A convenient conversion of substituted cyclohexenones into aryl methyl ketones

Article abstract of DOI:10.1055/s-0032-1316560

This work describes a straightforward multistep conversion of substrates containing a cyclohexenone moiety into mono-, bi- and tricyclic aryl methyl ketones in one single working process. Crucial steps are the addition of 1-ethoxyvinyllithium to the carbonyl group, followed by acid-catalyzed enol ether hydrolysis, dehydration, and dehydrogenation. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316560

PAPER
▌2441
paper
A Convenient Conversion of Substituted Cyclohexenones into Aryl Methyl
Ketones
Conversion of Cyclohexenones into Aryl Methyl Ketones
André P. Gehring, Franz Bracher*
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377 Munich, Germany
Fax +49(89)218077802; E-mail: franz.bracher@cup.uni-muenchen.de
Received: 19.04.2012; Accepted after revision: 22.05.2012
for the synthesis of substituted carbazoles, has been pub-
Abstract: This work describes a straightforward multistep conver-
lished in the last few decades, but these modern protocols
sion of substrates containing a cyclohexenone moiety into mono-,
have not found application in the synthesis of 1-acylcar-
bi- and tricyclic aryl methyl ketones in one single working process.
Crucial steps are the addition of 1-ethoxyvinyllithium to the carbon-
bazoles. Classical approaches to 2 by either AlCl3-medi-
yl group, followed by acid-catalyzed enol ether hydrolysis, dehy- ated Fries rearrangement12 or photo-Fries rearrangement13
dration, and dehydrogenation.
of N-acetylcarbazole are hampered by the formation of
mixtures of products (carbazole, 1-, 3-, and 4-acetylcarba-
zole, and diacetylcarbazoles) that are difficult to separate.
Base-induced fragmentations of pyrido[3,2,1-jk]carb-
azolones14 leading to 1-acylcarbazoles require starting
materials that are not commercially available and do not
always allow complete control of the regioselectivity.
Key words: ketones, acetyl anion equivalents, vinyl ether, carba-
zole, aromatization
The alkaloid 1-acetyl-β-carboline (1; Figure 1) has been
isolated from plants (e.g., Ailanthus malabarica,1 Lycium
chinense2), sponges (Tedania ignis3), and microorganisms
(Streptomyces species4), and it has been used by our group
as a versatile intermediate for the synthesis of the β-carbo-
line alkaloids annomontine, nitramarine, and 1-(1-hy-
droxyethyl)-β-carboline,5 as well as the canthin-4-one
alkaloid norisotuboflavine.6
These observations prompted us to investigate new ap-
proaches to 1-acetylcarbazole (2) and substituted deriva-
tives thereof. Compound 2 was easily obtained in the
manner we had previously used to synthesize 1-acetyl-β-
carboline (1).5 In this approach, 1-bromocarbazole (3),
which is easily obtained by Fischer reaction of cyclohex-
anone and 2-bromophenylhydrazine, followed by dehy-
drogenation of the crude tetrahydrocarbazole with
chloranil,15 was subjected to a Stille coupling with 1-eth-
oxyvinyl tributylstannane catalyzed by [PdCl2(Ph3P)2],
and the resulting enol ether was directly hydrolyzed to the
methyl ketone 2 in 61% overall yield (Scheme 1). This
protocol was suitable for the synthesis of large amounts of
the parent 1-acetylcarbazole (2), but, due to the fact that
ring C was aromatized in the penultimate step of the se-
quence, the approach did not allow for the controlled in-
troduction of additional substituents in this ring.
In previous investigations we developed approaches to 1-
acetyl-β-carboline (1) and other 1-acyl-β-carbolines using
techniques such as Stille cross-coupling,5 Minisci-type
homolytic acylation,6,7 Grignard addition to 1-cyano-β-
carboline,8 and trapping of a 1,9-dimetalated β-carboline
with electrophiles.9
N
N
H
N
H
O
O
2
1
OEt
Figure 1 Structures of 1-acetyl-β-carboline (1) and 1-acetylcarba-
zole (2)
1.
, PdCl2(Ph3P)2
SnBu3
2. HCl, H2O
2
Due to the close structural relationship between β-carbo-
lines and carbazoles, and the interesting pharmacological
activities of naturally occurring carbazole alkaloids,10 we
intended to synthesize carbazole analogues of the alka-
loids mentioned above. For this purpose we needed an ef-
ficient synthetic approach to 1-acetylcarbazole (2) and
ring-substituted analogues thereof as the central interme-
diates. Extensive work, mainly using iron-, molybdenum-
and palladium-mediated ring construction techniques11
N
H
Br
3
Scheme 1
Therefore, we worked out an alternative, more flexible ap-
proach to 1-acetylcarbazoles that is characterized by the
addition of 1-ethoxyvinyllithium (4) to 1-oxo-1,2,3,4-tet-
rahydrocarbazoles, followed by a sequence of enol ether
hydrolysis, dehydration, and dehydrogenation, to give the
target methyl ketones in one single operation without the
need for purification of intermediates.
SYNTHESIS 2012, 44, 2441–2447
Advanced online publication: 29.06.2012
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0
3
9
-
7
8
8
1
1
4
3
7
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2
1
0
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DOI: 10.1055/s-0032-1316560; Art ID: SS-2012-T0375-OP
© Georg Thieme Verlag Stuttgart · New York

2442
A. P. Gehring, F. Bracher
PAPER
1-Ethoxyvinyllithium (4) is readily prepared in situ by di- plished by the concentrated sulfuric acid in combination
rect metalation of ethyl vinyl ether with tert-butyllithium, with air. Finally, we found that it is even more effective
and can be regarded as an acetyl anion equivalent. Its and higher-yielding to perform the addition and aromati-
preparation and nucleophilic addition to benzaldehyde, zation steps without purification of the intermediate α-hy-
followed by hydrolysis to an α-hydroxyketone was de- droxyketones. After the first, mild hydrolysis step, the
scribed by Schöllkopf in 1972,16 and later Baldwin et al. lipophilic components were simply extracted with ethyl
reported analogous additions of 1-methoxyvinyllithium to acetate and, after evaporation of the solvent, the residue
ketones.17 The reactivity of metalated vinyl ethers has was treated with the mixture of acetic and sulfuric acids.
been reviewed,18 but until now only a limited number of In this way the 1-acetylcarbazoles 2 and 8–10 were ob-
examples of their addition to ketones are known. Few oth- tained in a single working process in 33–40% yield from
er methods for the conversion of ketones into α-hydroxy the ketones 6a–d (Scheme 2).
methyl ketones are known. 1-Tetralones have been con-
It should be pointed out that this new approach is compat-
verted into trimethylsilyl cyanohydrins, further reacted
ible with halogen substituents on the ring system, which
with methylmagnesium chloride or methyllithium, and
opens an approach to halogenated 1-acetylcarbazoles that
then hydrolyzed and dehydrated to 1-acetyl-3,4-dihydro-
would not be accessible by the Stille cross-coupling ap-
tetralines.19 Alternatively, lithium acetylide was added to
proach described above due to competing reactions in-
ketones, and the resulting acetylenic carbinols were con-
volving the halogen substituents.
verted into methyl ketones under mercury catalysis20 or by
heating to reflux with formic acid in a Rupe rearrange-
1. KOH
2. ArN2
3. HCOOH
ment.21 However, to the best of our knowledge, neither of
R1
+
these methodologies has been extended to the synthesis of
aryl methyl ketones.
O
R2
N
[GP 1]
H
R3
O
O
OEt
1-Oxo-1,2,3,4-tetrahydrocarbazole (6a) as well as its 6-
bromo-,22 6-iodo-,23 and 7,8-dichloro derivatives 6b–d
were obtained under standard conditions by Japp–
Klingemann reaction of ethyl 2-oxocyclohexanecarboxyl-
ate (5) with appropriate arenediazonium chlorides (pre-
pared in situ by diazotization of the anilines) to give
hydrazones, followed by Fischer cyclization with anhy-
drous formic acid.24 For the introduction of the acetyl
group and subsequent aromatization, we first developed a
two-step protocol. Thus, freshly prepared 1-ethoxyvinyl-
lithium (4) in tetrahydrofuran (THF) was cooled to
–35 °C, tetrahydrocarbazolone 6a was added slowly, and
the mixture was allowed to come to ambient temperature.
Mild hydrolysis with dilute hydrochloric acid gave the α-
hydroxyketone 7a in 74% yield after chromatography.
The substituted analogues 7b–d were obtained in the same
manner (Scheme 2). In order to obtain the target 1-acetyl-
carbazoles, there was a need to dehydrate the intermediate
α-hydroxyketones 7a–d and then to dehydrogenate the re-
sulting 3,4-dihydrocarbazoles. After exploring a number
of acids for the dehydration and oxidants (MnO2, KMnO4)
for in situ or subsequent dehydrogenation, we found that
best results were obtained by simply heating the interme-
diates 7a–d in a mixture of glacial acetic acid and concen-
trated sulfuric acid (5:1) at 75 °C for 30 minutes. The 1-
acetylcarbazoles 2 and 8–10 were obtained in yields of ap-
proximately 30%, usually accompanied by small amounts
(up to 10%) of the corresponding 1-acetyl-1,2,3,4-tetrahy-
drocarbazoles, as exemplified by the isolation and charac-
terization of the products 11 and 12. Clearly, these by-
products arise from partial disproportionation of the inter-
mediate dihydrocarbazoles, but addition of dehydrogena-
tion agents such as MnO2 did not change the product
distribution significantly. From a systematic investigation
of combinations of reagents and reaction conditions, we
deduced that the predominant dehydrogenation is accom-
5
6a R1 = R2 = R3 = H
6b R1 = Br, R2 = R3 = H
6c R1 = I, R2 = R3 = H
6d R1 = H, R2 = R3 = Cl
OEt
Li
1.
4
R1
R2
2. HCl, H2O, MeOH
6a–d
[GP 2]
N
OH
H
R3
O
7a R1 = R2 = R3 = H
7b R1 = Br, R2 = R3 = H
7c R1 = I, R2 = R3 = H
7d R1 = H, R2 = R3 = Cl
[GP 4]
[GP 3]
AcOH,
H2SO4
R1
R2
R1
+
R2
N
N
H
H
R3
R3
O
O
2 R1 = R2 = R3 = H
8 R1 = Br, R2 = R3 = H
9 R1 = I, R2 = R3 = H
11 R1 = Br, R2 = R3 = H
12 R1 = R1 = H, R2 = R3 = Cl
10 R1 = H, R2 = R3 = Cl
Scheme 2
To explore whether this protocol represents a general new
method for the synthesis of aryl methyl ketones, we react-
ed other substrates containing cyclohexenone partial
structures in the same manner.
6-Methoxy-1-tetralone (13) gave, after treatment with 1-
ethoxyvinyllithium (4) and hydrolysis with dilute hydro-
chloric acid, dihydronaphthaline 14,25 which was aroma-
tized with the mixture of acetic and sulfuric acids to give
Synthesis 2012, 44, 2441–2447
© Georg Thieme Verlag Stuttgart · New York

PAPER
Conversion of Cyclohexenones into Aryl Methyl Ketones
2443
acetylnaphthaline 15.26 Once again it was more effective
to perform both steps without purification of the interme-
diate, and 15 was obtained in 20% overall yield in this
way. In contrast, 2-tetralone failed to give the expected
methyl ketone, however, this is in accordance with obser-
vations of Smith et al.,27 who tried to add 1-methoxyvinyl-
lithium to 2-tetralones without success. 3,5-
Dimethylacetophenone (17)28 was obtained from 3,5-di-
methylcyclohex-2-en-1-one (16) in the same manner in
18% yield. The analogous reaction of carvone (18) gave
the isopropyl-substituted acetophenone 1929 in 29% yield.
In this latter reaction, it is apparent that the isomerization
of the double bond of the isopropenyl substituent into the
ring is more advantageous than the dehydrogenation step
(Scheme 3).
Palo Alto, USA). High-resolution mass spectra (HRMS) were ob-
tained with a Jeol JMS GCmate II (Jeol, Peabody, USA). IR spectra
were recorded as KBr discs or films on NaCl plates with Perkin
Elmer FT-IR Paragon 1000 (Perkin Elmer, Waltham, USA) or Jasco
FT/IR-410 (Jasco, Easton, USA) spectrophotometers. Melting
points were determined with a Büchi B-540 apparatus (Büchi,
Flawil, Switzerland) and are uncorrected. Elemental analyses were
performed with a CHN-Elementaranalysator Rapid (Heraeus,
Hanau, Germany) or Elementaranalysator Vario EL (Elementar,
Hanau, Germany). Purification by flash column chromatography
(FCC) was performed using Silica gel 60 (Merck, Darmstadt, Ger-
many). HPLC purities were obtained with a HP Agilent 1100 HPLC
equipped with a diode array detector (Agilent Technologies, Wald-
bronn, Germany) and an Agilent Poroshell column (120 EC-C18,
3.0 × 100 mm, 2.7 μm); the mobile phase consisted of MeCN–
H2O–THF–1 M NaOH (850:150:10:2); flow rate 0.7 mL/min; con-
stant temperature 45 °C; monitored at 210 nm (band width 4 nm);
injection volume 10 μL of a dilution of 100 μg/mL (sample in mo-
bile phase).
O
O
All chemicals were purchased from Sigma–Aldrich, Fluka or
Acros. PE = petroleum ether (bp 80–110 °C); EDMA = N-ethyl-
N,N-dimethylamine.
[GP 2]
MeO
MeO
Preparation of 1-(9H-Carbazol-1-yl)ethanone (2) by Stille
Cross-Coupling
13
14
A solution of 1-bromocarbazole15 (3; 523 mg, 2.10 mmol), 1-eth-
oxyvinyl tributylstannane (950 mg, 3.00 mmol), and [PdCl2(Ph3P)2]
(75 mg, 0.11 mmol) in toluene (20 mL) was heated at reflux for
13 h. After this time, 2 M HCl (3.0 mL) was added and the mixture
was heated at reflux for a further 2 h. Upon cooling to ambient tem-
perature, the mixture was extracted with EtOAc (3 × 40 mL), and
the combined organic layers were dried over Na2SO4 and the sol-
vents evaporated. The residue was purified by FCC (hexane–
EtOAc, 4:1).
[GP 3]
[GP 4]
O
MeO
15
O
Yield: 0.27 g (1.28 mmol, 61%); yellow powder; mp 131–133 °C
(Lit.13b 130–131 °C).
O
[GP 4]
IR (KBr): 3424, 3054, 1648, 1570, 1491, 1455, 1342, 1323, 1261,
1221, 1200, 1132, 1010, 964, 749, 731, 682, 640, 598, 499 cm–1.
16
17
1H NMR (500 MHz, CD2Cl2): δ = 10.62 (br s, 1 H, 9-H), 8.31 (d,
J = 7.6 Hz, 1 H, 4-H), 8.11 (dd, J = 7.9, 1.2 Hz, 1 H, 5-H), 8.00 (dd,
J = 7.7, 1.0 Hz, 1 H, 2-H), 7.56 (dt, J = 8.1, 0.9 Hz, 1 H, 8-H), 7.47
(ddd, J = 8.2, 7.1, 1.2 Hz, 1 H, 7-H), 7.29 (t, J = 7.7 Hz, 1 H, 3-H),
7.28 (ddd, J = 8.1, 7.1, 1.0 Hz, 1 H, 6-H), 2.73 (s, 3 H, 2′-H).
O
O
[GP 4]
13C NMR (125 MHz, CD2Cl2): δ = 200.6 (C=O), 140.4 (C-8a),
139.4 (C-9a), 128.4 (C-2), 126.9 (C-7), 126.3 (C-4), 125.2 (C-4a),
122.4 (C-4b), 120.7 (C-5), 120.5 (C-6), 119.8 (C-1), 118.7 (C-3),
111.7 (C-8), 27.0 (C-2′).
19
18
Scheme 3
MS (EI, 70 eV): m/z (%) = 209 (95) [M+·], 194 (100), 166 (50), 139
(25), 70 (10).
In conclusion, we have developed a straightforward mul-
tistep methodology for converting substrates containing a
cyclohexenone moiety into aryl methyl ketones in one sin-
gle working process. Although the yields are only moder-
ate, this protocol should be attractive for the preparation
of building blocks that are otherwise accessible only in
multistep procedures. Moreover, this approach gives
methyl ketones with complete and predictable regioselec-
tivity, thus competing favorably with classical Friedel–
Crafts chemistry.
HRMS (EI): m/z [M+] calcd for C14H11NO: 209.0841; found:
209.0867.
Preparation of 2,3,4,9-Tetrahydro-1H-carbazol-1-ones; Gener-
al Procedure (GP 1)
A mixture of ethyl 2-oxocyclohexanecarboxylate (26 mL, 164
mmol) and KOH (11.6 g, 207 mmol) in H2O (100 mL) was stirred
at 30 °C for 4 h and then cooled to 0 °C. In a separate flask, a solu-
tion of the appropriate aniline (150 mmol) in H2O (300 mL) and
concd HCl (33 mL) was cooled to 0 °C before NaNO2 (14.4 g, 209
mmol) was added in small portions. The mixture was stirred at 0 °C
for 1 h, then urea (10 g) was added and the solution was neutralized
with sat. aq NaHCO3 and stirred until gas evolution ceased. Both so-
lutions were then combined, immediately acidified with glacial ace-
tic acid (25 mL) and stirred at r.t. overnight. The resulting
precipitate was collected by filtration, then dissolved in anhydrous
formic acid (300 mL) and stirred at 80 °C for 12 h. The formic acid
was evaporated and the residue was treated with aq NaOH (2 M,
NMR spectra were recorded with a Jeol JNMR-GSX 400 or a Jeol
JNMR-GSX 500 (Jeol, Peabody, USA); chemical shifts are given in
ppm, coupling constants (J) in hertz. Mass spectra (EI, 70 eV) were
recorded with a Hewlett Packard 5989 A mass spectrometer with a
59980 B Particle Beam LC/MS-interface (Agilent Technologies,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2441–2447

2444
A. P. Gehring, F. Bracher
PAPER
100 mL) and extracted with EtOAc (3 × 100 mL). The combined or-
ganic layers were dried over Na2SO4 and the solvents evaporated.
The residue was crystallized from MeOH–H2O.
(2.65 mmol) in anhydrous THF (10 mL) was added and the mixture
was allowed to come to r.t. in about 2 h. The reaction was quenched
by the addition of 20 mL of a 1:1 mixture of MeOH and 2 M HCl,
and stirred for about 5 min. H2O (30 mL) was added and the mixture
was extracted with EtOAc (3 × 20 mL). The organic layers were
combined and the solvents were evaporated. The residue was dis-
solved in glacial AcOH (10 mL) and H2SO4 (2 mL), stirred at 75 °C
for 30 min, then cooled to r.t. and made alkaline by the addition of
aq NaOH (6 M, 25 mL). After extraction with EtOAc (3 × 20 mL),
the combined organic layers were dried over Na2SO4 and the sol-
vents were evaporated. Purification was accomplished by FCC.
2,3,4,9-Tetrahydro-1H-carbazol-1-one (6a)
Prepared from aniline.
Yield: 13.0 g (70.5 mmol, 47%); brown solid; mp 168–170 °C
(Lit.22 166–168 °C).
6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (6b)
Prepared from 4-bromoaniline.
Yield: 23.7 g (90 mmol, 60%); brown solid; mp 220–222 °C (Lit.22
222–223 °C).
1-(1-Hydroxy-2,3,4,9-tetrahydro-1H-carbazol-1-yl)ethanone
(7a)
Prepared from ketone 6a (GP 2) and purified by FCC (EtOAc–PE–
EDMA, 10:1:0.3).
6-Iodo-2,3,4,9-tetrahydro-1H-carbazol-1-one (6c)
Prepared from 4-iodoaniline.
Yield: 12.1 g (39 mmol, 26%); brown solid; mp 208–210 °C (Lit.23
213–216 °C).
Yield: 449 mg (1.96 mmol, 74%); pale-brown solid; mp 178–
180 °C; HPLC purity: >99%.
IR (KBr): 3425, 3254, 2934, 2842, 2361, 1708, 1654, 1438, 1350,
1310, 1216, 1168, 1143, 1088, 1022, 949, 799, 759, 740, 722, 643,
589, 502 cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 7.90 (br s, 1 H, NH), 7.55 (d, J =
7.9 Hz, 1 H, 5-H), 7.29 (d, J = 8.1 Hz, 1 H, 8-H), 7.17 (t, J = 8.2 Hz,
1 H, 7-H), 7.09 (t, J = 8.0 Hz, 1 H, 6-H), 4.35 (br s, 1 H, OH), 2.95–
2.88 (m, 1 H, 4-H), 2.76–2.67 (m, 1 H, 4-H), 2.20–2.13 (m, 1 H, 2-
H), 2.12 (s, 3 H, 2′-H), 2.11–1.97 (m, 2 H, 3-H), 1.97–1.90 (m, 1 H,
2-H).
13C NMR (100 MHz, CD2Cl2): δ = 210.7 (C=O), 137.0 (C-8a),
131.9 (C-9a), 127.3 (C-4b), 123.2 (C-7), 119.8 (C-6), 119.3 (C-5),
115.4 (C-4a), 111.6 (C-8), 76.6 (C-1), 35.8 (C-2), 24.8 (C-2′), 21.2
(C-4), 20.4 (C-3).
7,8-Dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (6d)
Prepared from 2,3-dichloroaniline.
Yield: 11.4 g (45 mmol, 30%); brown solid; mp 202–204 °C; HPLC
purity: >99%.
IR (KBr): 3420, 3277, 2362, 2344, 1654, 1560, 1458, 1294, 1233,
1121, 907, 807, 799, 788, 669, 570, 481 cm–1.
1H NMR (400 MHz, CD2Cl2): δ = 9.17 (br s, 1 H, NH), 7.53 (d, J =
8.5 Hz, 1 H, 5-H), 7.23 (dd, J = 8.5, 0.7 Hz, 1 H, 6-H), 2.98 (t, J =
6.1 Hz, 2 H, 4-H), 2.64 (t, J = 6.5 Hz, 2 H, 2-H), 2.30–2.22 (m, 2 H,
3-H).
13C NMR (100 MHz, CD2Cl2): δ = 191.2 (C=O), 136.2 (C-8a),
132.7 (C-9a), 130.3 (C-4a), 130.3 (C-7), 126.1 (C-4b), 122.8 (C-6),
120.9 (C-5), 116.4 (C-8), 38.5 (C-2), 25.2 (C-3), 21.7 (C-4).
MS (EI, 70 eV): m/z (%) = 229 (5) [M+·], 186 (100), 168 (10), 144
(10), 130 (10).
MS (EI, 70 eV): m/z (%) = 257 (10), 255 (70), 253 (100) [M+·], 224
(30), 212 (30), 198 (80), 162 (20), 127 (15), 99 (20), 81 (15), 63
(10).
HRMS (EI): m/z [M+] calcd for C14H15NO2: 229.1103; found:
229.1099.
HRMS (EI): m/z [M+] calcd for C12H9Cl2NO: 253.0061; found:
253.0056.
Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C,
73.05; H, 6.34; N, 6.08.
General Procedure 2 (GP 2)
1-(6-Bromo-1-hydroxy-2,3,4,9-tetrahydro-1H-carbazol-1-
yl)ethanone (7b)
Prepared from ketone 6b (GP 2) and purified by FCC (EtOAc–PE–
EDMA, 10:1:0.3).
A solution of ethyl vinyl ether (402 μL, 4.2 mmol) in anhydrous
THF (4 mL) under a nitrogen atmosphere was cooled to –65 °C, and
t-BuLi (1.6 M in pentane, 3.2 mL, 5.1 mmol) was added dropwise.
The reaction mixture was allowed to warm to –20 °C while stirring,
and then cooled to –35 °C. A solution of the cyclic ketone (2.65
mmol) in anhydrous THF (10 mL) was added slowly and the mix-
ture was allowed to come to r.t. in about 2 h. The reaction was
quenched by the addition of 20 mL of a 1:1 mixture of MeOH and
2 M HCl, and stirred for about 5 min. H2O (30 mL) was added and
the mixture was extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried over Na2SO4 and the solvents were evap-
orated. Purification was accomplished by FCC.
Yield: 490 mg (1.59 mmol, 60%); pale-brown solid; mp 158–
160 °C; HPLC purity: >99%.
IR (KBr): 3422, 3247, 2930, 2838, 2362, 2343, 1869, 1711, 1654,
1559, 1438, 1355, 1303, 1269, 1212, 1166, 1090, 1048, 1021, 950,
899, 852, 800, 719, 648, 518 cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 7.91 (br s, 1 H, NH), 7.59 (s, 1 H,
5-H), 7.18 (d, J = 8.6, 1 H, 7-H), 7.10 (d, J = 8.6, 1 H, 8-H), 4.28 (br
s, 1 H, OH), 2.82–2.74 (m, 1 H, 4-H), 2.64–2.56 (m, 1 H, 4-H),
2.11–2.06 (m, 1 H, 2-H), 2.04 (s, 3 H, 2′-H), 2.03–1.89 (m, 2 H, 3-
H), 1.88–1.82 (m, 1 H, 2-H).
13C NMR (100 MHz, CD2Cl2): δ = 210.4 (C=O), 135.6 (C-8a),
133.4 (C-9a), 129.1 (C-4b), 125.9 (C-7), 122.0 (C-5), 115.1 (C-4a),
113.2 (C-8), 112.9 (C-6), 76.5 (C-1), 35.7 (C-2), 24.9 (C-2), 21.1
(C-4), 20.4 (C-3).
General Procedure 3 (GP 3)
The product of general procedure 2 (0.65 mmol), either α-hy-
droxyketone or enone, was dissolved in a mixture of glacial AcOH
(5 mL) and concd H2SO4 (1 mL). The mixture was stirred at 75 °C
for 30 min, then cooled to r.t. and made alkaline by the addition of
aq NaOH (6 M, 25 mL). After extraction with EtOAc (3 × 20 mL),
the combined organic layers were dried over Na2SO4 and the sol-
vents were evaporated. Purification was accomplished by FCC.
MS (EI, 70 eV): m/z (%) = 309 [M+·] (10), 307 (10), 266 (100), 264
(100), 185 (10), 183 (10), 167 (15), 157 (15), 129 (10).
HRMS (EI): m/z [M+] calcd for C14H14BrNO2: 307.0208; found:
307.0211.
General Procedure 4 (GP 4)
A mixture of ethyl vinyl ether (402 μL, 4.2 mmol) in anhydrous
THF (4 mL) under a nitrogen atmosphere was cooled to –65 °C, be-
fore t-BuLi (1.6 M in pentane, 3.2 mL, 5.1 mmol) was added drop-
wise. The reaction mixture was allowed to warm to –20 °C while
stirring, and cooled again to –35 °C. A solution of the cyclic ketone
Anal. Calcd for C14H14BrNO2: C, 54.56; H, 4.58; N, 4.55. Found: C,
54.27; H, 4.72; N, 4.27.
Synthesis 2012, 44, 2441–2447
© Georg Thieme Verlag Stuttgart · New York

PAPER
Conversion of Cyclohexenones into Aryl Methyl Ketones
2445
1-(1-Hydroxy-6-iodo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)eth-
13C NMR (125 MHz, CD2Cl2): δ = 200.5 (C=O), 139.6 (C-9a),
139.0 (C-8a), 129.5 (C-7), 129.1 (C-2), 126.5 (C-4), 124.1 (C-4b),
124.0 (C-4a), 123.5 (C-5), 120.1 (C-1), 119.1 (C-3), 113.3 (C-8),
113.2 (C-6), 26.9 (C-2′).
anone (7c)
Prepared from ketone 6c (GP 2) and purified by FCC (PE–EtOAc–
EDMA, 6:3:0.1).
MS (EI, 70 eV): m/z (%) = 289 [M+·] (100), 287 (95), 274 (55), 272
(55), 246 (30), 244 (30), 165 (30), 137 (15), 83 (15), 69 (10).
Yield: 593 mg (1.67 mmol, 63%); yellow solid; mp 148–150 °C;
HPLC purity: >99%.
HRMS (EI): m/z [M+] calcd for C14H10BrNO: 286.9946; found:
286.9957.
IR (KBr): 3437, 3270, 2926, 2361, 1708, 1637, 1438, 1271, 1165,
1092, 1020, 799, 597 cm–1.
1H NMR (400 MHz, CD2Cl2): δ = 8.05 (br s, 1 H, NH), 7.89 (s, 1 H,
5-H), 7.42 (d, J = 8.5 Hz, 1 H, 7-H), 7.08 (d, J = 8.5 Hz, 1 H, 8-H),
4.34 (br s, 1 H, OH), 2.90–2.82 (m, 1 H, 4-H), 2.71–2.63 (m, 1 H,
4-H), 2.18–2.12 (m, 1 H, 2-H), 2.11 (s, 3 H, 2′-H), 2.10–1.98 (m,
2 H, 3-H), 1.96–1.91 (m, 1 H, 2-H).
13C NMR (100 MHz, CD2Cl2): δ = 210.4 (C=O), 136.1 (C-8a),
133.0 (C-9a), 131.4 (C-7), 129.9 (C-4b), 128.4 (C-5), 114.8 (C-4a),
113.7 (C-8), 83.0 (C-6), 76.4 (C-1), 35.7 (C-2), 24.9 (C-2), 21.1 (C-
4), 20.4 (C-3).
MS (EI, 70 eV): m/z (%) = 355 (5) [M+·], 312 (100), 185 (10), 83
(10), 55 (10).
HRMS (EI): m/z [M+] calcd for C14H14INO2: 355.0070; found:
355.0052.
1-(6-Iodo-9H-carbazol-1-yl)ethanone (9)
Purified by FCC (CH2Cl2).
Overall yield from 6c via 7c (GP 2 and GP 3): 160 mg (0.48 mmol,
18%). Yield from 7c (GP 4): 302 mg (0.9 mmol, 34%); yellow sol-
id; mp 199–201 °C; HPLC purity: 89%.
IR (KBr): 3421, 2924, 2363, 1654, 1637, 1618, 1560, 1508, 1458,
1261, 1100, 805, 788, 668 cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 10.63 (br s, 1 H, NH), 8.42 (s,
1 H, 5-H), 8.24 (d, J = 7.7 Hz, 1 H, 4-H), 8.02 (d, J = 7.8 Hz, 1 H,
2-H), 7.72 (d, J = 8.5 Hz, 1 H, 7-H), 7.35 (d, J = 8.5 Hz, 1 H, 8-H),
7.30 (t, J = 7.7 Hz, 1 H, 3-H), 2.73 (s, 3 H, 2′-H).
13C NMR (100 MHz, CD2Cl2): δ = 200.6 (C=O), 139.5 (C-8a),
139.3 (C-9a), 135.1 (C-7), 129.7 (C-5), 129.1 (C-2), 126.5 (C-4),
125.0 (C-4b), 123.9 (C-4a), 120.0 (C-1), 119.2 (C-3), 113.8 (C-8),
82.9 (C-6), 27.0 (C-2′).
MS (EI, 70 eV): m/z (%) = 335 (100) [M+·], 320 (55), 292 (30), 209
(35), 194 (40), 166 (20), 139 (20), 83 (10), 57 (30).
HRMS (EI): m/z [M+] calcd for C14H10INO: 334.9807; found:
334.9799.
1-(7,8-Dichloro-1-hydroxy-2,3,4,9-tetrahydro-1H-carbazol-1-
yl)ethanone (7d)
Prepared from ketone 6d (GP 2) and purified by FCC (CH2Cl2–
EtOAc–Et2NH, 9:1:0.1).
Yield: 173 mg (0.58 mmol, 22%); brown solid; mp 114–116 °C.
IR (KBr): 3321, 2940, 2843, 2358, 1709, 1618, 1450, 1357, 1227,
1160, 1095, 907, 798, 756 cm–1.
1H NMR (400 MHz, CD2Cl2): δ = 8.23 (br s, 1 H, NH), 7.40 (d, J =
8.4 Hz, 1 H, 5-H), 7.16 (d, J = 8.4 Hz, 1 H, 6-H), 4.43 (br s, 1 H,
OH), 2.95–2.86 (m, 1 H, 4-H), 2.76–2.65 (m, 1 H, 4-H), 2.33–2.16
(m, 1 H, 2-H), 2.15 (s, 3 H, 2′-H), 2.14–2.02 (m, 2 H, 3-H), 1.98–
1.91 (m, 1 H, 2-H).
1-(7,8-Dichloro-9H-carbazol-1-yl)ethanone (10)
Purified by FCC (CH2Cl2).
Overall yield from 6d via 7d (GP 2 and GP 3): 58 mg (0.21 mmol,
8%). Yield from 7d (GP 4): 260 mg (0.93 mmol, 35%); yellow sol-
id; mp 133–135 °C; HPLC purity: >99%.
13C NMR (100 MHz, CD2Cl2): δ = 210.2 (C=O), 135.1 (C-8a),
133.6 (C-9a), 127.2 (C-4b), 126.5 (C-7), 121.8 (C-6), 118.5 (C-5),
116.9 (C-4a), 115.4 (C-8), 76.6 (C-1), 35.8 (C-2), 24.9 (C-2), 21.2
(C-4), 20.2 (C-3).
MS (EI, 70 eV): m/z (%) = 299 [M+·] (5), 297 (5), 258 (10), 256
(65), 254 (100), 219 (10), 217 (10), 200 (10), 55 (10).
IR (KBr): 3426, 2923, 2360, 2341, 1654, 1587, 1496, 1427, 1373,
1307, 1270, 1213, 1160, 1122, 921, 779, 742, 669, 628, 568, 516,
410 cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 10.62 (br s, 1 H, NH), 8.24 (dd,
J = 7.7, 1.0 Hz, 1 H, 4-H), 8.02 (dd, J = 7.7, 1.0 Hz, 1 H, 2-H), 7.90
(d, J = 8.3 Hz, 1 H, 5-H), 7.34 (d, J = 8.3 Hz, 1 H, 6-H), 7.34 (t, J =
7.7 Hz, 1 H, 3-H), 2.74 (s, 3 H, 2′-H).
13C NMR (100 MHz, CD2Cl2): δ = 200.4 (C=O), 139.3 (C-9a),
138.6 (C-8a), 130.0 (C-7), 129.1 (C-2), 126.7 (C-4), 124.9 (C-4a),
122.3 (C-4b), 122.2 (C-6), 120.4 (C-1), 120.0 (C-3), 119.7 (C-5),
115.1 (C-8), 27.0 (C-2′).
HRMS (EI): m/z [M+] calcd for C14H13Cl2NO2: 297.0323; found:
297.0337.
Anal. Calcd for C14H13Cl2NO2: C, 56.40; H, 4.39; N, 4.70. Found:
C, 56.26; H, 4.63; N, 4.50.
MS (EI, 70 eV): m/z (%) = 281 (10), 279 (70) [M+·], 277 (100), 264
(70), 262 (100), 236 (30), 234 (50), 208 (10), 164 (10), 131 (40),
100 (15), 77 (15), 57 (15).
1-(9H-Carbazol-1-yl)ethanone (2)
Overall yield from 6a via 7a (GP 2 and GP 3): 0.58 mmol (22%).
Yield from 6a (GP 4): 0.87 mmol (33%). Analytical data as de-
scribed above.
HRMS (EI): m/z [M+] calcd for C14H9Cl2NO: 277.0061; found:
277.0034.
1-(6-Bromo-9H-carbazol-1-yl)ethanone (8)
Purified by FCC (CH2Cl2–EtOAc, 18:1).
1-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)ethanone (11)
Purified by FCC (CH2Cl2–EtOAc, 18:1). By-product in the synthe-
sis of 8 (eluting after 8).
Overall yield from 6b via 7b (GP 2 and GP 3): 144 mg (0.50 mmol,
19%). Yield from 6b (GP 4): 320 mg (1.1 mmol, 40%); yellow sol-
id; mp 230–231 °C; HPLC purity: >99%.
Overall yield from 6b via 7b (GP 2 and GP 3): 78 mg (0.27 mmol,
10%); orange resinous solid; mp 69–71 °C.
IR (KBr): 3419, 3313, 2360, 1645, 1585, 1492, 1387, 1338, 1297,
1272, 1224, 1197, 1136, 1053, 972, 865, 798, 748, 697, 614, 518
cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 10.65 (br s, 1 H, NH), 8.27 (dd,
J = 7.7, 1.0 Hz, 1 H, 4-H), 8.23 (s, 1 H, 5-H), 8.03 (dd, J = 7.7,
1.0 Hz, 1 H, 2-H), 7.56 (d, J = 8.6 Hz, 1 H, 7-H), 7.45 (d, J = 8.6 Hz,
1 H, 8-H), 7.31 (t, J = 7.7 Hz, 1 H, 3-H), 2.73 (s, 3 H, 2′-H).
IR (CHCl3, film): 3363, 2925, 2853, 2362, 1702, 1654, 1465, 1442,
1356, 1309, 1273, 1234, 1171, 1048, 800 cm–1.
1H NMR (400 MHz, CD2Cl2): δ = 8.45 (br s, 1 H, NH), 7.59 (s, 1 H,
5-H), 7.22–7.19 (m, 2 H, 7-H, 8-H), 3.79 (t, J = 7.4 Hz, 1 H, 1-H),
2.78–2.59 (m, 2 H, 4-H), 2.43–2.31 (m, 1 H, 2-H), 2.25 (s, 3 H, 2′-
H), 2.10–2.02 (m, 1 H, 3-H), 2.02–1.93 (m, 1 H, 2-H), 1.89–1.78
(m, 1 H, 3-H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2441–2447

2446
A. P. Gehring, F. Bracher
PAPER
13C NMR (100 MHz, CD2Cl2): δ = 209.5 (C=O), 135.2 (C-8a),
132.7 (C-9a), 129.4 (C-4b), 124.6 (C-7), 121.1 (C-5), 112.7 (C-8),
112.5 (C-6), 111.9 (C-4a), 48.3 (C-1), 28.2 (C-2´), 27.3 (C-2), 22.6
(C-3), 20.9 (C-4).
13C NMR (100 MHz, CDCl3): δ = 202.2 (C=O), 157.9 (C-6), 135.7
(C-4a), 135.4 (C-1), 132.1 (C-4), 127.9 (C-8), 126.8 (C-2), 125.7
(C-8a), 125.1 (C-3), 120.7 (C-7), 106.5 (C-5), 55.5 (OCH3), 30.1
(C-2′).
MS (EI, 70 eV): m/z (%) = 293 (35) [M+·], 291 (35), 266 (10), 264
MS (EI, 70 eV): m/z (%) = 200 (55) [M+·], 185 (100), 157 (60), 142
(10), 250 (100), 248 (100), 168 (60), 154 (10).
(20), 128 (15), 114 (20), 63 (15).
HRMS (EI): m/z [M+] calcd for C14H14BrNO: 291.0259; found:
HRMS (EI): m/z [M+] calcd for C13H12O2: 200.0837; found:
291.0287.
200.0837.
1-(7,8-Dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)ethanone
(12)
1-(3,5-Dimethylphenyl)ethanone (17)
Purified by FCC (CH2Cl2–PE, 9:1).
Purified by FCC (CH2Cl2). By-product in the synthesis of 10 (elut-
ing after 10).
Yield (GP 4): 71 mg (0.48 mmol, 18%); yellow oil.
IR (CHCl3, film): 3019, 2923, 2400, 1678, 1606, 1426, 1358, 1307,
1216, 855, 756, 668 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.57 (s, 2 H, 2-H, 6-H), 7.20 (s,
1 H, 4-H), 2.58 (s, 3 H, 2′-H), 2.37 (s, 6 H, 2 × CH3).
13C NMR (100 MHz, CDCl3): δ = 198.6 (C=O), 138.1 (C-3, C-5),
137.2 (C-1), 134.7 (C-4), 126.1 (C-2, C-6), 26.7 (C-2′), 21.2
(2 × CH3).
Overall yield from 6d via 7d (GP 2 and GP 3): 22 mg (0.08 mmol,
3%); red-brown resinous solid; mp 94–96 °C.
IR (KBr): 3366, 3269, 2926, 2848, 2356, 1699, 1617, 1452, 1358,
1321, 1261, 1218, 1155, 1116, 1021, 908, 799, 576, 551, 529, 482
cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 8.52 (br s, 1 H, NH), 7.33 (d, J =
8.4 Hz, 1 H, 5-H), 7.14 (d, J = 8.4 Hz, 1 H, 6-H), 3.82 (t, J = 7.1 Hz,
1 H, 1-H), 2.78–2.64 (m, 2 H, 4-H), 2.41–2.31 (m, 1 H, 2-H), 2.27
(s, 3 H, 2′-H), 2.08–2.02 (m, 1 H, 3-H), 2.02–1.98 (m, 1 H, 2-H),
1.88–1.79 (m, 1 H, 3-H).
MS (EI, 70 eV): m/z (%) = 148 (45) [M+·], 133 (100), 105 (80).
HRMS (EI): m/z [M+] calcd for C10H12O: 148.0888; found:
148.0887.
13C NMR (125 MHz, CD2Cl2): δ = 209.0 (C=O), 134.6 (C-8a),
132.9 (C-9a), 127.5 (C-4b), 125.2 (C-7), 121.3 (C-6), 117.8 (C-5),
114.8 (C-8), 113.7 (C-4a), 48.6 (C-1), 28.2 (C-2′), 27.2 (C-2), 22.3
(C-3), 21.0 (C-4).
1-(5-Isopropyl-2-methylphenyl)ethanone (19)
Purified by FCC (CH2Cl2–EtOAc, 18:1).
Yield (GP 4): 136 mg (0.77 mmol, 29%); brown oil.
MS (EI, 70 eV): m/z (%) = 283 (15), 281 (20) [M+·], 240 (60), 238
(100), 203 (35), 167 (10), 57 (10).
IR (CHCl3, film): 3400, 2961, 2927, 2870, 2358, 1683, 1531, 1456,
1354, 1245, 1197, 1066, 1035, 953, 889, 828, 723 cm–1.
HRMS (EI): m/z [M+] calcd for C14H13Cl2NO: 281.0374; found:
281.0356.
1H NMR (500 MHz, CD2Cl2): δ = 7.53 (d, J = 1.9 Hz, 1 H, 6-H),
7.26 (dd, J = 7.8, 1.9 Hz, 1 H, 4-H), 7.16 (d, J = 7.8 Hz, 1 H, 3-H),
2.96–2.88 (m, J = 6.9 Hz, 1 H, CH), 2.55 (s, 3 H, 2′-H), 2.44 (s, 3 H,
CH3), 1.25 (d, J = 6.9, 6 H, 2 × CH3).
13C NMR (125 MHz, CD2Cl2): δ = 202.2 (C=O), 146.8 (C-5), 138.3
(C-1), 135.7 (C-2), 132.2 (C-3), 129.8 (C-4), 127.7 (C-6), 34.1
(CH), 29.8 (C-2′), 24.1 (CH3), 21.1 (2 × CH3).
1-(6-Methoxy-3,4-dihydronaphthalin-1-yl)ethanone (14)
Purified by FCC (hexane–EtOAc, 9:5).
Yield (GP 2): 156 mg (0.77 mmol, 29%); yellow oil.
IR (CHCl3, film): 2999, 2940, 2834, 1671, 1605, 1565, 1495, 1427,
1350, 1303, 1250, 1163, 1124, 1040, 964, 915, 847, 826, 722, 677,
640 cm–1.
MS (EI, 70 eV): m/z (%) = 176 (50) [M+·], 161 (100), 143 (25), 115
(20), 105 (25), 91 (20).
1H NMR (500 MHz, CD2Cl2): δ = 7.68–7.63 (m, 1 H, 8-H), 6.93 (t,
J = 4.9, 1 H, 2-H), 6.74–6.70 (m, 2 H, 5-H, 7-H), 3.79 (s, 3 H,
OCH3), 2.71 (t, J = 7.8 Hz, 2 H, 4-H), 2.42 (s, 3 H, 2´-H), 2.41–2.37
(m, 2 H, 3-H).
HRMS (EI): m/z [M+] calcd for C12H16O: 176.1201; found:
176.1208.
13C NMR (100 MHz, CD2Cl2): δ = 199.6 (C=O), 159.3 (C-6), 139.1
(C-1), 138.7 (C-4a), 138.1 (C-2), 128.4 (C-8), 124.3 (C-8a), 113.8
(C-5), 111.2 (C-7), 55.2 (OCH3), 28.3 (C-4), 27.9 (C-2′), 24.1 (C-3).
Acknowledgment
We thank Andrea Ritter and Benjamin Strödke for support in the
synthesis of intermediates.
MS (EI, 70 eV): m/z (%) = 202 (90) [M+·], 159 (100), 144 (55), 128
(20), 115 (30), 91 (10), 77 (10), 63 (10), 51 (10).
HRMS (EI): m/z [M+] calcd for C13H14O2: 202.0994; found:
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Synthesis 2012, 44, 2441–2447
© Georg Thieme Verlag Stuttgart · New York

PAPER
Conversion of Cyclohexenones into Aryl Methyl Ketones
2447
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2441–2447