Cyclic ketones in spiroannulation

Article abstract of DOI:10.1080/00397910802590936

Conversion of a cyclic carbonyl carbon into a quaternary carbon has been effected by a Wittig-Horner reaction with diethyl (N-benzyliden) aminomethylphosphonate and a subsequent alkylation with a protected vinyl ketone. The product was a substrate for spiroannulation after initial hydrolysis. The reaction sequence was carried out as a one-pot reaction. Copyright Taylor & Francis Group, LLC.

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Cyclic Ketones in
Spiroannulation
a
a
Vidar Bj⊘rnstad & Kjell Undheim
a
Department of Chemistry, University of Oslo, Oslo,
Norway
Published online: 15 Apr 2009.
To cite this article: Vidar Bj⊘rnstad & Kjell Undheim (2009) Cyclic Ketones in
Spiroannulation, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:10, 1793-1800
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Synthetic Communications , 39: 1793–1800, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802590936
Cyclic Ketones in Spiroannulation
Vidar Bjørnstad and Kjell Undheim
Department of Chemistry, University of Oslo, Oslo, Norway
Abstract: Conversion of a cyclic carbonyl carbon into a quaternary carbon
has been effected by a Wittig–Horner reaction with diethyl (N-benzyliden)-
aminomethylphosphonate and a subsequent alkylation with a protected vinyl
ketone. The product was a substrate for spiroannulation after initial hydrolysis.
The reaction sequence was carried out as a one-pot reaction.
Keywords: Addition reactions, carbonyl quaternization, lithiation, spiroannula-
tion, Wittig–Horner reaction
INTRODUCTION
For some time, we have been interested in developing synthetic routes
for ready preparation of spiranes.
[1–6]
The two rings in a spirane are
interconnected through a common ring atom and have an orthogonal
relationship. Spiranes constructed from small- to medium-sized rings
possess a rigid skeleton and confer stiffness onto the structures in which
they are embedded, thereby providing a potentially useful structural
unit for attachment of configurationally highly oriented functional
0
substituents, especially in the a,a -positions next to the spiro center. This
report describes a method for the conversion of a carbonyl carbon in a
cyclic ketone into a quaternary carbon appropriately functionalized for
spiroannulation.
Received September 13, 2008.
Address correspondence to Kjell Undheim, Department of Chemistry,
University of Oslo, N-0315 Oslo, Norway. E-mail: kjell.undheim@kjemi.uio.no
1
793

1794
V. Bjørnstad and K. Undheim
RESULTS AND DISCUSSION
The starting material for the ketone spiroannulation reaction was
,2,3,9a-tetrahydro-9H-fluoren-3-one (1; Scheme 1). The initial conver-
1
sion of carbonyl carbon into a quaternary carbon was based on metho-
dology developed by Martin et al., who in 1980 reported an effective
procedure for geminal disubstitution at the carbonyl carbon atom of
[7]
aldehydes and ketones. The carbon–oxygen double bond of the car-
[
8]
bonyl function is replaced by an acyl group and an alkyl group.
Surprisingly, few subsequent reports have appeared in the literature
utilizing this methodology.
[9,10]
To effect quaternization of the ketone 1, the latter was initially
reacted with diethyl (N-benzyliden)aminomethylphosphonate (2). The
phosphonate was prepared as shown in Scheme 3. The reagent 2
was deprotonated in the cold with n-butyllithium and reacted with the
3
(
-fluorenone 1 to yield the imine 3 in a Wittig–Horner reaction
Scheme 1), and subsequently treated in situ with an excess of n-butyl-
lithium, which resulted in imine alkylation and the formation of a
metalloenamine 4. The solution of the lithiated enamine 4 in tetrahydro-
furan (THF) was subsequently treated with 1,3-dimethyl-3,4,5,6-tetrahy-
dropyrimidin-2(1H)-one (DMPU) to favor C-alkylation and reacted with
[
11]
a b-bromoketone, 2-(2-bromoethyl)-2-methyl-1,3-dioxolane,
to form
the alkylated product 5. The latter was hydrolyzed in situ with aqueous
hydrochloric acid to provide the deprotected dicarbonyl product 6,
which in methanolic potassium hydroxide was directly transferred by
ꢀ
Scheme 1. Reagents and conditions: (i) (a) n-BuLi, THF, À78 C, 1 h, (b) reflux,
ꢀ
2
h; (ii) THF, À78 C, 1 h; (iii) DMPU, rt, 20 h; (iv) rt, 6 h; and (v) MeOH, rt, 1 h.

Cyclic Ketones in Spiroannulation
1795
ꢀ
Scheme 2. Reagents and conditions: (i) KOH, EtOH, 40 C, 15 min; (ii) benzene,
reflux, 10 h; and (iii) THF, rt ꢁreflux, 8 h; (iv) rt, 5 h.
an intramolecular condensation to the spiroannulated target compound
7
, which was a 1:1 mixture of the two diastereomers in 43% overall yield.
It should be emphasized that the whole set of reactions was performed as
a one-pot reaction, which renders the methodology very convenient and
attractive. In the alkylation step in the tandem acylation–alkylation
methodology, carcinogenic hexamethylphosphoramide (HMPA) was ori-
[7]
ginally used as a cosolvent. According to our experience, HMPA can be
replaced by DMPU as a solvent in this reaction in accord with the general
[
12]
recommendation to replace HMPA with DMPU.
The fluorenone substrate 1 is reported to be available in 58% yield from
a Robinson annulation reaction with methyl vinyl ketone using a large
[
13]
excess of melted 1-indanone.
recovery of excess 1-indanone, we observed mainly self-condensation, with
Although the original report describes
[
14]
formation of the cis and trans isomers of 2-(1-indanyliden)indan-1-one,
which complicated isolation of the fluorenone 1 (Scheme 2). A more
effective enamine approach, however, has been developed for the synthesis
of the ketone 1. In this procedure, pyrrolidine enamine was prepared from
1
-indanone and treated with methyl vinyl ketone in THF. A ready C-alkyla-
tion of the enamine was evident followed by a spontaneous cyclization,
which furnished the product 9. Hydrolysis of the latter under acidic
conditions provided the desired ketone 1 in good yield.
The reagent 2 for the acylation–alkylation protocol was prepared by
Schiff base formation from diethyl aminomethylphosponate and benzal-
dehyde (Scheme 3). Dibenzylamine, diethyl phosphite, and aqueous for-
maldehyde were heated together in THF to furnish the aminomethylated
product 11 (Scheme 3) in close to quantitative yield. Hydrogenolysis of
1
1, as a hydrochloride in ethanol, produced the pure debenzylated pro-
duct, which could be transformed directly into the Schiff base 2. Alterna-
[
8,15]
tive, but less efficient, methods have been described in the literature.
ꢀ
Scheme 3. Reagents and conditions: (i) THF, 50 C, 20 h; (ii) [H
ꢀ
2
], Pd-C (10%),
EtOH; and (iii) PhCHO, 0 C.

1796
V. Bjørnstad and K. Undheim
CONCLUSION
Methodology has been developed for the preparation of spiranes from
cyclic ketones. The carbonyl carbon is initially converted into a quatern-
ary carbon by a tandem acylation–alkylation reaction and a subsequent
spiroannulation.
EXPERIMENTAL
1
13
H NMR and C NMR spectra were recorded in CDCl at 200 MHz and
3
5
0 MHz, respectively, with a Bruker DPX 200 instrument. Chemical
shifts are reported in parts per million (ppm) relative to residual CHCl3
7.24 ppm) and CDCl (77 ppm). The mass spectra were recorded at
(
3
7
0 eV ionizing potential. Infrared (IR) spectra were measured on a
Nicolet Magma 550 spectrometer using attenuated total reflection (ATR).
THF was dried by distillation from sodium benzophenone under
nitrogen. Reactions requiring dry and=or oxygen-free conditions were
run under the slight positive pressure of argon.
1
,2,3,9a-Tetrahydro-9H-fluoren-3-one (1)
Method (A)
Pyrrolidine (14.2 g, 0.200 mol) was added to 1-indanone (13.2 g,
0.100 mol) in benzene (100 mL). The mixture was heated under reflux
overnight with water trapping. The solvent and excess pyrrolidine were
removed in vacuo, and dry THF (40 mL) was added. After cooling to
ꢀ
0
C, neat methyl vinyl ketone (7.71 g, 0.110 mmol) was introduced drop-
wise with stirring. Hydrochloric acid (3 M, 50 mL) was added after 10 h,
and the mixture was vigorously stirred overnight. Saturated brine
(50 mL) was added, the layers were separated, and the aqueous layer
was extracted with diethyl ether (3 ꢁ 20 mL). The combined organic
layers were dried (MgSO ), the solvents were distilled off, and the resi-
4
dual matter was subjected to flash chromatography on silica gel 60 using
EtOAc–hexane 1:3; yield 12.4 g (67%). The product was a solid with mp
ꢀ
þ
28–130 C (cyclohexane). HRMS (EI, 70 eV): [M] calcd. for C H O:
13 12
1
1
1
1
84.0888; found: 184.0894; H NMR (200 MHz, CDCl ): d 1.7–1.9 (m,
3
H), 2.2–2.8 (m, 4H), 3.0–3.3 (m, 2H, H9), 6.24 (s, 1H, H4), 7.2–7.6
1
3
(
m, 4H, H-Ar); C NMR (50 MHz, CDCl ): d 29.1 (C1), 36.9 (C9),
3
3
8.0 (C2), 41.7 (C9a), 117.0 (C4), 122.6 (CH-Ar), 125.3 (CH-Ar), 126.6
CH-Ar), 131.5 (C4), 137.9 (C-Ar), 148.2 (C-Ar), 168.8 (C4a), 199.4
(
(
þ
C3); MS (EI, 70 eV): m=z (%) ¼ 184 (100) [M] , 156 (95), 128 (88), 115 (7).

Cyclic Ketones in Spiroannulation
1797
Method B
Methyl vinyl ketone (2.1 g, 30 mmol) was added to molten 1-indanone
ꢀ
(
(
10.0 g, 76 mmol) at 40 C, and 2 M potassium hydroxide in ethanol
2 mL) was added. The exothermic reaction was controlled by a water
bath at room temperature. The reaction mixture was stirred for 15 min
and subsequently poured into a 5% solution of NH Cl (100 mL) with stir-
4
ring. The resultant mixture was extracted with chloroform (3 ꢁ 30 mL).
The chloroform solution was dried (MgSO ) and concentrated on a
4
rotatory evaporator. Most of the excess 1-indanone was recovered by
vacuum distillation. The residue was subjected to flash chromatography
on silica gel 60 using EtOAc–hexane–chloroform 1:3:4. 1,2,3,9a-tetrahy-
dro-9H-fluoren-3-one (1) was the slower moving compound; yield 37%.
1
13
H and C NMR were in accordance with previously collected data.
0
0
The faster moving product was E-2,3-dihydro-3 H-[1,2 ]biindenyliden-
[14]
1
0
-one.
Diethyl (Benzyliden)aminomethylphosphonate (2)
To a solution of diethyl dibenzylaminomethylphosphonate (11) (68.0 g,
0
0
.195 mol) in ethanol (300 mL), 37% aqueous hydrochloric acid (19.2 g,
.195 mol) and 10% palladium on charcoal (10.4 g, 9.78 mmol Pd) were
added. The catalyst was slightly wetted with water to avoid ignition of
the ethanol. The reaction mixture was subjected to vigorous stirring
under a slight positive pressure of hydrogen until no more gas was
absorbed. NaOH–H O (11.31 g, 0.195 mol) was added, and the reaction
2
mixture was filtered through a bed of Celite. The volatiles were distilled
off at reduced pressure, and the residue was dissolved in diethyl ether.
The solution was dried (MgSO ) and concentrated at reduced pressure
4
1
to give a colorless oil; yield 30.3 g (92%). H NMR data were in accor-
dance with data from the literature.
0
0 0 0 0
,2 ,3 ,9a -Tetrahydro-9H-spiro[cyclohex-2-en-1,3 -fluoren]-4-one (7)
1
n-Butyllithium in heptane (2.7 M, 4.4 mL, 12 mmol) was added to dry
ꢀ
THF (50 mL) at ꢂ78 C under the slight positive pressure of argon.
Diethyl (N-benzyliden)aminomethylphosphonate (2) (3.1 g, 12 mmol) in
THF (5 mL) was slowly introduced, and the mixture was stirred at
ꢀ
ꢂ78 C for 1 h. 1,2,3,9a-Tetrahydrofluoren-3-one (1) (1.8 g, 10 mmol) in
THF (10 mL) was added, and the reaction mixture was heated under gen-
tle reflux for 2 h. The product was benzylidene-(1,2,3,9a)-tetrahydro-9H-
fluoren-3-ylidenemethyl)amine (3). The reaction mixture was cooled to

1798
V. Bjørnstad and K. Undheim
ꢀ
ꢂ78 C, and 2.7 M n-butyllithium (5.6 mL, 15 mmol) was added dropwise.
The n-BuLi adduct 4 was formed. Dry DMPU (35 mL) was added after
[
11]
stirring for 1 h, followed by 2-(2-bromoethyl)-2-methyl-1,3-dioxalane
2.9 g, 15 mmol) in THF (5 mL). The alkylated product was the enamine
(
5
2
. The reaction mixture was brought to room temperature and stirred for
0 h. Hydrochloric acid (1 M, 50 mL) was added, and the stirring contin-
ued for 6 h. Saturated brine (100 mL) was added, and the phases were
separated. The water phase was extracted with diethyl ether (3 ꢁ 150 mL),
and the combined extracts were washed with saturated NaHCO
(200 mL) and saturated brine (200 mL). The solvents were distilled off,
3
and the residue was dissolved in methanol (60 mL) to yield the dicarbonyl
product 6. Potassium hydroxide (KOH) (3.0 g, 53 mmol) in water (30 mL)
was added, and the mixture was stirred vigorously for 1 h. The methanol
was distilled off under reduced pressure. Saturated brine (50 mL) was
added, and the mixture was extracted with diethyl ether (3 ꢁ 20 mL).
The dried (MgSO ) ether solution was concentrated at reduced pressure,
4
and the residue was subjected to flash chromatography on silica gel 60
using EtOAc–hexane 1:3; yield 1.2 g (43%) of a yellow oil. The product
was a 1:1 mixture of the diastereomers of the spirane 7. HRMS (EI,
þ
7
v cm 3310 (w), 3038 (w), 2994 (m), 2911 (s), 2837 (s), 2237 (w), 1662
0 eV): [M] calcd. for C H O: 250.1358; found: 250.1368; IR (film):
ꢂ1
1
8
18
1
(
1
s), 1591 (m); H NMR (200 MHz, CDCl ): d 1.4–1.8 (m, 2H, CH ),
.9–2.2 (m, 4H, CH ), 2.4–2.6 (m, 3H, H9a and CH ), 2.7–2.9 (m, 1H,
3
0
2
2
2
0
0
0
0
H9 ), 3.1–3.2 (m, 1H, H9 ), 5.76 (s, 0.5H, H4 ), 5.88 (s, 0.5H, H4 ), 5.90
d, 0.5H, J ¼ 10.4 Hz, H2), 6.00 (d, 0.5H, J ¼ 10.4 Hz, H2), 6.63 (d,
.5H, J ¼ 10.4 Hz, H3), 6.78 (d, 0.5H, J ¼ 10.4 Hz, H3), 7.0–7.6 (m, 4H,
(
0
1
3
H-Ar); C NMR (50 MHz, CDCl ): d 26.3 (2 ꢁ CH ), 33.1 (2 ꢁ CH ),
3
2
2
3
(
4.6 (2 ꢁ CH ), 34.7 (CH ), 36.9 (CH ), 37.7 (C1), 38.1 (2 ꢁ CH ), 38.4
2
2
2
2
0
0
0
0
C1), 42.5 (C9a ), 43.0 (C9a ), 118.1 (C4 ), 121.1 (C4 ), 121.2 (2 ꢁ CH-
Ar), 125.8 (2 ꢁ CH-Ar), 126.2 (C3), 127.9 (2 ꢁ CH-Ar), 128.5 (C3),
0
1
1
7
29.0 (2 ꢁ CH-Ar), 141.1 (2 ꢁ C-Ar), 145.3 (2 ꢁ C-Ar), 147.0 (C4a ),
0
47.2 (C4a ), 158.6 (C2), 159.1 (C2), 199.8 (C4), 200.1 (C4); MS (EI,
0 eV): m=z (%) ¼ 250 (80) [M] , 222 (100), 208 (18), 194 (52), 179 (37).
þ
Diethyl Dibenzylaminomethylphosphonate (11)
Diethyl phosphite (33.1 g, 0.24 mol) and dibenzylamine (39.5 g, 0.20 mol)
were dissolved in THF (100 mL), and 36% aqueous formaldehyde (20 g,
0
.24 mol) was added. The reaction mixture was left stirring for 1 h and
ꢀ
subsequently heated at 50 C for 20 h. The solvents were distilled off on
a rotatory evaporator, and the residual oil was dissolved in hexane
(300 mL). The solution was washed with water (3 ꢁ 100 mL) and dried

Cyclic Ketones in Spiroannulation
1799
(
MgSO ). Concentration under vacuum yielded the pure title compound
4
1
as a colorless oil; yield 68.6 g (99%). H NMR (300 MHz, CDCl ): d 1.27
3
(
CH -Ph), 4.04 (quin, 4H, 7.1 Hz, OCH ), 7.1–7.4 (m, 10H, H-Ar);
t, J ¼ 7.1 Hz, 6H, CH ), 2.86 (d, J ¼ 10.2 Hz, 2H, PCH ), 3.76 (s, 4H,
3
2
1
3
C
2
2
NMR (75 MHz, CDCl ): d 16.4 (d, 5.9 Hz, CH ), 48.3 (d, J ¼ 157.3 Hz,
3
3
PCH ), 59.2 (d, 8.2 Hz, CH Ph), 61.6 (d, 6.7 Hz, OCH CH ), 127.2
2
2
2
3
(
CH-Ar), 128.1 (CH-Ar), 128.9 (CH-Ar), 138.6 (C-Ar).
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