Photocaged Hydrocarbons, Aldehydes, Ketones, Enones, and Carboxylic Acids and Esters that Release by the Norrish II Cleavage Protocol and Beyond: Controlled Photoinduced Fragrance Release

Article abstract of DOI:10.1055/s-0036-1588645

Five families of caged fragrance compounds that allow the storage and release of the following small volatile organic molecules are described: terpene hydrocarbons, aldehydes, ketones, Michael-type α,β-unsaturated enones, and carboxylic acids and esters. These caged molecules are released by photoexcitation via carbonyl-directed hydrogen-transfer processes and subsequent C-C bond cleavage (Norrish Type II) or by didenitrogenation of diazirines.

Full text of DOI:10.1055/s-0036-1588645

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–O
feature
A
A. G. Griesbeck et al.
Feature
Synthesis
Photocaged Hydrocarbons, Aldehydes, Ketones, Enones, and Car-
boxylic Acids and Esters that Release by the Norrish II Cleavage
Protocol and Beyond: Controlled Photoinduced Fragrance Release
Axel G. Griesbeck*a
Björn Porschena
Christian Kropf*b
Agnieszka Landesa
Olga Hinzea
Ursula Huchelb
Thomas Gerkeb
a Department of Chemistry, University of Cologne,
Greinstr. 4, 50939 Köln, Germany
griesbeck@uni-koeln.de
b Henkel AG & Co. KgaA, Henkelstr. 67, 40589 Düsseldorf,
Germany
Received: 13.10.2016
Accepted after revision: 13.10.2016
Published online: 01.12.2016
used for all cases and, thus, the absorptive properties (exci-
tation wavelength, absorbance, quantum yields of chemical
versus nonchemical pathways) and not chemical properties
are crucial for the decaging efficiency. The molecules that
are released by the different release mechanisms can have a
wide variety of potential functions. Clearly, pharmacologi-
cally active molecules are the most relevant group of tar-
gets that have to be selectively transported and site-specifi-
cally released.10 Possible advantages of the cage-and-release
concept can be summarized as follows: a) lower amounts of
the active compound are needed because of less undesired
effects during transport, b) spatial control of the release is
possible with spatially controllable techniques such as one-
or two-photon excitation by UV or visible light for photore-
lease or magnetic field activation for thermal release, c)
temporal control is possible for photoexcitation using
on/off irradiation periods and variable irradiation power.
Besides applications in drug release,11 use in numerous oth-
er fields is conceivable such as pheromone release,12 syn-
thetic chemistry as photolabile protecting groups (PPGs)13–
DOI: 10.1055/s-0036-1588645; Art ID: ss-2016-e0569-fa
Abstract Five families of caged fragrance compounds that allow the
storage and release of the following small volatile organic molecules are
described: terpene hydrocarbons, aldehydes, ketones, Michael-type
α,β-unsaturated enones, and carboxylic acids and esters. These caged
molecules are released by photoexcitation via carbonyl-directed hydrogen-
transfer processes and subsequent C–C bond cleavage (Norrish Type II)
or by didenitrogenation of diazirines.
Key words caged molecules, photochemistry, hydrogen transfer, car-
bonyl compounds, dinitrogen release
Chemical caging describes a technique that makes mole-
cules more stable, easier transportable, less reactive (or less
volatile, less sensitive, less aggressive) and eventually re-
leasable under controlled conditions.1–3 The term caging is
somewhat misleading because it is reminiscent of a bird in
a cage, i.e. a noncovalent interaction in a supramolecular
host–guest complex (like the legendary hemicarcerand-
caged cyclobutadiene).4 Many examples, however, refer to
covalently linked structures where specific chemical bonds
are designed that can be cleaved by controlled methods.
The tools for release can be diverse and include pH changes,
enzymatic processes, thermolysis or photolysis, to mention
just a few. It is of course relevant that the initial fragments
generated by decaging be rapidly converted into the desired
molecules and not lead to secondary chemistry as, for ex-
ample, in the concept of photoaffinity labeling.5,6 Photo-
cages are compounds that release the desired molecule ei-
ther by direct electronic excitation,7 by triplet sensitization8
or by photoinduced electron-transfer mechanisms.9 They
are especially valuable because light, a traceless reagent, is
and immunoassay screening.16,17 The caged molecules
15
can be as simple as nitrous oxide18,19 or carbon monoxide,3
or of medium complexity such as aliphatic ketones or lac-
tones20 up to large proteins useful for cell penetration and
release.21
In the context of this concept, we have developed sever-
al families of fragrance photocages. Fragrances are extract-
ed from natural sources or produced on large scales indus-
trially for numerous applications. In cleaning agents, fra-
grances mask the odor of other components; in perfumes,
fragrances are used to maintain the desired long-lasting ol-
factory effects. A characteristic property of fragrances is
their volatility, obviously the basic requirement for olfacto-
ry detection. This directly implies that the application of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

B
A. G. Griesbeck et al.
Feature
Synthesis
Biographical Sketches
Axel Griesbeck studied chem-
his Habilitation at the University
of Würzburg. After a guest pro-
fessorship at the University of
Madison at Wisconsin, he was
appointed Professor of Organic
Chemistry at the University of
Cologne. He has been a guest
professor at the Universities of
Tsukuba and Taipei, an IUPAC
fellow and secretary of the Or-
ganic Chemistry Division and
chairman of the Photochemistry
Section of the German Chemi-
cal Society, and has published
more than 275 papers and 20
patents in the area of organic
photochemistry. Currently, he is
an editor of ChemPhotoChem.
istry at the University of Munich
and graduated in the group of
Klaus Gollnick in 1984. After
postdoctoral research at the
University of Würzburg, ETH
Zürich and Weizmann Institute,
Rehovot (with Profs. Adam, See-
bach and Fischer), he finished
Björn
Porschen studied
ma). He joined Prof. Griesbeck’s
group and, within four years of
research, he earned his doctor-
ate degree studying the photo-
release of limonene from
photocages.
chemistry at the University of
Cologne from 2002–2011 (Diplo-
Christian
Kropf studied
technology (1998). In 1998, he
joined Henkel AG & Co. KGaA,
Henkel. After that, he returned
to Henkel corporate research as
a group leader. Since 2008, he
has been head of the synthesis
group within the international
research department of Hen-
kel’s laundry and home care di-
vision.
chemistry at Saarland University
(1986–1991) and the Leibniz In-
stitute for New Materials (1992,
Diploma thesis), both in Saar-
brücken, Germany. Under the
supervision of Prof. Dr. Helmut
K. Schmidt, he earned his doc-
torate degree studying nano-
Düsseldorf, as
a
laboratory
manager in corporate research.
From 2001–2002 he worked as
a technical director for SusTech
GmbH & Co. KGaA, Darmstadt,
a nanotechnology and materials
science start-up initiated by
Agnieszka Landes came from
Kędzierzyn-Koźle, Poland in
2005 to study chemistry at the
University of Cologne. In 2011
she was awarded with her Diplo-
ma and in 2015 she received her
PhD in the working group of
Prof. Griesbeck studying the
synthesis and photochemical as
well as photophysical properties
of photocage compounds.
Olga Mayer (formerly Hinze)
studied agricultural science at
the Agricultural Academy in
Yaroslavl, Russia (1995–2000,
Dipl. Ing.) and chemistry at the
University of Cologne (2002–
2007, Dipl. Chem.). She joined
Prof. Griesbeck’s group at the
University of Cologne in 2007
and obtained her PhD in 2011.
From 2012, Dr. Mayer has been
working at Dr. Knoell Consult
GmbH.
Ursula Huchel studied chemis-
try at the University of Konstanz
from 1989–1995 and received
her doctorate degree (1998) in
the field of carbohydrate chem-
istry with Prof. Dr. R. R. Schmidt
as supervisor. In 1999 Uschi
started her profession with Hen-
kel AG& Co KGaA as technical
marketer and changed to cor-
porate research in 2000 as labo-
ratory manager. From 2007 to
2015 she worked as head of
R&D for the Henkel Fragrance
Center. Since 2015, Uschi leads
a group with focus on fragrance
innovation in Henkel’s laundry
and home care division.
Thomas Gerke studied chem-
istry at the Technical University
in (West) Berlin from 1976 to
1982, finishing with a Diploma
degree in the group of Prof.
Kleinkauf. He then joined Prof.
Ferdinand Bohlmann’s group at
the same university and, in
1986, received his doctorate
degree working on structure
elucidation and synthesis of nat-
ural compounds. In 1987, he
started working at the Düssel-
KGaA in various positions and
countries. He is an inventor in
the field of active ingredients,
mainly fragrance and cosmetic
chemistry.
dorf-based Henkel AG
& Co.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

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A. G. Griesbeck et al.
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Synthesis
fragrances as flavoring agents or as perfume components is
time limited, because of the fragrance volatility. This could
be a disadvantage in commercial applications when, by pre-
mature volatilization, intended effects of fragrances are re-
duced or even completely lost. A solution to this problem
can be pro-perfumes, which are also termed fragcages.22
From these cages, fragrances can be released by cleaving a
covalent bond induced by an appropriate reaction.23 In the
following sections, we concentrate on photochemical re-
lease processes and describe the principles and a set of pho-
tocage families. Representative examples of fragrances for
these families are limonene (1), octanal (2), ethyl cin-
namate (3) and δ-damascone (4) (Figure 1).
processes do compete in certain ketones and the overall
quantum yields are particularly low whenever the Type II
process occurs. From a mechanistic point of view, the Type
II cleavage reaction can, in principle, be considered as a
concerted 1,5-hydrogen transfer accompanied by C–C bond
cleavage in a six-atom cyclic transition state leading to an
alkene and the enol tautomer, which was initially verified
by Calvert and Pitts using transient IR spectroscopy.27 The
competing cyclobutanol formation was discovered by Yang
and Yang, and they also suggested that cleavage and cycliza-
tion both arise from a 1,4-biradical intermediate formed by
γ-hydrogen abstraction by the excited carbonyl group.28
Subsequent trapping experiments and electron-transfer ex-
periments involving the intermediate 1-hydroxy-1,4-birad-
icals, and eventually transient absorption spectroscopy,29
established these species in the nano- to microsecond life-
time regime.30,31 In order to release diverse structure fami-
lies, the basic Norrish II substrates (that are able to produce
alkenes (a) beside the primary enols) have to be tuned to
the desired products by introducing further functional
groups that lead to the formation of aldehydes (b), Michael
ketones (c) or α,β-unsaturated carboxylic acid derivatives
(d) (Scheme 2).
Figure 1 Characteristic fragrance model compounds for caging
The Norrish Type II Photochemical Cleavage in a Nut-
shell
O
The hydrogen transfer from a γ-CH position followed by
cleavage of the α,β-carbon–carbon single bond, initiated
from an electronically excited state (singlet or triplet) of a
carbonyl compound, is one of the archetype reactions in or-
ganic photochemistry.24 Numerous carbonyl compounds
undergo this intramolecular hydrogen atom abstraction
and form 1-hydroxy-1,4-biradicals.25 These open-shell spe-
cies, that are well characterized when formed from their
triplet precursors, can undergo two competing reactions:
radical–radical coupling to produce cyclobutanols versus
homolytic cleavage of the central C2–C3 bond to produce
alkenes and enols (Scheme 1).
(a)
Ar
OH
hν
γ
R
R
R
Ar
ArCOMe
ArCOMe
H
O
O
O
OH
(b)
Ar
OH OH
hν
O
γ
R
O
R
O
R
Ar
Ar
Ar
H
(c)
Ar
OH
O
hν
γ
R
R
R
ArCOMe
H
COOR´
(d)
Ar
OH COOR´
COOR´
hν
γ
R
R
R
ArCOMe
H
H
H
γ
hν
O
O
Scheme 2 Cage and release strategies for four Norrish II carbonyl
routes
Norrish II - cleavage
ISC
hν
ISC
3
3
OH
Two Different Norrish Type II Approaches for Limo-
nene
H
*
OH
O
ISC
Yang
Norrish II
Limonene (1) is an inexpensive fragrance component,
utilized in nearly every cosmetics or laundry formulation.
As such, it might be the natural terpene to which humans
have the highest exposure. Due to its hydrophobicity and
volatility, limonene is often applied in excess in numerous
applications. Controlled release from a stable and less vola-
tile photocage stimulated by light therefore appeared as a
useful alternative. Limonene is an unfunctionalized 1,5-di-
ene and therefore a tricky substrate for the introduction of
photoreleasing groups: no anchoring groups are present
and the two double bonds have to be differentiated in the
caging strategy.
Scheme 1 Norrish II carbonyl photochemistry involving triplet states
(ISC = intersystem crossing)
The dominating path following an intramolecular hy-
drogen abstraction is the Type II photoelimination discov-
ered by Norrish, who described that dialkyl ketones with at
least one γ-C–H bond cleave to ketones and alkenes rather
than to acyl and alkyl radicals.26 The Norrish Type I path is
observed in the carbonyl photochemistry of substrates
without γ-C–H bonds that can form stabilized C-radicals,
such as tert-butyl phenyl ketone. Cleavage and cyclization
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D
A. G. Griesbeck et al.
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Synthesis
In a first approach, we designed a cage pathway gener-
ating the endocyclic double bond of limonene by photo-
cleavage: the appropriate substrates for this photocage are
(R)-limonene (1) itself and dihydrocarvone (5). Both are
commercially available, dihydrocarvone as a mixture of iso-
mers contains a small amount of isodihydrocarvone; how-
ever, this undesired byproduct can be easily separated
during the synthetic steps. Starting from (+)-dihydrocar-
vone (5), cage compounds 9 and 10 were synthesized by
HWE olefination to give the vinyl ester 6, followed by a re-
duction to the allyl alcohol 7 as described by Srikrishna et
al.32 Oxidation of 7 with manganese dioxide results in enal
8, the desired substrate for enantioselective reduction of
the carbon–carbon double bond of the Michael system with
Hantzsch esters as hydride donor.33 We envisaged the syn-
thesis of both possible diastereoisomers of 9 in order to in-
vestigate the differences in photorelease. Conversely, under
all conditions investigated, isomer 9 was formed as sole
product with all substituents of the cyclohexane chair in
equatorial position (Scheme 3). This is a result of complete
substrate control, so that the tert-butyl group of the reduc-
tion catalyst was not able to control the stereochemistry.
Aldehyde 9 was subjected to arylation with phenyllithium
or 4-methoxyphenyllithium34 and eventually by in situ oxi-
dation gave the phenones 10 (10a, Ar = Ph; 10b, Ar = p-
MeOC6H4).35 The overall yields for these Norrish II cages 10a
and 10b were 10% and 17%, respectively.
b
a
c
OH
OMs
11
12
1
R
d
N
NMe2
DMAH
Ar
Br
14a,b
13
O
Scheme 4 Reagents and conditions: a) 1. Sia2BH, Et2O, r.t., 3 h; 2. H2O2,
NaOH, THF, 16 h, r.t., 80%; b) MsCl, pyridine, r.t., 18 h, 99%; c) LiBr, THF,
reflux, 4 h, 65%; d) 1. n-BuLi, DMAH (R = H, p-OMe), 0 °C, 1 h; 2. 13, r.t.,
24 h (14a, Ar = Ph, 42%; 14b, Ar = p-MeOC6H4, 16%).
These different cage compounds 10a,b and 14a,b in
methanol solutions were irradiated with the emission of a
coated mercury low-pressure lamp centered around 350
nm. We discovered a distinct substituent effect on the pho-
tochemistry of the cage compounds 10a,b (Scheme 5):
whereas the phenyl derivative 10a was completely convert-
ed after 3 hours, the anisyl compound 10b needed more
than 18 hours for 75% conversion. From both substrates,
isolimonene (15) was formed as the major Norrish II cleav-
age product and, in the case of the phenyl substrate 10a,
also large amounts of the Norrish–Yang cyclization product
16 were formed. After longer irradiation time, the anisyl de-
rivative 10b delivered an inseparable mixture of isomeric
limonenes, substrate and further photoproducts that could
not be identified.
OH
O
COOEt
b
c
a
From the cage 14a, limonene and acetophenone were
the sole Norrish II cleavage products, however accompanied
by large amounts of the Yang cyclization product 17. 14b
did not deliver limonene even after prolonged irradiation
time. Thus, none of the Norrish II cages that were synthe-
sized from dihydrocarvone or limonene proved to be effi-
cient for limonene release. For compound 10a, this is most
probably a result of the energetically preferred chair-like
six-membered transition state for hydrogen transfer. Be-
cause all substituents are equatorial in the lowest energy
conformation, equatorial hydrogen transfer occurs prefer-
entially from the γ′-position, and either cleavage to give iso-
limonene (15) or cyclization follows. As we have already
found for other phenacyl cages,40 4-methoxyphenacyl com-
pounds such as 10b show retarded photochemistry and, for
the first time, also limonene formation was observed from
10b beside the dominating isolimonene (15) without Yang
cyclization products. The alternative photocage 14a
showed fast and selective hydrogen transfer, however with
preferential formation of the Yang photocyclization product
17. Limonene (1) was released in a maximum yield of 15%
after full conversion (Scheme 5).
6
7
5
O
Ar
CHO
γ
CHO
d
e
9
10
8
Scheme 3 Reagents and conditions: a) (EtO)2P(O)CH2CO2Et, NaH, THF,
r.t., 16 h, 95%; b) LiAlH4, Et2O, reflux, 1 h, 92%; c) MnO2, CH2Cl2, r.t.,
64 h, 60%; d) Hantzsch ester, MacMillan catalyst, CHCl3, –30 °C, 18 h,
79%; e) 1. ArBr, n-BuLi, Et2O, r.t., 16 h; 2. t-BuOOH, CrO3, CH2Cl2 (10a,
Ar = Ph, 25%; 10b, Ar = p-MeOC6H4, 42%).
The second approach targets the exocyclic double bond
of limonene. Hydroboration of the less hindered double
bond using disiamylborane is highly regioselective and de-
livers a 3:2 mixture of diastereoisomers (major shown in
Scheme 4).36 The major stereoisomer was purified via the
corresponding 3,5-dinitrobenzoates37 and transformed into
the bromide 13 via the mesylate 12.38 The phenone cages
14a,b were synthesized from 13 by treatment with the cor-
responding deprotonated acetophenone N,N-dimethylhy-
drazones.39
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

E
A. G. Griesbeck et al.
Feature
Synthesis
(Scheme 6). In aqueous solutions, the Norrish II cleavage of
valerophenone proceeds with near unity quantum yields in
an irradiation window of 290–330 nm.43
O
Ph
γ
a
+
Ph
OH
48%
γ
The octanal photocage 18a and many analogous com-
pounds (selected examples 18b–e are shown in Scheme 7)
were synthesized by syn-selective Mukaiyama aldol reac-
tions using titanium44 or tin enolate routes.45 In all cases,
photolyses of these photocages delivered the protected car-
bonyl compounds, among them important fragrance mole-
cules like myrtanal (19d) from 18d and the Michael system
α-ionone (19e) from 18e. The latter example is special in
two ways: a Michael ketone is formed in moderate quan-
tum yield and the hydrogen abstraction occurs only from a
nonactivated methyl group. The relative quantum yield for
this cleavage reaction (determined by GC for the formation
of propiophenone) is 0.67 relative to the chemical actin-
ometer, resulting in an absolute quantum yield for bond
cleavage of 0.44. This reflects the less efficient hydrogen
transfer from a methyl group relative to a tertiary hydrogen
as in the myrtanal cage 18d. In comparison with the other
carbonyl cages, 18e was very selective in Norrish II cleav-
age, also indicating that a high-energy intermediate (i.e.,
the triplet 1,4-biradical) is formed from this substrate that
is even more reactive than the corresponding intermediates
from 18a–d.
H
26%
10a
15
16
O
An
γ
b
1 + 15 + 10b
γ´
10b
c
1
+
45%
γ
HO
Ph
Ph
15%
14a
O
17
Scheme 5 Reagents and conditions: 20 mM cage solutions in MeOH, hν
(coated mercury low-pressure lamp, λ = 350 ± 20 nm), r.t., argon purg-
ing; a) 3 h for full conversion; b) 18 h for 75% conversion (An = anisyl); c)
8 h for full conversion. GC yields are given; acetophenone could not be
detected quantitatively.
The Photo-Retro-Aldol Approach for Cyclic and Long-
Chain Aliphatic Aldehydes and Michael Ketones
The photochemical release of aliphatic aldehydes fol-
lows the aldol route (b) as described in Scheme 2.40 Al-
though aldols are per se able to function as thermal cages
for the substrate carbonyl compounds because of their no-
torious retro-aldol reactivity, controlled release without
competing condensation to give Michael products is cum-
bersome. This is, fortunately, not the case for the photo-ret-
ro-aldol route.41 For the model compound octanal (2), the
photochemical release process was compared with the
valerophenone actinometer (Φ313 nm = 0.65 for acetophe-
none formation)42 and a 112% relative activity of cleavage
product formation was determined for the 300 nm photoly-
sis of cage 18a, resulting in a Φcl = 0.73. In methanol as sol-
vent, no other products were detected beside octanal and
acetophenone, corresponding to a >96% cleavage efficiency
O
OH
O
OH
Ph
Ph
i-Pr
18b
18c
75%a, 88% cleavage
rel = 1.14
90%a, 90% cleavage
rel = 1.11
Φ
Φ
O
Ph
chemical
actinometer
VP
rel = 1.00
Φ
O
OH
O
OH
Hγ
Ph
Ph
18d
72%a, 92% cleavage
18e
30%b, 95% cleavage
rel = 0.67
Φ
rel = 1.07
Φ
hν
hν
O
O
H
H
O
OH
(b)
Ar
OH OH
hν
O
γ
R
R
R
Ar
O
19e
19d
ArCOMe
H
Scheme 7 A series of phenacyl cages 18b–e, with their synthetic yields
and release properties. Reagents and conditions: a TiCl4, Bu3N, CH2Cl2,
–78 °C; b Sn(OTf)2, N-ethylpiperidine, 0 °C; cleavage: 20 mM cage solu-
tions in MeOH, hν (coated mercury low-pressure lamp, λ = 350 ± 20
nm), r.t. Relative quantum yields for decay were determined by GC with
respect to the decay quantum yield of valerophenone (VP), in part from
ref. 40.
O
OH
hν, MeOH
C7H15CHO
a
n-octanal
b
Ph
Ph
C7H15
>96% cleavage
18a
Scheme 6 Reagents and conditions: a) TiCl4, Bu3N, CH2Cl2, –78 °C, 80%,
syn/anti 95:5; b) 20 mM cage solution in MeOH, hν (coated mercury
low-pressure lamp, λ = 350 ± 20 nm), r.t.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

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A. G. Griesbeck et al.
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Synthesis
Two Norrish Type II Approaches for the Model Enone
δ-Damascone
route proved to be highly flexible and directly delivered
photoactive compounds that release enones in high yields
after short to medium irradiation times. As an additional
benefit, diverse ester groups can be introduced right from
the start, e.g. benzyl groups as in 22b or long alkyl chains as
in 22c that make these cages amphiphilic (from the corre-
sponding benzyl49 or dodecyl esters). Saponification and
acidic workup leads to the decarboxylated cage compound
23 (α-demethylated analogue of 20) with similar δ-
damascone release properties. The iron-catalyzed Michael
addition also works smoothly with other enones; only β,β′-
disubstituted enones gave lower yields (e.g., 25 from mesi-
tyl oxide, Figure 2).50
The damascones constitute a class of highly relevant fra-
grance components. Several constitutional isomers exist,
with the δ-isomer as one of the most prominent and indus-
trial relevant representatives.46 In contrast to α-ionone
(19e, see Scheme 7), δ-damascone (4) cannot be caged by a
classical aldol route. As shown in Scheme 8, a syn-selective
cerium enolate route47 was successfully applied for the syn-
thesis of 1,5-diketone 20 from propiophenone and δ-
damascone. Photocage 20 has two possible γ-hydrogen po-
sitions than can be activated by the electronically excited
phenacyl chromophore: the β-methyl group and the meth-
ylene group of the linear hydrocarbon chain. Hydrogen
transfer from the methyl group and subsequent Norrish
cleavage would lead to the deconjugated damascone iso-
mer, that was not observed. The cyclization (‘Yang’) product
21 is the only product from this obviously less efficient hy-
drogen transfer. In a detailed mechanistic study,40 we have
detected two transients with the short-lived component
(absorbing at 400 nm) interpreted as the triplet 1,4-biradi-
cal derived from γ-hydrogen transfer from the CH2 group.
The solvent-dependent lifetimes span 60–120 nanoseconds
and the transients are quenched by oxygen, in agreement
with literature data.29
O
O
O
O
a
Ph
OR
O
Ph
COOR
22a–c
b
c
hν
MeOH
O
O
Ph
4
23
Scheme 9 Reagents and conditions: a) δ-damascone (1 equiv),
FeCl3·6 H2O (10–20 mol%), CHCl3, 50 °C (22a, R = Et, 85%; 22b, R = Bn,
86%; 22c, R = n-C12H25, 88%; syn/anti ca. 55:45); b) from 22a: KOH,
MeOH, reflux, 16 h; then c) HCl to pH 1, 65%.
O
O
(c)
Ar
OH
O
O
hν
γ
R
Ar
R
O
O
R
ArCOMe
H
O
O
O
O
O
O
COOEt
24b (62%)
COOEt
24a (85%)
Ph
a
Ph
58% release (20 h)
41% release (15 h)
20
Hγ
O
CH2
O
O
O
O
O
O
hν, MeOH
Ph
O
b
Ph
Ph
Et
Hγ
4
COOEt
COOEt
+
20
OH
25 (51%)
88% release (6.5 h)
26 (79%)
35% release (20 h)
O
OH CH3
O
21
O
O
O
O
Ph
cleavage/Yang (4/21) = 75:25
cl. = 0.6 (MeOH)
Φ
COOEt
τ = 90 ns (MeOH, 254 nm excitation)
COOEt
27a (83%, d.r. 54:46)
12% release (20 h)
27b (71%, d.r. 74:26)
25% release (20 h)
Scheme 8 Reagents and conditions: a) LDA, THF, –78 °C, then CeCl3,
then δ-damascone, 80%, syn/anti >95:5; b) 20 mM cage solution in
MeOH, hν (coated mercury low-pressure lamp, λ = 350 ± 20 nm), r.t.;
from ref. 40.
Figure 2 A series of benzoylacetate cages 24–27, with their synthetic
yields (FeCl3 route) and release properties. Reagents and conditions:
20 mM cage solutions in MeOH, hν (coated mercury low-pressure lamp,
λ = 350 ± 20 nm), r.t. Cleavage determined by GC measurement of ethyl
benzoylacetate formation.
Due to the fact that the syntheses of 20 and other enone
cages were somewhat elaborate and could not easily be up-
scaled, we searched for more convenient routes to these
photocages. Useful alternative structures were benzoylace-
tate cages that could be synthesized following the FeCl3 ca-
talysis route developed by Christoffers (Scheme 9).48 This
The benzoylacetate cages show slow photoinduced
Norrish II cleavage in solution, with maximum conversions
of 60–90%. This is a consequence of the internal filter effect
that arises from the released benzoylacetate that complete-
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A. G. Griesbeck et al.
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ly covers the cage absorption at higher conversions. From
the diastereoisomeric mixture of cage 27, E/Z-chalcones are
released that add to this filter effect. As a characteristic ex-
ample, the UV/Vis absorption spectra of ethyl ester 22a and
its two cleavage products, in methanol, are shown in Figure
3. Two starting materials were detected by GC, correspond-
ing to the keto and enol form of 22a with the enol form ab-
sorption redshifted in the UV spectrum. This effect increas-
es for ethyl benzoylacetate, indicating that even more enol
form is present in the equilibrium.51
tomerization and subsequent photocleavage. The E,Z-
damascones increase in signal intensity and level out at 80%
conversion. The E/Z ratio of δ-damascone (4) remained con-
stant (10:1) over the whole irradiation period, indicating
that there is no direct or sensitized E/Z isomerization of 4.
As an additional route, Yang cyclization results in the for-
mation of a cyclobutanol of unknown structure (from
GC/MS analysis).
Another useful analytical tool to quantify cage release
during irradiation of a textile sample is diffuse reflectance
UV spectroscopy (DRS).52 Figure 5 shows the time profile
for the release of δ-damascone from the benzyl cage 22b
using this technique. Strongly absorbing compounds at the
surface of a solid sample lead to a corresponding decrease
in reflectance. This effect occurred in parallel with a red-
shift, also indicating the formation of the benzoylacetate
and its enol form.
Figure 3 UV absorption properties of the photocage 22a and its re-
lease products: the 290 nm maximum originates from the enol form of
ethyl benzoylacetate
The time profile for the photocage cleavage of dodecyl
ester 22c is shown in Figure 4. The photolysis mixture con-
sists of the keto isomer of 22c that is rapidly degraded and
the enol isomer that slowly disappears because of slow tau-
Figure 5 Diffuse reflectance UV/Vis spectroscopy (DRS) of photocage
22b impregnated on a white cotton sample, before and after photolysis
Norrish Type II Approach for Cinnamates: Reluctant,
Why?
Cinnamates constitute another important class of fra-
grance molecules and the Norrish II protocol was also ap-
plied to these compounds. Knoevenagel condensation of
chalcones with dialkyl malonates and subsequent saponifi-
cation and decarboxylation delivered the cinnamic acid
cages 29 in good yields (Scheme 10);53 esterification gave
the cinnamate cages 30.
From a dozen of these compounds 29, 30, however, we
did not detect notable release (only 5–10% cinnamates were
detected by GC and NMR spectroscopy, as E/Z mixtures),
even after prolonged irradiation. This effect was even stron-
ger than that already observed for the chalcone cage 27
(Figure 2) which is also rather reluctant under photolysis
conditions. Clearly, the β-phenyl substitution is obstructive
and precludes γ-hydrogen transfer in these cases. The ab-
sorption and emission properties of these photocages are
not altered relative to other phenone derivatives; taking
Figure 4 Time profile for the photolysis (350 nm) of 22c in MeOH (by
GC/MS); relative intensities of GC signals are shown with respect to
100% for the keto/enol mixture of 22c.
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A. G. Griesbeck et al.
Feature
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COOH
γ
N
O
O
O
N
a,b
c
a–c
R1
28
R1
R2
R2
29
COOR3
5
31
1
γ
O
d
OCH3
R1
30
+
+
R2
Scheme 10 Synthesis of cinnamic acid and cinnamate cages 29 and
30. Reagents and conditions: a) diethyl malonate, piperidine; b) NaOH; c)
HCl; d) R3OH, acid catalysis. R1 = H, Me; R2 = H, 4-Me, 4-OMe; R3 = Me,
Et.
32
15
Scheme 11 Diazirine synthesis and photolysis. Reagents and conditions:
a) NH3, MeOH, H2NOSO3H; b) CrO3, H2SO4; c) 2 mM cage solution in
MeOH, hν (coated mercury low-pressure lamp, λ = 350 ± 20 nm), r.t.;
for product GC, see Figure 6.
this into account, a possible explanation is that reversible β-
hydrogen transfer occurs from the more reactive β-CH posi-
tion with formation of the better stabilized benzylic radical
that, as part of a triplet 1,3-biradical, cannot undergo C–C
bond cleavage. Hydrogen abstraction from the β-CH posi-
tion in triplet excited carbonyls is often not detected be-
cause cyclopropane formation is less favored.54
diazirines photochemically release dinitrogen with forma-
tion of a carbene that undergoes, among other reactions,
1,2-hydrogen rearrangement to give the corresponding
alkene. For limonene (1) release, diazirine 31 was synthe-
sized from dihydrocarvone (5) (Scheme 11), already used as
starting material for the phenone cage 10 (see Scheme 3).
One disadvantage of cage 31 is its low absorbance in the
UV-A region:58 the extinction coefficient at λmax (366 nm)
for the strongly forbidden nπ* transition is around 50 which
is somewhat compensated by the excellent quantum yields
for didenitrogenation. The solution photochemistry (Figure
6) is efficient and selectively delivers limonene [with less
than 10% isolimonene (15) in the product mixture] and the
A New Diazirine Approach to Limonene by Photo-
didenitrogenation
An alternative approach to a photolabile limonene cage
(the phenone compounds 10 and 14 have already been de-
scribed, see Schemes 3 and 4) is the carbene route. As ex-
tensively investigated by the Brinker group55,56 and others,57
Figure 6 Gas chromatograms (from bottom to top) of isolimonene (15) (trace 4), limonene (1) (trace 3), cage 31 after photolysis for 2 h (trace 2), and
cage 31 (trace 1).
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A. G. Griesbeck et al.
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methanol-trapping product 32. When higher concentra-
tions of 31 were used, the well-known azine formation (ad-
dition of the carbene to the starting material) was also ob-
served. The preferred formation of the higher-substituted
alkene was also observed by Brinker and co-workers for the
diazirine from 2-methylcyclohexanone.59 From the view-
point of selective release, photocage 31 is highly useful. For
application as a pro-perfume, however, the volatility is too
high (in the same range as limonene itself).
hyperchromic absorption relative to the monomeric cage
compounds 34 and 35 that bear trialkylamino and tetraal-
kylammonium side chains as a means of improving the sol-
ubility properties (Figure 8).60
Photocaged Compounds: Is There a Perfect Solution?
In most applications of photocage release, the focus is
on the biologically active molecule or molecular fragment
and not on the supporting chromophore that is concurrent-
ly released. In the best case, this second fragment is unreac-
tive, easily separated and invisible (i.e., does not absorb in
the photocage region and thus does not operate as an inter-
nal filter). In reality, this is generally not the case. Even
worse, secondary photochemistry and undesired effects
such as oxidative aging can lead to colorization in solution
and on surfaces. Thus, better solutions are highly desirable
(Figure 7). From a substance-economic point of view, the
release of two target molecules from one photocage is an
improvement (A), the generation of a nonabsorbing volatile
component (e.g. molecular nitrogen or carbon dioxide) is
better (B) and the release of two target molecules without
any byproduct would be optimal (C). We have developed
examples for the first two alternatives: the dimeric cage 33
is available from δ-damascone and the bis-cerium enolate
from ethylenediol-linked bis-propiophenone. In the UV/Vis
absorption spectrum, cage 33 has a slightly redshifted and
Figure 8 UV spectra of the cage dimer 33 and compounds 34, 35
An example for concept (B) with an invisible and easily
removable carrier (dinitrogen) is the diazirine 31 that we
have developed as a volatile photocage for limonene. Final-
ly, the concept of the photo-retro-aldol route (as shown in
Scheme 6) might also be used for the realization of concept
(C): the acetophenone aldol dimer 36 is a labile aldol that
undergoes thermal retro-aldol reaction,61 and also photo-
chemical cleavage can be expected. This might serve as a
recipe for the design of ideal photocages.
In summary, we have proven that the Norrish II carbon-
yl cleavage protocol serves as a highly versatile guideline for
the design of photocages for the release of hydrocarbons,
cyclic and long-chain alkylated aldehydes and ketones, α,β-
unsaturated ketones and, albeit less efficient, also for car-
boxylic acids and esters. Diazirines, as exemplified by the
limonene cage 31, are another potential class of useful pho-
tocages for numerous applications.
A
B
C
O
O
O
γ
γ
O
The starting materials were commercially available. CDCl3, CHCl3,
CH2Cl2, MeOH, EtOAc, Et2O, MTBE, cyclohexane, acetone and THF
were used as solvents. 1H NMR spectra were recorded on Bruker
Avance II 300 and Avance 400 spectrometers operating at 300 and
400 MHz or on a Bruker Avance II+ 600 spectrometer operating at 600
MHz. Standard abbreviations are used for coupling patterns. 13C NMR
spectra were recorded on the above-mentioned NMR spectrometers
operating at 75, 100 and 150 MHz. Chemical shifts (δ) are reported in
ppm and coupling constants (J) in Hz. Solvent peaks were used as an
internal standard in all NMR spectra (CDCl3, δ = 7.26 and 77.2 ppm).
Mass spectra and accurate mass determinations were obtained with a
Finnigan MAT 900S mass spectrometer by electrospray ionization. In-
frared spectra were recorded with a Perkin-Elmer FT-IR-S 1600 fouri-
er-transform spectrometer. Elemental analyses were performed with
an Elementar Vario EL analyzer. For all new compounds, satisfactory
O
O
33
O
O
R
R = NMe2: 34
R = NMe2Cet+Br-: 35
O
O
OH
Ph
Ph
γ
N
N
31
36
Figure 7 The three golden routes and three examples of photocages
(33, 31, 36) that realize these concepts
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A. G. Griesbeck et al.
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elemental analyses or high-resolution mass spectra, as well as HPLC
analyses, were obtained confirming >95% purity. For UV/Vis absorp-
tion spectra, a Perkin-Elmer Lambda 35 UV/Vis spectrophotometer
was used with quartz cuvettes (d = 1.00 cm) and for DRS, a Perkin-
Elmer Lambda 1050 UV/Vis/NIR spectrophotometer with a 150 mm
InGaAs integrating sphere detector was used. For photolysis studies,
Rayonet RPR-208 chamber photoreactors equipped with 8 lamps
(phosphor coated with an emission maximum at 300 or 350 nm; 800
W) or a Luzchem LZC-4V photoreactor with 254, 300 or 350 nm (cen-
ter line positions) were used for irradiation.
(E)-2-[(2R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohexylidene]acet-
aldehyde (8)
(E)-2-[(2R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohexylidene]ethanol
(7) (11.8 g, 64.9 mmol, 1.0 equiv) was dissolved in CH2Cl2 (65 mL) and
MnO2 (electrolytically precipitated) (84.6 g, 973.4 mmol, 15.0 equiv)
was added. After stirring for 64 h at r.t., MnO2 was removed by filtra-
tion over Celite. The solvent was evaporated and the crude product
was purified by flash column chromatography on silica gel (cyclohex-
ane–EtOAc, 5:1) (Rf = 0.48) to afford 8 as a yellow liquid; yield: 6.9 g
(39.9 mmol, 60%).
1H NMR (600 MHz, CDCl3): δ = 9.99 (d, J = 8.0 Hz, 1 H), 5.74 (d, J = 8.0
Hz, 2 H), 4.68 (s, 1 H), 3.37 (m, 1 H), 2.15 (m, 1 H), 2.04 (m, 1 H), 1.94
(m, 2 H), 1.90 (m, 1 H), 1.79 (m, 1 H), 1.67 (s, 3 H), 1.42 (ddd, J = 3.9,
13.0, 25.3 Hz, 1 H), 1.00 (d, J = 6.5 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 190.6 (CH), 170.2 (Cq), 148.3 (Cq),
122.6 (CH), 109.4 (CH2), 47.5 (CH), 39.4 (CH), 36.4 (CH2), 35.0 (CH2),
31.4 (CH2), 20.5 (CH3), 17.4 (CH3).
MS (EI): m/z (%) = 178.2 (54) [M+], 163.1 (20), 145.1 (29), 135.2 (40),
121.1 (44), 119.1 (41), 117.1 (40), 115.1 (53), 107.1 (71), 105.1 (53),
95.1 (31), 93.1 (67), 91.1 (100), 81.1 (27), 79.1 (79), 77.1 (67), 67.2
(52), 65.1 (33), 53.1 (20), 51.1 (24).
Ethyl (E)-2-[(2R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-
ylidene]acetate (6)32
A suspension of NaH (60% in paraffin; 3.7 g, 91.5 mmol, 1.5 equiv) in
THF (70 mL) under argon atmosphere was cooled to 0 °C. Triethyl
phosphonoacetate (20.6 mL, 103.7 mmol, 1.7 equiv) in THF (14 mL)
was added dropwise. After stirring for 0.5 h at r.t., the mixture was
cooled to 0 °C and (+)-dihydrocarvone (5) (10 mL, 61.0 mmol, 1.0
equiv) in THF (9 mL) was added dropwise. After 16 h at r.t., sat. aq
NH4Cl solution (50 mL) was added and the layers were separated. The
aqueous layer was extracted with Et2O (2 × 50 mL) and the combined
organic layers were washed with brine (100 mL) and dried over
MgSO4. After evaporation of the solvent, the crude product was puri-
fied by flash column chromatography on silica gel (cyclohexane–
EtOAc, 19:1) to afford 6 as a yellow oil; yield: 12.9 g (58.0 mmol, 95%).
HRMS (ESI): m/z [M + H]+ calcd for C12H19O: 179.14304; found:
179.14332.
1H NMR (600 MHz, CDCl3): δ = 5.53 (s, 1 H), 4.67 (m, 2 H), 4.08 (m, 2
2-[(1S,2R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohexyl]acetalde-
hyde (9)
H), 2.29–1.63 (m, 8 H), 1.68 (s, 3 H), 1.22 (m, 3 H), 1.09 (d, J = 7.2 Hz, 3
H).
(E)-2-[(2R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohexylidene]acetal-
dehyde (8) (3.5 g, 19.6 mmol, 1.0 equiv) was dissolved in CHCl3
(98 mL) and cooled to –30 °C. 2-tert-Butyl-3-methyl-4-oxoimidazoli-
din-1-ium trifluoroacetate (1.1 g, 3.9 mmol, 0.2 equiv) and diethyl
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (6.0 g, 23.6 mmol,
1.2 equiv) were added and the mixture was stirred for 18 h at –30 °C.
Then, Et2O (100 mL) was added and the solution was filtered over sili-
ca gel. The solvent was evaporated and the crude product was puri-
fied by flash column chromatography on silica gel (cyclohexane–EtOAc,
5:1) (Rf = 0.56) to afford 9 as a yellow liquid; yield: 2.8 g (15.5 mmol,
79%).
13C NMR (150 MHz, CDCl3): δ = 172.0 (Cq), 166.4 (Cq), 149.1 (Cq), 110.5
(CH), 108.9 (CH2), 59.4 (CH2), 47.2 (CH), 43.7 (CH), 41.4 (CH2), 38.1
(CH2), 32.5 (CH2), 20.6 (CH3), 18.3 (CH3), 14.3 (CH3).
MS (EI): m/z (%) = 222.1 (19) [M+], 193.1 (23), 179.1 (95), 177.1 (23),
176.1 (56), 161.1 (22), 151.1 (35), 149.1 (23), 148.2 (39), 147.2 (26),
133.1 (59), 121.1 (29), 119.1 (48), 109.1 (25), 107.1 (60), 105.1 (100),
93.1 (66), 91.1 (76), 79.1 (62), 77.1 (31), 67.1 (28), 65 (20).
(E)-2-[(2R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohexylidene]eth-
anol (7)32
IR (ATR): 2921 (w), 2857 (w), 1724 (vs), 1643 (w), 1597 (w), 1448 (m),
1372 (m), 1284 (m), 1230 (s), 1044 (m), 805 (m), 773 cm–1 (m).
LiAlH4 (6.6 g, 172.6 mmol, 2.0 equiv) was suspended in Et2O (173 mL)
and
ethyl
(E)-2-[(2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-
1H NMR (600 MHz, CDCl3): δ = 9.69 (dd, J = 2.6, 1.3 Hz, 1 H), 4.60 (d, J =
5.2 Hz, 2 H), 2.40 (dd, J = 15.6, 4.6 Hz, 1 H), 2.34 (m, 1 H), 2.28 (ddd, J =
15.6, 8.5, 2.7 Hz, 1 H), 1.69–1.67 (m, 1 H), 1.64 (m, 1 H), 1.61 (s, 3 H),
1.58 (m, 2 H), 1.46–1.37 (m, 3 H), 1.08 (dd, J = 12.6, 3.1 Hz, 1 H), 0.79
(d, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 203.0 (CH), 149.7 (Cq), 108.5 (CH2),
41.6 (CH2), 38.5 (CH), 36.1 (CH2), 34.5 (CH), 33.4 (CH), 31.3 (CH2), 29.4
(CH2), 20.9 (CH3), 19.6 (CH3).
ylidene]acetate (6) (19.2 g, 86.3 mmol, 1.0 equiv) dissolved in Et2O
(35 mL) was added dropwise. After reflux for 1 h, the mixture was
cooled to 0 °C and water was added dropwise until no more hydrogen
gas was formed. The precipitate was dissolved by adding 2.5 M aq
H2SO4. The layers were separated and the aqueous layer was extracted
with Et2O (3 × 100 mL). The combined organic layers were washed
with sat. aq NaHCO3 solution (200 mL) and brine (200 mL), and dried
over MgSO4. The solvent was evaporated and the crude product was
purified by flash column chromatography on silica gel (cyclohexane–
EtOAc, 9:1) (Rf = 0.45) to afford 7 as a colorless liquid; yield: 14.3 g
(79.4 mmol, 92%).
MS (EI): m/z (%) = 136.1 (68), 121.1 (89), 119.1 (23), 107.1 (45), 105.1
(26), 95.1 (20), 93.1 (100), 92.1 (24), 91.1 (49), 81.1 (27), 79.1 (81),
77.1 (44), 67.2 (63).
HRMS (ESI): m/z [M + H]+ calcd for C12H21O: 181.15869; found:
1H NMR (600 MHz, CDCl3): δ = 5.26 (t, J = 6.7 Hz, 1 H), 4.65 (m, 2 H),
4.12 (m, 2 H), 2.64 (m, 2 H), 2.00–1.46 (m, 6 H), 1.67 (s, 3 H), 0.99 (d,
J = 6.6 Hz, 3 H).
181.15884.
13C NMR (150 MHz, CDCl3): δ = 149.7 (Cq), 146.3 (Cq), 118.3 (CH),
108.6 (CH2), 58.5 (CH2), 46.8 (CH), 37.8 (CH), 36.6 (CH2), 34.6 (CH2),
31.9 (CH2), 20.7 (CH3), 18.0 (CH3).
2-[(1S,2R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohexyl]-1-phenyl-
ethanone (10a)
PhBr (1.8 mL, 16.6 mmol, 1.5 equiv) was dissolved in Et2O (16 mL) and
cooled to 0 °C. n-BuLi (2.5 M in n-hexane; 5.3 mL, 13.3 mmol,
1.2 equiv) was added dropwise. The mixture was stirred for 10 min at
0 °C and 20 min at r.t. After cooling to 0 °C, aldehyde 9 (2.0 g,
MS (EI): m/z (%) = 147.2 (26), 119.1 (66), 107.1 (23), 105.1 (69), 93.1
(46), 91.1 (100), 81.1 (22), 79.1 (85), 77.1 (60), 67.1 (39), 65.1 (21).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

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A. G. Griesbeck et al.
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11.1 mmol, 1.0 equiv) in Et2O (8 mL) was added dropwise. The mix-
ture was stirred for a further 16 h at r.t. and then sat. aq NH4Cl solu-
tion (30 mL) was added. The layers were separated, the aqueous layer
was extracted with Et2O (2 × 30 mL), and the combined organic layers
were washed with brine. After drying over MgSO4, the solvent was
evaporated. The intermediate was added to a solution of CrO3 (56 mg,
555 μmol, 0.05 equiv) and t-BuOOH (9.1 mL, 66.6 mmol, 6.0 equiv) in
CH2Cl2 (56 mL). After stirring for 2 h, sat. aq NaSO3 solution was added
until no more gas evolved. The layers were separated and the aqueous
layer was extracted with Et2O (2 ×). The combined organic layers were
washed with brine and dried over MgSO4, and the solvent was evapo-
rated. The crude product was purified by flash column chromatogra-
phy on silica gel (cyclohexane–EtOAc, 9:1) (Rf = 0.20) to afford 10a as
a yellow liquid; yield: 0.7 g (2.8 mmol, 25%).
MS (EI): m/z (%) = 150.1 (35), 136.1 (22), 135.1 (100), 121.1 (20), 92.1
(25), 79.1 (20), 77.1 (50).
HRMS (ESI): m/z [M + H]+ calcd for C19H27O2: 287.20056; found:
287.20102.
(2R)-2-[(1R)-4-Methylcyclohex-3-en-1-yl]propan-1-ol (11)36
Borane–dimethyl sulfide complex (25.0 mL, 263.6 mmol, 1.0 equiv)
was cooled to –21 °C. 2-Methyl-2-butene (58.7 mL, 553.6 mmol,
2.1 equiv) was added dropwise and the mixture was stirred for 1.5 h
at 0 °C. Then, Et2O (41 mL) was added and the mixture was stirred for
1 h at r.t. Then, the thus-formed disiamylborane was added dropwise
at 0 °C to (+)-limonene (38.5 mL, 237.3 mmol, 0.9 equiv) and the mix-
ture was stirred for 3 h at r.t. After that, all volatile components were
removed in vacuo and the remaining liquid was dissolved in THF
(475 mL). The solution was cooled to 0 °C and 3.0 M aq NaOH
(79.1 mL, 237.3 mmol, 0.9 equiv) was added dropwise. Finally, 30%
H2O2 (80.8 mL, 790.9 mmol, 3.0 equiv) was added dropwise and the
mixture was stirred for 16 h at r.t. Then, NaCl was added and the lay-
ers were separated. The aqueous layer was extracted with Et2O
(3 × 150 mL) and the combined organic layers were washed with
brine. After drying over MgSO4, the solvent was evaporated. The
crude product was purified by fractional distillation (120 °C/35 mbar)
to afford product 11 as a colorless liquid; yield: 29.1 g (188.7 mmol,
80%; 3:2 mixture of isomers).
IR (ATR): 2919 (w), 2852 (w), 1682 (s), 1643 (w), 1597 (w), 1448 (m),
1373 (w), 1209 (m), 1159 (m), 1108 (m), 1014 (m), 885 (m), 752 (s),
690 (s), 654 cm–1 (m).
1H NMR (600 MHz, CDCl3): δ = 7.98 (d, J = 7.8 Hz, 2 H), 7.57 (t, J = 7.4
Hz, 1 H), 7.49 (t, J = 7.7 Hz, 2 H), 4.66 (s, 2 H), 3.03 (dd, J = 16.0, 4.5 Hz,
1 H), 2.91 (dd, J = 15.9, 9.4 Hz, 1 H), 2.52 (m, 2 H), 2.11 (t, J = 11.5 Hz, 1
H), 1.79–1.70 (m, 3 H), 1.67 (s, 3 H), 1.55 (m, 1 H), 1.31–1.25 (m, 2 H),
0.93 (d, J = 6.9 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 201.1 (Cq), 151.0 (Cq), 138.2 (Cq), 133.3
(CH), 129.1 (CH), 128.6 (CH), 108.6 (CH2), 39.3 (CH), 36.3 (CH2), 36.2
(CH2), 35.7 (CH), 35.6 (CH), 32.1 (CH2), 30.2 (CH2), 21.2 (CH3), 20.0
(CH3).
Next, the isomeric mixture of 11 (29.1 g, 188.7 mmol, 1.0 equiv) was
dissolved in pyridine (377 mL) and 3,5-dinitrobenzoyl chloride
(69.6 g, 301.9 mmol, 1.6 equiv) was added. After 4 h of stirring, water
(400 mL) was added and the mixture was extracted with Et2O
(3 × 400 mL). The combined organic layers were washed with sat. aq
CuSO4 solution (3 × 200 mL) and brine (1 × 200 mL). After drying over
MgSO4, the solvent was evaporated. The crude product was recrystal-
lized from n-heptane–DCE (2:1), then from n-hexane at –23 °C and fi-
nally from n-hexane at r.t. to afford (2R)-2-[(1R)-4-methylcyclohex-3-
en-1-yl]propyl 3,5-dinitrobenzoate as a colorless solid; yield: 10.5 g
(30.2 mmol, 16%); mp 70–72 °C.
MS (EI): m/z (%) = 105.0 (62), 93.0 (32), 79.0 (34), 77.0 (100).
HRMS (ESI): m/z [M + H]+ calcd for C18H25O: 257.18999; found:
257.19017.
1-(4-Methoxyphenyl)-2-[(1S,2R,5R)-2-methyl-5-(prop-1-en-2-
yl)cyclohexyl]ethanone (10b)
4-Bromoanisole (2.1 mL, 16.6 mmol, 1.5 equiv) was dissolved in Et2O
(16 mL) and cooled to 0 °C. n-BuLi (2.5 M in n-hexane; 5.3 mL,
13.3 mmol, 1.2 equiv) was added dropwise. The mixture was stirred
for 10 min at 0 °C and 20 min at r.t. After cooling to 0 °C, aldehyde 9
(2.0 g, 11.1 mmol, 1.0 equiv) in Et2O (8 mL) was added dropwise. The
mixture was stirred for a further 16 h at r.t. and then sat. aq NH4Cl
solution (30 mL) was added. The layers were separated, the aqueous
layer was extracted with Et2O (2 × 30 mL), and the combined organic
layers were washed with brine. After drying over MgSO4, the solvent
was evaporated. The intermediate was added to a solution of CrO3
(56 mg, 555 μmol, 0.05 equiv) and t-BuOOH (9.1 mL, 66.6 mmol,
6.0 equiv) in CH2Cl2 (56 mL). After stirring for 2 h, sat. aq NaSO3 solu-
tion was added until no more gas evolved. The layers were separated
and the aqueous layer was extracted with Et2O (2 ×). The combined
organic layers were washed with brine and dried over MgSO4, and the
solvent was evaporated. The crude product was purified by flash col-
Finally, the 3,5-dinitrobenzoate (5.1 g, 14.7 mmol, 1.0 equiv) was sus-
pended in MeOH (50 mL) and KOH (1.5 g, 26.5 mmol, 1.8 equiv) was
added. After reflux for 18 h, water (100 mL) was added and the layers
were separated. The aqueous layer was extracted with Et2O
(3 × 300 mL) and the combined organic layers were washed with
brine (300 mL). After drying over MgSO4, the solvent was evaporated
and the crude product was purified by bulb-to-bulb distillation to af-
ford product 11 as a colorless liquid; yield: 2.0 g (13.0 mmol, 88%).
1H NMR (400 MHz, CDCl3): δ = 5.33 (s, 1 H), 3.56 (m, 1 H), 3.40 (m, 1
H), 1.90 (m, 3 H), 1.67 (m, 2 H), 1.59 (s, 3 H), 1.53 (m, 2 H), 1.30 (m, 1
H), 0.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 133.9 (Cq), 120.7 (CH), 66.1 (CH2), 40.1
(CH), 35.0 (CH), 30.8 (CH2), 27.5 (CH2), 27.3 (CH2), 23.5 (CH3), 13.2
(CH3).
umn chromatography on silica gel (cyclohexane–EtOAc, 9:1) (Rf
0.22) to afford 10b as a yellow liquid; yield: 1.3 g (4.4 mmol, 42%).
=
MS (EI): m/z (%) = 121.0 (26), 107.0 (32), 95.0 (40), 94.0 (100), 93.0
(78), 91.0 (37), 81.0 (45), 79.0 (95), 77.0 (34), 68.0 (44), 67.0 (81), 55.0
(28), 53.0 (20).
IR (ATR): 2927 (w), 1656 (vs), 1614 (m), 1597 (w), 1442 (m), 1371 (w),
1254 (s), 1158 (w), 1110 (m), 1024 (m), 869 (m), 756 (s), 685 cm–1 (s).
1H NMR (600 MHz, CDCl3): δ = 7.96 (m, 2 H), 6.96 (m, 2 H), 4.67 (m, 2
H), 3.86 (s, 3 H), 2.88–2.75 (m, 1 H), 2.64–2.50 (m, 1 H), 2.13–1.13 (m,
9 H), 1.67 (s, 3 H), 0.94 (m, 3 H).
(2R)-2-[(1R)-4-Methylcyclohex-3-en-1-yl]propyl Methanesulfon-
ate (12)62
13C NMR (150 MHz, CDCl3): δ = 199.5 (Cq), 163.9 (Cq), 151.0 (Cq), 131.2
(Cq), 130.8 (CH), 114.2 (CH), 108.6 (CH2), 56.0 (CH3), 45.8 (CH), 43.7
(CH2), 38.0 (CH), 36.3 (CH2), 35.6 (CH), 32.1 (CH2), 30.2 (CH2), 21.3
(CH3), 20.0 (CH3).
(2R)-2-[(1R)-4-Methylcyclohex-3-en-1-yl]propan-1-ol (11) (20.0 g,
129.7 mmol, 1.0 equiv) was dissolved in CH2Cl2 (260 mL) and cooled
to 0 °C. Pyridine (27.0 mL, 194.5 mmol, 1.5 equiv) was added, and
then MsCl (11.0 mL, 142.6 mmol, 1.1 equiv) was added dropwise. The
mixture was stirred for 0.5 h at 0 °C and 18 h at r.t. Then, sat. aq
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

L
A. G. Griesbeck et al.
Feature
Synthesis
NaHCO3 solution (200 mL) was added. The layers were separated and
the aqueous layer was extracted with Et2O (2 ×). The combined organ-
ic layers were dried over MgSO4, and the solvent was evaporated to
afford 12 as a colorless liquid; yield: 30.1 g (129.6 mmol, 99%).
1H NMR (400 MHz, CDCl3): δ = 5.33 (s, 1 H), 4.19 (dt, J = 9.4, 4.6 Hz, 1
H), 4.07 (m, 1 H), 2.98 (s, 3 H), 1.97–1.67 (m, 6 H), 1.61 (s, 3 H), 1.57–
1.11 (m, 2 H), 0.96 (t, J = 7.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 134.0 (Cq), 120.2 (CH), 73.2 (CH2), 37.3
(CH), 37.1 (CH3), 35.0 (CH), 30.5 (CH2), 27.7 (CH2), 26.9 (CH2), 23.4
(CH3), 13.3 (CH3).
(4S)-1-(4-Methoxyphenyl)-4-[(1R)-4-methylcyclohex-3-en-1-
yl]pentan-1-one (14b)
n-BuLi (2.5 M in hexane; 5.4 mL, 13.4 mmol, 1.2 equiv) was added
dropwise to (E)-2-[1-(4-methoxyphenyl)ethylidene]-1,1-dimethylhy-
drazine (2.4 g, 12.3 mmol, 1.1 equiv) in THF (25 mL) at 0 °C. The mix-
ture was stirred for 1 h at 0 °C, and 13 (2.4 g, 11.2 mmol, 1.0 equiv)
was added. After stirring for 15 h at r.t., 2.0 M aq HCl (15 mL) was add-
ed and the mixture was stirred for 24 h. The solution was washed
with sat. aq NaHCO3 solution (2 ×) and the combined aqueous layers
were extracted with Et2O (2 × 100 mL). The combined organic layers
were washed with brine (100 mL) and dried over MgSO4. The crude
product was purified by flash column chromatography on silica gel
(cyclohexane–EtOAc, 9:1) (Rf = 0.23) to afford 14b as a colorless solid;
yield: 0.5 g (1.8 mmol, 16%); mp 62 °C.
MS (EI): m/z (%) = 94.0 (53), 93.0 (31), 91.0 (28), 79.0 (100), 77.0 (24),
67.0 (39).
(4R)-4-[(2R)-1-Bromopropan-2-yl]-1-methylcyclohex-1-ene (13)38
IR (ATR): 2923 (w), 1672 (vs), 1564 (w), 1404 (m), 1354 (w), 1207
(m), 1168 (m), 1111 (m), 1009 (m), 976 (m), 801 (s), 686 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.8 Hz, 2 H), 6.89 (d, J = 8.9
Hz, 2 H), 5.34 (s, 1 H), 3.82 (s, 3 H), 2.88 (m, 2 H), 2.01–1.17 (m, 10 H),
1.61 (s, 3 H), 0.88 (t, J = 6.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.3 (Cq), 163.3 (Cq), 133.9 (Cq), 130.3
(CH), 130.2 (Cq), 120.9 (CH), 113.7 (CH), 55.4 (CH3), 38.2 (CH), 37.1
(CH), 36.3 (CH2), 30.9 (CH2), 29.0 (CH2), 27.6 (CH2), 27.1 (CH2), 23.5
(CH3), 15.8 (CH3).
LiBr (33.8 g, 388.7 mmol, 3.0 equiv) was suspended in THF (555 mL),
and methanesulfonate 12 (30.1 g, 129.6 mmol, 1.0 equiv) was added.
After reflux for 4 h, water (300 mL) was added. The layers were sepa-
rated and the aqueous layer was extracted with Et2O (3 × 100 mL).
The combined organic layers were dried over MgSO4, and the solvent
was evaporated. The crude product was purified by fractional distilla-
tion (98 °C/1.7 mbar) to afford 13 as a colorless liquid; yield: 18.3 g
(84.2 mmol, 65%).
1H NMR (400 MHz, CDCl3): δ = 5.32 (s, 1 H), 3.43 (m, 1 H), 3.37 (m, 1
H), 2.01–1.88 (m, 3 H), 1.70 (m, 4 H), 1.62 (s, 3 H), 1.32–1.22 (m, 1 H),
0.98 (m, 3 H).
MS (EI): m/z = 150.1 (30), 135.1 (100), 121.1 (30), 119.1 (39), 77.0
(53).
HRMS (ESI): m/z [M + H]+ calcd for C19H27O2: 287.20056; found:
287.19941.
13C NMR (100 MHz, CDCl3): δ = 133.9 (Cq), 120.4 (CH), 40.0 (CH2), 39.6
(CH), 36.5 (CH), 30.5 (CH2), 27.7 (CH2), 27.0 (CH2), 23.6 (CH3), 15.7
(CH3).
Ethyl 2-Benzoyl-3-methyl-5-oxo-5-(2,6,6-trimethylcyclohex-3-
enyl)pentanoate (22a)
MS (EI): m/z (%) = 95.0 (88), 93.0 (39), 91.0 (44), 81.0 (64), 79.0 (71),
77.0 (47), 67.1 (100).
A
mixture of ethyl benzoylacetate (1.73 g, 1.56 mL, 9.00 mmol,
1.0 equiv), δ-damascone (1.73 g, 1.86 mL, 9.00 mmol, 1.0 equiv) and
FeCl3·6 H2O (243.0 mg, 0.90 mmol, 0.1 equiv) in CHCl3 (2 mL) was
stirred for 24 h at 50 °C. Column chromatography (MTBE–cyclohex-
ane, 1:4) gave 22a as a yellow oil; yield: 2.94 g (7.65 mmol, 85%).
(4S)-4-[(1R)-4-Methylcyclohex-3-en-1-yl]-1-phenylpentan-1-one
(14a)
n-BuLi (2.5 M in hexane; 5.4 mL, 13.4 mmol, 1.2 equiv) was added
dropwise
to
(E)-1,1-dimethyl-2-(1-phenylethylidene)hydrazine
IR (ATR): 3018 (w), 2960 (m), 2878 (m), 1737 (s), 1686 (s), 1448 (m),
1367 (m), 1261 (m), 1213 cm–1 (m).
(2.1 mL, 12.3 mmol, 1.1 equiv) in THF (25 mL) at 0 °C. The mixture
was stirred for 1 h at 0 °C, and 13 (2.4 g, 11.2 mmol, 1.0 equiv) was
added. After stirring for 15 h at r.t., 2.0 M aq HCl (15 mL) was added
and the mixture was stirred for 24 h. The solution was treated with
sat. aq NaHCO3 solution (2 ×) and the combined aqueous layers were
extracted with Et2O (2 × 100 mL). The combined organic layers were
washed with brine (100 mL) and dried over MgSO4. The crude prod-
uct was purified by flash column chromatography on silica gel (cyclo-
hexane–EtOAc, 9:1) (Rf = 0.52) to afford 14a as a yellow liquid; yield:
1.2 g (4.7 mmol, 42%).
1H NMR (600 MHz, CDCl3): δ (mixture of diastereoisomers) = 8.40–
7.95 (m, 2 H), 7.55–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 5.48 (m, 1 H),
5.39 (m, 1 H), 4.62–4.48 (m, 1 H), 4.09–4.07 (m, 2 H), 2.89 (m, 2 H),
2.66 (m, 1 H), 2.44 (m, 1 H), 2.15 (m, 1 H), 1.94–1.89 (m, 1 H), 1.66–
1.62 (m, 1 H), 1.30 (m, 3 H), 1.10 (m, 3 H), 0.90 (m, 3 H), 0.85 (m, 6 H).
13C NMR (150 MHz, CDCl3): δ (mixture of diastereoisomers) = 213.5,
213.3 (2 × Cq), 195.1 (Cq), 169.2 (Cq), 136.5, 136.4 (2 × Cq), 133.6 (CH),
131.9 (CH), 128.6 (CH), 128.5 (CH), 124.2, 124.1 (2 × CH), 62.6, 62.5
(2 × CH), 61.2, 61.1 (2 × CH2), 57.6, 57.3 (2 × CH), 52.1 (2 × CH2), 41.8
(2 × CH2), 35.7 (Cq), 31.7, 31.6 (2 × CH), 28.8 (CH3), 28.7 (CH), 20.7,
20.6 (2 × CH3), 17.2, 17.2 (2 × CH3), 14.2 (CH3).
IR (ATR): 2913 (w), 1685 (s), 1597 (w), 1580 (w), 1448 (w), 1377 (w),
1267 (w), 1206 (m), 1178 (m), 1116 (w), 1001 (m), 974 (m), 914 (w),
797 (m), 741 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.1 Hz, 2 H), 7.51 (ddd, J =
7.4, 2.7, 1.3 Hz, 1 H), 7.41 (td, J = 7.5, 1.9 Hz, 2 H), 5.35 (s, 1 H), 2.94
(m, 2 H), 2.00–1.18 (m, 10 H), 1.61 (s, 3 H), 0.81 (t, J = 5.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.5 (Cq), 137.1 (Cq), 133.8 (Cq), 132.8
(CH), 128.5 (CH), 128.0 (CH), 120.9 (CH), 38.2 (CH), 37.0 (CH), 36.5
(CH2), 30.9 (CH2), 28.7 (CH2), 27.5 (CH2), 27.1 (CH2), 23.4 (CH3), 15.8
(CH3).
GC/MS [50 °C (5 min), 20 °C/min, 280 °C (10 min); H2, 2.0 mL/min]:
isomer A: tR = 16.457 min, m/z (%) = 261 (42) [M – C9H15], 105 (100),
81 (24), 77 (57); isomer B: tR = 16.407 min, m/z (%) = 261 (36) [M –
C9H15], 105 (100), 81 (25), 77 (61).
HRMS (ESI): m/z [M + H]+ calcd for C24H33O4: 385.23733; found:
385.23782.
UV/Vis (MeOH, c = 10–4 M, d = 1 cm): λmax (log ε) = 247 (4.15), 281 nm
MS (EI): m/z (%) = 119.1 (52), 105.0 (71), 79.0 (36), 77.0 (100), 67.0
(3.38).
(29).
Anal. Calcd for C24H32O4: C, 74.97; H, 8.39. Found: C, 74.40; H, 8.31.
HRMS (ESI): m/z [M + H]+ calcd for C18H25O: 257.18999; found:
257.18841.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

M
A. G. Griesbeck et al.
Feature
Synthesis
Benzyl 2-Benzoyl-3-methyl-5-oxo-5-(2,6,6-trimethylcyclohex-3-
enyl)pentanoate (22b)
Ethyl (R*,R*)- and (R*,S*)-2-Benzoyl-5-oxo-3-phenylhexanoate
(27b) (Diastereoisomeric Chalcone Photocages)
A mixture of benzyl benzoylacetate (2.29 g, 9.00 mmol, 1.0 equiv), δ-
damascone (1.73 g, 1.86 mL, 9.00 mmol, 1.0 equiv) and FeCl3·6 H2O
(486.0 mg, 1.80 mmol, 0.2 equiv) in CHCl3 (2 mL) was stirred for 48 h
at 50 °C. Column chromatography (MTBE–cyclohexane, 1:4) gave 22b
as a yellow oil; yield: 3.46 g (7.74 mmol, 86%).
A mixture of ethyl benzoylacetate (1.73 g, 9.00 mmol, 1.0 equiv), ben-
zalacetone (1.32 g, 9.00 mmol, 1.0 equiv) and FeCl3·6 H2O (24.3 mg,
0.09 mmol, 0.01 equiv) in CHCl3 (1.5 mL) was stirred for 24 h at 50 °C.
Column chromatography (MTBE–cyclohexane, 1:3) gave a 26:74 dia-
stereoisomeric mixture [yield: 2.48 g (6.39 mmol, 71%)] that was sep-
arated into the (R*,R*)- and (R*,S*)-diastereoisomers by column chro-
matography.
IR (ATR): 3012 (w), 2959 (m), 2883 (m), 2832 (w), 1740 (s), 1686 (s),
1449 (m), 1366 (s), 1264 (s), 1212 cm–1 (s).
1H NMR (600 MHz, CDCl3): δ (mixture of diastereoisomers) = 8.40–
7.95 (m, 2 H), 7.56–7.54 (m, 1 H), 7.44–7.42 (m, 2 H), 7.25 (m, 3 H),
7.19 (m, 2 H), 5.50 (m, 1 H), 5.41 (m, 1 H), 5.09 (m, 2 H), 4.72–4.55 (m,
1 H), 2.96–2.93 (m, 1 H), 2.72–2.59 (m, 1 H), 2.50–2.40 (m, 2 H), 2.20–
2.12 (m, 1 H), 1.94–1.90 (m, 1 H), 1.66–1.64 (m, 1 H), 1.08–1.04 (m, 3
H), 0.96–0.80 (m, 9 H).
13C NMR (150 MHz, CDCl3): δ (mixture of diastereoisomers) = 213.7,
213.5, 213.3 (3 × Cq), 195.0, 194.9 (2 × Cq), 169.1, 169.0 (2 × Cq), 136.7
(Cq), 135.4 (Cq), 133.6 (CH), 131.9, 131.8 (2 × CH), 128.8 (CH), 128.7
(CH), 128.5 (CH), 128.3, 128.2 (2 × CH), 124.3, 124.2 (2 × CH), 66.9
(CH2), 62.7, 62.6, 62.5 (3 × CH), 57.8, 57.6, 57.3 (3 × CH), 52.1 (CH2),
41.7 (CH2), 33.1, 33.0 (2 × Cq), 31.8, 31.7 (2 × CH), 29.3, 29.0 (2 × CH3),
28.8, 28.6 (2 × CH), 20.8, 20.7 (2 × CH3).
(R*,R*)-Isomer
Yellow solid; mp 70 °C.
1H NMR (300 MHz, CDCl3): δ = 8.09–8.06 (d, JH,H = 7.3 Hz, 2 H), 7.61
3
(m, 1 H), 7.49 (m, 2 H), 7.35–7.28 (m, 4 H), 7.25–7.22 (m, 1 H), 4.84–
3
3
4.81 (d, JH,H = 10.2 Hz, 1 H), 4.27–4.19 (m, 1 H), 3.87–3.80 (q, JH,H
=
3
7.0 Hz, 2 H), 2.86–2.84 (m, 2 H), 2.02 (s, 3 H), 0.92–0.87 (t, JH,H = 7.1
Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 206.6 (Cq), 193.7 (Cq), 167.9 (Cq), 140.4
(Cq), 136.5 (Cq), 133.9 (CH), 128.9 (2 × CH), 128.6 (2 × CH), 127.4 (CH),
61.6 (CH2), 59.8 (CH), 47.1 (CH2), 41.1 (CH), 30.4 (CH3), 13.8 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C21H23O4: 339.40492; found:
339.40814.
UV/Vis (MeOH, c = 10–4 M, d = 1 cm): λmax (log ε) = 248 (4.01), 289 nm
(3.26).
HRMS (ESI): m/z [M + Na]+ calcd for C29H34O4Na: 469.23493; found:
469.23452.
UV/Vis (MeOH, c = 10–4 M, d = 1 cm): λmax (log ε) = 247 (4.14), 281 nm
(3.40).
(R*,S*)-Isomer
Anal. Calcd for C29H34O4: C, 78.00; H, 7.67. Found: C, 78.01; H, 7.78.
Orange solid; mp 161 °C.
1H NMR (300 MHz, CDCl3): δ = 7.85–7.82 (d, 3JH,H = 7.8 Hz, 2 H), 7.52–
Dodecyl 2-Benzoyl-3-methyl-5-oxo-5-(2,6,6-trimethylcyclohex-3-
enyl)pentanoate (22c)
7.49 (m, 1 H), 7.40–7.36 (m, 2 H), 7.26–7.08 (m, 5 H), 4.83–4.80 (d,
3
3JH,H = 9.6 Hz, 1 H), 4.22–4.09 (m, 3 H), 3.02–3.00 (d, JH,H = 6.9 Hz, 2
H), 2.04 (s, 3 H), 0.92–0.87 (t, 3JH,H = 7.1 Hz, 3 H).
A mixture of dodecyl benzoylacetate (2.99 g, 9.00 mmol, 1.0 equiv),
δ-damascone (1.73 g, 1.86 mL, 9.00 mmol, 1.0 equiv) and FeCl3·6 H2O
(243.0 mg, 0.90 mmol, 0.1 equiv) in CHCl3 (2 mL) was stirred for 48 h
at 50 °C. Column chromatography (MTBE–cyclohexane, 1:5) gave 22c
as an orange oil; yield: 4.16 g (7.93 mmol, 88%).
13C NMR (75 MHz, CDCl3): δ = 206.5 (Cq), 193.7 (Cq), 168.6 (Cq), 141.0
(Cq), 136.6 (Cq), 133.5 (CH), 128.7 (2 × CH), 128.2 (2 × CH), 127.1 (CH),
61.8 (CH2), 59.2 (CH), 47.4 (CH2), 40.8 (CH), 30.4 (CH3), 14.0 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C21H23O4: 339.40492; found:
339.405243.
IR (ATR): 3012 (w), 2956 (s), 2926 (s), 2854 (m), 1739 (s), 1687 (s),
1466 (m), 1366 (m), 1212 cm–1 (m).
UV/Vis (MeOH, c = 10–4 M, d = 1 cm): λmax (log ε) = 248 (4.25), 285 nm
(3.01).
1H NMR (600 MHz, CDCl3): δ (mixture of diastereoisomers) = 8.40–
7.95 (m, 2 H), 7.54–7.52 (m, 1 H), 7.45–7.41 (m, 2 H), 5.47 (m, 1 H),
5.40 (m, 1 H), 4.62–4.47 (m, 1 H), 4.03–3.99 (m, 2 H), 2.95–2.87 (m, 1
H), 2.69–2.65 (m, 1 H), 2.59–2.52 (m, 1 H), 2.50–2.40 (m, 1 H), 2.21–
2.13 (m, 1 H), 1.94–1.88 (m, 1 H), 1.65–1.60 (m, 1 H), 1.48–1.47 (m, 2
H), 1.21–1.15 (m, 18 H), 1.06–1.01 (m, 3 H), 0.96–0.90 (m, 3 H), 0.87–
0.83 (m, 9 H).
13C NMR (150 MHz, CDCl3): δ (mixture of diastereoisomers) = 213.7,
213.5, 213.2 (3 × Cq), 194.1, 194.0 (2 × Cq), 169.3, 169.2 (Cq), 136.6,
136.5 (2 × Cq), 133.5 (2 × CH), 131.9, 131.8 (2 × CH), 128.8 (CH), 128.6
(CH), 124.2, 124.1 (2 × CH), 65.1 (CH2), 62.4, 62.3 (2 × CH), 58.1, 57.7
(2 × CH), 52.1 (CH2), 41.8 (CH2), 33.0, 33.1 (2 × Cq), 31.9 (CH2), 31.8,
31.7, 31.6 (3 × CH), 29.7, 29.6 (2 × CH), 28.7, 28.6 (2 × CH3), 25.8
(2 × CH2), 22.7 (CH2), 20.8, 20.7 (2 × CH3), 19.8, 19.7 (2 × CH3), 14.2
(CH3).
(4R,7R)-4-Methyl-7-(prop-1-en-2-yl)-1,2-diazaspiro[2.5]oct-1-ene
(31)
(+)-Dihydrocarvone (5) (5.0 mL, 30.6 mmol, 1.0 equiv) was added
dropwise to 7.0 M methanolic NH3 (44 mL, 305.5 mmol, 10.0 equiv) at
0 °C. After stirring for 2 h, the mixture was cooled to –18 °C and hy-
droxylamine-O-sulfonic acid (8.6 g, 76.4 mmol, 2.5 equiv) was added
in portions. The mixture was slowly warmed to r.t. and stirred for
20 h at r.t. Then, the solvent and the remaining ammonia were evapo-
rated and the intermediate was dissolved in acetone (153 mL). CrO3
(4.6 g, 48.8 mmol, 1.5 equiv) was dissolved in 3.8 M aq H2SO4 (66 mL)
and added dropwise within 45 min to the solution of the intermedi-
ate. After stirring for 4 h, water (150 mL) was added. After extraction
with CH2Cl2 (3 × 150 mL), the combined organic layers were washed
with brine (150 mL) and dried over MgSO4. The solvent was evaporat-
ed and the crude product was purified by flash column chromatogra-
phy on silica gel (cyclohexane–EtOAc, 9:1) (Rf = 0.67) to afford 31 as a
colorless liquid; yield: 1.8 g (11.0 mmol, 36%).
HRMS (ESI): m/z [M + H]+ calcd for C34H53O4: 525.39384; found:
525.39415.
UV/Vis (MeOH, c = 10–4 M, d = 1 cm): λmax (log ε) = 246 (4.26), 283 nm
(3.45).
IR (ATR): 2930 (m), 2855 (w), 1739 (w), 1645 (m), 1569 (m), 1438
(m), 1378 (m), 1179 (m), 1048 (m), 983 (m), 891 (s), 818 (m), 791 (m),
722 (m), 697 cm–1 (m).
Anal. Calcd for C34H52O4: C, 74.82; H, 9.99. Found: C, 74.28; H, 9.94.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

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A. G. Griesbeck et al.
Feature
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1H NMR (400 MHz, CDCl3): δ = 4.59 (s, 1 H), 4.56 (s, 1 H), 2.21 (tt, J =
12.0, 3.3 Hz, 1 H), 1.90 (m, 1 H), 1.84 (m, 1 H), 1.77 (m, 1 H), 1.67 (m, 1
H), 1.58 (s, 3 H), 1.38 (m, 1 H), 1.20 (m, 1 H), 0.37 (ddd, J = 13.8, 3.8,
2.1 Hz, 1 H), 0.11 (d, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.3 (Cq), 109.1 (CH2), 43.4 (CH2),
37.5 (CH2), 33.9 (CH), 33.0 (Cq), 31.4 (CH), 31.0 (CH2), 20.7 (CH3), 17.1
(CH3).
References
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MS (EI): m/z (%) = 93.0 (92), 91.0 (72), 79.0 (100), 77.0 (43), 67.0
(100).
HRMS (ESI): m/z [M + H]+ calcd for C10H17N2: 165.13863; found:
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Bis-damascone Photocage 33
Under an argon atmosphere in a three-neck 50-mL flask, i-Pr2NH
(2.02 g, 2.81 mL, 20.00 mmol, 2.0 equiv) in THF (7 mL) was cooled to
–78 °C. To this solution, 2.5 M n-BuLi in n-hexane (9.62 mL, 24 mmol,
2.4 equiv) was added dropwise over 20 min, and then the mixture
was stirred for 40 min. Subsequently, a solution of 1,1′-(4,4′-(ethan-
1,2-diylbis(oxy))bis(4,1-phenylene))dipropan-1-one (3.26 g, 10 mmol,
1.0 equiv) in THF (20 mL) was added to the LDA solution over 1 h. Af-
ter an additional hour stirring at –78 °C, CeCl3 (5.77 g, 23.4 mmol,
2.3 equiv) was added over 20 min and, over an additional 30 min, δ-
damascone (3.84 g, 4.12 mL, 20.00 mmol, 2.0 equiv) was added. The
reaction mixture was stirred for 12 h at 0 °C and then quenched with
sat. aq NH4Cl solution (20 mL) and extracted with Et2O (3 × 30 mL).
The organic phases were combined, washed with sat. aq NaCl solution
(30 mL) and dried over MgSO4, and then the solvent was removed by
rotary evaporation. Column chromatography (MTBE–cyclohexane,
1:4) gave 33 as a yellow oil; yield: 5.54 g (7.79 mmol, 78%).
IR (ATR): 3336 (w), 3012 (w), 2960 (m), 2868 (m), 2826 (w), 1705 (m),
1670 (s), 1599 (s), 1456 (m), 1366 (s), 1222 (s), 1171 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.93–7.90 (m, 2 H), 6.95–6.93 (m,
3JH,H = 8.4 Hz, 1 H), 6.88–6.86 (m, JH,H = 8.6 Hz, 1 H), 5.46–5.35 (m, 2
3
H), 4.36 (s, 2 H), 3.51–3.43 (m, 1 H), 2.94–2.88 (m, 1 H), 2.47–2.36 (m,
3 H), 2.19–2.14 (m, 1 H), 1.97–1.91 (m, 1 H), 1.69–1.63 (m, 1 H), 0.99–
0.98 (m, 3 H), 0.90 (m, 6 H), 0.87 (m, 3 H), 0.72–0.71 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 214.0 (Cq), 202.9 (Cq), 162.3 (Cq), 132.2
(Cq), 130.9 (CH), 130.6 (CH), 124.1 (CH), 114.5 (CH), 66.5 (CH2), 62.6
(CH), 50.2 (CH2), 44.4 (CH), 41.7 (CH2), 33.1 (Cq), 31.4 (CH), 30.7 (CH),
29.8 (CH3), 20.0 (CH3), 19.8 (CH3), 12.7 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C46H63O6: 711.46192; found:
711.46216; m/z [M + Na]+ calcd for C46H62O6Na: 733.44386; found:
733.44349.
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UV/Vis (MeOH, c = 10–4 M, d = 1 cm): λmax (log ε) = 286 nm (4.34).
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Acknowledgment
This work was supported by Henkel AG & Co. KGaA and the University
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