-containing products easily undergo 1,3-dipolar cycloaddition with alkynes, our report represents a novel route to analogues of sensitive complex molecules. Click into place! An operationally simple, direct azidation of 1,3-dicarbonyl compounds has been developed (see scheme). The reaction proceeds readily under ambient conditions using sodium azide and an iodine-based oxidant, such as I₂ or 2-iodoxybenzoic acid (IBX)-SO₃K/NaI. The oxidative methods show excellent functional-group tolerance and substrate scope and thus allow access to a variety of tertiary 2-azido and 2,2-bisazido 1,3-dicarbonyl compounds. Copyright

Full text of DOI:10.1002/chem.201102680

FULL PAPER
DOI: 10.1002/chem.201102680
Practical Azidation of 1,3-Dicarbonyls
Tobias Harschneck,[a] Sara Hummel,[a] Stefan F. Kirsch,*[a, b] and Philipp Klahn[a, b]
Abstract: An operationally simple,
direct azidation of 1,3-dicarbonyl com-
pounds has been developed. The reac-
tion proceeds readily under ambient
conditions using sodium azide and an
iodine-based oxidant such as I2 or 2-io-
doxybenzoic acid (IBX)-SO3K/NaI. In
particular, the latter method, as a new
and well-balanced oxidizing agent,
shows excellent functional group toler-
ance and substrate scope and thus
allows access to a variety of tertiary 2-
azido and 2,2-bisazido 1,3-dicarbonyl
compounds that would be more diffi-
cult to access by using traditional meth-
ods. Because the azide-containing
products easily undergo 1,3-dipolar cy-
cloaddition with alkynes, our report
represents a novel route to analogues
of sensitive complex molecules.
Keywords: azides · chemoselectivi-
ty · click chemistry · hypervalent
compounds · oxidation
Introduction
Several common methods for the construction of alkyl
azides[8] are based on classical nucleophilic substitution reac-
tions (such as the Mitsunobu reaction with alcohols[9] or sub-
stitution with alkyl halides).[10] Unlike the click reaction
itself, however, when these methods are applied to multiply
functionalized molecules, often, protecting group strategies
or lengthy synthetic sequences are necessary due to chemo-
and regioselectivity issues during the azidation (or the pre-
requisite halogenation to access alkyl halides). These diffi-
culties prompted chemists to develop other modes of azida-
tion, such as the conversion of primary amines into azides
through diazo transfer, which has become particularly at-
tractive for functionalizing natural products.[11] Some oxida-
tive methods have been reported that employ azide radicals
to introduce the azide functionality by substitution of active
hydrogen atoms.[12] For example, Magnus and others have
studied the azidation of enolic bonds and amines with hy-
The chemoselective functionalization of molecules by the
use of click chemistry is a powerful tool for a diverse range
of important tasks, from dendrimer design[1] to drug discov-
ery[2] and bioorthogonal labeling of biomolecules.[3] Because
of this, easy-to-perform click chemistry that is insensitive to
oxygen and water, and that uses readily available reagents,
is of tremendous value and is a field of ongoing interest.[4]
Over the last decade, major breakthroughs in this area have
been made in the realm of Huisgenꢀs 1,3-dipolar cycloaddi-
tion[5] of alkynes and azides, yielding triazoles.[6] In particu-
lar, the inert nature of these functional groups towards bio-
logical molecules and towards living systems have led to the
development of a remarkable range of applications based
on this reaction.[7] Given the high chemoselectivity of the
azide–alkyne coupling, click approaches that aim to react
densely functionalized molecules (e.g., natural secondary
metabolites) for drug discovery issues and for testing biolog-
ical functions are only hampered by the fact that either a
terminal alkyne or an azide moiety must be installed into
the targeted molecule. It is somewhat surprising, therefore,
that methods for the direct azidation of complex starting
materials are sparse.
pervalent iodineACTHNUTRGNEUNG(III) compounds and azidotrimethylsilane in
great detail.[13] In a series of works, Bols et al. have demon-
strated that iodine azide can be used not only for the addi-
tion to olefins, as pioneered by Hassner et al.,[14,15] but also
for the azidation of aldehydes, benzal acetals, and benzyl
ethers.[16] However, these methods (the mechanisms of
which have been assumed to occur through azide radicals)
are somewhat lacking in practice; they were mostly utilized
to azidate rather simple molecules that do not bear other
functional groups. We feel that a complementary method for
the azidation of complex starting materials that is compati-
ble with dense functionality and therefore holds potential, in
combination with a click approach, for the easy derivatiza-
tion of natural products and medicinal compounds is still in
demand.
[a] T. Harschneck, S. Hummel, Prof. Dr. S. F. Kirsch, P. Klahn
Department of Chemistry
Technische Universitꢁt Mꢂnchen
Lichtenbergstr. 4, 85747 Garching (Germany)
Fax : (+49) 8928913315
E-mail: stefan.kirsch@ch.tum.de
[b] Prof. Dr. S. F. Kirsch, P. Klahn
Fachbereich C-Organic Chemistry
Bergische Universitꢁt Wuppertal
Gaußstraße 20, 42119 Wuppertal (Germany)
E-mail: sfkirsch@uni-wuppertal.de
Inspired by our recent study on the oxygenation of 3-ox-
oesters,[17] and given their inherent reactivity with various
electrophiles,[18,19] our goal was to develop a reliable and op-
erationally simple azidation reaction that provides straight-
forward access to a variety of organic azides. We anticipated
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102680.
Chem. Eur. J. 2012, 18, 1187 – 1193
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1187

Table 1. Reaction conditions for the conversion of 1a into 2a.
a route to 2-azido-3-oxoesters that would involve selective
oxidation of the enolizable position and concomitant intro-
duction of the azide with a suitable azide source as simple
as NaN3 (Scheme 1). The oxidative azidation of 1,3-dicar-
Conditions
Time Yield[a]
[h]
[%]
1
2
3
4
5
6
7
8
I2 (1.5 equiv), NaN3, RT, DMSO/H2O
I2 (1.5 equiv), NaN3, 408C, THF/H2O
I2 (1.5 equiv), NaN3, 408C, MeCN/H2O
NIS (1.5 equiv), NaN3, RT, DMSO/H2O
H2O2, NaI (0.2 equiv), NaN3, RT, DMSO/H2O
TBHP, NaI (0.2 equiv), NaN3, RT, DMSO/H2O
oxone, NaI (0.2 equiv), NaN3, RT, DMSO/H2O
IBX (1.5 equiv), NaI (0.2 equiv), NaN3, RT,
DMSO/H2O
3
24
24
3
86
67
56
67
0.5 decomp.
3
3
0.5
no conv.
61
91
Scheme 1. Envisioned approach to 2-azido-3-oxoesters.
9
IBX-SO3K (1.5 equiv), NaI (0.2 equiv), NaN3, RT,
DMSO/H2O
0.5
2
91
90
31
10 IBX-SO3K (1.5 equiv), NaI (0.2 equiv), NaN3
(1.1 equiv), RT, DMSO/H2O
bonyl compounds dates back to the works of Moriarty et al.
in 1988, who reported on the hypervalent iodine oxidation
of 1,3-diketone compounds in the presence of azidotrime-
thylsilane;[20] to date, however, this potential has remained
largely unrealized with more complex starting material-
s.[12a,21,22] In this article, we delineate the scope, limitations,
and first applications of a novel and highly practical one-
step reaction that transforms 1,3-dicarbonyl compounds into
their azide-containing analogues with high chemoselectivity.
11 IBX-SO3K (1.5 equiv), NaBr (0.2 equiv), NaN3, RT,
DMSO/H2O
4
12 IBX-SO3K (1.5 equiv), NaN3, RT, DMSO/H2O
13 NaI (0.2 equiv), NaN3, RT, DMSO/H2O
14 IBX-SO3K (1.5 equiv), Ph3PBnI (0.2 equiv), NaN3,
RT, EtOAc/H2O
24
24
4
<2
no conv.
74
[a] Isolated yield after column chromatography.
ized molecules,[25] we then investigated the use of catalytic
amounts of iodides in the presence of mild oxidants.[26] To
this end, 3-oxoester 1a was treated with various oxidants in
an aqueous solution of NaI (0.2 equiv) and NaN3 (excess) in
DMSO. Whereas the use of oxidative agents such as H2O2,
tert-butyl hydroperoxide (TBHP), and oxone was only par-
tially successful (leading either to decomposition or low con-
version; Table 1, entries 5–7), 2-iodoxybenzoic acid (IBX;
3)[27] was found to be an effective oxidant, yielding the de-
sired azide 2a in excellent yield (91%) after 30 min
(Table 1, entry 8). Although IBX is easy to handle and envi-
ronmentally benign, we felt that the fact that IBX rapidly
oxidizes alcohols and many other functionalities might
render it less useful for the purpose of chemoselective azida-
tion. In principle, an oxidative agent that parallels the action
of IBX on iodide ions would provide a facile and valuable
route to 2-azido-3-oxoesters if it is mild enough to tolerate a
range of functional groups, including sensitive moieties, such
as alcohols, thus obviating the need for protecting-group op-
erations. Consequently, we turned our attention to the
newly developed IBX-derivative 4 (IBX-SO3K), which, at
room temperature, is water soluble and fully lacks reactivity
towards primary and secondary alcohols (Scheme 3).[28–30] To
our delight, 3-oxoester 1a was rapidly converted into the
corresponding azide 2a when IBX-SO3K and catalytic
amounts of NaI were used to generate the active oxidant in
situ (Table 1, entry 9). The procedure for the direct azida-
Results and Discussion
Initial studies and optimization: The 1,3-dicarbonyl motif is
ubiquitous in polyketide-derived natural products and is
easily synthesized through the application of aldol-type
methodologies.[23] To our surprise, a protocol that is simple
to perform and that results in the direct azidation of 3-ox-
oesters and related 1,3-dicarbonyl substrates by the use of
simple azide nucleophiles is unknown.[24] Our plan was ac-
tualized first when 3-oxoester 1a was exposed to an excess
of sodium azide (approximately 4 equiv) in the presence of
iodine (1.5 equiv), being the terminal oxidant, in aqueous
DMSO (0.1m, DMSO/H2O=2:1). The reaction reached
completion within 3 h at room temperature and furnished
the azidated product 2a in 86% yield after isolation
(Scheme 2). This result is interesting because the introduc-
tion of the azide smoothly occurs at a tertiary carbon, a task
not many methods are successful in.[20–22]
Scheme 2. Initial findings on the formation of 2-azido-3-oxoester 2a.
In light of this initial discovery, the reaction of 3-oxoester
1a with NaN3 to form azido ester 2a was examined in the
presence of a variety of oxidants. It became clear that elec-
trophilic iodine sources in aqueous DMSO performed best
(Table 1). Because, occasionally, the use of stoichiometric
amounts of I2 is not truly compatible with highly functional-
Scheme 3. Structures of IBX and IBX-SO3K.
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Azidation of 1,3-Dicarbonyls
FULL PAPER
tion of 3-oxoesters is very simple: NaI (0.2 equiv) and IBX-
SO3K (4; 1.5 equiv) were added to a vigorously stirred solu-
tion of 1a and NaN3 (excess) in a mixture of DMSO and
water at room temperature, followed by workup with an
aqueous Na2S2O3 solution when the reaction had run to
completion. Importantly, through the use of stoichiometric
amounts of NaN3, the yield of the azidation remained high
without requiring significantly longer reaction times
(Table 1, entry 10). The use of NaBr rather than NaI led to
markedly reduced yields (Table 1, entry 11). When Ph3PBnI
was employed as a phase-transfer catalyst, a biphasic mix-
ture of EtOAc and water could be substituted for the
DMSO/H2O solution (Table 1, entry 14).
From this survey, two particularly useful conditions were
identified; Method A (IBX-SO3K (1.5 equiv), NaI
(0.2 equiv), NaN3, room temperature, DMSO/H2O), and
Method B (I2, NaN3, room temperature, DMSO/H2O). Both
protocols are simple to perform, are run under air at room
temperature, and exhibit broad substrate scope (see below).
Due to the mild oxidation power of IBX-SO3K, Method A
is particularly well suited for modifying complex molecules
with a multitude of functional groups. Method B, on the
other hand, requiring only an inexpensive oxidant (I2, which
has a current price of less than 0.5 Euro per gram) and a
very cheap azide source (NaN3, currently less than 0.3 Euro
per gram), proved to be quite scalable with 1a and delivered
76% yield of the desired product 2a on a multigram scale
(see the Supporting Information).
tion with NaN3 then proceeds quite smoothly to produce 2a
(Scheme 4). Due to the low stability of the 2-iodo-3-oxoester
intermediate at room temperature, this two-step sequence
provides azide 2a in poor overall yields, thus demonstrating
the experimental advantage of the use of a high-yielding,
one-pot protocol (Method B).
Interestingly, the azidation with IBX-SO3K/NaI (Meth-
od A) showed a dramatically enhanced rate compared to
the conversion performed with stoichiometric amounts of
I2.[34] We also note that the results of the NMR experiments
do not indicate the intermediary occurrence of ethyl-1-iodo-
2-oxocyclohexanecarboxylate when 1a is reacted according
to Method A. Although we feel a detailed discussion of the
mechanism in the case of the IBX-SO3K/NaI system is pre-
mature at this point, the introduction of the azide substitu-
ent may not be rationalized by a mechanism as discussed
above in which IBX-SO3K would be only responsible for
the in situ formation of I2 through oxidation of iodide. In-
stead, various hypervalent iodine species appear to be in-
volved, the exact identity of which is under investigation.
Scope and limitations of the direct azidation: Under the two
conditions identified in our optimization studies, a range of
1,3-dicarbonyl compounds were reacted with sodium azide.
As shown in Table 2, 3-oxoesters, 3-oxoamides (e.g., 2e and
2 f), malonates (e.g., 2d), and 3-oxoketones (e.g., 2b and
2c), all proved to be viable substrates for the transformation
into tertiary azides. In most cases, both Method A and
Method B provide the azide products in similar yields. It is
worth mentioning that azidation can proceed in the presence
of a multitude of functional groups, including acetals, di-
thianes, silyloxy ethers, epoxides, amides, amines, and ole-
fins, many of which are reactive under traditional azidation
conditions.[8–16,20–22] Of primary importance for our purposes,
tertiary, secondary, primary, and even benzylic alcohols were
tolerated (e.g., 2n–p). At room temperature, reaction times
between 30 min and 3 h were typically required to fully con-
vert the starting substrates 1 into the azide-containing prod-
ucts 2. In some cases, higher temperatures were required;
this can be attributed to the low reactivity of the sterically
demanding carboxylic acid derivatives (e.g., 2k and 2m).[34]
To date, almost no other azidation protocol has been shown
to have a substrate scope as broad as that shown herein.
Despite the high level of generality, we identified a few
limitations with regard to the substrate scope. Primary alkyl
halides were subject to azide substitution under the reaction
conditions and failed to deliver the desired product. Sterical-
ly demanding substituents at the 4-position of 3-oxoesters
lead to poor reactivity, even at elevated temperatures (e.g.,
2w).
In the presence of I2 and NaN3 (Method B), the net trans-
formation most likely involves two steps, one of which is
iodine transfer onto the activated carbon followed by substi-
tution at the tertiary center to give the organic azide. We
assume that I2 or IN3 are the electrophilic iodine sources re-
sponsible for the first step.[14,15] The subsequent substitution
might follow
a radical mechanism as delineated in
Scheme 4;[16,31] however, a classical SN2 mechanism, as pro-
posed previously even for tertiary carbon atoms adjacent to
carbonyl groups, cannot be ruled out.[32,33]
Scheme 4. Proposed mechanism for the reaction with I2/NaN3.
The reaction was then screened against 1,3-dicarbonyl
compounds 5 that do not have an additional substituent at
the 2-position (R2 =H). To our surprise, rather stable 2,2-bi-
sazido-1,3-dicarbonyl compounds 6 were easily obtained in
good yields after only 10 min reaction under slightly modi-
fied conditions (3 equiv of IBX-SO3K, 0.2 equiv. NaI, NaN3,
RT, DMSO/H2O; Method C). It is noteworthy that the prod-
Support for the intermediacy of iodinated compounds is
gained from the observation that the use of molecular
iodine allows for the isolation of ethyl-1-iodo-2-oxocyclo-
hexanecarboxylate when 1a is reacted with I2; the substitu-
Chem. Eur. J. 2012, 18, 1187 – 1193
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1189

S. F. Kirsch et al.
Table 2. Scope of the azidation of 1,3-dicarbonyl compounds.[a]
addition[6,7] for their ready
modification. To this end, both
monoazido and bisazido com-
pounds (2 and 6) were treated
with phenylacetylene in the
presence of CuSO4 (20 mol%),
tris[(1-benzyl-1H-1,2,3-triazol-4-
yl)methyl]amine (TBTA;
mol%) and sodium ascorbate
(0.4 equiv) in tBuOH/H2O
1
(Method D). As summarized in
Table 3, 1,2,3-triazoles 7 were
obtained in excellent yields
from monoazides 2. Moreover,
bisazides 6 were also converted
smoothly into the stable bistria-
zoles 8, thus providing easy
access to this class of com-
pounds.[38]
It is worth mentioning that
introduction of the azide by
using Method A can be coupled
with triazole formation in
a
one-pot manner. For example,
ester 1a was directly trans-
formed into 1,2,3-triazole 7a in
82% yield, thus avoiding the
need for isolation of the azido
intermediate 2a or changing
the solvent. The one-pot proce-
dure requires an excess of
sodium ascorbate to fully
reduce the IBX-SO3K still pres-
ent from the preceding azida-
[a] Method A: IBX-SO3K (1.5 equiv), NaI (0.2 equiv), NaN3, RT, DMSO/H2O; Method B: I2, NaN3, RT,
DMSO/H2O; Method C: IBX-SO3K (3 equiv), NaI (0.2 equiv), NaN3, RT, DMSO/H2O. See the Supporting In-
formation for reaction times. [b] 408C. [c] 508C. [d] PMB=4-methoxybenzyl. [e] TBS=tBuMe2Si.
tion
step:
1) IBX-SO3K
Table 3. Modification of 2 and 6.[a,b]
ucts of monoazidation, as reported under the conditions de-
veloped by Moriarty and others,[20–22] were not found under
these conditions. Extended reaction times resulted in dra-
matic decomposition of this somewhat neglected class of
compounds.[35,36] Although not investigated in detail at this
stage, the novel double azidation that took place by using
Method C shows promise for tolerating a great variety of
functional groups, as does Method A. Interestingly, neither
bisazides 6 nor the products of monoazidation were formed
from 5 when treated with I2/NaN3.
Modifications through a click approach: One strength of
this azidation strategy lies in its ability to rapidly deliver
azide-containing cores that can be further functionalized by
applying standard 1,3-dipolar cycloaddition reactions with
terminal alkynes. Because the location of the azido substitu-
ents adjacent to two carbonyl groups distinguishes products
2 and 6 from all the other organic azides utilized in click ap-
proaches until now,[37] we realized the need to briefly test
the viability of the CuI-catalyzed azide–alkyne [3+2] cyclo-
ꢀ
[a] Method D: PhC CH, CuSO4 (20 mol%), TBTA (1 mol%), sodium
ascorbate (0.4 equiv), RT, tBuOH/H2O (1:1). See the Supporting Infor-
mation for reaction details. [b] tri=4-phenyl-1H-1,2,3-triazol-1-yl.
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Azidation of 1,3-Dicarbonyls
FULL PAPER
(1.5 equiv), NaI (0.2 equiv), NaN3 (1.1 equiv), RT, DMSO/
H2O (1:1), 1 h; 2) phenylacetylene (1.1 equiv), CuSO4
alization through standard CuI-catalyzed [3+2] cycloaddi-
tion reactions. Exceptionally high chemoselectivity and func-
tional group tolerance are distinctive features of the azida-
tion reaction and will likely render it a powerful tool for
late-stage derivatization of sensitive complex molecules. In
combination with a click approach, one can imagine applica-
tions in numerous fields of research.
(0.2 equiv),
TBTA
(0.02 equiv),
sodium
ascorbate
(1.6 equiv), RT, 24 h.
Applications to late-stage modifications of complex struc-
tures: A striking demonstration of the generality and func-
tional-group tolerance of the title reaction is displayed in
the modification of complex target molecules of biological
interest. Scheme 5 shows the functionalization of two natu-
Experimental Section
Method A: Formation of 2a[33b]: Compound 1a (25.0 mg, 147 mmol) was
dissolved in DMSO (1 mL), and aqueous NaN3 (1m, 0.5 mL) was added.
NaI (4.4 mg, 29.4 mmol, 0.2 equiv) and IBX-SO3K (87.8 mg, 220 mmol,
1.5 equiv) were added in one portion and the solution was stirred for
30 min at RT. The reaction was quenched by the addition of saturated
aqueous Na2S2O3 (10 mL). The reaction mixture was extracted with Et2O
(3ꢄ10 mL) and the combined organic phases were washed with brine
and dried over MgSO4. The solvent was evaporated and the residue was
purified by flash chromatography on silica (pentanes/EtOAc, 95:5). The
azido compound 2a was obtained as a pale-yellow oil (28.1 mg, 133 mmol,
1
91%). Rf =0.32 (pentanes/Et2O, 90:10); H NMR (250 MHz, CDCl3): d=
1.32 (t, J=7.1 Hz, 3H), 1.69–1.88 (m, 4H), 1.89–2.03 (m, 1H), 2.37–2.53
(m, 2H), 2.58–2.68 (m, 1H), 4.31 (q, J=7.1 Hz, 1H), 4.31 ppm (q, J=
7.1 Hz, 1H); 13C NMR (91 MHz, CDCl3): d=14.3, 21.5, 26.6, 35.6, 39.8,
62.9, 74.1, 167.8, 202.6 ppm; IR (film): n˜ =2943, 2870, 2108, 1728, 1448,
1234, 1142, 1094, 1012, 855 cmÀ1; MS (EI): m/z (%): 183 (1) [M+ÀN2],
110 (68), 82 (100), 55 (70). HRMS (EI): m/z calcd for C9H13O3N [M+
ÀN2]: 183.0890; found: 183.0887.
Method B: Formation of 2a[33b]: Compound 1a (25.5 mg, 150 mmol) was
dissolved in DMSO (1 mL), and aqueous NaN3 (1m, 0.5 mL) was added.
I2 (57.1 mg, 225 mmol, 1.5 equiv) was added and the solution was stirred
for 4 h at RT. The reaction was quenched by the addition of saturated
aqueous Na2S2O3 (10 mL). The reaction mixture was extracted with Et2O
(3ꢄ10 mL) and the combined organic phases were washed with brine
and dried over MgSO4. The solvent was evaporated and the residue was
purified by flash chromatography on silica (pentanes/EtOAc, 95:5). The
azido compound 2a was obtained as a pale-yellow oil (27.4 mg, 130 mmol,
86%).
Method C: Formation of 6a:[20,35] Dimethyl malonate (20.0 mg, 151 mmol)
was dissolved in DMSO (1 mL), and aqueous NaN3 (1m, 0.5 mL) was
added. NaI (4.5 mg, 30.0 mmol, 0.2 equiv) and IBX-SO3K (176.6 mg,
454 mmol, 3.0 equiv) were added and the solution was stirred for 10 min
at RT. The reaction was quenched by the addition of a saturated aqueous
Na2S2O3 (10 mL). The reaction mixture was extracted with Et2O (3ꢄ
10 mL) and the combined organic phases were washed with brine and
dried over MgSO4. The solvent was evaporated and the residue was puri-
fied by flash chromatography on silica (pentanes/EtOAc, 90:10). The bi-
sazido compound 6a was obtained as a pale-yellow oil (16.0 mg, 74 mmol,
50%). Rf =0.40 (pentanes/EtOAc, 80:20); 1H NMR (250 MHz, CDCl3):
d=3.92 ppm (s, 6H); 13C NMR (63 MHz, CDCl3): d=54.6, 80.1,
164.1 ppm; IR (film): n˜ =2963, 2920, 2850, 2360, 2123, 1759, 1437, 1297,
1237, 1070, 1049, 790, 732 cmÀ1. Direct mass analysis of the bisazido com-
pound was not possible. The MS and HRMS data of bistriazole 8a de-
rived from 6a are given below.
Method D: Formation of 8a: Bisazido compound 6a[35] (15.7 mg,
73.3 mmol) was dissolved in a 2:1 mixture of tBuOH and water (250 mL).
Phenylacetylene (17.7 mL, 16.5 mg, 161 mmol, 2.2 equiv), CuSO4·5H2O
(3.7 mg, 14.7 mmol, 0.2 equiv), sodium ascorbate (5.8 mg, 29.3 mmol,
0.4 equiv), and TBTA (0.8 mg, 1.5 mmol, 2 mol%) were added, and the
solution was stirred at RT for 1 h. The reaction mixture was diluted with
water (15 mL) and extracted with CH2Cl2 (3ꢄ15 mL). The combined or-
ganic phases were dried over MgSO4 and the solvent was evaporated.
The residue was purified by flash chromatography on silica (pentanes/
EtOAc, 80:20) to give 8a as a white solid (30.4 mg, 72.7 mmol, 99%). Rf =
0.27 (pentanes/EtOAc, 80:20); 1H NMR (360 MHz, CDCl3): d=4.09 (s,
Scheme 5. Applications to natural-product analogues.
ral products, b-estradiol (9) and strychnine (11), attached to
1,3-dicarbonyl units. Although the complex molecules con-
tain sensitive functionalities, such as oxidizable hydroxyl
groups, electron-rich alkenes, and nucleophilic nitrogen cen-
ters, the formation of the azido derivatives (and the subse-
quent cycloaddition tested with phenylacetylene) takes
place with a high degree of chemoselectivity. In all cases,
the modified natural products were formed in good yields
under the standard conditions without requiring any protect-
ing groups, thus highlighting the utility of this azidation pro-
tocol in the derivatization and late-stage diversification of
sensitive structures.
Conclusion
A practical method that can be used to achieve the direct
azidation of 1,3-dicarbonyl compounds has been developed.
By the use of sodium azide as an inexpensive azide source,
the starting dicarbonyl compound is oxidized with either I2
or IBX-SO3K/NaI. The reaction can be used conveniently
from milligram to multigram scales and provides easy access
to tertiary 2-azido and 2,2-bisazido-1,3-dicarbonyl com-
pounds, both of which are ideally suited for further function-
Chem. Eur. J. 2012, 18, 1187 – 1193
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1191

S. F. Kirsch et al.
6H), 7.31–7.36 (m, 2H), 7.38–7.43 (m, 4H), 7.80–7.85 (m, 4H), 8.46 ppm
(s, 2H); 13C NMR (91 MHz, CDCl3): d=55.4, 79.7, 120.6, 126.0, 128.9,
129.0, 129.5, 148.4, 161.2 ppm; MS (ESI): m/z (%): 361 (100), 282 (70);
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2+
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Acknowledgements
We gratefully acknowledge the opening works of Alexander Duschek
and Wolfgang Heydenreuther. S. H. thanks the Erasmus program and the
University of Glasgow. T. H. and P. K. thank the TUM Graduate School
for support. This research was supported by the Deutsche Forschungsge-
meinschaft (DFG) and the Fonds der Chemischen Industrie (FCI).
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1192
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Chem. Eur. J. 2012, 18, 1187 – 1193

Azidation of 1,3-Dicarbonyls
FULL PAPER
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[35] Caution! Although we have never encountered any problems when
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explosive compounds that should be handled with great care.
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[28] IBX-SO3K does not react with primary and secondary alcohols at
room temperature. At 608C in DMSO/H2O, secondary benzylic and
propargylic alcohols are smoothly oxidized to the corresponding car-
bonyls in high yields, whereas alkyl-substituted alcohols remain un-
touched under the conditions.
[37] Although a plethora of organic azides were submitted to 1,3-dipolar
cycloaddition reactions and variants thereof (see ref. [1–7]), surpris-
ingly, the reactivity of monoazido 1,3-dicarbonyls 2 and 2,2-bisazido-
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Received: August 27, 2011
Published online: December 21, 2011
Chem. Eur. J. 2012, 18, 1187 – 1193
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1193