Photocyclization to cis-Hexahydrocarbazol-4-ones: Substrate Modification, Mechanism, and Scope

Article abstract of DOI:10.1021/acs.joc.8b03144

Upon irradiation at = 366 nm, tertiary N-alkoxycarbonyl-N-aryl-β-enaminones furnished exclusively the trans-hexahydrocarbazol-4-ones by a conrotatory [6π] photocyclization but epimerized on silica to cis-hexahydrocarbazol-4-ones (14 examples, 44-98% yield). The acceptor substitution on the nitrogen atom enhanced the stability of the cyclized products compared to N-alkyl-N-aryl-β-enaminones reported previously. The mechanism of the [6π] photocyclization was investigated by quenching experiments, deuterium-labeling experiments, and DFT calculations, suggesting a triplet pathway for the conrotatory ring closure followed by a suprafacial [1,4] hydrogen migration.

Full text of DOI:10.1021/acs.joc.8b03144

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Featured Article
[6#] Photocyclization to cis-Hexahydrocarbazol-4-
ones: Substrate Modification, Mechanism and Scope
Sachin G. Modha, Alexander Pöthig, Andreas Dreuw, and Thorsten Bach
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[
6π] Photocyclization to cis-Hexahydrocarbazol-4-ones: Substrate
Modification, Mechanism and Scope
†
†

*†
Sachin G. Modha , Alexander Pöthig , Andreas Dreuw , Thorsten Bach
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†Department of Chemistry and Catalysis Research Center (CRC), Technical University of
Munich, Lichtenbergstr. 4, 85747 Garching, Germany
Interdisciplinary Center for Scientific Computing, Ruprecht-Karls University, Im Neuenheimer
Feld 205A, 69120 Heidelberg, Germany
Corresponding Author
*Email: thorsten.bach@ch.tum.de
ABSTRACT
O
O
H
H
h ( = 366 nm)
R1
rt (CH2Cl2)
R1
X
N
N
X
14 examples
O
OR
O
OR
H
O
O
H
R1
R1
[
1,4-H]
SiO2
4-98%
X
N
X
N
4
H
H
O
OR
O
OR
Upon irradiation at  = 366 nm, tertiary N-alkoxycarbonyl-N-aryl--enaminones furnished
exclusively the trans-hexahydrocarbazol-4-ones by a conrotatory [6π] photocyclization, but
epimerized on silica to cis-hexahydrocarbazol-4-ones (14 examples, 44-98% yield). The acceptor
substitution on the nitrogen atom enhanced the stability of the cyclized products compared to N-
alkyl-N-aryl--enaminones reported previously. The mechanism of the [6π] photocyclization was
investigated by quenching experiments, deuterium labelling experiments and DFT calculations
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suggesting a triplet pathway for the conrotatory ring closure followed by a suprafacial [1,4]
hydrogen migration.
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INTRODUCTION
Photochemical organic transformations provide easy access to molecular structures that are
difficult, if not impossible, to obtain via conventional reactions. Numerous approaches towards
natural product synthesis have been reported where a photochemical transformation represents a
1
key step. Indoline derivatives are a very important class of heterocyclic compounds due to their
presence as core structures in many naturally occurring alkaloids and pharmaceutical
2
3
compounds. In pioneering work, Chapman and co-workers demonstrated that N-alkyl-N-aryl-
enamines produce upon irradiation mainly trans-fused hexahydrocarbazoles while Schultz et al.4
reported the formation of cis-fused dihydrobenzofurans from -aryloxyenones via photochemical
conrotatory ring closure followed by epimerization. These and other reports proved the efficiency
of a [6π] photocyclization reaction in the generation of complex carbo- and heterocycles from
simple starting materials.5,6 In 1988, Gramain, Husson, and co-workers reported the synthesis of
cis-hexahydrocarbazol-4-ones
from
tertiary
N-alkyl-N-aryl--enaminones
by
[6π]
photocyclization and subsequent base-mediated epimerization (Scheme 1, PMB = para-
7
methoxybenzyl). The presence of a carbonyl functional group in the photoproduct allowed for
further transformations to various cis-hexahydrocarbazol-4-ones and pentacyclic alkaloid
8
skeletons. It is worth noting that despite the importance of these cis-hexahydrocarbazol-4-ones
as precursors to pentacyclic alkaloid skeletons, a mechanistic study has not been carried out nor
have detailed analytical data for trans- and cis-hexahydrocarbazol-4-ones been reported. This is
most probably due to the instability of trans- and cis-products (2 and 3, scheme 1) at room
9
temperature. Our interest in the photochemistry of enones led us to investigate this classical
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photoreaction. Apart from the fact that we aimed to isolate and characterize the
hexahydrocarbazol-4-one products we were interested to see whether the enaminones would be
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b
amenable towards a chromophore activation by a Lewis acid.
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Scheme 1. [6π] Photocyclization of N-Alkyl-N-aryl--enaminones 1 and further Transformations
of Primary Products 2 as reported by Gramain et al.7
O
N
R
1, R = Me, Bn, PMB
h, rt
h
benzene)
1
(
O
H
unstable
(
3 examples)
N
R
H
2
o
o
i) KH, (THF) 0 C
i) KH, (THF) 0 C
o
o
ii) H O, 0 C to rt
ii) R'X, 0 C to rt
2
O
H
O
R'
N
H
Bn
N
R
H
3a, unstable
4
Enone substrates generally demonstrate a strong bathochromic shift in absorption upon
9
coordination with a Lewis acid, but enaminone 1a (R = Me) exhibited a bathochromic shift of
only  = 10 nm (see Supporting Information, Fig. S1), suggesting a coordination of the Lewis
acid at the nitrogen instead of the enone oxygen atom. Indeed, no conversion was observed upon
irradiation of 1a in the presence of 0.5 equivalents of EtAlCl , indicating that the lone pair of
2
nitrogen that is necessary for the [6π] photocyclization was no longer available. This observation
led to the idea to introduce an electron withdrawing group at the nitrogen atom. After some
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experimentation we found that a methoxycarbonyl-substituted enaminone demonstrated a strong
bathochromic shift in the presence of Lewis acid (see Supporting Information, Fig. S2). This
observation triggered a more extensive study of the [6π] photocyclization of N-alkoxycarbonyl-
N-aryl--enaminones which is reported here in detail.
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RESULTS AND DISCUSSION
Reaction Conditions and Scope. Upon irradiation at a wavelength of  = 366 nm in degassed
dichloromethane under argon, enaminone 6a was completely converted to a single product in 3 h
but surprisingly the product turned out to be the cis-hexahydrocarbazol-4-one (Table 1, entry 1,
1
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8% yield). H NMR spectral data of the crude reaction mixture established the exclusive
formation of trans-hexahydrocarbazol-4-one 7a upon irradiation but complete conversion to the
thermodynamically stable cis-hexahydrocarbazol-4-one 8a took place, presumably by
epimerization on silica. The relative configuration of 8a was confirmed by single crystal X-ray
diffraction (see Supporting Information). It is worth noting that in Gramain’s work,7,8 a base-
mediated epimerization was necessary to convert the trans to the cis isomer (Scheme 1) while in
our case the epimerization occurred under much milder conditions. In addition, cis-product 8a is
a bench stable white solid compound, proving that the introduction of an acceptor substitution on
the nitrogen atom leads to more stable hexahydrocarbazol-4-ones. With this result in hand, we
used enaminone 6a as the standard substrate to perform further irradiation and epimerization
experiments. Irradiation at 350 nm gave a similar result as above while at 419 nm no conversion
was observed (Table 1, entries 2 and 3). A longer irradiation time of 20 h at  =366 nm led to the
formation of tetrahydrocarbazol-4-one 9a suggesting that trans-isomer 7a was not stable under
irradiation and underwent oxidation. Compound 9a exhibits a higher molar absorption coefficient

1
1
1
1
at  = 366 nm (366 = 40 M cm ) than 7a ( = 6 M cm ) and once it is present at a certain
366
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concentration it does not allow for further photooxidation of 7a (Table 1, entry 4). Stirring the
trans isomer in the presence of silica for 1 h furnished complete epimerization while interestingly
no epimerization took place in the presence of acetic acid (2 equiv) after 16 h at room tem-
perature (Table 1, entries 5 and 6). Trifluoroacetic acid proved more effective as 2 equiv was suf-
ficient for complete epimerization in 3 h at room temperature (Table 1, entry 7). Stirring the trans
photoproduct in the presence of 10 equiv of deuterated trifluoroacetic acid produced cis com-
pound 8a with a deuterium to hydrogen ratio of 7:3 at position α to carbonyl (Table 1, entry 8).
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Table 1. Reaction Optimization with N-Methoxycarbonyl-N-phenyl--enaminone 6a.
O
O
H
h (), [20 mM]
N
(
CH Cl ) rt, t
2
2
1
N
O
H
O
O
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O
N
O
6a
7a
O
H
N
conditions
t2
H
O
O
O
O
8a
9a

t1
t2
ratio
entry
conditions
[
nm] [h]
[h]




1
8a/7a
on silicaa
on silicaa
b
1
2
3
4
5
6
7
8
366
350
3
2
98 /0
b
95 /0
419 20
366 20

0/0
on silicaa
on silicad
74 /0
b
c
366
366
366
366
3
3
3
3
100/0
0/100
100/0
100/0e
AcOH (2 eq) 16
TFA (2 eq)
3
3
TFA-d (10 eq)
1
For the emission spectra of the light sources, see ref.10 Reactions carried out on 0.2 mmol scale of 6a using a Duran
1
a
phototube. The ratio of 8a/7a was determined by H NMR integration. Epimerization occurred on silica during
b
c
d
column chromatography. Yield of isolated product 8a. By-product 9a isolated in 12% yield. After irradiation the
e
reaction mixture was transferred to a round bottom flask and stirred over silica (2 g). Ratio of deuterium to hydrogen
7
1
:3 at position α to carbonyl. AcOH = Acetic acid, TFA = trifluoroacetic acid, TFA-d = monodeuterated TFA.
Having optimized conditions in hand for the photocyclization we synthesized various tertiary aryl
enaminones. The preparation of these enaminones was straightforward and relied on a two-step
sequence in which different anilines were coupled with cyclic 1,3-diones using Yb(OTf) (2
3
mol%) as the catalyst to get N-aryl-β-enaminones 5 in the first step.11
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Scheme 2. Synthesis of Variously Substituted N-alkoxycarbonyl-N-aryl--enaminones 6a-u.
A. i) nBuLi (1.02 eq)
(THF) 78 oC, 20 min
O
O
ii) ClCOOR (1.2 eq)
78 oC to rt

R1
N
or
N
X
R1
X
H
B. Boc2O (1.5 eq)
O
OR
5
DMAP (10 mol%)
MeCN) 0 oC to rt
6
1
1
1
1
1
1
1
1
1
1
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2
2
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2
2
2
2
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0
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(
O
O
O
N
N
N
O
O
O
O
O
O
6a, 80%
6b, 67%
6c, 74%
O
O
O
O
N
N
N
O
O
O
O
O
O
6d, 83%
6e, 78%
6f, 71%
O
O
O
N
N
N
O
O
O
O
O
O
6g, 67%
6h, 89%
6i, 80%
O
O
O
Br
NC
N
N
N
t
t
O
O Bu
O
O Bu
t
O
O Bu
6j, 67%
6k, 69%
6l, 62%
O
O
O
HO
O
O
N
O
N
N
t
O
O Bu
t
t
O
O Bu
O
O Bu
6m, 78%
6n, 68%
6o, 48%
O
O
O
N
N
N
N
O
O
N
O
O
O
O
O
6p, 91%
6q, 79%
6r, 58%
O
F
O
F
F
N
N
N
F
t
F
O
O Bu
t
O
O
O
O Bu
6s, 77%
6t, 93%
6u, 96%
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In the second step, compounds 5 were either deprotonated by nBuLi followed by addition of
chloroformates (procedure A, for compounds 6a-6i, 6u)12 or tert-butyloxycarbonyl(Boc)-
protected under standard conditions (procedure B, for compounds 6j-6t, Boc O = di-tert-butyl
2
0
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dicarbonate, DMAP = 4-dimethylaminopyridine) to get variously substituted N-alkoxycarbonyl-
N-aryl--enaminones 6a-6u in moderate to good yields (Scheme 2). These enaminones were
subjected to irradiation at  = 366 nm to obtain the respective cis-hexahydrocarbazol-4-ones. As
evident from scheme 3, the yields of cis-hexahydrocarbazol-4-ones were good to excellent.
Enaminone 6b with a tethered alkene exclusively went through [6π] photocyclization to give 8b
in 85% yield and a [2+2] photocycloaddition product was not detected. L-menthol as potential
chiral auxiliary did not influence the photoreaction and 8c was isolated in 95% yield with a
diastereomeric ratio (dr) of 1:1. Protecting groups like fluorenylmethyloxycarbonyl (Fmoc),
carboxybenzyl (Cbz) and Boc were well tolerated giving the desired compounds in good to
excellent yields (8d, 8f, 8j, 8m, 8n). Substitutions like phenyl, propargyl, bromine, nitrile were
also accommodated nicely producing cis-hexahydrocarbazol-4-ones in moderate to excellent
yields (8e, 8g, 8k, 8l). Interestingly, substrate 6h with a tert-butyl substitution in meta position on
phenyl produced 8h with complete regioselectivity in which the photocyclization took place in
para position to the sterically bulky tert-butyl group but not in ortho position. Cyclopentene
enaminone 6i gave no conversion at 366 nm but rather produced the expected product at an
irradiation wavelength of  = 300 nm. A longer reaction time of 20 h was required and cis-
product 8i could be isolated in a moderate yield of 52%. Enaminones 6o and 6p did not give any
conversion and were re-isolated quantitatively, suggesting that free hydroxyphenyl and 2-pyridyl
as aryl component are not compatible with the [6] photocyclization. Ortho substitution on
phenyl was not tolerated either due to steric reasons and thus no reaction occurred upon
irradiation of enaminones 6q-s. While tetrafluoro-substituted enaminone 6t produced a complex
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reaction mixture upon irradiation, substrate 6u gave a spot-to-spot conversion but the cis-product
was found to decompose slowly at room temperature storage.
Scheme 3. [6π] Photocyclisation to cis-Hexahydrocarbazol-4-ones 8a-n.
1
1
1
1
1
1
1
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O
O
H
N
h ( = 366 nm),
R1
R1
[20 mM]
N
X
X
(CH Cl ) rt, 3 h
2
2
H
O
OR
O
OR
6
8
O
O
O
H
H
H
N
N
N
H
H
H
O
O
O
O
O
O
O
8
a, 98%
8b, 85%
8
c, 95% (dr 1:1)
O
O
H
N
O
H
H
H
N
H
O
O
O
N
H
O
O
O
8d, 75%
8e, 94%
8f, 80%
O
O
O
H
H
H
N
N
H
O
H
N
H
O
O
O
O
O
8g, 68%
8h, 95%
8i, 52%a
O
O
O
NC
H
Br
H
H
N
N
O
N
H
H
H
t
t
O
O Bu
t
O Bu
O
O Bu
8j, 95%
8k, 44%
8l, 91%
O
O
O
H
O
H
tBuO
N
N
H
H
t
t
O
O Bu 8m, 80%
O
O Bu 8n, 81%
All reactions were carried out with 0.2 mmol of 6 using degassed and dried dichloromethane (10 mL) as solvent in a
Duran phototube under argon at 366 nm for 3 h. Complete epimerization was observed after silica gel column
a
chromatography in all cases. Irradiated at 300 nm for 20 h.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
A gram-scale reaction was carried out at a very high substrate concentration of 500 mM (Scheme
4
). As expected a longer irradiation time of 48 h was required for complete conversion but, to our
delight, product 8a could be isolated in an excellent yield of 95% (1.17 g). It is interesting to note
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
that the decomposition of photoproduct that was observed with a longer irradiation time of 20 h
(Table 1, entry 4) at 20 mM concentration did not occur in the scale-up reaction. This is likely
due to the fact that the molar absorption coefficient of starting enaminone is higher than that of
the trans-photoproduct and until all starting material is consumed the photoproduct does not
significantly decompose.
Scheme 4. Gram Scale [6π] Photocyclization at 500 mM Concentration.
O
i) h ( = 366 nm),
500 mM],
(CH Cl ) rt, 48 h
O
H
N
[
2
2
N
ii) Epimerization
on silica
H
O
O
O
O
6a, 1.23 g
8a, 95%, 1.17 g
Mechanism and DFT calculations. Based on previous work5,13 the reaction course of a [6]
photocyclization is suggested to include a conrotatory ring closure as depicted for photoexcited
substrate 6a* in Scheme 5. The subsequent rearrangement of zwitterion 10a to the primary
product 7a is typically formulated as a supramolecular [1,4] hydrogen shift ([1,4-H]) but there
have been also suggestions that the rearrangement occurs by two consecutive suprafacial [1,2]
migrations ([1,2-H]) which would lead to the same result. Subsequent epimerization of product
7a to the cis-product 8a is clearly an ionic reaction, which is promoted by acid presumably via an
enol intermediate.
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Scheme 5. Mechanistic Picture of the [6] Photocyclization
O
H
H
[1,4-H]
6a*
7a
8a
N
O
O
10a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In order to shed some light on the nature of the photoexcited state 6a* that undergoes the
photocyclization, its detailed mechanism, as well as on the subsequent hydrogen shift (leading to
7
a), quantum chemical calculations using density functional theory (DFT) as well as linear-
response time-dependent DFT (TDDFT) were performed as implemented into Q-Chem 5.0.14 In
a first step, the equilibrium geometry of the substrate 6a was optimized at the theoretical level of
DFT/B3LYP/6-31G*,15 which is by no means planar, but instead the π-systems of the bond-
forming carbon atoms face each other with an interatomic distance of 3.5 Å (cf. Figures 1 and 2).
To understand the light-activated photocyclization, i.e. the C-C bond formation, the energetically
lowest excited electronic singlet and triplet states were computed at the theoretical level of
16
TDDFT using the long-range corrected CAM-B3LYP exchange-correlation functional and the
6
-31G* basis set.17 CAM-B3LYP has turned out recently18 to yield accurate results for the
excitation energies of the relevant S , S , T and T states and also for charge-transfer excited
1
2
1
2
states of organic compounds. Since the state order does not change when exchange-functionals
with varying amounts of non-local orbital exchange are used, 6a and its photocyclization can thus
be reliably described with TDDFT.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. Frontier molecular orbitals of 6a.
The lowest excited singlet S state exhibits a computed excitation energy of 3.83 eV at
1
TDDFT/CAM-B3LYP level and practically no oscillator strength. In the single-particle picture,
this state is well represented by a HOMO-1 to LUMO transition (Figure 1), and its character is
mostly of nπ* type. However, due to the non-planarity of 6a the n-orbital of the carbonyl oxygen
mixes with the π-system of the adjacent benzene ring to the HOMO-1. The S state is found at
2
4
.91 eV with a substantial oscillator strength of 0.31. This state corresponds to the peak in the
experimental absorption spectrum observed at 280 nm and is the HOMO-LUMO transition with
essentially ππ* excitation character (Figure 1).
For the photocyclization to proceed the energetically low-lying triplet states are relevant and it is
expected that the presence of triplet quenchers reduces the experimental reaction yield
substantially (vide infra). Since singlet-triplet intersystem crossing (ISC) is usually slower than
internal conversion, ISC will occur at the relaxed equilibrium geometry of the S state. At this
1
geometry, optimized at the TDDFT/CAM-B3LYP level, the nπ* S state exhibits an excitation
1
energy of 3.2 eV corresponding to a fluorescence wavelength of 387 nm. The overall geometrical
structure of 6a does not change, in particular, the relevant C-C distance of the bond forming
coordinate is not altered.
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The lowest triplet state T has an excitation energy 2.66 eV and has the same electronic structure
1
as S , i.e. it is the same nπ* state. Interestingly, at 2.76 eV the T state is found, which has the
1
2
same electronic structure as S , i.e. being represented as HOMO-LUMO transition with ππ*
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
character (Figure 1). This energetic ordering allows for efficient ISC according to El Sayed's
rules,19 which predicts a high ISC rate for S (nπ*) → T (ππ*). Having arrived in the triplet
1
2
excitation manifold the excited molecules with decay further via internal conversion, and the
photocyclization reaction proceeds in T1.
Starting at the T equilibrium structure of 6a we have computed the minimum energy reaction
1
pathway for the photocyclization reaction by using unrestricted Kohn-Sham DFT in combination
2
0
with the B3LYP functional with D3 dispersion correction and the 6-31G* basis set. Only the
distance between the C-C bond forming atoms has been constrained and all other geometrical
parameters were allowed to relax freely along the path. Following this approach, an energy
barrier of only 27.9 kJ/mol has been found for the photocyclization reaction, which considering
the thermal excess excitation energy of 42.5 kJ/mol after ISC is readily accessible. For
comparison, the energy barrier for photocyclization has also been computed in the singlet S0
ground state as well as the first singlet excited state S and much higher energy barriers have been
1
found with values of 256 kJ/mol and 120 kJ/mol, respectively. Hence, the photocyclization
clearly proceeds in the T state, in particular, as in addition the intermediate photoproduct 10a is
1
2
0 kJ/mol more stable in the triplet state than 6a at the theoretical level of DFT/B3LYP.
After ylide 10a is formed the molecule arrives most likely at the electronic ground state before
undergoing a terminal hydrogen shift to form the trans-product 7a. To answer the question
whether the hydrogen shift occurs via one [1,4] or two consecutive [1,2] shifts, both pathways
were computed at the theoretical level of DFT-D3/B3LYP. In both computations only the
distance between the transferred hydrogen and the acceptor carbon atom was constrained and all
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1
1
1
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
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5
5
5
5
6
other parameters were freely optimized along the reaction path. According to these calculations,
the hydrogen shift clearly occurs via a [1,4] mechanism, since the energy barrier exhibits only
43.2 kJ/mol, while the [1,2] shift would require 178 kJ/mol. The [1,4] hydrogen shift is in
addition largely exothermic with a computed reaction energy of 282 kJ/mol. The [1,4] shift is
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1
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7
8
9
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7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
also unlikely to occur in the triplet T state, since an energy barrier of at least 213 kJ/mol was
1
computed at DFT-D3/B3LYP level.
Figure 2. Computation-based reaction pathway for the photocyclization of 6a. After excitation of
6
a internal conversion and intersystem crossing lead to the equilibrium structure of the T state.
1
In the T state photocyclization takes place (black curve) to yield 10a. After return to the ground
1
state [1,4] hydrogen shift takes place (blue curve). Barrier heights and reaction energies are given
in kJ/mol relative to the substrate of the reaction.
The calculated reaction course via a triplet intermediate T was further substantiated by
1
quenching experiments. The reactions were performed qualitatively by adding a triplet quencher
to the reaction mixture and monitoring the reaction yield after a reaction time of 3 h. The reaction
in the absence of a quencher had led to a complete conversion and to formation of product 8a in
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8% yield (vide supra). Addition of 5 and 10 equiv of trans-piperylene to the reaction mixture
led under standard irradiation conditions to a significant rate reduction and furnished only 63%
and 51% of 8a, respectively (Scheme 6). Unreacted starting material was recovered indicating
that the triplet quencher reduces the reaction rate and it was also seen that a higher quencher
concentration correlates with a lower reaction rate. Further studies to completely suppress the
reaction by increasing the piperylene concentration were not performed.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Qualitative Triplet Quenching Experiments with trans-Piperylene.
O
O
i) h ( = 366 nm), [20 mM]
H
N
piperylene, (CH Cl ) rt, 3 h
2
2
N
ii) Epimerization on silica
H
O
O
O
O
6a
8a
5
eq of piperylene
63% (25% rsm)
51% (35% rsm)
10 eq of piperylene
The fate of the migrating hydrogen atom was studied via the deuterium-labeled enaminone 6j-d5
2
2
which was synthesized from aniline-d using standard reaction conditions (Scheme 2). After an
5
1
irradiation time of 3 h, H NMR spectra revealed the presence of 7j-d and 7j-d in a ratio of
5
4
8
4:16 when the reaction was carried out in dichloromethane. In deuterated dichloromethane
(
CD Cl ) the ratio increased further to 91:9 (Scheme 7). The finding provides evidence for a
2
2
suprafacial [1,4] hydrogen migration after conrotatory ring closure. It is not completely clear,
though, why the deuterium incorporation is not complete but the result with deuterated
dichloromethane seems to indicate that the zwitterion 10a is at least partially protonated by the
solvent or by a deuterated acid component in the solvent. There was no evidence for deuterium
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
23
incorporation at the -position to the carbonyl group which makes it unlikely that successive
[
1,2] hydrogen atom migrations have occurred. This result is also in line with the calculations.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Experiment with Deuterium Labeled Tertiary Enaminone 6j-d5
O
O
O
D5
D4
D4
h
H
N
H
N
( = 366 nm)
N
[
20 mM],
rt, 3 h
D
H
O
O
O
O
O
O
6
j-d5
7j-d5
7j-d4
CH Cl
84:16
91:9
2
2
Ratio by 1H-NMR
CD Cl
2
2
Additional Transformations. While an acid mediated epimerization of trans-compound 7a was
confirmed earlier (cf. Table 1) base mediated epimerization reactions have also been reported in
7
the literature (Scheme 1). Following literature conditions the solvent was evaporated after
irradiation of compound 6a and the residue was dissolved in THF under argon followed by
o
addition of NaH (1.05 equiv) at 0 C. After 15 min, upon quenching the enolate with water, the
expected cis-hexahydrocarbazol-4-one 8a could surprisingly not be detected but a new spot was
visible on TLC. Careful NMR analysis of the isolated compound and a single crystal X-ray
analysis revealed that the product was C4a-hydroxy-cis-hexahydrocarbazol-4-one 11a. The
compound is likely formed by diastereoselective oxygenation of the enolate upon exposure of the
basic solution to air.24 The different reactivity profile of the N-alkoxycarbonyl substituted
photoproducts compared to the previously reported N-alkyl photoproducts (Scheme 1) is evident
by this transformation. Further optimization of the oxygenation revealed that catalytic sodium
hydroxide (20 mol%) under air was sufficient to perform the transformation and the desired
product 11a was isolated in 75% yield (Scheme 8). The perfect diastereoselectivity of the
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tranformation is due to the convex shape of the intermediate enolate and it was expected that
other transformations would also proceed diastereoselectively. Indeed, reduction of the carbonyl
group with sodium borohydride produced alcohol 12a as a single diastereoisomer in an excellent
yield of 93%. Grignard addition also worked with complete diastereoselectivity to furnish the
addition product 13a in 70% yield. Enolate formation with sodium hydride and quenching with
methyl iodide produced C4a-methylated cis-hexahydrocarbazol-4-one 14a in 70% yield. All
these transformations from compound 8a give rise to indolines with additional substituents with a
potential for being used in the synthesis of libraries of biologically interesting indoline
compounds.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 8. Further Diastereoselective Transformations of cis-Hexahydrocarbazol-4-one 8a.
O
NaOH 0.2 eq
0.1 M in water)
HO
(
Air balloon,
THF) rt, 20 h
N
(
H
O
O
11a, 75%
OH
H
H
NaBH (1.1 eq)
4
(
MeOH)
N
o
H

78 C, 16 h
O
O
O
H
N
12a, 93%
OH
H
H
N
O
O
EtMgBr (1.3 eq)
8a
o
(
Et O) 20 C
H
2
O
O
13a, 70%
O
Me
N
i) NaH (1.1 eq)
o
(THF) 0 C, 15 min
H
ii) MeI (1.2 eq)
O
O
14a, 70%
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CONCLUSION
In summary, the introduction of an acceptor substitution, namely alkoxy- and aryloxycarbonyl, at
the nitrogen atom of N-aryl-β-enaminones allowed to isolate stable cis-products from the [6]
photocyclization reaction after column purification. The labile trans-products could be identified
as intermediates but epimerized rapidly on silica. The mechanism of the reaction could be
elucidated and further diastereoselective transformations were performed which illustrate the
potential of the [6] photocyclization products. Indeed, one direction of future research relates to
total synthetic applications of the reaction. Another intriguing aspect of the N-alkoxycarbony-N-
aryl--enaminones is their strong response to Lewis acid coordination which might enable
enantioselective transformations with chiral Lewis acids.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
General Methods:
Air and moisture sensitive reactions were carried out in oven-dried glassware sealed with rubber
septa under a positive pressure of dry argon. Irradiation experiments were conducted in a
photochemical reactor equipped with 16 fluorescence lamps (λmax = 366 nm). Dry
tetrahydrofuran (THF), dichloromethane (CH Cl ), and diethyl ether (Et O) were obtained from a
2
2
2
solvent purification system. Other dry solvents, e.g. methanol (MeOH), were obtained in the
highest purity available stored over molecular sieves. Solvents for photoreactions were degassed
via freeze-pump-thaw method and stored over molecular sieves under inert atmosphere.
Analytical thin layer chromatography (TLC) was performed on silica gel 60 (F ) glass plates.
254
The TLC plates were visualized by either ultraviolet (UV) light (λ = 254 nm) or treatment with
KMnO stain followed by gentle heating. Purification of products was accomplished by flash
4
chromatography on silica gel 60 (230-400 mesh). All solvents for chromatography, e.g. ethyl
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acetate (EtOAc), were distilled prior to use. NMR spectra were measured on either a 300, or a
4
00 or a 500 MHz nuclear magnetic resonance spectrometer. The NMR spectra were calibrated
1
13
1
against the residual solvent e.g. chloroform ( H NMR: δ = 7.26 ppm, C{ H} NMR: δ = 77.16
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
ppm). Data for H NMR spectra were reported as follows: chemical shift in parts per million
(ppm), peak shape (s = singlet, d = dublet, t = triplet, q = quartet, quin = quintet, h = sextet, m =
multiplet, br = broad, virt = virtual), coupling constant in Hertz (Hz), and integration. Infrared
spectra were recorded by attenuated total reflection (ATR) technique and are reported as wave
–1
numbers ṽ (cm ). High resolution mass spectrometry (HRMS) were performed by electrospray
ionization (ESI) on a linear ion trap instrument with a Fourier transform ion cyclotron resonance
detector. UV/Vis spectra were recorded on a Lambda 35 UV/Vis spectrometer using a precision
cell made of quartz with a pathway of 1 mm.
General experimental procedure for the synthesis of 5a-m: A mixture of the 1,3-
cyclohexanedione (1.0 equiv), aniline (1.0 equiv) and Yb(OTf) (2 mol%) in dry acetonitrile (0.5
3
mL/mmol) was stirred at room temperature for overnight under argon. After completion of the
reaction as indicated by thin-layer chromatography (100% EtOAc) the mixture was diluted by
dichloromethane (5 mL/mmol). Insoluble catalyst removed by filtration followed by evaporation
of volatiles under reduced pressure furnished residue which was triturated in pentane and EtOAc
(v/v = 3:1). Filtration, washing with pentane and drying afforded 5a-m.
3
-(Phenylamino)cyclohex-2-en-1-one (5a). According to the general procedure, compound 5a
was synthesized starting from 1,3-cyclohexanedione (3.00 g, 26.80 mmol, 1.0 equiv) and aniline
o
(2.44 mL, 26.8 mmol, 1.0 equiv). Yellow solid (4.66 g, 93%), m.p. 177-179 C. TLC: R = 0.30
f
1
(
EtOAc) [UV]. H NMR (500 MHz, DMSO-d ): δ 8.83 (s, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.18-
6
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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7
.11 (m, 3H), 5.31 (s, 1H), 2.51-2.49 (m, 2H), 2.16 (t, J = 6.4 Hz, 2H), 1.91-1.86 (m, 2H).
1
3
1
C{ H} NMR (100 MHz, DMSO-d ): δ 195.7, 161.9, 139.1, 129.1, 124.3, 123.0, 98.0, 36.4,
6
-1
28.5, 21.5. IR (ATR): ṽ (cm ) = 3258, 3065, 1590, 1567, 1518, 752, 702. MS (ESI): m/z (%) =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
1
88 (100) [(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 188.1075; found = 188.1069.
12 14
Data of this compound were in accordance with those reported in literature.11
3-[(4-Methoxyphenyl)amino]cyclohex-2-en-1-one (5b). According to the general procedure,
compound 5b was synthesized starting from 1,3-cyclohexanedione (1.82 g, 16.24 mmol, 1.0
equiv) and 4-methoxyaniline (2.00 g, 16.24 mmol, 1.0 equiv). Off white solid (3.42 g, 97%), m.p.
o
1
165-167 C. TLC: R = 0.24 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ 8.67 (s, 1H), 7.10
f
6
(virt d, J = 8.9 Hz, 2H), 6.95 (virt d, J = 8.9 Hz, 2H), 5.10 (s, 1H), 3.75 (s, 3H), 2.52-2.45 (m,
1
3
1
2
H), 2.16-2.11 (m, 2H), 1.89-1.85 (m, 2H). C{ H} NMR (75 MHz, DMSO-d ): δ 195.2, 162.9,
6
-1
156.4, 131.63, 125.3, 114.3, 97.0, 55.2, 36.4, 28.3, 21.6. IR (ATR): ṽ (cm ) = 3212, 3030, 2943,
+
1
568, 1504, 1237, 802, 714. MS (ESI): m/z (%) = 218 (100) [(M+H) ]. HRMS (ESI): calc. for
+
C H NO [(M+H) ] = 218.1183; found = 218.1175. Data of this compound were in accordance
1
3
16
2
with those reported in literature.11
5
,5-Dimethyl-3-(phenylamino)cyclohex-2-en-1-one (5c). According to the general procedure,
compound 5c was synthesized starting from 5,5-dimethyl-1,3-cyclohexanedione (1.00 g, 7.14
mmol, 1.0 equiv) and aniline (652 µL, 7.14 mmol, 1.0 equiv). White solid (1.51 g, 98%), m.p.
o
1
1
7
81-183 C. TLC: R = 0.60 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ 8.78 (s, 1H),
f 6
.40-7.34 (m, 2H), 7.19-7.10 (m, 3H), 5.32 (s, 1H), 2.38 (s, 2H), 2.05 (s, 2H), 1.02 (s, 6H).
1
3
1
C{ H} NMR (75 MHz, DMSO-d ): δ 195.3, 160.0, 139.1, 129.1, 124.2, 122.9, 96.7, 50.1, 42.0,
6
-1
3
2.2, 27.9. IR (ATR): ṽ (cm ) = 3234, 3063, 2960, 1566, 1510, 1242, 1148, 765, 704. MS (ESI):
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+
m/z (%) = 216 (100) [(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 216.1388; found =
1
4
18
2
16.1382. Data of this compound were in accordance with those reported in literature.25
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
1
2
3
4
5
6
7
8
9
0
3
-{[3-(tert-Butyl)phenyl]amino}cyclohex-2-en-1-one (5d). According to the general procedure,
compound 5d was synthesized starting from 1,3-cyclohexanedione (368 mg, 3.29 mmol, 1.0
equiv) and 3-(tert-butyl)aniline (490 mg, 3.29 mmol, 1.0 equiv). White solid (702 mg, 86%),
o
1
m.p. 177-179 C. TLC: R = 0.46 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ 8.84 (s, 1H),
f
6
7
2
.30 (t, J = 8.0 Hz, 1H), 7.18-7.15 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H) 5.31 (s, 1H), 2.51-2.48 (m,
1
3
1
H), 2.16 (t, J = 6.1 Hz, 2H), 1.90-1.86 (m, 2H), 1.27 (s, 9H). C{ H} NMR (75 MHz, DMSO-
d6): δ 195.6, 162.0, 151.8, 138.7, 128.8, 121.3, 120.1, 120.0, 97.8, 36.4, 34.4, 31.0, 28.5, 21.5. IR
-1
(
ATR): ṽ (cm ) = 3257, 2956, 1583, 1536, 1485, 1246, 1183, 793, 703. MS (ESI): m/z (%) = 244
+
+
(
100) [(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 244.1701; found = 244.1695.
1
6
22
3
-(Phenylamino)cyclopent-2-en-1-one (5e). According to the general procedure, compound 5e
was synthesized starting from 1,3-cyclopentanedione (350 mg, 3.57 mmol, 1.0 equiv) and aniline
o
(
326 µL, 3.57 mmol, 1.0 equiv). White solid (610 mg, 98%), m.p. 222-224 C. TLC: R = 0.22
f
1
(EtOAc) [UV]. H NMR (400 MHz, DMSO-d ): δ 9.57 (s, 1H), 7.37-7.33 (m, 2H), 7.19 (d, J =
6
7
.9 Hz, 2H), 7.09-7.06 (m, 1H), 5.41 (s, 1H), 2.73-2.70 (m, 2H), 2.24-2.21 (m, 2H).
1
3
1
C{ H} NMR (100 MHz, DMSO-d ): δ 203.9, 171.8, 140.4, 129.2, 123.4, 119.9, 100.9, 32.8,
6
-1
28.4. IR (ATR): ṽ (cm ) = 2990, 2950, 1738, 1704, 1598, 1481, 1443, 1276, 1055, 755. MS
+
+
(
ESI): m/z (%) = 174 (100) [(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 174.0919;
11 12
found = 174.0913.
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6
3
-[(4-Bromophenyl)amino]-5,5-dimethylcyclohex-2-en-1-one (5f). According to the general
procedure, compound 5f was synthesized starting from 5,5-dimethyl-1,3-cyclohexanedione (800
mg, 5.70 mmol, 1.0 equiv) and 4-Bromoaniline (981 mg, 5.70 mmol, 1.0 equiv). White solid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
(1.52 g, 89%), m.p. 217-219 C. TLC: R = 0.63 (EtOAc) [UV]. H NMR (400 MHz, DMSO-d ):
f
6
δ 8.84 (s, 1H), 7.52 (virt d, J = 8.6 Hz, 2H), 7.15 (virt d, J = 8.6 Hz, 2H), 5.35 (s, 1H), 2.38 (s,
H), 2.07 (s, 2H), 1.03 (s, 6H). 13C{ H} NMR (100 MHz, DMSO-d ): δ 195.6, 159.3, 138.7,
1
2
6
-1
132.0, 124.5, 115.8, 97.3, 50.1, 42.0, 32.2, 27.9. IR (ATR): ṽ (cm ) = 3239, 3172, 2957, 1568,
+
+
1
401, 1147, 807, 718 MS (ESI): m/z (%) = 335 (15) [(M+H+MeCN) ], 294 (100) [(M+H) ].
+
HRMS (ESI): calc. for C H BrNO [(M+H) ] = 294.0494; found = 294.0487. Data of this
1
4
17
compound were in accordance with those reported in literature.25
4
-[(5,5-Dimethyl-3-oxocyclohex-1-en-1-yl)amino]benzonitrile (5g). According to the general
procedure, compound 5g was synthesized starting from 5,5-dimethyl-1,3-cyclohexanedione (1.13
g, 8.06 mmol, 1.0 equiv) and 4-aminobenzonitrile (952 mg, 8.06 mmol, 1.0 equiv). White solid
o
1
(1.90 g, 98%), m.p. 214-216 C. TLC: R = 0.62 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ):
f
6
δ 9.14 (s, 1H), 7.80-7.77 (m, 2H), 7.34-7.32 (m, 2H), 5.58 (s, 1H), 2.42 (s, 2H), 2.12 (s, 2H), 1.03
1
3
1
(s, 6H). C{ H} NMR (75 MHz, DMSO-d ): δ 196.3, 157.8, 144.1, 133.5, 121.2, 118.9, 101.6,
6
-1
1
1
00.0, 50.0, 42.1, 32.25, 27.8. IR (ATR): ṽ (cm ) = 3260, 3185, 3101, 2957, 2226, 1606, 1573,
+
510, 1243, 831, 717. MS (ESI): m/z (%) = 341 (65) [(M+H+NH +2MeCN) ], 282 (25)
4
+
+
+
[(M+H+MeCN) ], 241 (100) [(M+H) ]. HRMS (ESI): calc. for C H N O [(M+H) ] =
1
5
17
2
2
41.1341; found = 241.1335. Data of this compound were in accordance with those reported in
literature.26
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-[(4-Hydroxyphenyl)amino]cyclohex-2-en-1-one (5h). According to the general procedure,
compound 5h was synthesized starting from 1,3-cyclohexanedione (978 mg, 8.73 mmol, 1.0
equiv) and 4-hydroxyaniline (952 mg, 8.73 mmol, 1.0 equiv). Off white solid (1.77 g, 98%), m.p.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
2
08-210 C. TLC: R = 0.24 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ 9.45 (s, 1H), 8.58
f 6
(s, 1H), 6.97 (virt d, J = 8.6 Hz, 2H), 6.77 (virt d, J = 8.6 Hz, 2H), 5.04 (s, 1H), 2.47-2.43 (m,
1
3
1
2
H), 2.14-2.10 (m, 2H), 1.90-1.82 (m, 2H). C{ H} NMR (75 MHz, DMSO-d ): δ 195.1, 163.3,
6
-1
154.8, 129.9, 125.6, 115.6, 96.8, 36.4, 28.3, 21.6. IR (ATR): ṽ (cm ) = 3216, 3058, 2943, 2800,
+
1
491, 1232, 1185, 819, 716. MS (ESI): m/z (%) = 245 (10) [(M+H+MeCN) ], 204 (100)
+
+
[(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 204.1025; found = 204.1019. Data of
12 14 2
this compound were in accordance with those reported in literature.25
3
-[(5-Methylpyridin-2-yl)amino]cyclohex-2-en-1-one (5i). To a solution of 5-methyl-2-
aminopyridine (500 mg, 4.63 mmol, 1.0 equiv) in toluene (20 mL) at room temperature were
added 1,3-cyclohexanedione (648 mg, 5.78 mmol, 1.25 equiv) and p-toluene sulfonic acid
monohydrate (176 mg, 0.93 mmol, 0.2 equiv).27 Reaction mixture was refluxed for 5 h and
complete conversion was confirmed by thin-layer chromatography (methanol/EtOAc 5:95).
Reaction mixture treated with 5% aqueous NaHCO3 (30 mL) and extracted with
dichloromethance (40 mL x 3). Combined organic layers dried over anhydrous sodium sulfate
and evaporated under reduced pressure to obtain residue which was dry loaded on silica gel
column chromatography and purified (methanol/EtOAc 1:50). Compound 5i was isolated as light
o
1
yellow solid (625 mg, 67%), m.p. 159-151 C. TLC: R = 0.30 (EtOAc) [UV]. H NMR (300
f
MHz, DMSO-d ): δ 9.16 (s, 1H), 813-8.12 (m, 1H), 7.53 (ddd, J = 8.4, 2.4, 0.5 Hz, 1H), 6.95 (d,
6
J = 8.4 Hz, 1H), 6.73 (s, 1H), 2.55-2.50 (m, 2H), 2.22-2.16 (m, 5H), 1.95-1.86 (m, 2H).
1
3
1
C{ H} NMR (75 MHz, DMSO-d ): δ 197.2, 158.2, 152.0, 147.0, 138.4, 126.2, 113.4, 104.0,
6
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
3
6.4, 28.7, 21.6, 17.2. IR (ATR): ṽ (cm ) = 3287, 3197, 2934, 1574, 1475, 1284, 1137, 827, 738.
+
+
MS (ESI): m/z (%) = 203 (100) [(M+H) ]. HRMS (ESI): calc. for C H N O [(M+H) ] =
1
2
15
2
203.1184; found = 203.1178. Data of this compound were in accordance with those reported in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
literature.27
3
-(Naphthalen-1-ylamino)cyclohex-2-en-1-one (5j). According to the general procedure,
compound 5j was synthesized starting from 1,3-cyclohexanedione (785 mg, 7.00 mmol, 1.0
equiv) and 1-naphthylamine (1.00 g, 7.00 mmol, 1.0 equiv). Light yellow solid (1.52 g, 92%),
o
1
m.p. 182-184 C. TLC: R = 0.35 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ 9.02 (s, 1H),
f
6
8.01-7.87 (m, 3H), 7.59-7.53 (m, 3H), 7.40 (d, J = 7.3 Hz, 1H), 4.67 (s, 1H), 2.69-2.65 (m, 2H),
.18-2.13 (m, 2H), 1.99-1.91 (m, 2H). 13C{ H} NMR (75 MHz, DMSO-d ): δ 195.1, 164.6,
1
2
6
1
34.6, 134.0, 129.0, 128.2, 126.6, 126.3, 126.3, 125.7, 124.0, 122.9, 98.0, 36.4, 28.0, 21.6. IR
-1
(ATR): ṽ (cm ) = 3235, 3029, 1564, 1514, 1246, 1184, 1140, 774. MS (ESI): m/z (%) = 238
+
+
(
100) [(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 238.1232; found = 238.1226.
16 16
Data of this compound were in accordance with those reported in literature.28
3-(Quinolin-8-ylamino)cyclohex-2-en-1-one (5k). According to the procedure used for 5i,
compound 5k was synthesized starting from 1,3-cyclohexanedione (353 mg, 3.15 mmol, 1.0
equiv) and 8-aminoquinoline (500 mg, 3.47 mmol, 1.1 equiv). Light brown solid (566 mg, 68%),
o
1
m.p. 117-119 C. TLC: R = 0.35 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ 9.05 (s, 1H),
f
6
8
2
.94 (dd, J = 4.2, 1.7 Hz, 1H), 8.42 (dd, J = 8.3, 1.7 Hz, 1H), 7.75-7.58 (m, 4H), 5.60 (s, 1H),
1
3
1
.72 (t, J = 6.1 Hz, 2H), 2.25-2.21 (m, 2H), 1.99-1.90 (m, 2H). C{ H} NMR (75 MHz, DMSO-
d6): δ 196.2, 161.1, 149.3, 140.5, 136.5, 135.4, 128.5, 126.6, 123.0, 122.2, 120.3, 100.0, 36.4,
-1
2
8.9, 21.6. IR (ATR): ṽ (cm ) = 3171, 3003, 2945, 1587, 1530, 1322, 1244, 1186, 792, 767. MS
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+
+
(
ESI): m/z (%) = 239 (100) [(M+H) ]. HRMS (ESI): calc. for C H N O [(M+H) ] = 239.1184;
1
5
15
2
found = 239.1178. Data of this compound were in accordance with those reported in literature.29
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
-[(2-Fluorophenyl)amino]-5,5-dimethylcyclohex-2-en-1-one (5l). According to the general
procedure, compound 5l was synthesized starting from 5,5-dimethyl-1,3-cyclohexanedione (1.20
g, 8.57 mmol, 1.0 equiv) and 2-fluoroaniline (827 µL, 8.57 mmol, 1.0 equiv). White solid (1.89
o
1
g, 94%), m.p. 139-141 C. TLC: R = 0.67 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ
f
6
8
.65 (s, 1H), 7.35-7.23 (m, 4H), 4.86 (s, 1H), 2.40 (s, 2H), 2.05 (s, 2H), 1.03 (s, 6H).
1
3
1
C{ H} NMR (75 MHz, DMSO-d ): δ 195.1, 161.2, 156.0 (d, J = 247 Hz), 127.6 (d, J = 1.5 Hz),
6
127.5 (d, J = 7.7 Hz), 126.2 (d, J = 12.3 Hz), 124.9 (d, J = 3.6 Hz), 116.4 (d, J = 19.7 Hz), 97.0,
-1
5
0.1, 41.4, 32.4, 27.9. IR (ATR): ṽ (cm ) = 3235, 3052, 2961, 1572, 1491, 1227, 1146, 757, 682.
+
+
MS (ESI): m/z (%) = 234 (100) [(M+H) ] HRMS (ESI): calc. for C H FNO [(M+H) ] =
1
4
17
234.1294; found = 234.1288. Data of this compound were in accordance with those reported in
literature.30
3
-[(2,3,4,5-Tetrafluorophenyl)amino]cyclohex-2-en-1-one (5m). According to the general
procedure, compound 5m was synthesized starting from 1,3-cyclohexanedione (1.36 g, 12.12
mmol, 1.0 equiv) and 2,3,4,5-tetrafluoroaniline (2.00 g, 12.12 mmol, 1.0 equiv). Off white solid
o
1
(
2.85 g, 91%), m.p. 184-186 C. TLC: R = 0.50 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ):
f
6
δ 8.84 (s, 1H), 7.44-7.34 (m, 1H), 4.97 (s, 1H), 2.53-2.49 (m, 2H) 2.20-2.15 (m, 2H), 1.94-1.86
13
1
(
m, 2H). C{ H} NMR (75 MHz, DMSO-d ): δ 195.9, 162.2, 147.8-144.3 (m), 143.7-140.2 (m),
6
1
42.6-139.4 (m), 138.8-135.8 (m), 123.4 (m), 109.5 (dd, J = 20.5, 2.1 Hz), 99.7, 36.3, 27.7, 21.4.
-1
IR (ATR): ṽ (cm ) = 3205, 3059, 2962, 1573, 1518, 1488, 1187, 1135, 1063, 949, 715. MS
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3
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5
5
5
5
5
5
5
6
+
+
(
ESI): m/z (%) = 301 (60) [(M+H+MeCN) ], 260 (100) [(M+H) ]. HRMS (ESI): calc. for
+
C H F NO [(M+H) ] = 260.0699; found = 260.0692.
1
2
10 4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
1
2
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6
7
8
9
0
3
-[(Phenyl-d )amino]cyclohex-2-en-1-one (5a-d ). According to the general procedure,
5 5
compound 5a-d was synthesized starting from 1,3-cyclohexanedione (343 mg, 3.06 mmol, 1.0
5
equiv) and aniline-d (279 µL, 3.06 mmol, 1.0 equiv). Yellow solid (555 mg, 94%), m.p. 177-179
5
o
1
C. TLC: R = 0.30 (EtOAc) [UV]. H NMR (300 MHz, DMSO-d ): δ 8.82 (s, 1H), 5.31 (s, 1H),
f
6
13
1
2
1
.51-2.49 (m, 2H), 2.19-2.14 (m, 2H), 1.93-1.85 (m, 2H). C{ H} NMR (75 MHz, DMSO-d ): δ
6
95.7, 161.8, 138.9, 128.5 (t, J = 25.0 Hz), 122.9-122.2 (m), 97.9, 36.4, 28.5, 21.5. IR (ATR): ṽ
-1
+
(cm ) = 3258, 3065, 1590, 1567, 1518, 752, 702. MS (ESI): m/z (%) = 193 (100) [(M+H) ].
1
2
+
HRMS (ESI): calc. for C H H NO [(M+H) ] = 193.1389; found = 193.1383.
1
2
9
5
General experimental procedure for the synthesis of 6 (Procedure A): To a solution of 5 (1.0
equiv) in tetrahydrofuran (5 mL/mmol) was added n-butyllithium (2.5 M in hexane, 1.03 equiv)
o
dropwise at 78 C and stirred at this temperature for 20 min. Chloroformate (1.2 equiv) added
o
dropwise followed by stirring for 1 h at 78 C temperature was allowed to rise to room
temperature. After completion of the reaction as indicated by thin-layer chromatography (100%
EtOAc) the solvent was removed under reduced pressure and the residue was dissolved in
dichloromethane (20 mL/mmol). Washed with water (50 mL) and brine (50 mL), dried over
anhydrous sodium sulfate and evaporated to obtain residue. Column chromatographic
purification (dry loading, pentane/EtOAc eluent system) afforded tertiary enaminones 6.
General experimental procedure for the synthesis of 6 (Procedure B): To a solution of 5 (1.0
equiv) in anhydrous acetonitrile (5 mL/mmol) was added dimethylaminopyridine (10 mol%) and
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7
8
9
o
di-tert-butyl dicarbonate (1.5 equiv) at 0 C and mixture stirred at this temperature for 15 min.
Temperature allowed to rise to room temperature and mixture stirred for overnight. After
completion of the reaction as indicated by thin-layer chromatography (100% EtOAc) the solvent
was removed under reduced pressure and the residue was dissolved in dichloromethane (20
mL/mmol). Washing with water (50 mL) and brine (50 mL) followed by drying on sodium
sulfate and evaporation of volatiles afforded residue. Column chromatographic purification (dry
loading, pentane/EtOAc eluent system) afforded tertiary enaminones 6.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methyl N-(3-oxocyclohex-1-en-1-yl)-N-(phenyl)carbamate (6a). According to the general
procedure A, compound 6a was synthesized starting from 5a (4.00 g, 21.36 mmol, 1.0 equiv) and
methylchloroformate (1.98 mL, 25.63 mmol, 1.2 equiv). Column chromatographic purification
(
SiO , pentane/EtOAc 1:1, UV) afforded the product as white solid (4.20 g, 80%), m.p. 100-102
2
o
1
C. TLC: R = 0.53 (pentane/EtOAc 1:1) [UV]. H NMR (300 MHz, CDCl ): δ 7.44-7.32 (m,
f
3
3
1
1
H), 7.14-7.10 (m, 2H), 5.45 (s, 1H), 3.70 (s, 3H), 2.85-2.80 (m, 2H), 2.38-2.34 (m, 2H), 2.07-
1
3
1
.98 (m, 2H). C{ H} NMR (75 MHz, CDCl ): δ 199.2, 162.2, 153.9, 139.8, 129.6, 128.2, 128.0,
3
-1
17.4, 53.6, 36.7, 29.3, 22.8. IR (ATR): ṽ (cm ) = 2955, 1717, 1656, 1590, 1439, 1292, 1237,
+
+
760, 706. MS (ESI): m/z (%) = 246 (100) [(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ]
1
4
16
3
=
246.1130; found = 246.1124.
Allyl N-(3-oxocyclohex-1-en-1-yl)-N-(phenyl)carbamate (6b). According to the general
procedure A, compound 6b was synthesized starting from 5a (1.00 g, 5.34 mmol, 1.0 equiv) and
allyl chloroformate (681 µL, 6.41 mmol, 1.2 equiv). Column chromatographic purification (SiO2,
pentane/EtOAc 1:1, UV) afforded the product as oil (978 mg, 67%). TLC: R = 0.24
f
1
(
pentane/EtOAc 4:1) [UV]. H NMR (300 MHz, CDCl ): δ 7.44-7.32 (m, 3H), 7.15-7.11 (m,
3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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5
5
5
5
5
5
5
5
6
2
H), 5.80 (ddt, J = 17.1, 10.6, 5.3 Hz, 1H), 5.46 (s, 1H), 5.16-5.05 (m, 2H), 4.59 (dt, J = 5.3, 1.5
Hz, 2H), 2.86-2.81 (m, 2H), 2.39-2.34 (m, 2H), 2.07-1.98 (m, 2H). 13C{ H} NMR (75 MHz,
1
CDCl ): δ 199.3, 162.4, 153.2, 139.9, 131.6, 129.7, 128.4, 128.2, 118.1, 117.5, 67.1, 36.8, 29.4,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
2
2
2
2.9. IR (ATR): ṽ (cm ) = 2949, 1722, 1654, 1586, 1233, 1192, 760, 705. MS (ESI): m/z (%) =
+
+
72 (100) [(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 272.1287; found =
1
6
18
3
72.1280.
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl N-(3-oxocyclohex-1-en-1-yl)-N-(phenyl)carba-
mate (6c). According to the general procedure A, compound 6c was synthesized starting from 5a
(0.50 g, 2.67 mmol, 1.0 equiv) and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl
carbonochloridate (687 µL, 3.20 mmol, 1.2 equiv). Column chromatographic purification (SiO2,
pentane/EtOAc 2:1, UV) afforded the product as white solid (730 mg, 74%). TLC: R = 0.55
f
1
(pentane/EtOAc 4:1) [UV]. H NMR (300 MHz, CDCl ): δ 7.42-7.30 (m, 3H), 7.11-7.06 (m,
3
2
1
0
H), 5.39 (s, 1H), 4.56 (td, J = 10.7, 4.3 Hz, 1H), 2.88-2.84 (m, 2H), 2.38-2.34 (m, 2H), 2.09-
.98 (m, 3H), 1.65-1.55 (m, 3H), 1.51-1.38 (m, 1H), 1.16-1.06 (m, 1H), 1.04-0.93 (m, 1H), 0.91-
1
3
1
.84 (m, 4H), 0.82-0.71 (m, 7H). C{ H} NMR (75 MHz, CDCl ): δ 199.4, 162.8, 153.2, 140.0,
3
129.6, 128.2, 128.2, 116.5, 46.9, 40.8, 36.8, 34.1, 31.4, 29.5, 26.3, 23.4, 23.0, 22.0, 20.7, 16.4. IR
-1
(ATR): ṽ (cm ) = 2950, 2928, 2869, 1721, 1652, 1584, 1241, 1203, 971, 760, 704. MS (ESI): m/z
+
+
+
(%) = 433 (20) [(M+Na+MeCN) ], 370 (40) [(M+H) ], 188 (100) [(M-C H O +2H) ]. HRMS
1
1
19
2
+
(ESI): calc. for C H NO [(M+H) ] = 370.2382; found = 370.2376.
2
3
32
3
(9H-Fluoren-9-yl)methyl N-(4-methoxyphenyl)-N-(3-oxocyclohex-1-en-1-yl)carbamate (6d).
According to the general procedure A, compound 6d was synthesized starting from 5b (0.50 g,
2
.3 mmol, 1.0 equiv) and (9H-fluoren-9-yl)methyl carbonochloridate (714 mg, 2.76 mmol, 1.2
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equiv). Column chromatographic purification (SiO , pentane/EtOAc 1:1, UV) afforded the
2
1
product as white solid (836 mg, 83%). TLC: R = 0.13 (pentane/EtOAc 4:1) [UV]. H NMR (300
f
MHz, CDCl ): δ 7.69 (virt d, J = 7.5 Hz, 2H), 7.38-7.33 (m, 2H), 7.19 (td, J = 7.4, 1.1 Hz, 2H),
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1
.14-7.11 (m, 2H), 6.99-6.88 (m, 4H), 5.42 (s, 1H), 4.43 (d, J = 6.7 Hz, 2H), 4.03 (t, J = 6.6 Hz,
1
3
1
H), 3.87 (s, 3H), 2.79-2.75 (m, 2H), 2.35-2.31 (m, 2H), 2.01-1.93 (m, 2H). C{ H} NMR (75
MHz, CDCl ): δ 199.4, 162.7, 159.4, 153.5, 143.3, 141.3, 132.3, 129.3, 127.8, 127.0, 124.9,
3
-1
120.0, 116.4, 115.0, 68.2, 55.7, 46.8, 36.7, 29.2, 22.9. IR (ATR): ṽ (cm ) = 2950, 1723, 1648,
+
1
586, 1508, 1236, 1192, 738. MS (ESI): m/z (%) = 901 (10) [(2M+Na) ], 503 (10)
+
+
+
[
(M+Na+MeCN) ], 440 (15) [(M+H) ], 218 (100) [(M-C H O +2H) ]. HRMS (ESI): calc. for
15 11 2
+
C H NO [(M+H) ] = 440.1862; found = 440.1854.
2
8
26
4
Phenyl N-(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)-N-(phenyl)carbamate (6e). According to
the general procedure A, compound 6e was synthesized starting from 5c (0.50 g, 2.32 mmol, 1.0
equiv) and phenylchloroformate (350 µL, 2.79 mmol, 1.2 equiv). Column chromatographic
purification (SiO , pentane/EtOAc 3:1, UV) afforded the product as white solid (606 mg, 78%),
2
o
1
m.p. 90-92 C. TLC: R = 0.46 (pentane/EtOAc 4:1) [UV]. H NMR (300 MHz, CDCl ): δ 7.48-
f
3
7.41 (m, 2H), 7.40-7.30 (m, 3H), 7.26-7.17 (m, 3H), 7.07-7.03 (m, 2H), 5.51 (s, 1H), 2.79 (s,
13
1
2
1
H), 2.24 (s, 2H), 1.10 (s, 6H). C{ H} NMR (75 MHz, CDCl ): δ 199.3, 160.4, 152.0, 150.6,
3
-1
40.0, 129.9, 129.5, 128.6, 128.0, 126.1, 121.3, 118.2, 50.6, 43.2, 34.0, 28.2. IR (ATR): ṽ (cm )
= 2960, 1735, 1651, 1593, 1434, 1266, 1197, 744, 704. MS (ESI): m/z (%) = 336 (100)
+
+
[
(M+H) ]. HRMS (ESI): calc. for C H NO [(M+H) ] = 336.1600; found = 336.1594.
21 22 3
Benzyl N-(3-oxocyclohex-1-en-1-yl)-N-(phenyl)carbamate (6f). According to the general
procedure A, compound 6f was synthesized starting from 5a (0.30 g, 1.60 mmol, 1.0 equiv) and
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