Hydrogen peroxide and arenediazonium salts as reagents for a radical beckmann-type rearrangement

Article abstract of DOI:10.1055/s-0030-1260006

The reductive ring-opening of hydroperoxides derived from cyclic ketones leads to alkyl radicals which can effectively be trapped by arenediazonium salts. This synthetic transformation yielding azo carboxylic acids or lactams, after a reductive step, can be classified as a radical version of the well-known Beckmann rearrangement. In this article, we present results on the scope, the limitations and possible applications of this new reaction type. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260006

FEATURE ARTICLE
1515
Hydrogen Peroxide and Arenediazonium Salts as Reagents for a Radical
Beckmann-Type Rearrangement
Radical
B
eckmann
g
-Type
R
earr
n
angement es Prechter, Markus R. Heinrich*
Department für Chemie und Pharmazie, Pharmazeutische Chemie, Friedrich-Alexander-Universität Erlangen-Nürnberg,
Schuhstraße 19, 91052 Erlangen, Germany
Fax +49(9131)8522585 ; E-mail: Markus.Heinrich@medchem.uni-erlangen.de
Received 20 December 2010; revised 14 March 2011
strate tolerance, expensive reagents, or demanding
conditions are potentially remaining drawbacks of the
classical Beckmann rearrangement in spite of the newly
reported methodologies. For this reason, we turned our in-
Abstract: The reductive ring-opening of hydroperoxides derived
from cyclic ketones leads to alkyl radicals which can effectively be
trapped by arenediazonium salts. This synthetic transformation
yielding azo carboxylic acids or lactams, after a reductive step, can
be classified as a radical version of the well-known Beckmann rear- terest to alternative reaction types that would lead to com-
rangement. In this article, we present results on the scope, the limi-
tations and possible applications of this new reaction type.
parable overall transformations, but could be conducted
under significantly milder conditions. In this article we
Key words: radical reaction, rearrangement, ketones, carboxylic
acids, azo compounds
present a conceptual study in which radical chemistry has
been employed for this purpose.
OH
classical
Beckmann
rearrangement
N
The acid-catalyzed rearrangement of ketoximes, accessi-
ble from the corresponding ketones by standard proce-
dures,1 to amides is widely known as the Beckmann
rearrangement (Scheme 1). The reaction, named after
Ernst Otto Beckmann, was first described by its inventor
in 1886 and has since then become a well-known and
widely applied method in organic chemistry.2,3 The most
prominent example of its industrial use is probably the
large-scale production of the Nylon 6 precursor e-capro-
lactam from cyclohexanone oxime.4
H2NOH
H2SO4
O
O
H
N
n
3
1) FeSO4
Ar-N2+ 5
2) H2
HO OOH
n
n
H2O2
1
4
radical
Beckmann-type
rearrangement
n
2
Scheme 1 Classical and radical version of the Beckmann rearrange-
ment
Most commonly, the Beckmann rearrangement is carried
out in strongly acidic and dehydrating media such as
phosphorus pentachloride, concentrated sulfuric acid, or
the so-called ‘Beckmann’s mixture’ which contains acetic Inspired by current research in the field of nitrogen-
acid, acetic anhydride, and hydrogen chloride.3a Since centered radical scavengers,19 which comprises reagents
these reagents are not suitable for a large number of sen- such as sulfonyl azides,20 nitroso compounds,21 imines,22
sitive substrates, several attempts have been made to azo compounds,23 and diazirines,24 we focused on a possi-
achieve the Beckmann rearrangement under significantly ble application of arenediazonium ions25 in a radical
milder conditions. In these studies, thionyl chloride,5 sili- Beckmann-type rearrangement (Scheme 1). Instead of
ca gel,6 molybdenum trioxide on silica gel,7 montmorillo- employing cyclic ketoximes 3, which traditionally lead to
nite KSF,8 ruthenium(III) chloride,9 yttrium(III) triflate,10
ring enlargement and the formation of lactams 4, we
bismuth(III) chloride,11 2,4,6-trichloro-1,3,5-triazine,12 planned to replace the cyclic oximes 3 by hydroperoxides
and gallium(III) triflate13 have been evaluated as substi- 2 which would also be readily accessible from ketones 1,26
tutes for the traditionally employed reagents. Recently, and which could be reacted with arenediazonium salts 5
several lanthanide-containing catalysts [with Ce(III), under reductive conditions (Scheme 1).27 Comparable to
La(III), and Sm(III) among others] have also been found the ionic reaction, lactams 4 would be accessible by a fur-
to effect the rearrangement.14,15 The reaction could be per- ther reductive step such as hydrogenation.28 In addition,
formed in the vapor phase,16 a process which has been the radical pathway from hydroperoxide 2 could open up
shown to be applicable even on an industrial scale with the several further synthetic routes since it passes through an
use of a high-silica MFI zeolite as catalyst.16c It is also acyclic azo carboxylic acid intermediate.
possible to initiate the Beckmann rearrangement in super-
The designated reaction course is presented in detail in
critical water17 or ionic liquids.18 However, limited sub-
Scheme 2. Pioneering work on the generation of oxygen-
centered radicals from hydroperoxides has been published
by Walling29a,b and Schreiber.29c,d Recent advances in the
field of oxyl radicals30 have been reported by the groups
of Suarez31a,b and Schoening.31c In our case, very well-
SYNTHESIS 2011, No. 10, pp 1515–1525
Advanced online publication: 15.04.2011
DOI: 10.1055/s-0030-1260006; Art ID: T55210SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

1516
A. Prechter, M. R. Heinrich
FEATURE ARTICLE
defined reductive conditions are required to induce the product.3c Under certain reaction conditions isomerization
formation of oxyl radicals 6 by cleavage of the O–O bond of the oxime has been observed prior to the migration
in hydroperoxide 2, since the diazonium ions 5 need to re- step, which can occasionally be either helpful or compli-
main stable.32 Reversible ring-opening of oxyl radical 6 cating with respect to predictable reaction outcomes.3d
and trapping of the newly formed alkyl radicals 7 by dia- The selectivity of the radical reaction (Scheme 3, lower
zonium ions 5 leads to radical cations 8.27,33 These are pathway), in contrast, is controlled by the relative stability
quickly further reduced by iron(II) to azo carboxylic acids of the alkyl radicals arising from the fragmentation of
9, which represent the key intermediates of the reaction oxyl radical 14 as well as thermochemical aspects. Given
pathway.
that R1 is a better radical-stabilizing substituent or group
than R2, the ring opening will preferably occur towards
the R1 side,34 as long as an increase in temperature does
not displace the equilibrium towards the less stable radi-
cal.35,36 Since the configuration of the hydroperoxide 13 is
unimportant (compared to that of oxime 10), the product
of the radical reaction will in most cases be well predict-
able. On the other hand, there is only a small possibility of
opening the oxyl radical 14 towards the less radical-stabi-
lizing substituent.
R
HO
O
OH
n
O
OH
n
OH
n
N2+
O
Fe2+
5
– Fe3+
7
2
6
R
R
OH
OH
O
O
classical Beckmann
rearrangement
selectivity dependent on the
oxime configuration
N
N
Fe2+
+N
N
– Fe3+
+
OH2
OH
N
n
n
H
O
N
8
9
R1
R2
N
R1
R2
R1
R2
H+
Scheme 2 Formation of azo carboxylic acids 9 as key intermediates
n
n
n
The typical feature of the Beckmann rearrangement is the
migration of a substituent from carbon to nitrogen
(Scheme 3, upper pathway). Regarding the regioselectiv-
ity of the classical reaction, the migrating substituent is
generally in the E position to the leaving group (11, R1 in
E position to H2O), so that the structure of the lactam 12
depends on the configuration of the oxime 10 rather than
on the nature of the substituents R1 and R2. Given that
there is no simplification due to symmetry (R1 = R2), care
has to be taken that the oxime 10 can be prepared with the
correct configuration which will later lead to the desired
10
11
12
radical Beckmann-type
rearrangement
selectivity dependent on the relative
stability of the generated radicals
and reaction temperature
H
O
O
OH
HO
R1
O
OH
R1
R2
R2
N
R1
R2
Fe2+
– Fe3+
n
n
n
12
14
13
Scheme 3 Comparison of the regioselectivity of the classical
Beckmann rearrangement and its radical version
Biographical Sketches
Agnes Prechter (born 1985) Ph.D. student in the group on the development of new
studied pharmacy at the of Markus Heinrich. In the synthetic methods for the
Friedrich-Alexander-Univer-
same year she was awarded preparation of chiral azo
sität Erlangen-Nürnberg. a fellowship of the ‘Bay- compounds and amines.
After receiving her approba- erische Eliteförderung’. Her
tion in 2009 she became a current research is centered
Prof. Dr. Markus Heinrich Zard at the Ecole Polytech- trial, medicinal, and radiop-
(born 1975) studied chemis- nique in Palaiseau/France harmaceutical purposes in
try at the Ludwig-Maximil- he returned to Germany in 2009. In the same year,
ians-Universität München 2005, where started inde- Markus Heinrich was ap-
and received his Ph.D. un- pendent research at the TU pointed as an associate pro-
der the supervision of Prof. München associated to Prof. fessor for pharmaceutical
Dr. Wolfgang Steglich in Dr. Thorsten Bach. He fin- chemistry at the Friedrich-
2003. After a postdoctoral ished his habilitation on new Alexander-Universität Er-
stay with Prof. Dr. Samir radical reactions for indus- langen-Nürnberg.
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

FEATURE ARTICLE
Radical Beckmann-Type Rearrangement
1517
Table 2 Formation of Hydroperoxides 2 from Cyclic Ketones 1a
Although the synthesis of hydroperoxides 2 from cyclic
ketones 1 has been reported in the literature and quite dif-
ferent conditions can be found to effect this conversion,37
almost no practically useful data on equilibria or reaction
rates were available.38 Even more disturbingly, several of
the synthetic studies revealed the formation of complex
product mixtures, in which the desired 1-hydroxycy-
cloalkyl hydroperoxides 2 only occurred as minor constit-
uents.37 Radical reactions using these not clearly defined
intermediates as starting materials led to varying yields of
the respective products.39
Entry Cyclic ketone 1
Time (h) Hydroperoxide 2 Ratiob 2/1
O
1
0.1
2a
2b
7.3:1
1a
O
2
16
2.3:1c
1b
We, therefore, first reinvestigated the formation of hydro-
peroxide 2a from ketone 1a. With respect to the further
transformation planned, the conditions were chosen in a
way to allow a simple separation of the hydroperoxide 1a
from the reaction mixture by extraction with an organic
solvent.27b Selected results from this study are summa-
rized in Table 1.
O
d
3
24
24
16
–
–
1c
O
4
2d
–
12:1e
1d
Table 1 Hydroperoxide Formation from Cyclohexanone (1a)a
O
d
5
–
O
HO
O OH
conditions
1e
O
1a
2a
d
6
24
–
–
Entry
Ratio 1a/H2O2
Time (min)
Ratiob 2a/1a
0.7:1
1f
1
2
3
4
5
6
1:3
1:5
1:3
1:3
1:3
1:3c
30
30
O
7
–
–
lactonee
3.3:1
0.9:1
60
0.8:1
1g
150
225
5
1.6:1
O
8
20
16
2h
2i
2.6:1
1h
7.3:1
O
a Reaction conditions: 1a, 30% H2O2, r.t.
b Determined by 1H NMR after extraction with CDCl3.
c HCl (0.06 equiv) was added.
9
2.5:1
1i
O
10
16
2j
0.6:1
A virtually clean formation of hydroperoxide 2a, with
only minor quantities of 1a remaining, could be achieved
in the presence of catalytic amounts of hydrochloric acid
(entry 6) (see 13C NMR spectra in the Supporting Informa-
tion). Without the use of acid (entries 1–5), the reactions
also showed no major detectable byproducts, but signifi-
cantly longer reaction times were required. Under the op-
timized conditions, we attempted the synthesis of various
hydroperoxides 2 as potential intermediates for the
Beckmann-type rearrangement (Table 2). The ketones 1
were selected to allow an investigation of the effects of
ring size and substitution in a-positions.
1j
a Reaction conditions: 1, 30% H2O2 (3 equiv), HCl (0.06 equiv), r.t.
b Determined by 1H NMR after extraction with CDCl3.
c A mixture of two stereoisomers of 2b was formed in a ratio of 1:0.4.
d No conversion.
e Formation of lactones by Baeyer–Villiger reaction of 1d or 1g:
2-oxabicyclo[3.2.l]octan-3-one (13% from 1d), 4-butyldihydrofuran-
2-one (quant. from 1g).
sterically more demanding ketones 2,2,6-trimethylcyclo-
hexanone (1c) and camphor (1e) (entries 3 and 5). The fact
that tetralone (1f) could not be converted into its hydro-
peroxide is probably due to the conjugation of the ketone
and the, therefore, increased stability of the reactant (entry
6). This assumption was further supported by an also un-
successful experiment with 2-cyclohexen-1-one. From
the attempt with 3-butylcyclobutanone (1g) (entry 7), the
As evidenced by entries 1 to 5, further substituents on the
cyclohexanone moiety were only tolerated to a moderate
extent. While the less hindered reactants 1a, 1b, and 1d
gave the hydroperoxides in good reactant to product ratios
(entries 1, 2, and 4), no conversion was observed for the
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

1518
A. Prechter, M. R. Heinrich
FEATURE ARTICLE
rearranged g-lactone40 was isolated instead of the desired hydrazones by column chromatography were not fully
hydroperoxide. Several variations of the reaction condi- successful since partial decomposition of the azo com-
tions failed to prevent formation of the undesired lac- pounds was observed (entries 1, 2, and 5, Table 3). As an
tone.38 Five-, seven-, and eight-membered cyclic ketones example, NMR spectra of azo compound 9aa before and
1h–j again yielded the desired 1-hydroxycycloalkyl hy- after column chromatography are included in the Support-
droperoxides 2 with reasonable product/reactant ratios ing Information. Due to the excess of iron(II) sulfate used
(entries 8–10). No evidence for cyclic peroxides could be in the reactions, no unreacted peroxides were found along
found by inspection of the 13C NMR spectra. Prior to the with the desired products.
following series of experiments, the hydroperoxides 2
were prepared as described above and separated from ex-
cess aqueous hydrogen peroxide by extraction with
Table 3 Synthesis of Azo Carboxylic Acids 9 from Hydroperoxides
2 and Arenediazonium Salts 5a
dichloromethane. In contrast to some of the previously re-
ported procedures, the cyclic hydroperoxyacetals 2 can
further be used in solution and no concentration or isola-
tion of these potentially explosive substances is neces-
sary.37a–c We, therefore, consider the danger of handling
as very limited. Furthermore, the preliminary determina-
tion of the hydroperoxide 2/ketone 1 ratios by NMR
(Table 2) allowed us to circumvent a titration step. The
equilibrium data now available might also be useful for
future preparative studies using cyclic hydroperoxyace-
tals.
Entry 2
5
Azo carboxylic acid 9
Yieldb
(%)
MeO
42
(32)
N
N
COOH
1
2
3
4
5
2a
5a
9aa
Cl
68
(46)
N
N
COOH
2a
2a
2b
2b
5b
5c
5a
5b
The organic solution containing the hydroperoxide 2 and
unreacted ketone 1 was then added to a mixture of iron(II)
sulfate and a diazonium salt 5 in aqueous acetic acid and
dimethyl sulfoxide. To explore the scope and limitations
of the reaction, the six previously investigated hydroper-
oxides 2a, 2b, 2d and 2h–j were reacted with three arene-
diazonium salts 5a–c (Figure 1), which were prepared by
previously reported procedures.41 To allow a comparison
of substituent effects, the three salts 5a–c were chosen in
a way that either an electron-donating (R = OMe, 5a), a
more or less neutral (R = Cl, 5b), or an electron-with-
drawing substituent (R = CN, 5c) was present on the aro-
matic core. In the case that arenediazonium salts take a
role as nitrogen-centered radical scavengers, as it is true
for this study, substituents effects have not yet been deter-
mined. When the salts are otherwise employed as sources
for aryl radicals, radical generation by reduction is easier
with electron-withdrawing groups on the aromatic core.42
9ab
NC
N
N
COOH
COOH
COOH
COOH
53c
9ac
MeO
N
N
79d
9ba
Cl
89d
(60)
N
N
9bb
NC
MeO
Cl
NC
N
N
6
7
8
2b
2d
2h
5c
5a
5a
74d
49c
48c
–
–
N2+ BF4
N2+ BF4
–
N2+ BF4
9bc
MeO
5a
5b
5c
HOOC
Figure 1 Diazonium tetrafluoroborates 5a–c
N
N
The results of the synthetic study are summarized in
Table 3.
9da
MeO
From the first row of experiments using cyclohexanone
(1a) as the starting material (entries 1–3), we obtained the
azo carboxylic acids 9aa–ac in high purity and moderate
yields. Unexpectedly, the new samples of this practically
unknown compound class showed a remarkable tendency
to isomerize to the corresponding hydrazones upon stand-
ing at room temperature (Scheme 4).43–45 Attempts to sep-
arate the nonisomerized azo compounds from the
N
N
COOH
9ha
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

FEATURE ARTICLE
Radical Beckmann-Type Rearrangement
1519
Table 3 Synthesis of Azo Carboxylic Acids 9 from Hydroperoxides
2 and Arenediazonium Salts 5a (continued)
sponding methyl ester 15 of 9ab showed comparable re-
activity.
Since we have so far not observed this difficulty with sec-
ondary alkyl groups attached to the N=N moiety, we cur-
rently assign this special behavior to the primary alkyl
chain, which probably facilitates the isomerization of the
azo compounds to hydrazones 16. Among the three diaz-
onium salts, 5a and 5b appear to be better suited for the
radical Beckmann-type rearrangement than 5c since the
methoxyphenyl- and chlorophenyl-substituted products
9aa and 9ab showed superior properties with respect to
stability and handling.
Entry 2
5
Azo carboxylic acid 9
Yieldb
(%)
Cl
N
N
9
10
11
12
2h
5b
86
78
63
56
COOH
COOH
9hb
MeO
N
N
2i
2i
2j
5a
5b
5b
With 2-methylcyclohexanone (1b) as reactant, the ring-
opening of the corresponding cyclic hydroperoxide 2b
(step 6 → 7, Scheme 2) occurs with clear preference (re-
gioselectivity ≥ 10:1) towards the secondary alkyl radical.
Only small amounts of regioisomers were, therefore,
found along with the desired products (Table 3). The
Beckmann rearrangement of 2-methylcyclohexanone
oxime under classical conditions, for comparison, does
not necessarily lead to a comparable preference for one of
the two possible lactams.46,47 Moreover, the products
9ba–bc (entries 4–6) appeared more stable than those
bearing primary alkyl chains on the N=N moiety.44,45 As
evidenced by the following entries 7–12, the methodology
can be well extended to bicyclic as well as five-, seven-,
and eight-membered monocyclic ketones.
9ia
Cl
COOH
N
N
9ib
HOOC
N
Cl
N
9jb
a Reaction conditions: 2, 5 (1.2 equiv), FeSO4·7 H2O (3 equiv), H2O–
DMSO–AcOH (4:3:3), r.t., 15 min.
b Yields are based on the hydroperoxide/ketone ratios previously de-
termined (Table 2); yields in brackets refer to products submitted to
column chromatography.
Nearly all azo compounds shown in Table 3 were ob-
tained from the two-step sequence without remarkable
impurities other than the unreacted cyclic ketones remain-
ing from the hydroperoxidation step.48 In the case of suf-
ficiently low boiling points, these could easily be removed
under reduced pressure, leading to virtually pure azo car-
boxylic acids (see Supporting Information). Given the
sensitivity of the azo carboxylic acids, we consider a fur-
ther direct conversion of products 9 as the most practical
procedure.
c Products 9 were isolated without side products except for the follow-
ing examples: products 9ac, 9da, and 9ha accompanied by hydra-
zone; 9/hydrazone, 2:1, 3:1, and 2:1, respectively.
d Products 9ba–bc contained minor amounts of the isomers resulting
from ring opening towards the primary alkyl radical: 9ba and 9bb: re-
gioselectivity ≥ 10:1, 9bc: regioselectivity ≥ 14:1.
2a + 5b
With regard to the known abilities of arenediazonium salts
as nitrogen-centered radical scavengers, it is interesting to
note that good results were obtained even from those re-
actions featuring the trapping of primary alkyl radicals
(Scheme 2, step 7 → 8).19,27a Due to their lower nucleophi-
licity,49 this radical type has so far been considered as less
well suited for additions to the N≡N moiety of diazonium
ions. In our case, a relatively low excess of diazonium
ions (1.2 equiv per hydroperoxide, initially 0.2 mol/L)
was sufficient to achieve good to high efficiency of alkyl
radical trapping.
see Table 3
Cl
Cl
N
COOH
N
H
COOH
N
N
H
9ab
16ab
CH2N2, Et2O
Cl
N
COOMe
N
As a primary application for the azo carboxylic acids 9,
we envisaged the synthesis of indoles via a Fischer-type
cyclization.50 We considered this potential transformation
as especially appropriate, since the more or less pro-
nounced tendency of the azo compounds to form hydra-
zones would be a part of the desired reaction course. An
example employing the previously prepared azo carboxy-
lic acid 9bb is depicted in Scheme 5.
15 (33% from 2a)
Scheme 4 Conversion of carboxylic acid 9ab into methyl ester 15
or hydrazone 16ab
Our suspicion that the instability of 9aa–ac might be en-
hanced by the free carboxylic acid functionality present in
the molecules could not be confirmed, since the corre-
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

1520
A. Prechter, M. R. Heinrich
FEATURE ARTICLE
synthesis, can serve as valuable intermediates for a large
number of products including long-chain amino acids,
lactams, and heterocycles.
Cl
N
COOH
COOH
N
H
Solvents and reagents were used as received. 1H NMR were record-
ed on 360 and 600 MHz spectrometers using CDCl3 and C6D6 as
solvents referenced to TMS (d = 0 ppm), CHCl3 (d = 7.26 ppm), or
C6HD5 (d = 7.15 ppm). 13C NMR were recorded at 90.6 or 151 MHz
in CDCl3 or C6D6 using CDCl3 (d = 77.0 ppm) or C6D6 (d = 128.0
ppm) as standard. Mass spectra were recorded using electron impact
(EI). Analytical TLC was carried out on Merck silica gel plates us-
ing short wave (254 nm) UV light or a KMnO4 color reagent
[KMnO4 (3.00 g), K2CO3 (20.0 g), aq NaOH (5% w/w, 5.00 mL),
H2O (300 mL)] to visualize components. Silica gel (Kieselgel 60,
40–63 mm, Merck) was used for flash column chromatography. Re-
actions were performed at r.t. unless otherwise indicated. Diazoni-
um tetrafluoroborates 5a–c were prepared by previously reported
procedures.41
16bb
Cl
HO
O OH
N
see Table 3
N
2b
9bb
COOEt
Cl
H2SO4, EtOH
N
H
17 (37% yield from 2b)
Scheme 5 Synthesis of indole 17 using azo carboxylic acid 9bb as
an intermediate
4-Methoxybenzenediazonium Tetrafluoroborate (5a)
1H NMR (360 MHz, CD3CN): d = 4.06 (s, 3 H), 7.35 (d, J = 9.5 Hz,
2 H), 8.40 (d, J = 9.5 Hz, 2 H).
A product comparable to those available from the classi- Analytical data was in accordance with literature data.41
cal Beckmann rearrangement was prepared by reductive
cyclization of azo carboxylic acid 9hb (Scheme 6).51 Re-
4-Chlorobenzenediazonium Tetrafluoroborate (5b)
1H NMR (600 MHz, CD3CN): d = 7.94 (d, J = 9.2 Hz, 2 H), 8.46 (d,
garding the transformation of 18 to lactam 19 by reductive
J = 9.2 Hz, 2 H).
cleavage of the N–N bond, several potentially useful reac-
13C NMR (151 MHz, CD3CN): d = 113.9 (Cq), 133.2 (2 CH), 134.8
(2 CH), 150.0 (Cq).
Analytical data was in accordance with literature data.54
tion conditions have already been reported.52 To obtain pi-
peridin-2-one (19), we evaluated different methods
including reductions with Raney nickel/hydrogen,52a zinc
in hydrochloric acid, and borane–tetrahydrofuran.52e The
best results were observed with magnesium monoperox-
yphthalate hexahydrate (MMPP·6 H2O).52d,53 The volatil-
ity of compound 19 made its isolation on a small scale
somewhat inconvenient.
4-Cyanobenzenediazonium Tetrafluoroborate (5c)
1H NMR (600 MHz, CD3CN): d = 8.25 (d, J = 9.2 Hz, 2 H), 8.63 (d,
J = 9.2 Hz, 2 H).
13C NMR (90.6 MHz, CD3CN): d = 116.6 (Cq), 120.3 (Cq), 124.9
(Cq), 133.8 (2 CH), 136.3 (2 CH).
Analytical data was in accordance with literature data.54a
Cl
HO
O
OH
Hydroperoxides 2 from Cyclic Ketones 1; General Procedure
The ketone 1 was introduced into a pear-shaped flask and 3 M HCl
(0.06 equiv) and 30% aq H2O2 (3 equiv) were added. The mixture
was left to stir for the time indicated in Table 2 and was then extract-
ed with CH2Cl2 (2 × 2 mL).
N
see Table 3
Cl
N
COOH
2h
9hb
The conversions reported in Table 2 were determined from test re-
actions on a 0.30–5.00 mmol scale. Extraction of the aqueous phase
was performed with CDCl3 (1–2 mL) and an aliquot of the organic
H
NH
MMPP
MeOH
Zn, AcOH
EtOH
N
O
N
O
1
phase was analyzed by H NMR. The equilibrium data obtained
from these test reactions was used to calculate the amounts of start-
ing materials for the experiments on the preparative scale. In the
case of less favorable equilibria (hydroperoxide 2/ketone 1), the
preceding hydroperoxyacetal formation was simply conducted on a
larger scale. In this way, constant amounts of all hydroperoxides
were available for the radical rearrangements.
18 (75% from 9hb)
19 (~50%)
Scheme 6 Synthesis of lactams 18 and 19 from azo carboxylic acid
9hb
Starting from cyclic ketones, hydrogen peroxide and
arenediazonium salts have been shown to be useful re-
agents to achieve a transformation comparable to the well-
known Beckmann rearrangement. The radical reaction
leading to azo carboxylic acids proceeds under mild con-
ditions and, in contrast to the classical version, its regiose-
lectivity is governed by radical stability and not oxime
configuration. Azo carboxylic acids, which have so far
been a compound class practically unknown in organic
1-Hydroperoxycyclohexanol (2a)
Prepared according to the general procedure from cyclohexanone
(1a, 491 mg, 0.52 mL, 5.00 mmol) and 30% aq H2O2 (1.53 mL,
15.0 mmol).
1H NMR (360 MHz, CDCl3): d = 1.40–1.52 (m, 2 H), 1.54–1.65 (m,
4 H), 1.79–1.96 (m, 4 H).
13C NMR (151 MHz, CDCl3): d = 22.5 (2 CH2), 25.3 (CH2), 29.8 (2
CH2), 111.1 (Cq).
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

FEATURE ARTICLE
Radical Beckmann-Type Rearrangement
1521
1-Hydroperoxy-2-methylcyclohexanol (2b)
(5a, 1.33 g, 6.00 mmol); Rf = 0.40 (hexane–EtOAc, 3:1, 1% AcOH)
[UV].
Prepared according to the general procedure from 2-methylcyclo-
hexanone (1b, 561 mg, 0.60 mL, 5.00 mmol) and 30% aq H2O2
(1.53 mL, 15.0 mmol). A mixture of two stereoisomers (ratio 1:0.4)
was observed after stirring for 16 h.
1H NMR (360 MHz, CDCl3): d = 1.07 (d, J = 7.2 Hz, 3 H, major),
1.10 (d, J = 7.2 Hz, 3 H, minor), 1.33–2.48 (m, 9 H, major + minor).
1H NMR (360 MHz, CDCl3): d = 1.45–1.55 (m, 2 H), 1.63–1.78
(m, 2 H), 1.87–1.98 (m, 2 H), 2.38 (t, J = 7.5 Hz, 2 H), 3.85 (s, 3 H),
4.00 (t, J = 7.1 Hz, 2 H), 6.95 (d, J = 9.1 Hz, 2 H), 7.66 (d,
J = 9.1 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 24.5 (CH2), 26.9 (CH2), 27.6
(CH2), 33.8 (CH2), 55.5 (CH3), 68.8 (CH2), 114.0 (2 CH), 123.9 (2
CH), 146.2 (Cq), 161.5 (Cq), 179.2 (Cq).
MS (EI): m/z (%) = 250 (10) [M+], 160 (46), 123 (42), 122 (87), 108
(60), 85 (60), 83 (100), 80 (41), 45 (49), 37 (89).
HRMS (EI): m/z calcd [M+] for C13H18N2O3: 250.1317; found:
2-Hydroperoxybicyclo[2.2.1]heptan-2-ol (2d)
Prepared according to the general procedure from norcamphor (1d,
110 mg, 1.00 mmol) and 30% aq H2O2 (0.31 mL, 3.00 mmol). H
1
NMR indicated the formation of 2-oxabicyclo[3.2.l]octan-3-one
(ca. 13%) as side-product from a Baeyer–Villiger reaction.55
1H NMR (600 MHz, CDCl3): d = 1.26–2.21 (m, 8 H), 2.31–2.38 (m,
1 H), 2.53–2.59 (m, 1 H).
250.1317.
6-(4-Chlorophenylazo)hexanoic Acid (9ab)
Prepared according to the general procedure from cyclohexanone
(1a, 560 mg, 0.59 mL, 5.71 mmol), 30% aq H2O2 (1.75 mL,
17.1 mmol), and 4-chlorobenzenediazonium tetrafluoroborate (5b,
1.36 g, 6.00 mmol); Rf = 0.45 (hexane–EtOAc, 3:1, 1% AcOH)
[UV].
1H NMR (600 MHz, CDCl3): d = 1.46–1.54 (m, 2 H), 1.69–1.76
(m, 2 H), 1.91–1.98 (m, 2 H), 2.39 (t, J = 7.5 Hz, 2 H), 4.05 (t,
J = 7.1 Hz, 2 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.61 (d, J = 8.7 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 24.4 (CH2), 26.9 (CH2), 27.5
(CH2), 33.8 (CH2), 69.2 (CH2), 123.5 (2 CH), 129.2 (2 CH), 136.3
(Cq), 150.3 (Cq), 179.6 (Cq).
MS (EI): m/z (%) = 256 (26) [37Cl-M+], 254 (77) [35Cl-M+], 168
(29), 140 (39), 129 (40), 128 (50), 127 (100), 126 (100), 111 (55),
99 (65).
1-Hydroperoxycyclopentanol (2h)
Prepared according to the general procedure from cyclopentanone
(1h, 421 mg, 0.44 mL, 5.00 mmol) and 30% aq H2O2 (1.53 mL,
15.0 mmol).
1H NMR (360 MHz, CDCl3): d = 1.70–1.82 (m, 4 H), 1.92–2.12 (m,
4 H).
13C NMR (151 MHz, CDCl3): d = 24.6 (2 CH2), 33.3 (2 CH2), 122.5
(Cq).
1-Hydroperoxycycloheptanol (2i)
Prepared according to the general procedure from cycloheptanone
(1i, 561 mg, 0.59 mL, 5.00 mmol) and 30% aq H2O2 (1.53 mL,
15.0 mmol).
1H NMR (360 MHz, CDCl3): d = 1.53–1.79 (m, 8 H), 1.89–2.07 (m,
4 H).
HRMS (EI): m/z calcd [M+] for C12H15ClN2O2: 254.0822; found:
13C NMR (151 MHz, CDCl3): d = 22.8 (2 CH2), 29.8 (2 CH2), 33.0
(2 CH2), 116.3 (Cq).
254.0821.
6-(4-Cyanophenylazo)hexanoic Acid (9ac)
Prepared according to the general procedure from cyclohexanone
(1a, 560 mg, 0.59 mL, 5.71 mmol), 30% aq H2O2 (1.75 mL,
17.1 mmol), and 4-cyanobenzenediazonium tetrafluoroborate (5c,
1.30 g, 6.00 mmol); Rf = 0.45 (hexane–EtOAc, 2:1, 1% AcOH)
[UV].
1H NMR (600 MHz, CDCl3): d = 1.48–1.55 (m, 2 H), 1.70–1.77
(m, 2 H), 1.94–2.01 (m, 2 H), 2.40 (t, J = 7.4 Hz, 2 H), 4.12 (t,
J = 7.1 Hz, 2 H), 7.72 (d, J = 8.7 Hz, 2 H), 7.76 (d, J = 8.7 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 24.4 (CH2), 26.8 (CH2), 27.4
(CH2), 33.7 (CH2), 69.8 (CH2), 113.7 (Cq), 118.3 (Cq), 122.8 (2
CH), 133.2 (2 CH), 153.9 (Cq), 179.2 (Cq).
MS (EI): m/z (%) = 245 (10) [M+], 145 (25), 130 (80), 118 (49), 103
(19), 102 (100), 69 (31), 57 (24), 55 (32), 41 (23).
1-Hydroperoxycyclooctanol (2j)
Prepared according to the general procedure from cyclooctanone
(1j, 126 mg, 1.00 mmol) and 30% aq H2O2 (0.31 mL, 3.00 mmol).
1H NMR (360 MHz, CDCl3): d = 1.50–1.71 (m, 10 H), 1.80–2.06
(m, 4 H).
Carboxylic Acids 9aa–ja; General Procedure
Unless otherwise indicated, the amount of cyclic ketone 1 necessary
to yield approximately 5 mmol of hydroperoxide 2 (calculated from
the reactant/product ratios given in Table 2) was mixed with 3 M
HCl (0.06 equiv) and 30% aq H2O2 (3 equiv) and left to stir for the
time given in Table 2. The mixture was then extracted with CH2Cl2
(2 × 2 mL) and immediately used for the consecutive step.
To a mixture of H2O–DMSO–AcOH (4:3:3, 30 mL) were added
FeSO4·7 H2O (4.17 g, 15.0 mmol) and diazonium tetrafluoroborate
5 (6.00 mmol). The previously prepared soln containing hydroper-
oxide 2 and unreacted ketone 1 in CH2Cl2 (see above) was added
dropwise over 5 min. Stirring was continued for 15 min and the
mixture was diluted with H2O (30 mL) and extracted with Et2O
(3 × 50 mL). The combined organic phases were washed with H2O
(1 × 100 mL) and brine (1 × 100 mL) and dried (Na2SO4). The sol-
vent was removed in vacuo, yielding orange to dark red thick oils as
products. In the case of sufficiently low boiling points [e.g. for cy-
clopentanone (1h)], the ketones remaining from the hydroperoxide
formation could be removed in vacuo.
HRMS (EI): m/z calcd [M+] for C13H15N3O2: 245.1164; found:
245.1164.
6-(4-Methoxyphenylazo)heptanoic Acid (9ba)
Prepared according to the general procedure from 2-methylcyclo-
hexanone (1b, 804 mg, 0.86 mL, 7.17 mmol), 30% aq H2O2
(2.20 mL, 21.5 mmol), and 4-methoxybenzenediazonium tetrafluo-
roborate (5a, 1.33 g, 6.00 mmol); Rf = 0.65 (hexane–EtOAc, 2:1,
1% AcOH) [UV].
1H NMR (600 MHz, CDCl3): d = 1.27–1.43 (m, 5 H), 1.60–1.76
(m, 3 H), 1.88–1.98 (m, 1 H), 2.34 (t, J = 7.5 Hz, 2 H), 3.65–3.72
(m, 1 H), 3.85 (s, 3 H), 6.95 (d, J = 9.0 Hz, 2 H), 7.66 (d,
J = 9.0 Hz, 2 H).
6-(4-Methoxyphenylazo)hexanoic Acid (9aa)
Prepared according to the general procedure from cyclohexanone
(1a, 560 mg, 0.59 mL, 5.71 mmol), 30% aq H2O2 (1.75 mL,
17.1 mmol), and 4-methoxybenzenediazonium tetrafluoroborate
13C NMR (151 MHz, CDCl3): d = 19.0 (CH3), 24.6 (CH2), 25.7
(CH2), 33.9 (CH2), 34.9 (CH2), 55.5 (CH3), 72.5 (CH), 114.0 (2
CH), 123.9 (2 CH), 146.2 (Cq), 161.4 (Cq), 179.3 (Cq).
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

1522
A. Prechter, M. R. Heinrich
FEATURE ARTICLE
MS (EI): m/z (%) = 264 (4) [M+], 135 (94), 108 (25), 107 (100), 92
MS (EI): m/z (%) = 262 (4) [M+], 135 (90), 108 (21), 107 (100), 92
(25), 83 (23), 77 (51), 69 (18), 55 (19), 42 (23).
(19), 85 (15), 83 (24), 77 (46), 67 (33), 41 (17).
HRMS (EI): m/z calcd [M+] for C14H20N2O3: 264.1474; found:
HRMS (EI): m/z calcd [M+] for C14H18N2O3: 262.1318; found:
264.1478.
262.1316.
6-(4-Chlorophenylazo)heptanoic Acid (9bb)
5-(4-Methoxyphenylazo)pentanoic Acid (9ha)
Prepared according to the general procedure from 2-methylcyclo-
hexanone (1b, 804 mg, 0.86 mL, 7.17 mmol), 30% aq H2O2
(2.20 mL, 21.5 mmol), and 4-chlorobenzenediazonium tetrafluo-
roborate (5b, 1.36 g, 6.00 mmol); Rf = 0.30 (hexane–EtOAc, 3:1,
1% AcOH) [UV].
1H NMR (600 MHz, CDCl3): d = 1.29–1.41 (m, 5 H), 1.60–1.77
(m, 3 H), 1.91–1.99 (m, 1 H), 2.34 (t, J = 7.5 Hz, 2 H), 3.70–3.78
(m, 1 H), 7.41 (d, J = 8.8 Hz, 2 H), 7.61 (d, J = 8.8 Hz, 2 H).
13C NMR (90.6 MHz, CDCl3): d = 18.8 (CH3), 24.6 (CH2), 25.6
(CH2), 33.7 (CH2), 34.8 (CH2), 73.0 (CH), 123.5 (2 CH), 129.1 (2
CH), 136.2 (Cq), 150.4 (Cq), 178.9 (Cq).
MS (EI): m/z (%) = 270 (1) [37Cl-M+], 268 (4) [35Cl-M+], 141 (31),
139 (92), 113 (44), 111 (100), 85 (26), 83 (53), 69 (57), 55 (53), 42
(44).
Prepared according to the general procedure from cyclopentanone
(1h, 701 mg, 0.74 mL, 8.33 mmol), 30% aq H2O2 (2.56 mL,
25.0 mmol), and 4-methoxybenzenediazonium tetrafluoroborate
(5a, 1.33 g, 6.00 mmol). This experiment was conducted with an
unusual ratio of hydrogen peroxide/ketone, which led to a mixture
of hydroperoxide/ketone (1.5:1) after 4 h; Rf = 0.25 (hexane–
EtOAc, 4:1, 1% AcOH) [UV].
1H NMR (600 MHz, CDCl3): d = 1.76–1.84 (m, 2 H), 1.93–2.00
(m, 2 H), 2.44 (t, J = 7.5 Hz, 2 H), 3.86 (s, 3 H), 4.01 (t, J = 7.0 Hz,
2 H), 6.95 (d, J = 9.0 Hz, 2 H), 7.66 (d, J = 9.0 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 22.7 (CH2), 27.4 (CH2), 33.6
(CH2), 55.5 (CH3), 68.4 (CH2), 114.0 (2 CH), 123.9 (2 CH), 146.2
(Cq), 161.5 (Cq), 178.2 (Cq).
MS (EI): m/z (%) = 236 (18) [M+], 160 (23), 135 (23), 123 (33), 122
(100), 108 (40), 107 (21), 85 (40), 83 (56), 37 (62).
HRMS (EI): m/z calcd [M+] for C12H16N2O3: 236.1161; found:
HRMS (EI): m/z calcd [M+] for C13H17ClN2O2: 268.0979; found:
268.0979.
236.1173.
6-(4-Cyanophenylazo)heptanoic Acid (9bc)
Prepared according to the general procedure from 2-methylcyclo-
hexanone (1b, 804 mg, 0.86 mL, 7.17 mmol), 30% aq H2O2
(2.20 mL, 21.5 mmol), and 4-cyanobenzenediazonium tetrafluo-
roborate (5c, 1.30 g, 6.00 mmol); Rf = 0.45 (hexane–EtOAc, 2:1,
1% AcOH) [UV].
1H NMR (600 MHz, CDCl3): d = 1.27–1.42 (m, 5 H), 1.60–1.72
(m, 2 H), 1.73–1.81 (m, 1 H), 1.94–2.02 (m, 1 H), 2.35 (t,
J = 7.4 Hz, 2 H), 3.78–3.85 (m, 1 H), 7.72 (d, J = 8.8 Hz, 2 H), 7.76
(d, J = 8.8 Hz, 2 H).
5-(4-Chlorophenylazo)pentanoic Acid (9hb)
Prepared according to the general procedure from cyclopentanone
(1h, 548 mg, 0.58 mL, 6.52 mmol), 30% aq H2O2 (2.00 mL,
19.6 mmol), and 4-chlorobenzenediazonium tetrafluoroborate (5b,
1.36 g, 6.00 mmol); Rf = 0.45 (hexane–EtOAc, 3:1, 1% AcOH)
[UV].
1H NMR (360 MHz, CDCl3): d = 1.73–2.05 (m, 4 H), 2.44 (t,
J = 7.4 Hz, 2 H), 4.06 (t, J = 7.0 Hz, 2 H), 7.42 (d, J = 8.9 Hz, 2 H),
7.61 (d, J = 8.9 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 18.8 (CH3), 24.5 (CH2), 25.6
(CH2), 33.8 (CH2), 34.7 (CH2), 73.6 (CH), 113.6 (Cq), 118.4 (Cq),
122.8 (2 CH), 133.2 (2 CH), 154.0 (Cq), 179.1 (Cq).
13C NMR (151 MHz, CDCl3): d = 22.5 (CH2), 27.2 (CH2), 33.7
(CH2), 68.9 (CH2), 123.5 (2 CH), 129.2 (2 CH), 136.4 (Cq), 150.3
(Cq), 179.6 (Cq).
MS (EI): m/z (%) = 259 (2) [M+], 130 (32), 129 (53), 111 (62), 102
(85), 83 (100), 69 (92), 55 (67), 45 (20), 41 (50).
HRMS (EI): m/z calcd [M+] for C14H17N3O2: 259.1321; found:
259.1320.
MS (EI): m/z (%) = 242 (24) [37Cl-M+], 240 (76) [35Cl-M+], 139
(40), 128 (46), 127 (92), 126 (100), 113 (28), 111 (81), 99 (67), 83
(34).
HRMS (EI): m/z calcd [M+] for C11H13ClN2O2: 240.0666; found:
240.0665.
[3-(4-Methoxyphenylazo)cyclopentyl]acetic Acid (Mixture of
Diastereoisomers) (9da)
Prepared according to the general procedure from norcamphor (1d,
7-(4-Methoxyphenylazo)heptanoic Acid (9ia)
Prepared according to the general procedure from cycloheptanone
(1i, 785 mg, 0.83 mL, 7.00 mmol), 30% aq H2O2 (2.14 mL,
21.0 mmol), and 4-methoxybenzenediazonium tetrafluoroborate
(5a, 1.33 g, 6.00 mmol); Rf = 0.25 (hexane–EtOAc, 3:1, 1% AcOH)
[UV].
1H NMR (360 MHz, CDCl3): d = 1.39–1.80 (m, 6 H), 1.85–1.97
(m, 2 H), 2.35 (t, J = 7.4 Hz, 2 H), 3.85 (s, 3 H), 3.96–4.03 (m, 2 H),
6.95 (d, J = 9.1 Hz, 2 H), 7.66 (d, J = 9.1 Hz, 2 H).
13C NMR (90.6 MHz, CDCl3): d = 24.6 (CH2), 27.1 (CH2), 27.8
(CH2), 28.9 (CH2), 34.0 (CH2), 55.5 (CH3), 69.0 (CH2), 114.0 (2
CH), 123.8 (2 CH), 146.3 (Cq), 161.4 (Cq), 179.1 (Cq).
MS (EI): m/z (%) = 264 (8) [M+], 135 (91), 122 (24), 108 (28), 107
(100), 92 (33), 85 (18), 83 (27), 77 (63), 42 (20).
596 mg, 5.41 mmol), 30% aq H2O2 (1.65 mL, 16.2 mmol), and 4-
methoxybenzenediazonium
tetrafluoroborate
(5a,
1.33 g,
6.00 mmol). In this case, the hydroperoxide soln contained small
amounts (ca. 13%) of 2-oxabicyclo[3.2.1]octan-3-one. The product
was obtained as a mixture of diastereoisomers; Rf = 0.40 (hexane–
EtOAc, 2:1, 1% AcOH) [UV].
1H NMR (600 MHz, CDCl3,): d = 1.40–2.60 (m, 8 H, major + mi-
nor), 2.69–2.78 (m, 1 H, major), 2.84–2.92 (m, 1 H, minor), 3.85 (s,
3 H, major), 3.86 (s, 3 H, minor), 4.00–4.05 (m, 1 H, minor), 4.15–
4.23 (m, 1 H, major), 6.92–6.97 (m, 2 H, major + minor), 7.64–7.68
(m, 2 H, major + minor).
13C NMR: (151 MHz, CDCl3): d = 28.8, 29.2, 30.2, 30.8, 31.0, 31.7,
32.1, 32.4, 33.2, 34.7, 34.9, 35.1, 35.5, 36.0, 37.7, 38.0, 38.3, 39.2,
39.3, 39.8, 39.9, 43.4, 44.5, 55.1, 55.5, 55.7, 73.6, 77.1, 77.6,
113.99 (2 C), 114.02 (2 C), 114.7 (2 C), 123.90 (2 C), 123.91 (2 C),
123.93 (2 C), 146.05, 146.07, 146.3, 161.4, 161.5, 178.5 (a third
isomer which could not be detected by 1H NMR was formed upon
standing in CDCl3).
HRMS (EI): m/z calcd [M+] for C14H20N2O3: 264.1474; found:
264.1474.
7-(4-Chlorophenylazo)heptanoic Acid (9ib)
Prepared according to the general procedure from cycloheptanone
(1i, 785 mg, 0.83 mL, 7.00 mmol), 30% aq H2O2 (2.14 mL,
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

FEATURE ARTICLE
Radical Beckmann-Type Rearrangement
1523
21.0 mmol), and 4-chlorobenzenediazonium tetrafluoroborate (5b,
1.36 g, 6.00 mmol); Rf = 0.40 (hexane–EtOAc, 3:1, 1% AcOH)
[UV].
13C NMR (151 MHz, CDCl3): d = 24.7 (CH2), 27.0 (CH2), 27.5
(CH2), 33.9 (CH2), 51.5 (CH3), 69.3 (CH2), 123.5 (2 CH), 129.2 (2
CH), 136.3 (Cq), 150.4 (Cq), 174.0 (Cq).
1H NMR (360 MHz, CDCl3): d = 1.22–1.77 (m, 6 H), 1.86–1.98
(m, 2 H), 2.36 (t, J = 7.5 Hz, 2 H), 4.01–4.08 (m, 2 H), 7.42 (d,
J = 8.9 Hz, 2 H), 7.61 (d, J = 8.9 Hz, 2 H).
13C NMR (90.6 MHz, CDCl3): d = 24.5 (CH2), 27.1 (CH2), 27.6
(CH2), 28.8 (CH2), 33.9 (CH2), 69.4 (CH2), 123.4 (2 CH), 129.2 (2
CH), 136.3 (Cq), 150.4 (Cq), 179.3 (Cq).
MS (EI): m/z (%) = 270 (3) [37Cl-M+], 268 (8) [35Cl-M+], 141 (27),
139 (84), 113 (47), 111 (100), 75 (21), 69 (18), 55 (14), 41 (16).
HRMS (EI): m/z calcd [M+] for C13H17ClN2O2: 268.0979; found:
268.0979.
6-[(4-Chlorophenyl)hydrazono]hexanoic Acid (16ab)
The carboxylic acid 9ab (10.0 mg, 0.04 mmol) isomerized to the
hydrazone upon standing in CDCl3 (0.70 mL) overnight. Com-
pound 16ab was obtained as a mixture of E/Z isomers (ratio 3:1).
1H NMR (600 MHz, CDCl3): d = 1.55–1.89 (m, 4 H, major + mi-
nor), 2.20–2.45 (m, 4 H, major + minor), 6.51 (t, J = 5.1 Hz, 1 H,
minor), 6.90 (d, J = 8.9 Hz, 2 H, major), 6.97 (d, J = 8.9 Hz, 2 H,
minor), 7.06 (t, J = 5.3 Hz, 1 H, major), 7.17 (d, J = 8.9 Hz, 2 H,
major), 7.19 (d, J = 8.9 Hz, 2 H, minor).
MS (EI): m/z (%) = 270 (1) [37Cl-M+], 268 (3) [35Cl-M+], 139 (48),
113 (26), 111 (79), 85 (65), 83 (100), 55 (18), 47 (24), 42 (21).
HRMS (EI): m/z calcd [M+] for C13H17ClN2O2: 268.0979; found:
268.0979.
8-(4-Chlorophenylazo)octanoic Acid (9jb)
Prepared according to the general procedure from cyclooctanone
(1j, 1.68 g, 13.3 mmol), 30% aq H2O2 (4.09 mL, 40.0 mmol), and 4-
chlorobenzenediazonium
6.00 mmol); Rf = 0.65 (hexane–EtOAc, 2:1, 1% AcOH) [UV].
tetrafluoroborate
(5b,
1.36 g,
The identity of the hydrazone is supported by data reported the lit-
erature.58
1H NMR (600 MHz, CDCl3): d = 1.35–1.48 (m, 6 H), 1.61–1.68
(m, 2 H), 1.85–1.93 (m, 2 H), 2.35 (t, J = 7.5 Hz, 2 H), 4.02–4.06
(m, 2 H), 7.42 (d, J = 8.8 Hz, 2 H), 7.61 (d, J = 8.8 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 24.6 (CH2), 27.2 (CH2), 27.8
(CH2), 28.9 (CH2), 29.0 (CH2), 34.0 (CH2), 69.6 (CH2), 123.5 (2
CH), 129.2 (2 CH), 136.3 (Cq), 150.4 (Cq), 179.9 (Cq).
MS (EI): m/z (%) = 284 (2) [37Cl-M+], 282 (5) [35Cl-M+], 241 (23),
239 (72), 113 (31), 111 (100), 85 (17), 83 (26), 55 (21), 41 (17).
HRMS (EI): m/z calcd [M+] for C14H19ClN2O2: 282.1135; found:
282.1134.
Ethyl 4-(5-Chloro-2-methyl-1H-indol-3-yl)butyrate (17)59
Carboxylic acid 9bb (150 mg of the crude product, ca. 0.50 mmol)
was dissolved in a mixture of EtOH (2.5 mL) and concd H2SO4
(0.30 mL, 5.40 mmol). The mixture was refluxed for 3.5 h under
N2. After cooling to r.t. H2O (10 mL) was added and the aqueous
soln was extracted with EtOAc (3 × 10 mL). The combined organic
phases were washed with H2O (1 × 30 mL) and brine (1 × 30 mL)
and dried (Na2SO4). The solvent was removed in vacuo. Column
chromatography (100% CHCl3) gave 17 as a brown oil (58.0 mg,
0.21 mmol, 37% overall yield); Rf = 0.40 (100% CHCl3) [UV].
1H NMR (600 MHz, CDCl3): d = 1.24 (t, J = 7.2 Hz, 3 H), 1.93
(quint, J = 7.4 Hz, 2 H), 2.31 (t, J = 7.4 Hz, 2 H), 2.33 (s, 3 H), 2.69
(t, J = 7.4 Hz, 2 H), 4.10 (q, J = 7.2 Hz, 2 H), 7.03 (dd, J = 2.0 Hz,
J = 8.5 Hz, 1 H), 7.14 (dd, J = 0.5 Hz, J = 8.5 Hz, 1 H), 7.43 (d,
J = 2.0 Hz, 1 H), 7.82 (br, 1 H).
13C NMR (151 MHz, CDCl3): d = 11.7 (CH3), 14.2 (CH3), 23.2
(CH2), 25.6 (CH2), 33.7 (CH2), 60.3 (CH2), 110.9 (Cq), 111.0 (CH),
117.5 (CH), 121.0 (CH), 124.8 (Cq), 129.9 (Cq), 132.8 (Cq), 133.6
(Cq), 173.7 (Cq).
MS (EI): m/z (%) = 281 (13) [37Cl-M+], 279 (42) [35Cl-M+], 234
(17), 191 (25), 180 (64), 179 (29), 178 (100), 143 (21), 85 (21), 83
(32).
Methyl 6-(4-Chlorophenylazo)hexanoate (15)56
For the preparation of N-methyl-N-nitrosourea,57 N-methylurea
(14.8 g, 200 mmol) was dissolved in H2O (120 mL). NaNO2
(15.2 g, 220 mmol) was added and the mixture cooled to 0 °C in an
ice bath. Concd aq HCl (26.7 mL, 0.26 mol) was added dropwise
over a period of 1 h. The mixture was left to stir for 30 min at 0 °C.
The precipitate that had formed was filtered off, washed with H2O
(ca. 20 mL), and dried in vacuo. N-Methyl-N-nitrosourea was ob-
tained as a light beige powder (16.4 g, 159 mmol, 79%) and was
found to be sufficiently pure for further reactions. It was stored at
–28 °C.
N-Methyl-N-nitrosourea (850 mg, 8.25 mmol) was introduced into
an Erlenmeyer flask containing Et2O (20 mL) and 40% aq KOH
(6 mL) previously cooled to 0 °C in an ice bath. The mixture was
left to stand for 30 min at this temperature, carefully shaking it sev-
eral times. The organic phase containing the generated diazo-
methane was decanted and dried (KOH pellets) at 0 °C for 3 h.
Carboxylic acid 9ab (300 mg of the crude product, ca. 0.85 mmol)
was dissolved in a mixture of Et2O (15 mL) and MeOH (10 mL) and
cooled to 0 °C. The soln of diazomethane in Et2O was added drop-
wise. After stirring for 15 min at 0 °C, AcOH (2.50 mL, 43.7 mmol)
was added to quench unreacted diazomethane. After stirring for an-
other 15 min, the soln was washed with sat. aq NaHCO3
(1 × 50 mL) and brine (1 × 50 mL), and the solvent was removed in
vacuo. Column chromatography (hexane–EtOAc, 4:1) gave the
product as a red oil (111 mg, 0.41 mmol, 33% overall yield); Rf =
0.55 (hexane–EtOAc, 4:1) [UV].
HRMS (EI): m/z calcd [M+] for C15H18ClNO2: 279.1026; found:
279.1025.
1-(4-Chlorophenylamino)piperidin-2-one (18)51
Carboxylic acid 9hb (125 mg, 0.52 mmol) was dissolved in EtOH
(10 mL) under an argon atmosphere and Zn dust (600 mg,
9.17 mmol) and AcOH (5 mL) were added. The mixture was stirred
for 5 min (until it had become nearly colorless) and the remaining
Zn powder was filtered off. The soln was refluxed under an argon
atmosphere for 5 h. After cooling to r.t. the solvent was removed in
vacuo. The pure product was obtained after column chromatogra-
phy (100% EtOAc) as a brownish powder (88.4 mg, 0.39 mmol,
75%); Rf = 0.25 (EtOAc) [UV].
1H NMR (360 MHz, CDCl3): d = 1.84–1.94 (m, 2 H), 1.94–2.04 (m,
2 H), 2.53 (t, J = 6.6 Hz, 2 H), 3.57 (t, J = 6.0 Hz, 2 H), 6.69 (d,
J = 8.8 Hz, 2 H), 6.76 (br, 1 H), 7.18 (d, J = 8.8 Hz, 2 H).
13C NMR (90.6 MHz, CDCl3): d = 21.3 (CH2), 23.6 (CH2), 32.5
(CH2), 51.3 (CH2), 115.3 (2 CH), 126.3 (Cq), 129.2 (2 CH), 145.3
(Cq), 169.9 (Cq).
1H NMR (360 MHz, C6D6): d = 1.15–1.25 (m, 2 H), 1.45–1.56 (m,
2 H), 1.63–1.73 (m, 2 H), 2.04 (t, J = 7.4 Hz, 2 H), 3.34 (s, 3 H),
3.86 (t, J = 7.1 Hz, 2 H), 7.07 (d, J = 8.8 Hz, 2 H), 7.55 (d,
J = 8.8 Hz, 2 H).
Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York

1524
A. Prechter, M. R. Heinrich
FEATURE ARTICLE
MS (EI): m/z (%) = 226 (34) [37Cl-M+], 224 (100) [35Cl-M+], 139
(61), 127 (55), 126 (71), 113 (30), 111 (92), 99 (44), 70 (42), 42
(42).
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HRMS (EI): m/z calcd [M+] for C11H13ClN2O: 224.0716; found:
224.0716.
Piperidin-2-one (19)
Compound 19 was prepared from lactam 18 according to literature
procedures.52d,53
Rf = 0.15 (EtOAc, 5% MeOH) [KMnO4].
1H NMR (360 MHz, CDCl3): d = 1.72–1.89 (m, 4 H), 2.38 (t,
J = 6.4 Hz, 2 H), 3.30–3.36 (m, 2 H).
Analytical data was in accordance with literature.60
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(17) For Beckmann rearrangements in supercritical water, see:
(a) Ikushima, Y.; Hatakeda, K.; Sato, O.; Yokoyama, T.;
Arai, M. J. Am. Chem. Soc. 2000, 122, 1908. (b) Boero, M.;
Ikeshoji, T.; Liew, C. C.; Terakura, K.; Parrinello, M. J. Am.
Chem. Soc. 2004, 126, 6280.
Acknowledgment
The authors would like to thank the Deutsche Forschungsgemein-
schaft (DFG) and the FAU Erlangen-Nürnberg for generous finan-
cial support. A. Prechter is grateful for a ‘Bayerische Elitefördung’
fellowship. We would also like to thank Prof. Samir Z. Zard for
helpful discussions.
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Radical Beckmann-Type Rearrangement
1525
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Synthesis 2011, No. 10, 1515–1525 © Thieme Stuttgart · New York