The von auwers reaction - history and synthetic applications

Article abstract of DOI:10.2533/chimia.2014.522

Dienones obtained from the facile dearomatization of phenols, can be further transformed to semibenzenes prone to rearomatize in clean, but sometimes unexpected, fashion. Over a hundred years ago, K. von Auwers found that adding Grignards on dienones would lead spontaneously to subsequent dehydration and a novel aromatizing rearrangement. This reaction was ignored for 50 years before Melvin Newman re-investigated these findings, studied the mechanism, and developed variations on the same theme. Since then, despite the tremendous potential of the reactions, those studies were only rarely mentioned, before finally falling into oblivion. This review aims to provide the reader with a detailed history and comprehensive bibliography of the von Auwers rearrangement, some of its synthetic applications, and new unpublished material in the hope to open new perspectives on this forgotten reaction.

Full text of DOI:10.2533/chimia.2014.522

522 CHIMIA 2014, 68, Nr. 7/8
doi:10.2533/chimia.2014.522
Note
Chimia 68 (2014) 522–530 © Schweizerische Chemische Gesellschaft
The von Auwers Reaction – History and
Synthetic Applications
Raphaël Dumeunier* and Simon Jaeckh
Abstract: Dienones obtained from the facile dearomatization of phenols, can be further transformed to semi-
benzenes prone to rearomatize in clean, but sometimes unexpected, fashion. Over a hundred years ago, K. von
Auwers found that adding Grignards on dienones would lead spontaneously to subsequent dehydration and a
novel aromatizing rearrangement. This reaction was ignored for 50 years before Melvin Newman re-investigated
these findings, studied the mechanism, and developed variations on the same theme. Since then, despite the
tremendous potential of the reactions, those studies were only rarely mentioned, before finally falling into oblivion.
This review aims to provide the reader with a detailed history and comprehensive bibliography of the von Auwers
rearrangement, some of its synthetic applications, and new unpublished material in the hope to open new
perspectives on this forgotten reaction.
Keywords: Radical · Rearomatization · Rearrangement · Semi-benzene · von Auwers reaction
Scheme 1. Known
von Auwers
rearrangements; both
variants.
1. Introduction
[1,5]-Shift
Upon standing or
ThermalorLight
Von Auwers rearrangements are
encompassed by the two generic reactions
depicted in Scheme 1. Two variants of this
2
1
1
reaction – also known as ‘semi-benzene
rearrangement’ – exist, namely the [1,5]-
and the [1,3]-migration. Semi-benzenes 1
(X = carbon) and 3 are not often observed
or isolated, but rather prepared in situ
from suitable precursors, as the [1,n]-shift
occurs rapidly at room temperature or
upon standing – especially when R2 is a
stable radical.
R =Me
X=CH2,C
H
R, CR2,S
2
R =C 3
Cl ,CHCl2,and also
CH3,Allyl, Propargyl, Benzyl, cPrMethyl
[1,3]-Shift
Upon standing or
ThermalorLight
4
1
R =Me, Et, nPr
This review describes the history of
3
2
R =C 3
Cl ,CHCl2,CBr3 andBenzyl
these reactions, in an attempt to provide the
reader with a comprehensive bibliography,
from their discovery in 1903 to the latest
examplepublishedin1996. Unprecedented
extensions of the reactions, like a new
[1,7]-shift as well as a few synthetic
applications will be disclosed.
3
R =OAc,Cl, Br,Ph
4
R =H,Me
cyclohexadienone 10. Nowadays dienones
arising from these reactions are called
abnormal Reimer-Tiemann products.
Von Auwers started shortly afterwards
Von Auwers soon extended the scope of
this reaction and reported in a series of
publications the formation of chlorinated
cyclohexadienones from ortho- and para-
substituted phenols (Scheme 2).[2] The
to investigate the functionalization of
these abnormal products and in 1903,
reported the effect of the addition of
methyl Grignard on dienones 10 and 12.[3]
simplest example, p-cresol, gives a 1:1
mixture of the expected arylaldehyde
11, together with the chlorinated
2. History of the von Auwers
Rearrangement
2.1 The Early Years (1903–1922);
Karl von Auwers and Theodor
Zincke
Scheme 2. Discovery
of the abnormal
Reimer-Tiemann
reaction by Karl von
Auwers.
In 1876, a salicylaldehyde synthesis
a
q. Na
O
H,HCCl3
from phenol, chloroform and alkali was
[1]
60 °C
published by Reimer and Tiemann.
7
2%
8
6
45%
5%
5
*Correspondence: Dr. R. Dumeunier
Syngenta Crop Protection
a
q. Na
O
H,HCCl3
Münchwilen AG, Schaffhauserstrasse
CH-4332 Stein
Tel.: +41 62 866 0271
60 °C
10
11
26%
25%
9
E-mail: raphael.dumeunier@syngenta.com

Note
CHIMIA 2014, 68, Nr. 7/8 523
Scheme 3.
As the carbonyl group of 12 is hindered
by the α-quaternary center, the Grignard
reagent added in a 1,4-manner. But in the
case of dienone 10, where the degenerate
1,4-positions are neopentylic, the Grignard
only added onto the carbonyl group, and
even though alcohol 15 could be observed
and isolated, it spontaneously rearranged
by loss of water to the aromatic compound
Seminal example
of the von Auwers
rearrangement.
MeMgI
MeMgI
12
13
via
and
14 (Scheme 3). This seminal example of
the von Auwers rearrangement is a formal
1,5-sigmatropic shift of the dichloromethyl
group occurring in semi-benzene 16.
16
10
14
15
In 1906, another way to dearomatize
phenols was reported by Zincke and
Suhl who treated p-cresol with aluminum
trichloride in carbon tetrachloride (Scheme
Scheme 4.
Trichloromethyl-
[1,5]-migration
4).[4] Two years later, they reported the use
in von Auwers
rearrangement.
AlCl ,CCl4
3
MeMgI
of the von Auwers rearrangement on 17.[5]
It is worthy of note that both von
Auwers and Zincke had also found that
their dienones could easily rearomatize
under acidic conditions by a 1,2-shift of
the alkyl group (Scheme 5, products 19
and 21b).[6] Such kinds of rearomatization
had already been reported by Andreocci
in 1893,[7] and are nowadays known as
Djerassi dienone–phenol rearrangements.
40-43%
17
9
18
Scheme 5. Other
ways of forming C–C
bonds from 17.
PCl5
This topic will not be discussed further in
this review, although von Auwers formed
19
17
aryl–aryl C–C bonds from aryl-Grignard
reagents using this [1,2]-shift (21b) or
reductively towards 21a, two reactions
confirmed and reproduced by Newman in
1959.[8]
R
MgX
During these early 20th century
studies,[3-6,9] other kinds of organometallic
nucleophiles were reacted with 10 and 17
and a few examples are given in Scheme
6. All examples reported belong to the
[1,5]-class of migrations of either dichloro-
or trichloro-methyl groups. It would take
another 50 years before a [1,3]-version of
this reaction was discovered by Melvin
Newman.
HCOOH
H2SO4cc
R=Ph,Me
R=Ph
20
21a
21b
Scheme 6. Further
examples from Karl
von Auwers early
studies.
Zn°
2.2 1956–1970; M. Newman’s
Contribution
2.2.1 1,5-Migration
10
22
After a 30-year absence from the
literature, this chemistry resurfaced in
a single paper from Fuson and Miller
(Scheme 7), who extended it to the
naphthalene series.[10]
Then,
in 1956 Newman initiated
the work which led to a series of seven
publications, the first of which[11] displayed
a non-conventional method to form semi-
benzenes. Where von Auwers and Zincke
both used C-nucleophiles, which allow the
loss of water from the alcohol produced,
NewmanconsideredinsteadusingaMeyer-
Schuster rearrangement[12] (Scheme 8).
All intermediate steps happened during
work-up or upon standing, and only the
desired product 28 was isolated in good
1
0
2
3
1
2
R =Me, Et,and R =H
1
2
R =R =Me
1
7
24

524 CHIMIA 2014, 68, Nr. 7/8
Note
Scheme 7. Extension
of the rearrangement
to the naphthalene
series.
polyphosphoric acid (PPA) to initiate semi-
benzene formation leads to the formation
of 2-chloro-4,5-dimethylbenzoic acid
(after hydrolysis of acid chloride 37).[16]
Similar observations were made
again in 1962 on 46[17] (from the more
elaborate 2,4,5-trimethyl-phenol) as well
as independently by Miller who used
sulphuric acid instead of PPA.[18]
EtMgBr
Yieldnot give
Na
OH
HCCl3
42%
n
26
2
5
27
Scheme 8. Tandem
Meyer-Schuster/
von Auwers
The
seminal [1,3]-rearrangement
depicted in Scheme 11 was reproduced
successfully by Newman, from the
dichloromethyl analogue 39, although the
migration of dichloromethane is slower
and required harsher conditions.[19] It is
surprising that von Auwers did not invent,
or at least did not report, the [1,3]-version
of the rearrangement, as he had had access
rearrangements.
78% isolated
17
28
[1,2]-methyl shifts promoted by PCl
yield. This paper also contained a first
5
to compounds 6 and 39. von Auwers
(Scheme 5) in analogous fashion to
prepare 3,5-dimethyl-4-trichloromethyl
chlorobenzene (33) starting from ketone
32 (Scheme 10). However, failure to form
33 led Newman instead to the discovery
of the [1,3]-version of the von Auwers
rearrangement.
tentative explanation for the mechanism of
the trichloromethyl migration, involving a
zwitterionic species and bridging chlorine.
Newman’s mechanistic hypothesis
was immediately questioned by Bird
and Cookson, who published in 1959
convincingevidencethattherearrangement
takes place via a free-radical chain reaction
(Scheme 9).[13] Alongside a kinetic study
of the rearrangement of 29, the authors
mention that the temperature-dependent
did report though the methyl Grignard
addition on both substrates (Scheme 13),
but although two semi-benzenes a and b
might have been formed from each of the
intermediate alcohols (and the [1,3]-shift
discovered from a), only the cross-
conjugated 42b and 43b seemed to have
been generated, as the single products 44
and 45 were isolated from each reaction.[20]
Newman observed exactly the same
2.2.2 1,3-Migration from Dienone
Dehydration
In fact, the action of PCl5 on 32 led
Scheme 9. Proposed
mechanism of the
[1,5]-migration of
dichloromethyl.
Initiation
PCl5
29
19
17
Propagation
Propagation
PCl5
30
33
32
Scheme 10. Thwarted attempt of a Djerassi
dienone-phenol rearrangement on 32.
apparently to semi-benzene 35 (not ob-
served:Scheme11)asanewrearrangement
took place: the [1,3]-sigmatropic shift of
the trichloromethyl group, which resulted
induction period of the rearrangement
can be shortened by addition of benzoyl
peroxide or by UV irradiation, whereas
the reaction can be inhibited by addition
Ac O, cat. H2SO4
2
in the formation of 34 in high yield.[14]
of duroquinone. The activation energy
>95%
Activating ketone 32 with acetic
anhydride[15] also triggers rearrangement
to 36 (Scheme 12), but surprisingly,
for a hitherto unknown reason, using
of the initiation step had been estimated
experimentally to be around 40 kcal/mol.
In the meantime, what interested
Newman was to make use of the
36
3
2
PPA
Scheme 11.
Fortuitous discovery
of the [1,3]-version
of the von Auwers
37
38
PCl5
56%
3%
rearrangement.
via
88%isolated
34
32
Scheme 12. Unprecedented (and yet
unexplained) rearrangement to 37.
35

Note
CHIMIA 2014, 68, Nr. 7/8 525
selective semi-benzene formation when
adding MeMgBr to 32 (30–50% yield
in 1,2-dimethyl-4-(2,2,2-trichloroethyl)
benzene).[21]
As could be seen from Scheme 13,
when alcohols 40 or 41 have the choice
to eliminate water by giving [1,5]- or
[1,3]-migration precursors a and b, cross-
conjugated semi-benzenes are formed
exclusively. Newman was then interested
in creating two competing reactions,
a dehydration or a rearrangement, for
the formation of semi-benzenes a and
b (Scheme 14). If, instead of a Grignard
reagent, an alkynyl anion would be added
to 32, the alcohol would have the choice to
eliminatewater(leadingtoa1,3-migration)
or to proceed through a Meyer-Schuster
rearrangement(leadingtoa1,5-migration).
Results teach us that, with ethoxyethynyl
magnesium bromide, be it on 32 or 46, the
only products observed and isolated came
from [1,5]-migration (51 and 52, Scheme
14), regardless of the extra steric hindrance
from the 2-methyl of 46 (Scheme 14).[21]
4
2
a R=H
4
3a R=Me
-HO
2
3
9 R=H
6 R=Me
4
0 R=H
4
1 R=Me
4
2
b R=H
4
4 R=H
4
3
b R=Me
45 R=Me
Scheme 13. Selective cross-conjugated semi-benzene formation and [1,5]-shifts.
-HO
2
4
9
a R=H
5
0a R=Me
4
4
7 R=H
8 R=Me
3
2 R=H
4
6 R=Me
2.2.3 1,3-Migration with C–C Bond
Formation
4
9
b R=H
5
0b R=Me
When dienone 32 was treated
with phenyl magnesium bromide,
[1,3]-rearranged product 53 was obtained
directly from the reaction in 87% yield
(Scheme 15). No intermediate alcohol
or semi-benzene could be observed or
isolated.[21]
In a later study, Newman extended this
[1,3]-shift to the dichloromethyl group
with PhMgBr addition on 39, as well as
in the naphthalene series.[19] In the former
case, as the induction period for migration
is longer with dichloromethyl group,
Newman was able to trap the intermediate
semi-benzene with tetracyanoethylene
5
1 R=H
6
1
% fro
m 32
5
2 R=Me
77
% from 46
Scheme 14. Selective Meyer-Schuster rearrangements and [1,5]-shifts.
Scheme 15. Direct
aryl-aryl C–C bond
formation, coupled
with [1,3]-shift of
-CCl3.
87% yield
53
32
(TCNE) in an excellent yield (Scheme 16).
Scheme 16. Trapping
of the semi-benzene
intermediate.
2.2.4 Mechanistic Studies from
TCNE
PhMgBr
Newman – 1,5-Migration
D
C
M, ꢁ
Cold W-U
Apparently unaware of the publication
by Bird et al.,[13] Newman prepared a
single enantiomer of 46 and wondered if
a [1,5]-migration of the trichloromethyl
group would occur with some degree of
stereoretention.[22] (+)-46 was obtained
from fractional recrystallization of the two
epimers 56 and 57, followed by heating
pure (–)-epimer with levulinic acid
(Scheme 17).
9
1% yield
5
4
55
39
Scheme 17.
Preparation of a
single enantiomer
of 46.
(+)-
ꢀ
pTSA, AcOH, ꢁ
46
Following the steps depicted in Scheme
14, (+)-46 was readily converted to alcohol
(+)-48, and rearranged to (–)-50b under
mild acidic conditions (still confirmed
as being a single enantiomer). However,
on warming to 85 °C in cyclohexane
or exposure to light, 52 rearranged to a
racemic mixture.
5
6
5
7
ꢀ
ꢀ
HCl, ꢁ
Fractional recrystallizations
*
Isolationofthe (-)-isomer
(+)-46
Newman ruled out any post-
rearrangement epimerization of the

526 CHIMIA 2014, 68, Nr. 7/8
Note
Scheme 18. Further
ester 52 as an alternative explanation
to racemization. He indeed reproduced
this study by preparing 58, which cannot
epimerize after the [1,5]-shift, but was
nevertheless still obtained as a racemate,
fromtheadditionofEtMgBrtoenantiopure
(+)-46 (Scheme 18).
evidence of the
radical nature of the
[1,5]-shift.
*
*
EtMgBr
-H O
Hexane
2
Sunlight
Severalhours
(+)-46
rac-58
Predominantly(NMR)
The kinetic study of the transformation
of 50b to 52, the observations of the
effect of radical trapping agents, as well
was reproduced and communicated by
A last few elements worthy of note
as results of performing the [1,5]-shift
thermally in thiophenol provided Newman
with strong evidence of a postulated free-
radical mechanism – essentially the same
as already published by Bird et al.
Rozenberg et al.[26] Low yields of semi- are depicted in Scheme 23: compound
benzene were obtained from the iso- 73, the only semi-benzene reported to
propyl Grignard addition (25%), but the be resistant to thermal rearrangement,[28]
subsequent rearrangement occurred quite and rearrangements on phosphorylated
efficiently given the hindrance of the materials.[29]
Even such a mechanism might have
led to some transfer of stereochemistry,
if the incoming trichloromethyl radical
would have felt the influence of the
asymmetric quaternary center. Newman
postulated that even though it did not
happen during the [1,5]-shift, the exocyclic
double bond and the quaternary center
being contiguous in the [1,3]-case might
lead to stereospecific transfers. Also, a
concerted electrocyclic mechanism – a
priori unlikely in the [1,5]-shift – cannot
be as easily ruled out in the [1,3]-series on
geometric considerations. Unfortunately,
Newman never published the results of his
mechanisticinvestigationsinthe[1,3]-case,
and the interesting question of possible
stereo-transfer remains unanswered.
double bond (60% yield) at 70 °C only.
Even more spectacular – for steric and 3.2 [1,7]-Migration[30]
stereoelectronic reasons – is the [1,5]-re-
Another extension of the von Auwers
arrangementonthedimedoneKnoevenagel rearrangement was invented recently by
adduct 70 (Scheme 22).[27] Under us, as we wondered if the semi-benzene
thermolysis conditions, the rearranged 76 would rearrange in an unprecedented
product 71 could be isolated together with [1,7]-fashion. We therefore added allyl
lactone 72, which is reminiscent of the magnesium bromide to 17 and indeed
unexplained [1,3]-shift seen in Scheme 12. obtained 77 (Scheme 24). Compounds
4eq
(pMeOC6H P(S)S)
4
2
1
0
0°C
% isolate
ref24(c)
Benze
ne, 80 °C,4h
59
51
d
>
8
4
% isolated
17
10
64
Scheme 19. [1,5]-Migration to a sulfur atom.
Scheme 20. Unexpected aromatization with
the nitrogen analogues of semi-benzenes.
3. Extensions of the von Auwers
Rearrangement
Scheme 21. An
example of formation
of a quaternary
center.
R
=Me,H
3.1 Migrations on Heteroatoms or
‘Contrary to Wisdom’
hꢂ
67
17
68
The application of Lawesson’s reagent
69
onto 17 leads to a migration on a sulfur
atom, as was shown by Nikaronov et al. in
1995 (Scheme 19).[23]
However, the application of nitrogen
nucleophiles on 17 or 10 does not lead to
von Auwers [1,5]-shifts, as the adducts
rearomatize following various different
pathways instead, an example of which is
depicted in Scheme 20.[24]
Scheme 22.
Remarkable formation
of a quaternary center
from an electron-poor
olefin.
180°C
Finally,
a few spectacular [1,5]-
migrations ought to be mentioned, in which
the trichloromethyl radical attacks a fully
substituted olefin. In 1967, a von Auwers
rearrangement was fortuitously observed
during photochemical studies of 17
(Scheme 21).[25] After [2+2] cycloaddition
of 32 with methyl-2-butene or isobutylene,
followed by retro-[2+2], semi-benzene 68
was formed and rearranged thermally into
69, alas without much detail being given
about conditions and yield.
70
71
40%
72 14%
Scheme 23. Last
known examples of
trichlomethyl-radical
migration.
73
VonAuwershadalreadyaddediPrMgBr
on ketone 10, the dichloroanalogue of 17,
to form quaternary centers as early as
1916, with little detail about the results,
but in 1984, this exact same chemistry
C
DCl3,70°Corhꢂ
ObservedbyN
MR
74
X=Cl or OMe
75

Note
CHIMIA 2014, 68, Nr. 7/8 527
of the type 77 have already been used by
others, for example as precursor of enynes
80, from a Fritsch–Buttenberg–Wiechell
rearrangement via compound 79.[31]
1.
2. Et O, HClaq.
Tolu
ene
60-80 °C,2
h
3N
2
7
8:1
8
7
7
1
7
3.3 Complementary [1,5]-Products
vs [1,7]-Products
5
3
% yield
over threesteps
76
Diene 79 would then come from a
new [1,7]-shift, obtained exclusively from
addition of allyl magnesium bromide to
17. From the same starting material it is
possible to obtain isomeric diene 84, from
a [1,5]-rearrangement, by using cPrMgBr
as a surrogate of allyl magnesium bromide.
Indeed, addition of cPrMgBr to 17 leads
to alcohol 81, which, when dehydrated
with POCl3, rearranges by opening
the cyclopropyl first, generating semi-
benzene 82 (postulated, not observed) to
finally give in situ 83 (Scheme 25). Double
elimination of HCl was done efficiently by
Me
ONa
Reference3
1
7
9
80
Scheme 24. First example of a [1,7]-von Auwers rearrangement.[30]
distribution of D-labelled startingmaterials
such as 91, as well as by the detrimental
action of radical inhibitors.
mechanisms (double [3,3]-, or single
[5,5]-sigmatropic shifts), the free-radical
chain transfer mechanism was again
unambiguously evidenced by the product
The same research group also perform-
d
ecalin,1
65 °C
9
0
% yield
62-75% yield
85
86
17
81
POCl3,80°C
via
48-75% yield
88
d
ecalin, 1
6
5 °C
86
MeONa
82
5
5
%yield
87
84
83
89
Scheme 25. A way to access the complementary dienes from [1,5]-
rather than [1,7]-shift.[30]
90
Scheme 26. Radical methyl migration in the von Auwers rearrangements.
Scheme 27.
Allyl, benzyl and
cyclopropylmethyl
radicals as chain
carriers.
using methanolate as a base and provided
the diene 84, otherwise inaccessible by the
reaction in Scheme 24.
rt,onsta
nding
Quantitative
92
3.4 Other Migrating Groups than
–CHCl2 or –CCl3
91
Merchant et al. reported that the
tribromomethyl-group behaves exactly as
its chloro congener.[32] In 1968, Hart et
al. could show that even a methyl radical
can migrate very efficiently,[33] although
it does require high temperatures for the
TsCl,Py, 0°C
Qu ntitative
a
93
94
initiation (Scheme 26). The intermolecular
methyl radical chain carrier mechanism
n
e
at,1
10 °C
was confirmed by starting from deuterated
material 87 and observing indeed a pure
statistical mixture of all four possible
products 86–90.
Yieldnot mentionned
95
96
Shortly after this publication, Miller et
al. successfully made use of allyl, benzyl
and cyclopropylmethyl radicals as chain
carriers in 1,5-von Auwers rearrangements
(Scheme 27).[34] For allyl- and benzyl
radicals, as the [1,5]-product can also
theoretically be obtained by concerted
neat,200 °C
R1=R3=H ;R=
R1=R2=H;R3=Me2
R1=Me;R2=R3=H 2
2 Me 4
4%
3
%
1%
98
97

528 CHIMIA 2014, 68, Nr. 7/8
Note
Scheme 28.
[1,3]-radical von
Auwers shift preferred
over [3,3]-sigmatropic
shift.
ed the [1,3]-transfer of a benzyl radical
from 99 (Scheme 28).[35] In this case, any
direct [3,3]-sigmatropic shift of the benzyl
group would have led to a different product
101, which was never formed, even at high
165 °C,Diglyme
Notformed:
temperatures.Thisobservationmightspeak
99
100
101
again in favor of a vonAuwers typical free-
radical chain reaction. On the contrary, it is
worthy of note that attempts by Miller to
have an allyl- or crotyl group migrating in
a [1,3] shift proceeded exclusively through
[3,3]-sigmatropic Cope rearrangements
instead.
Pd(PPh ) cat.
3 4
N-methylmorp
holine
53%
1
0
5
18%
102
D
MF, rt,th n 60 °C
e
103
106
104
All these observations find an echo
in the more recent studies made by the
group of Frantz et al., who observed minor
[1,3]-von Auwers shifts while studying
[3,3]-Cope rearrangements on putative
dearomatized pyrazole 104 (Scheme
29).[36] As can be seen from the Scheme,
product 105 would come from a [1,3]-von
Auwers shift whereas product 106 would
be formed via a [3,3]-sigmatropic shift of
the propargyl moiety.
Scheme 29. Competing von Auwers [1,3]-shift and sigmatropic [3,3]-shift.
AIBN
50° C
[3,3]
N-methylmorp
holine
81%
reflux,3h
110
40%
109
107
108
While propargyl groups have
a
preference for [3,3]- over [1,3]-shifts,
benzyl groups may be effectively diverted
from this course. Indeed, their relatively
easy [3,3]-shift does not lead directly to
a final, fully rearomatized product, but
actuallytoasemi-benzene,suchasdepicted
in Scheme 30 with semi-naphthalene
Scheme 30. Radical AIBN-promoted [1,3]-shift preferred over ionic proton transfer in 109.
Direct [1,3]ofbenzyl radical
[3,3]
109.[37] The rearomatization of such semi-
MeNH-NH2
[1,3]
175 °C
175 °C
benzenes by proton transfer being very
slow under neutral conditions,[38] Frantz et
al. couldthenisolateandcharacterizesemi-
naphtalene 109, before engaging it into a
[1,3]-von Auwers shift by the use of AIBN
(Scheme 30). Inversely, in the presence of
radical quenchers, semi-naphtalene 109
delivered only the aromatized product
of the [3,3]-sigmatropic shift by proton
transfer.
Suchconsecutiverearrangementsmight
actually have been discovered as early as
1968 by Manning et al.,[39] but were not
recognized as such. Indeed, the formation
of 114, coming formally from a direct
[1,3]-shift of the benzyl group from 112,
might also have come from a consecutive
[3,3]-sigmatropic shift followed by
[1,3]-radical shift of the pyrazole-methyl
radical (Scheme 31). If this hypothesis
was not mentioned by the authors, the
remarkable mechanistic studies of Frantz
et al. on their related pyrazole system make
it quite plausible indeed.
111
112
60%
113
114
85%
Putative
Scheme 31. Direct [1,3]- and/or seminal example of consecutive [3,3]+[1,3]-rearrangement?
benzenes 1 and 3. Drawing all possible
semi-heteroarenes that could engage in
[1,3]- or [1,5]-von Auwers shifts is a
daunting task, especially if one wants to
cover multiple ring sizes (5, 6, etc.) and
polycyclic structures. Notwithstanding
the high number of those possibilities, our
literature searches in this area were only
and the positive effect of radical initiators
on rate and yield, a typical free-radical
chain transfer mechanism was put forward
by the authors, when two consecutive
[3,3]-sigmatropic shifts might have been a
valid alternative explanation.
From the [1,3]-rearrangement observed
with 104, and maybe with 112, it seems
that the von Auwers rearrangements can
be extended to dearomatized heteroaryls
(semi-heteroarenes such as 104) instead
of being limited to the generic semi-
rewarded by a single additional example
of a [1,3]-shift in a semi-heteroarene, as
depictedby118inScheme33.[41] Thisisthe
only report – to the best of our knowledge –
of a polyfluoroalkyl radical as chain carrier
in a von Auwers rearrangement.
Thefreeradicalsreportedinthissection
CCl4,77°C
are the only examples that were found,
notwithstanding di- and tri-chloromethyl,
to have been used as chain carriers in von
Auwers rearrangements.
71%
116
If propargyl groups do prefer
sigmatropic shifts over [1,3]-radical
migrations, it may be different against
[1,5]-von Auwers shifts, as was shown
in 1985 by the group of Heimgartner.
115
Scheme 32. Propargyl radical as chain carrier
in a [1,5]-shift.
They indeed successfully, from 115,
Scheme 33. [1,3]-von
Auwers shift in the
heterocyclic series.
(nBu) N
3
took a propargyl radical through a [1,5]-
von Auwers rearrangement to afford 116
(Scheme 32).[40] Once again, due to the
detrimental action of radical inhibitors
[1,3]-shift
Thermal
tetraglyme
74%
83%
1
1
7
1
1
8
119

Note
CHIMIA 2014, 68, Nr. 7/8 529
[5] T. Zincke, F. Schwabe, Ber. Dtsch. Chem. Ges.
1908, 41, 897.
[6] a) K. von Auwers, Ber. Dtsch. Chem. Ges. 1905,
wonder what else would migrate, or what
other kinds of Ar–C bonds can be made
concomitantly, by simple nucleophilic
additions on dienones, etc. As the drop
in energy is so high, we learned from
the examples of this review that, when
aromatization happens, it usually does so
efficiently and cleanly, to a single product.
Also, in a modern context where more
4. Synthetic Applications of von
Auwers Rearrangements
38, 1693; b) K. von Auwers, W. Julicher, Ber.
Alongside the work reviewed here,
which were all inventions, mechanistic
investigations and scope studies, there are
only very few reports describing practical
applicationsofvonAuwersrearrangements
for the synthesis of targeted compounds of
Dtsch. Chem. Ges. 1922, 55, 2167; c) T. Zincke,
F. Schwabe, Ber. Dtsch. Chem. Ges. 1908, 41,
897; d) T. Zincke, F. Schwabe, Ber. Dtsch.
Chem. Ges. 1908, 41, 1922
[7] A. Andreocci, Gazz. Chim. Ital. 1893, 23, 468.
[8] M. S. Newman, J. Eberwein, L. L. Wood Jr., J.
Am. Chem. Soc. 1959, 81, 6454.
[9] a) K. von Auwers, Ber. Dtsch. Chem. Ges. 1905,
transformations have been invented from
interest. In 1962, the preparation of DDT
33, 1697; b) K. von Auwers, Ber. Dtsch. Chem.
trichloromethyl- or dichlorovinyl groups,
where numerous ways to dearomatize
phenols have been found, the von Auwers
reactions lead undeniably to useful
intermediates, from readily accessible
dienones. With this review, the authors
analoguesbyadditionofaryl-phophoniums
or -phosphonates on 17 (Scheme 34) was
reported by Keaveney et al.[42]
Apart from this single report, we are
unaware of any published uses of the
von Auwers rearrangement in attempts to
Ges. 1906, 39, 3748; c) K. von Auwers, Ber.
Dtsch. Chem. Ges. 1911, 44, 588; d) K. von
Auwers, Ber. Dtsch. Chem. Ges. 1911, 44, 788;
e) K. von Auwers, Ber. Dtsch. Chem. Ges. 1911,
44, 1595; f) K. von Auwers, Ber. Dtsch. Chem.
Ges. 1916, 49, 2389.
[10] R. C. Fuson, T. G. Miller, J. Org. Chem. 1952,
hope to attract the attention of a part
prepare target molecules. The synthetic
17, 316.
of the scientific community to such
aromatizations, and more humbly, to pay
homage to great chemists and chemistries
of the past.
usefulness of this methodology is certain
though. As a contemporary example, in
our laboratory, grams of an elaborated
phenylacetic acid 125 (en route to
insecticidal products) were obtained in
three steps only (Scheme 35). Compound
125 proved very difficult to obtain
otherwise.
[11] R.L.Tse,M.Newman,J.Org.Chem.1956,21,638.
[12] For a review, see S. Swaminathan, K. V.
Narayanan, Chem. Rev. 1971, 71, 429.
[13] C. W. Bird, R. C. Cookson, J. Org. Chem. 1959,
24, 441.
[14] a) M. S. Newman, L. L. Wood Jr, J. Am. Chem.
Soc. 1958, 1236. It is unclear whether this
[1,3]-sigmatropic shift has the same mechanism
as the von Auwers [1,5]-shift (thermal radical
dissociation and chain transfer as depicted in
Received: June 10, 2014
[1] a) K. Reimer, Ber. Dtsch. Chem. Ges. 1876, 9,
423; K. Reimer, F. Tiemann, Ber. Dtsch. Chem.
Finally, we are currently using von
Auwers rearrangements to access building
blocks to prepare various heterocycles.
Scheme 9) or if it goes via a pericyclic concerted
Ges. 1876, 9, 824; b) K. Reimer, F. Tiemann,
mechanism. As is well documented, concerted
Ber. Dtsch. Chem. Ges. 1876, 9, 1268; c) K.
[1,3]-sigmatropic shifts are ‘disfavored’ (the
Reimer, F. Tiemann, Ber. Dtsch. Chem. Ges.
required antarafacial geometry cannot be
These will be reported in due course.
1876, 9, 1285.
achieved easily) under thermal conditions.
However, a C–C bond may migrate [1,3] with
inversion of the stereochemistry as antarafacial
interaction may happen with the sp3 orbital of
[2] a) K. von Auwers, Ber. Dtsch. Chem. Ges. 1884,
17, 2976; b) K. von Auwers, L. Hof, Ber. Dtsch.
Chem. Ges. 1896, 29, 1110; c) K. von Auwers,
5. Conclusion
V. Erggelet, Ber. Dtsch. Chem. Ges. 1899, 32,
the migrating carbon. See: b) J. A. Berson, G.
3598; d) K. von Auwers, F. Winternits, Ber.
L. Nelson, J. Am. Chem. Soc. 1970, 1096 and
The ground-breaking experiment of
Dtsch. Chem. Ges. 1902, 35, 465; e) K. von
references therein.
Auwers, G. Keil, Ber. Dtsch. Chem. Ges. 1902,
35, 4207.
Hart et al., in which a methyl radical was
shown to migrate, is a striking example
of the potential of semi-benzenes to (re)
aromatize. Hanging on the brink of a 36
kcal/mol drop in the potential energy
surface, these molecules will rearrange
at all cost, even if it means overcoming a
homolytic cleavage of a C–CH3 bond. In
front of such a demonstration, one can only
[15] M. S. Newman, F. Bayerlein, J. Org. Chem.
1963, 28, 2804. (Reproduced in D. I. Schuster,
K. J. Smith, A. C. Brisimitzakis, J. Org. Chem.
1981, 46, 473.)
[16] M. S. Newman, L. L. Wood Jr, J. Am. Chem.
Soc. 1959, 81, 6450.
[3] a) K. von Auwers, G. Keil, Ber. Dtsch. Chem.
Ges. 1903, 36, 1861; b) K. von Auwers, G. Keil,
Ber. Dtsch. Chem. Ges. 1903, 36, 3902; c) K.
von Auwers, Ber. Dtsch. Chem. Ges. 1908, 41,
1790.
[17] M. S. Newman, D. Pawellek, S. Ramachandran,
[4] T. Zincke, R. Suhl, Ber. Dtsch. Chem. Ges.
J. Am. Chem. Soc. 1962, 84, 995.
1906, 39, 4148. (Improved protocols can be
found in: M. S. Newman, A. G. Pinkus, J. Org.
Chem. 1954, 19, 978.)
[18] T. G. Miller, J. Org. Chem. 1962, 27, 1549.
[19] M. S. Newman, W. X. Bajzer, J. Org. Chem.
1970, 35, 270.
[20] a) K. von Auwers, Justus Liebigs Annalen der
Chemie 1906, 219; b) K. von Auwers, Justus
Liebigs Annalen der Chemie 1906, 278; c)
Scheme 34.
Preparation of DDT
analogues using
a von Auwers
K. von Auwers, Justus Liebigs Annalen der
Chemie 1906, 288; d) K. von Auwers, Justus
Liebigs Annalen der Chemie 1906, 352.
Et O, then
2
[21] M. S. Newman, J. A. Eberwein, J. Org. Chem.
1964, 29, 2516.
[22] M. S. Newman, R. L. Layton, J. Org. Chem.
rearrangement.
THF. ꢁ
121
48%
17
120
1968, 33, 2338.
[23] V. A. Nikanorov, A. D. Rogachev, E. I. Mysov,
Russ. Chem. Bull. 1995, 44, 964.
[24] a) A. J. Fry, J. Am. Chem. Soc. 1965, 87, 1816;
Scheme 35.
b) T. G. Miller, J. Org. Chem. 1966, 31, 3178;
c) K. Nagarajan, A. Venkateswarlu, Tetrahedron
Lett. 1967, 4, 293; d) T. G. Miller, R. C.
Hollander, J. Org. Chem. 1980, 45, 1334; e) K.
Transition-metal-free
synthesis of Aryl-
substituted phenyl
acetic acid.[30]
122
3steps
Abe, M. Takahashi, Synthesis 1990, 10, 939; f)
No transitionmetals
V. A. Nikanorov, O. L. Tok, S. G. Novikov, S.
V. Sergeev, E. V. Vorontsov, I. D. Gridnev, D. V.
AlCl
CCl4
3
125
68%
Zverev, A. T. Lebedev, Russ. Chem. Bull. 1997,
46, 350.
[25] D. J. Patel, D. I. Schuster, J. Am. Chem. Soc.
1967, 89, 184.
NaO
H
50%
[26] V. I. Rozenberg, V. A. Nikanorov, G. V.
Gavrilova, B. I. Ginzburg, O. A. Reutov,
Zhurnal Organicheskoi Khimii 1984, 20, 208.
[27] V. A. Nikanorov, S. V. Sergeev, P. V. Petrovskii,
D. V. Zverev, N. A. Klyuev, A. I. Gamazade, G.
>95%
123
124

530 CHIMIA 2014, 68, Nr. 7/8
Note
E. Vainer, F. M. Dolgushin, A. I.Yanovskii,Y. T.
[34] a) B. Miller, K.-H. Lai, Tetrahedron Lett. 1971,
Compound 83 δ ppm 2.37 (s, 3 H) 2.53 (dddd,
J=14.21, 11.37, 5.04, 3.85 Hz, 1 H) 2.79 (dddd,
J=13.89, 10.68, 5.87, 2.93 Hz, 1 H) 3.15 (td,
J=10.73, 4.95 Hz, 1 H) 3.51–3.58 (m, 1 H) 3.90
(dd, J=11.37, 2.93 Hz, 1 H) 7.19 (d, J=7.70 Hz,
2 H) 7.33 (d, J=7.62 Hz, 2 H); Compound 84 δ
ppm 2.38 (s, 3 H) 4.85 (dd, J=17.24, 1.47 Hz,
1 H) 5.31 (dd, J=10.64, 1.10 Hz, 1 H) 7.01 (dd,
J=17.24, 10.64 Hz, 1 H) 7.05 (d, J=8.07 Hz, 2
H) 7.21 (d, J=7.87 Hz, 2 H); Compound 124 δ
ppm 2.40 (s, 6 H) 4.12 (s, 2 H) 7.38 (bs, 1 H)
7.39 (d, J=8.44 Hz, 2 H) 7.51 (d, J=8.80 Hz, 2
H) 7.54 (d, J=1.83 Hz, 1 H); Compound 125 δ
ppm 2.24 (s, 3 H) 2.35 (s, 3 H) 3.75 (s, 2 H) 7.23
(bs, 1 H) 7.30 (bs, 1 H) 7.37 (d, J=8.80 Hz, 2 H)
7.48 (d, J=8.80 Hz, 2 H).
Struchov, Russ. Chem. Bull. 1996, 45, 989.
[28] B. Miller, Tetrahedron Lett. 1972, 11, 1019.
[29] a) V. I. Rozenberg, V. A. Nikanorov, B. I.
Ginzburg, O. A. Reutov, Bull. Acad. Sci. USSR,
Chem. Sci. 1983, 32, 1102; b) V. A. Nikanorov,
B. I. Ginzburg,V. I. Bakhmutov, V. I. Rozenberg,
O. A. Reutov, Bull. Acad. Sci. USSR, Chem. Sci.
1986, 35, 2099.
[30] Results from this section are all from R.
Dumeunier, S. Jaeckh, A. Scherrer, unpublished
material. 1H NMR of new compounds: (400
MHz, chloroform-d) Compound 76 δ ppm
1.54 (s, 3 H) 5.26 (d, J=10.27 Hz, 1 H) 5.37
(d, J=16.51 Hz, 1 H) 5.97–6.15 (m, 3 H) 6.35
(dd, J=9.90, 1.83 Hz, 1 H) 6.78–6.91 (m, 2
H); Compound 77 δ ppm 2.34 (s, 3 H) 3.53
(dd, J=7.34, 1.10 Hz, 2 H) 6.27 (dt, J=15.77,
6.97 Hz, 1 H) 6.61 (d, J=15.77 Hz, 1 H) 7.15
(d, J=8.07 Hz, 2 H) 7.32 (d, J=8.07 Hz, 2 H);
Compound 81 δ ppm 0.41–0.49 (m, 4 H) 0.95–
1.05 (m, 1 H) 1.48 (s, 3 H) 1.61 (s, 1 H) 5.94
(d, J=9.79 Hz, 2 H) 6.07 (d, J=9.79 Hz, 2 H);
20, 1617; b) B. Miller, K.-H. Lai, J. Am. Chem.
Soc. 1972, 94, 3472.
[35] a) B. Miller, M. R. Saidi, Tetrahedron Lett.
1975, 21, 1691; b) B. Miller, M. R. Saidi, J. Am.
Chem. Soc. 1978, 98, 2544.
[36] D. J. Babinski, H. R. Aguilar, R. Still, D. E.
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A. Hrovat, W. T. Borden, D. E. Frantz, J. Am.
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[38] M. Bao, H. Nakamura, Y. Yamamoto, J. Am.
Chem. Soc. 2001, 123, 759.
[39] D. T. Manning, H. A. Coleman, R. A. Langdale-
Smith, J. Org. Chem. 1968, 33, 4413.
[40] J. Lukac, H. Heimgartner, Helv. Chim. Acta
1985, 68, 355.
[41] S. Bartlett, R. D. Chambers, N. M. Kelly,
Tetrahedron Lett. 1980, 21, 1891.
[42] W. P. Keaveney, D. J. Hennessy, J. Org. Chem.
1962, 27, 1057.
[31] J. Villieras, P. Perriot, J. F. Normant, Synthesis
1975, 458.
[32] a) J. R. Merchant, V. B. Desai, J. Chem. Soc.
1964, 2258; b) J. R. Merchant, V. B. Desai, J.
Chem. Soc. C 1968, 499.
[33] H. Hart, J. D. DeVrieze, Tetrahedron Lett. 1968,
40, 4257.