Synthetic study on 2,2′-(1,4-phenylene)bis(3-alkyl-1H-inden-1-ones): The first application of a sodium enolate as a 'protecting group' in the Grignard reaction

Article abstract of DOI:10.1055/s-2008-1067043

A new series of 2,2'-(l,4-phenylene)bis(3-substituted-1H-inden-l-ones) were prepared and their structures were established by ¹H and ¹³C NMR, IR, and HRMS spectroscopy. One molecular structure was further confirmed by single crystal X-ray crystallography. The synthetic mechanism was studied in detail. The key step involves the reaction of the Grignard reagent with the sodium enolate of 2,2'-(l,4-phenylene)bis[lH-indene-l, 3(2H)-di-one]. This is the first example of a sodium enolate being employed as the protecting reagent for a carbonyl group in the Grignard reaction.

Full text of DOI:10.1055/s-2008-1067043

PAPER
1725
Synthetic Study on 2,2¢-(1,4-Phenylene)bis(3-alkyl-1H-inden-1-ones): The
First Application of a Sodium Enolate as a ‘Protecting Group’ in the Grignard
Reaction
S
ynthetic Study on 2, 2
e
¢
-(1,4-Phe
n
i
ylene)b
-
is(3-alk
L
H
-inden-1-
o
i
nes) Pang,* Ying Wang, Xiang-Qing Feng, Yong Chen, Jie Han, Ji-Ben Meng*
Department of Chemistry, Nankai University, Tianjin 300071, P. R. of China
Fax +82(22)23502230; E-mail: pangmeili@nankai.edu.cn; E-mail: mengjiben@nankai.edu.cn
Received 4 February 2008; revised 27 February 2008
ones] 4a–g were synthesized (Scheme 1) and fully charac-
Abstract: A new series of 2,2¢-(1,4-phenylene)bis(3-substituted-
1H-inden-1-ones) were prepared and their structures were estab-
lished by 1H and 13C NMR, IR, and HRMS spectroscopy. One mo-
lecular structure was further confirmed by single crystal X-ray
crystallography. The synthetic mechanism was studied in detail.
The key step involves the reaction of the Grignard reagent with the
sodium enolate of 2,2¢-(1,4-phenylene)bis[1H-indene-1,3(2H)-di-
one]. This is the first example of a sodium enolate being employed
as the protecting reagent for a carbonyl group in the Grignard reac-
tion.
terized by spectroscopy. The structure of one of them, 4a,
was further confirmed by single crystal X-ray crystallog-
raphy.
O
O
NaOH
O
O
O
2
Key words: 2,2¢-(1,4-phenylene)bis(3-alkyl-1H-inden-1-one),
enols, Grignard reactions, protecting groups, regioselectivity
ONa
(1) N2, RMgX
(2) N2, H+
17–22%
Biindenylidenedione derivatives, which are derived from
1H,1¢H-2,2¢-biindene-1,1¢,3,3¢(2H,2¢H)-tetrone (1,
Figure 1), are a class of unique photochromic compounds.
They can simultaneously generate stable radicals and un-
dergo photochromism in the crystalline state.1–5 This
property is particularly promising for their potential use in
optoelectronic devices.6,7
O
R
NaO
O
3
4a R = Et
4b R = n-Pr
4c R = n-Bu
4d R = n-C5H11
4e R = n-C6H13
4f R = n-C8H17
4g R = 4-EtOC6H4
O
R
4a–g
Scheme 1
O
O
O
O
In previous reports,1–5 compound 1 was reacted with Grig-
nard reagent directly in moderate to good yield, when a
similar procedure was employed in the reaction between
2 and a Grignard reagent, no major product was obtained
and the byproducts were complex, showing a long line on
TLC (Scheme 2). The failure of this reaction may be at-
tributed to the different existence of the forms of 1 and 2.
In compound 1, the enolic form is highly preferred as the
two carbonyl groups and the two neighboring enol hy-
droxy groups are strongly tied by forming intramolecular
hydrogen bonds. When treated with a Grignard reagent,
the active hydroxy hydrogen reacts with R– firstly to re-
lease RH, and then, only two positions (the two remaining
carbonyl groups in the 3- and 3¢-positions) in intermediate
5 can accept the nucleophilic addition of the Grignard re-
agent, hence the desired product was obtained successful-
ly (Scheme 3). When a similar procedure was employed
with compound 2, the situation was quite different. The
favored structure of compound 2 is the keto form
(Scheme 2). This can be clearly seen from the color and
appearance of 2 in comparison with that of 1. For 1, the
dark purple color shows the existence of extended conju-
gation in the enolic form and the good planar properties
O
O
O
O
1
2
Figure 1
In connection with our previous work and with the aim of
expanding the scope of biindenylidenedione derivatives,
we extended the conjugated system by embedding a
phenylene group in the middle of compound 1 to form
2,2¢-(1,4-phenylene)bis[1H-indene-1,3(2H)-dione]
(2,
Figure 1).8 In this paper, the reaction between compound
2 and Grignard reagents was studied in detail. A plausible
synthetic mechanism was proposed and compared with
the reaction mechanism of compound 1 and Grignard re-
agents. For the first time, we introduced a sodium enolate
as the protecting group for a carbonyl group in the
Grignard reaction. Through this procedure, a new series
of 2,2¢-(1,4-phenylene)bis[3-substituted-1H-inden-1(2H)-
SYNTHESIS 2008, No. 11, pp 1725–1728
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067043; Art ID: F02808SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

1726
M.-L. Pang et al.
PAPER
leads to the ease of forming p–p stacking crystals. For 2, The successful regioselective reaction between 1 and a
the white color shows that no extended conjugation exists. Grignard reagent encouraged us to make a deeper analysis
This can be attributed to a lack of intramolecular hydro- of its reaction mechanism (Scheme 3).3 We can see that
gen bonding owing to the embedding of the phenylene the existence of the enolic form plays an important role in
group which increases the distance between the enol hy- the regioselectively nucleophilic addition. Although com-
droxy group and the neighboring carbonyl group, thus the pound 2 is difficult to change into its enolic form sponta-
enolic form is not sufficiently stable. On the other hand, neously (which is the case for 1), we can use sodium
the existence of two sp3 carbons in the indanyl ring leads hydroxide to accomplish the transformation from ketone
to the torsional structure of 2, and hence its difficulty in form 2 to the sodium enolate 3. The enolate 3 has a very
forming crystals. Only amorphous powders can be ob- similar structure to intermediate 5. The reaction of 3 and
tained for 2 despite many attempts at crystallization. the Grignard reagent was expected to proceed similarly to
When 2 was treated with a Grignard reagent, all four car- that of 5 (Scheme 4). Fortunately, we obtained the desired
bonyl groups have the same priority for nucleophilic addi- product 4a in 22% yield according to our expectations,
tion of R–, thus obviously, the reaction is rather complex and its structure was further confirmed by single crystal
and no separable products can be obtained.
X-ray crystallography.
O
O
OH O
O
O
NaOH
O
O
O
2
O
O
HO
white amorphous powder
1
dark purple crystals
O
O
Na
R
O
O
R
(1) N2, RMgX
(2) N2, H+
Na
O
O
ONa
O
O
O
O
2 RMgX
(1) N2, RMgX
(2) N2, H+
no main
product
obtained
O
NaO
3
O
2
dark purple crystals
white amorphous powder
R
O
ONa
O
Scheme 2
O
O
O
O
OH O
NaO
R
R
ONa
O
O HO
or
1
dark purple crystals
OMgX
O
O
O
NaO
R
2 RMgX 2 RH
R
O
R
2 RMgX
H+
– 2 H2O
OMgX
5
O
4a–g
R
R
OMgX
O
OMgX
O
orange crystals
or
Scheme 4
O
R
OMgX
O
OMgX
R
5
A perspective view of molecule of 4a with the crystallo-
graphic atom numbering is presented in Figure 2. Com-
pound 4a has central symmetry with two indenone
moieties linked by a phenylene group. Two loops of in-
denone are almost perfectly planar, while the deviation of
the planes of the two indenones relative to the plane of the
phenylene ring is +47.42° for one ring and –47.42° for the
other. This phenomenon may be interpreted by the signif-
R
OMgX
R
OMgX
O
R
H+
– 2 H2O
R
O
OMgX
OMgX
6
Scheme 3
Synthesis 2008, No. 11, 1725–1728 © Thieme Stuttgart · New York

PAPER
Synthetic Study on 2,2¢-(1,4-Phenylene)bis(3-alkyl-1H-inden-1-ones)
1727
Disodium 2,2¢-(1,4-Phenylene)bis(3-oxo-3H-inden-1-olate) (3)
Compound 2 (1.83 g, 5 mmol) was added in one portion to a soln of
NaOH (0.4 g, 10 mol) in H2O (10 mL); the mixture was allowed to
stir for 5 min. The solvent was removed under reduced pressure. So-
dium enolate 3 was obtained almost quantitatively as a dark purple
powder and can be used for the next step without further purifica-
tion.
icant steric hindrance between the carbonyl or ethyl group
in the indanone and the hydrogen atom in phenylene
group, and hence only partial conjugation is present in this
molecule. This can also be shown by the orange-colored
tint of 4a due to the low extent of the conjugation even
though all sp2 carbon atoms in the indenone and phe-
nylene moieties are linked directly without any interrup-
tion.
2,2¢-(1,4-Phenylene)bis(3-substituted-1H-inden-1-ones) 4a–g;
General Procedure
To a soln of alkyl- or arylmagnesium bromide [prepared from bro-
moalkane (50 mmol) and Mg (40 mmol) in anhyd THF (50 mL)], 3
(5 mmol) suspended in anhyd THF (120 mL) was added portion-
wise over a period of 10 min. The dark green mixture was refluxed
for an additional 6 h under N2 at which point the mixture turned yel-
low. The reaction was quenched by the addition of sat. aq NH4Cl
soln (30 mL) and the organic fraction was separated and dried
(MgSO4). Filtration and removal of the solvent under reduced pres-
sure afforded crude products 4a–g, which were purified by column
chromatography (silica gel, petroleum–EtOAc, 8:1). Compound 4a
was further crystallized (CH2Cl2) to give crystals suitable for X-ray
analysis.
Figure 2
2,2¢-(1,4-Phenylene)bis(3-ethyl-1H-inden-1-one) (4a)
Orange needle-shaped crystals; yield: 22%; mp 207–208 °C.
Though the yield is lower, this reaction has fascinated us
because this is the first report of a sodium enolate acting
as a carbonyl ‘protecting group’ in the Grignard reaction.
We have, therefore, used various alkylmagnesium bro-
mides and 4-methoxyphenylmagnesium bromide to react
with 3, and obtained a new series of the desired 2,2¢-(1,4-
phenylene)bis[3-substituted-1H-inden-1(2H)-ones] 4a–g
in reasonable yields (17–22%). After acidification with
hydrochloric acid, the unreacted sodium enolate 3 can be
reclaimed almost quantitatively to give the keto form 2,
and reclaimed 2 can be reused without any loss of reactiv-
ity.
IR (KBr): 3063, 2965, 2868 (C–H), 1708 (C=O), 1595, 1457, 1339,
1178, 1080, 1054 cm–1.
1H NMR (CDCl3): d = 7.41–7.53 (m, 8 H, ArH), 7.21–7.30 (m, 4 H,
ArH), 2.75–2.83 (q, 4 H, 2 CH2), 1.37 (t, J = 7.5 Hz, 6 H, 2 CH3).
13C NMR (CDCl3): d = 13.1, 20.3, 120.1, 122.6, 129.0, 129.5, 130.9,
131.0, 132.6, 133.8, 145.1, 160.4, 197.0.
MS (ESI): m/z = 413.54 [M + Na]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C28H22NaO2: 413.1512;
found: 413.1504.
X-ray Crystal Structure of 4a:9 Compound 4a with formula
C28H22O2 crystallizes in the triclinic system, space group P1, with
unit cell parameters a = 7.801(3), b = 8.438(4), c = 8.844(4) Å, a =
96.408(7)°, b = 100.485(8)°, g = 115.993(7)°, V = 502.3(4) Å3, Z =
1. A total of 1773 independent reflections [R(int) = 0.0321] were
collected on a sample (size 0.24 × 0.20 × 0.18 mm) using MoKa ra-
diation (l = 0.71073 Å) on a Bruker SMART 1000 diffractometer
and the q scan mode at r.t. The structure solution and refinement
were carried out using the programs SHELXS9710 and
SHELXL97.11 Final R indices for I > 2s(I) were equal R1 = 0.0479,
In summary, a new series of 2,2¢-(1,4-phenylene)bis[3-
substituted-1H-inden-1(2H)-ones)] were synthesized, and
the structure of one of them was further confirmed by sin-
gle crystal X-ray crystallography. The synthetic mecha-
nism was studied in detail. The results show that the
enolic form plays an important role in the reaction be-
tween the tetrone and a Grignard reagent. For the first wR2 = 0.0910, and R1 = 0.1094, wR2 = 0.1111 for all data. The ex-
tinction coefficient was refined and converged to 0.080. The final
time, a sodium enolate was introduced as a selective car-
bonyl ‘protecting group’ in the Grignard reaction. The po-
tential application and derivation from this series of
difference Fourier map of electron density was featureless with the
largest peak and hole at 0.132 and –0.173 eA–3, respectively.
compounds are currently under investigation.
2,2¢-(1,4-Phenylene)bis(3-propyl-1H-inden-1-one) (4b)
Orange needle-shaped crystals; yield: 22%; mp 194–196 °C.
All chemicals were purchased from commercial sources, and sol-
vents were dried by refluxing under N2 over an appropriate drying
agent and distilled prior to use. Compound 2 was synthesized ac-
cording to the literature.8 Melting points were determined with a
Yanagimoto MP-35 melting point apparatus and were uncorrected.
1H NMR and 13C NMR spectra were recorded on a Bruker AC-P300
and Oxford 400 respectively. MS were recorded on Thermo Finni-
gan LCQ Advantage spectrometer in ESI mode-I with spray voltage
4.8 kV. HRMS spectra were performed on an Ionspec. 7.0T. FTMS
apparatus. IR were recorded on a Nicolet-380-FT-IR spectropho-
tometer. X-ray data collection was performed on a Bruker SMART
1000 diffractometer with MoKa radiation.
IR (KBr): 3063, 2957, 2863 (C–H), 1704 (C=O), 1602, 1462, 1337,
1181, 1087, 1060 cm–1.
1H NMR (CDCl3): d = 7.40–7.53 (m, 8 H, ArH), 7.29–7.19 (m, 4 H,
ArH), 2.71–2.77 (t, J = 8.1 Hz, 4 H, 2 CH2), 1.73–1.80 (m, 4 H, 2
CH2), 1.05–1.10 (t, J = 7.2 Hz, 6 H, 2 CH3).
13C NMR (CDCl3): d = 14.8, 22.0, 29.1, 120.3, 122.6, 129.1, 129.6,
131.0, 131.9, 133.9, 145.7, 159.2, 197.0.
MS (ESI): m/z = 441.39 [M + Na]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C30H26NaO2: 441.1825;
found: 441.1825.
Synthesis 2008, No. 11, 1725–1728 © Thieme Stuttgart · New York

1728
M.-L. Pang et al.
PAPER
2,2¢-(1,4-Phenylene)bis(3-butyl-1H-inden-1-one) (4c)
13C NMR (CDCl3): d = 14.1, 22.6, 27.0, 28.3, 29.2, 29.3, 30.0, 31.8,
120.0, 122.4, 128.8, 129.3, 130.8, 130.9, 132.8, 133.6, 145.3, 159.2,
196.7.
Orange crystals; yield: 20%; mp 148–151 °C.
IR (KBr): 3064, 2950, 2930, 2863 (C–H), 1710 (C=O), 1594, 1511,
1457, 1370, 1337, 1175, 1063 cm–1.
MS (ESI): m/z = 1139.06 [2 M + Na]+.
1H NMR (CDCl3): d = 7.40–7.52 (m, 8 H, ArH), 7.19–7.29 (m, 4 H,
ArH), 2.73–2.78 (t, J = 8.1 Hz, 4 H, 2 CH2), 1.66–1.76 (m, 4 H, 2
CH2), 1.45–1.52 (m, 4 H, 2 CH2), 0.94–0.98 (t, J = 7.2 Hz, 6 H, 2
CH3).
13C NMR (CDCl3): d = 13.8, 23.1, 26.7, 30.4, 120.0, 122.4, 128.8,
129.3, 130.8, 132.9, 133.6, 145.3, 159.2, 196.7.
HRMS (QFT-ESI): m/z [M + H]+ calcd for C40H47O2: 559.3570;
found: 559.3568.
2,2¢-(1,4-Phenylene)bis-[3(4-ethoxyphenyl)-1H-inden-1-one]
(4g)
Red crystals; yield: 20%; mp 292–294 °C.
IR (KBr): 3064, 2988, 2930 (C–H), 1702 (C=O), 1599, 1503, 1474,
1453, 1387, 1337, 1283, 1254, 1171, 1109, 1043 cm–1.
1H NMR (CDCl3): d = 7.28–7.58 (m, 12 H, ArH), 6.88–7.21 (m, 8
H, ArH), 4.03–4.10 (q, 4 H, 2 CH2), 1.42–1.46 (t, J = 7.2 Hz, 6 H,
2 CH3).
13C NMR (CDCl3): d = 14.8, 63.5, 114.7, 121.2, 122.8, 124.7, 128.9,
129.0, 129.6, 130.2, 130.3, 130.4, 133.2, 145.7, 155.4, 185.6.
MS (ESI): m/z = 915.20 [2 M + Na]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C32H30NaO2: 469.2138;
found: 469.2140.
2,2¢-(1,4-Phenylene)bis(3-pentyl-1H-inden-1-one) (4d)
Orange powder; yield: 17%; mp 122–125 °C.
IR (KBr): 3064, 2955, 2922, 2851 (C–H), 1702 (C=O), 1615, 1590,
1512, 1458, 1366, 1333, 1171, 1076 cm–1.
MS (ESI): m/z = 575.37 [M + H]+.
1H NMR (CDCl3): d = 7.40–7.52 (m, 8 H, ArH), 7.19–7.29 (m, 4 H,
ArH), 2.72–2.77 (t, J = 7.8 Hz, 4 H, 2 CH2), 1.68–1.77 (m, 4 H, 2
CH2), 1.19–1.49 (m, 8 H, 2 CH2CH2), 0.89–0.93 (t, J = 6.9 Hz, 6 H,
2 CH3).
13C NMR (CDCl3): d = 13.9, 22.4, 26.8, 28.0, 32.1, 120.0, 122.4,
128.8, 129.3, 130.8, 130.9, 133.6, 145.3, 159.2, 196.7.
MS (ESI): m/z = 497.49 [M + Na]+.
HRMS (QFT-ESI): m/z [M + H]+ calcd for C34H35O2: 475.2632;
HRMS (MALDI) m/z [M + Na]+ calcd for C40H30NaO4: 597.2036;
found: 597.2039.
Acknowledgment
We thank the National Nature Science Foundation of China (grant
no. 20602020, 20490210) and N & T Joint Academy of China for
financial support.
found: 475.2628.
References
2,2¢-(1,4-Phenylene)bis(3-hexyl-1H-inden-1-one) (4e)
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IR (KBr): 3058, 2960, 2926, 2851 (C–H), 1711 (C=O), 1615, 1590,
1466, 1445, 1379, 1337 cm–1.
1H NMR (CDCl3): d = 7.40–7.52 (m, 8 H, ArH), 7.19–7.29 (m, 4 H,
ArH), 2.72–2.77 (t, J = 8.1 Hz, 4 H, 2 CH2), 1.70–1.77 (m, 4 H, 2
CH2), 1.15–1.48 [m, 12 H, 2 (CH2)3], 0.87–1.91 (t, J = 6.9 Hz, 6 H,
2 CH3).
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(9) The data were deposited at the Cambridge Crystallographic
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can be obtained free of charge from The Director, CCDC, 12
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13C NMR (CDCl3): d = 14.0, 22.6, 26.9, 28.2, 29.6, 31.9, 120.0,
122.3, 128.8, 129.3, 130.8, 132.8, 133.6, 145.3, 159.1, 196.7.
MS (ESI): m/z = 525.47 [M + Na]+.
HRMS (QFT-ESI): m/z [M + H]+ calcd for C36H39O2: 503.2945;
found: 503.2939.
2,2¢-(1,4-Phenylene)bis(3-octyl-1H-inden-1-one) (4f)
Orange powder; yield: 20%; mp 97–99 °C.
IR (KBr): 3070, 2951, 2913, 2843 (C–H), 1706 (C=O), 1615, 1586,
1466, 1449, 1366, 1292, 1180, 1084 cm–1.
1H NMR (CDCl3): d = 7.40–7.52 (m, 8 H, ArH), 7.19–7.29 (m, 4 H,
ArH), 2.72–2.77 (t, J = 7.8 Hz, 4 H, 2 CH2), 1.67–1.77 (m, 4 H, 2
CH2), 1.47–1.52 (m, 4 H, 2 CH2), 1.27–1.46 [m, 16 H, 2 (CH2)4],
0.85–0.90 (t, J = 6.9 Hz, 6 H, 2 CH3).
Synthesis 2008, No. 11, 1725–1728 © Thieme Stuttgart · New York