The first ionic liquid-promoted Kabbe condensation reaction for an expeditious synthesis of privileged bis-spirochromanone scaffolds

Article abstract of DOI:10.1016/j.tetlet.2009.03.104

A variety of privileged bis-spirochromanones were synthesized for the first time from 4,6-diacetyl resorcinol in one-pot by carrying out the Kabbe condensation in room temperature ionic liquid [bbim]Br.

Full text of DOI:10.1016/j.tetlet.2009.03.104

Tetrahedron Letters 50 (2009) 2643–2648
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The first ionic liquid-promoted Kabbe condensation reaction for an expeditious
synthesis of privileged bis-spirochromanone scaffolds
a
b
M. Muthukrishnan a, , U. M. V. Basavanag , Vedavati G. Puranik
*
a Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
b Centre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of privileged bis-spirochromanones were synthesized for the first time from 4,6-diacetyl resor-
cinol in one-pot by carrying out the Kabbe condensation in room temperature ionic liquid [bbim]Br.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 January 2009
Revised 7 March 2009
Accepted 14 March 2009
Available online 20 March 2009
Keywords:
Kabbe condensation
Bis-spirochromanone
Ionic liquid
Morpholine
1. Introduction
Kabbe condensation between enamine and 2-hydroxy aceto-
phenone is a commonly employed method for the construction
Chromone derivatives,1 in particular 2-spiro-chroman-4(1H)-
ones are ubiquitous in nature and possess various biological activ-
ities which include antiarrhythmic,2 anti-HIV,3 antidiabetic,4 ACC
inhibitor,5 vanilloid receptor antagonist,6 growth hormone secret-
agogues,7 histamine receptor antagonist,8 and antiviral.9 Further-
more, these 2-spiro-chroman-4(1H)-ones serve as an important
precursor for the synthesis of other medicinally important com-
pounds such as rotenoids10 and xanthones.11 Recently, these struc-
tural scaffolds have been assigned as privileged structures for drug
development.12
During the last few years, the concept of bivalency or homodi-
mer strategy (i.e., combination into a single molecule of two iden-
tical structural entities or fragments of well known biologically
active natural products or synthetic drugs) has emerged as a pow-
erful tool in the medicinal chemistry research to improve either
the overall potency of the parent compounds or could result in
an entirely new complementary biological activity.13 Although,
there are numerous homodimers of chromones such as bis-flav-
ones, bis-coumarins, and bis-flavanones whose biological activities
are well documented,14 there are no attempts made so far, to syn-
thesize bis-2-spirochromanone scaffolds despite their propitious
biological functions. Intrigued by these facts, we surmised whether
a library of bis-spirochromanones could be synthesized conve-
niently for biological testing (Scheme 1).
of 2-spirochromanone skeleton.15 The other two general ap-
proaches are: (1) the cross aldol condensation of lithium enolate
of 2-hydroxy acetophenone with ketone, followed by dehydra-
tion16 (2) Mukaiyama aldol condensation of bis-silyl enol ether de-
rived from 2-hydroxy acetophenone with ketone, followed by
acidic ring closure.17 Although these methods have wide utility, of-
ten they suffer due to multi-step processes,16,17 tedious work-up,
and the usage of stoichiometric quantities of Lewis acids such as
BF3ꢀEt2O, SnCl4, AlCl3, and TiCl4.17 In the context of our ongoing re-
search program dealing with drug discovery, we were encountered
with a need for an efficient methodology for the synthesis of bis-
spirochromanone libraries and we were interested in exploring
the possibility of conducting the Kabbe condensation reaction in
ionic liquids. Applications of ionic liquids in chemical processes
have blossomed only within the last decade and they have been
used successfully for a variety of organic transformations.18 We
herein describe an extremely facile and environmentally friendly
synthesis of bis-2-spirochromanones in one-pot by carrying out
Kabbe condensation in an ionic liquid [bbim]Br catalyzed by
morpholine.
2. Results and discussion
Initially, the Kabbe condensation of 4,6-diacetyl resorcinol 1
with cyclohexanone 2a was chosen as a model and the influence
of various ionic liquids and bases was examined to find the optimal
conditions for the reaction. The results are summarized in Table 1.
* Corresponding author. Tel.: +91 20 25902571; fax: +91 20 25902629.
E-mail address: m.muthukrishnan@ncl.res.in (M. Muthukrishnan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.104

2644
M. Muthukrishnan et al. / Tetrahedron Letters 50 (2009) 2643–2648
2a-j
R
cyclic or acyclic ketone (
morpholine
)
R
O
O
O
O
HO
O
OH
O
R'
R'
H3C
CH3
N
Br
Bu
3a-j
N
1
Bu
Scheme 1.
As canbe seen fromTable 1, the ionicliquid [bbim]Brwas found tobe
most effective for this transformation providing 80% yield of the de-
sired product (Table 1, entry 3). Moreover, the nature of a base also
has a pronounced impact on the reaction, morpholine appears to
Table 1
Screening the optimized reaction conditions for Kabbe condensation of 4,6-diacetyl
resorcinol (1) with cyclohexanone (2a)a
O
be better than pyrrolidine and L-proline. On further modification of
the reaction conditions, we were delighted to find that the usage of
stoichiometric quantity of morpholine was not necessary; only cat-
alytic amount was sufficient to effect this transformation efficiently.
It is noteworthy to mention here that utilization of weakly basic
morpholine as a catalyst in organic transformation has not been ex-
plored much in the literature except in a recent report by Wu et al.19
Thus, in a typical experiment, treatment of 4,6-diacetyl resorcinol
(1 equiv) with cyclohexanone (2.2 equiv) in ionic liquid [bbim]Br
with catalytic amount of morpholine (0.5 equiv) at 95 °C for 8 h
afforded the corresponding bis-spirochromanone 3a in 80% yield.
The product 3a was characterized using standard spectroscopic
techniques. In the IR spectrum, a signal corresponding to the chro-
manone carbonyl was observed at 1701 cmꢁ1. The signal corre-
sponding to the C3 protons of chromanone skeleton was
observed at d 2.68 ppm in the 1H NMR spectrum and the corre-
sponding 13C resonance signal was observed at d 47.8 ppm. In
the 13C NMR spectrum, the spirocarbon was discernible at d
81.0 ppm. Conclusive evidence for its structure was obtained from
O
O
O
O
HO
H3C
OH
O
2a
CH3
O
3a
1
Entry
1
Ionic liquid
[bbim]PF6
Base
Yieldb (%)
Pyrrolidine
20
32
30
L
-Proline
Morpholine
2
3
[bmim]Br
[bbim]Br
Pyrrolidine
40
40
50
L
-Proline
Morpholine
Pyrrolidine
50
65
80
L
-Proline
Morpholine
4
5
a
[Hbim]ClO4
[Hbim]Br
L
-Proline
24
20
Morpholine
20,21
single-crystal X-ray analysis (Fig. 1).
L
-Proline
15
<10
Using the optimized conditions in hand, we subjected a series of
cyclic and acyclic ketones for this modified Kabbe condensation
protocol to explore the generality and scope of the process and
the results are summarized in Table 2. The results indicate that
the enolizable cyclic ketones (2b–g) were successfully reacted with
Morpholine
Reaction conditions: 1 (2.5 mmol), 2a (5.5 mmol), base (5.5 mmol) in ionic
liquid (2g) 95–100 °C for 12 h.
b
Yields were isolated and unoptimized.
Figure 1. ORTEP structure of compound 3a.

M. Muthukrishnan et al. / Tetrahedron Letters 50 (2009) 2643–2648
2645
Table 2
Reaction of 4,6-diacetyl resorcinol with various cyclic and acyclic ketones
Entry
Ketone
Product 3a
Time (h)
Yieldb (%)
O
O
O
O
1
8
80
2a
O
3a
Bn
N
Bn
N
O
O
O
O
O
2
3
4
5
8
75
78
55
72
N
Bn
Boc
Bu
2b
2c
2d
2e
3b
Boc
N
Boc
N
O
O
O
O
O
9
N
O
O
3c
Bu
N
Bu
N
O
O
12
12
N
O
O
3d
O
O
O
O
3e
O
NC
CN
CN
O
O
O
MeO
MeO
OMe
OMe
6
12
58
2f
O
OMe
3f
MeO
O
O
O
O
O
7
12
61
2g
3g
O
O
O
O
8
9
8
84d
2h
O
3h
O
O
O
O
10
74
2i
O
3i
(continued on next page)

2646
M. Muthukrishnan et al. / Tetrahedron Letters 50 (2009) 2643–2648
Table 2 (continued)
Entry
Ketone
Product 3a
Time (h)
Yieldb (%)
O
O
O
O
O
10
12
70
2j
3j
HO
O
O
O
O
11
12
12
82d
2k
3k
O
n.r.c
F
F
2l
O
13
n.r.c
Cl
Cl
2m
a
All the products were characterized by spectroscopic data.
Yields were isolated and unoptimized.
n.r. = No reaction.
b
c
d
Known compounds.
4,6-diacetyl resorcinol under this procedure, providing moderate
to good yields of desired bis-spirochromanones (3b–g). The meth-
od is well amenable for acyclic ketones as well (Table 2, entries 8–
10). However, with cyclopentanone (2k), the reaction was very
sluggish and we could isolate only one side condensed product
3k which may be attributed to the less reactive nature of the cyclo-
pentanone ring. Non-enolizable ketones 4,40-difluorobenzophe-
none (2l) and 4,40-dichlorobenzophenone (2m) did not give any
desired condensation products probably due to steric hindrance
of the bulky phenyl groups.17 It is noteworthy to mention here that
the only known compound in the series 3h was previously pre-
pared using photo-Fries methodology in very poor yield,22 in com-
parison to the 84% yield in the present one-pot procedure (Table 2,
entry 8).
In conclusion, we describe here a facile and environmentally be-
nign synthesis of novel bis-spirochromanones by modifying Kabbe
condensation using the advantage of ionic liquid as a solvent and
promoter. Moreover, usage of catalytic quantity of inexpensive
and weakly basic morpholine make this method more attractive.
Easy workup, moderate to good isolated yield and reusability of io-
nic liquid makes this method simple for operation and useful to
generate a vast array of bis-spirochromanone libraries for biologi-
cal screening.
3. Experimental
3.1. Preparation of bis-spirochroman-4(1H)-ones; general
procedure
The role of the ionic liquid [bbim]Br in the Kabbe condensation
may be attributed to its inherent Bronsted/Lewis acidity and high sol-
vatingability.23 Probably,thehighlyacidic2Hprotonof[bbim]Bracti-
vates the carbonyl carbon of both alkanone and acetophenone, thus
facilitates the enamine formation as well as the ready cyclization of
unsaturated ketone intermediate 4 to the final product 3 (Fig. 2)
The advantage of the use of ionic liquid as a novel reaction med-
ium for this Kabbe condensation is that this ionic liquid can be eas-
ily recovered and reused. The products can be easily separated
from the ionic liquid medium by simple extraction with ethylace-
tate. We successfully reused this ionic liquid up to three runs with-
out much loss of activity for a selected compound 3a (run 1, 80%;
run 2, 81%; run 3; 78%).
A mixture of 4,6-diacetyl resorcinol (0.48 g; 2.5 mmol), ketone
(5.5 mmol), and morpholine (1.2 mmol) was added to an ionic li-
quid [bbim]Br (2g)23 and stirred at 95–100 °C for the time indi-
H
O
H
O
4
O
H
O
H
Bu
Bu
N
On comparison of our results with those in some of the pub-
lished procedures,16,17 we find that this protocol provides signifi-
cant advantages in terms of mild reaction conditions, single-step,
circumventing the use of stoichiometric quantities of Lewis acids,
and reusability of ionic liquid.
N
Br
Br
N
N
Bu
Bu
Figure 2.

M. Muthukrishnan et al. / Tetrahedron Letters 50 (2009) 2643–2648
2647
cated in Table 2. After completion, (TLC; EtOAc/hexane, 1:3) the
reaction mixture was extracted with EtOAc (3 ꢂ 10 mL). The com-
bined EtOAc extracts were concentrated in vacuo and the resulting
product was directly charged on a small silica gel column and
eluted with a mixture of 15% EtOAc/hexane to afford the pure
bis-spirochromanone. The IL was solubilized in acetonitrile, trea-
ted with charcoal, and filtered. The filtrate was evaporated and
the IL was dried under vacuum for further reuse. All products were
characterized by IR, NMR, mass spectrometry, and elemental anal-
ysis. All new compounds gave satisfactory spectroscopic data in
accordance with their structures.
3.1.6. Bis-spirochroman-4(1H)-one 3f (Table 2, entry 6)
White solid; mp 169–170 °C; IR (neat): 3613, 2936, 2836, 2231,
1696, 1608, 1561, 1467, 1413, 1346, 1299, 1256, 1148, 1024, 984,
l
936, 850 cmꢁ1; H NMR (200 MHz, CDCl3): d = 1.98–2.31 (m, 16H),
2.78 (br s, 4H), 3.88 (s, 6H), 3.92 (s, 6H), 6.52 (s, 1H, aromatic),
6.89–7.03 (m, 6H, aromatic), 8.52 (s, 1H, aromatic); l3C NMR
(50 MHz, CDCl3): d = 190.4, 165.6, 148.2, 147.3, 136.9, 127.8,
125.3, 119.6, 115.5, 112.3, 105.2, 81.2, 55.8, 47.3, 36.7, 34.2, 25.4;
ESI-MS: m/z = 699 [M+Na]+, 523, 458, 306; Anal. Calcd for
C40H40N2O8: C, 70.99; H, 5.96; N, 4.14. Found: C, 70.67; H, 6.32;
N, 3.96.
Selected data for the new compounds:
3.1.7. Bis-spirochroman-4(1H)-one 3g (Table 2, entry 7)
White solid; mp 141–142 °C; IR (neat): 3684, 3019, 2932, 2860,
2400, 1692, 1558, 1467, 1306, 1250, 1215, 1157, 1021, 928,
3.1.1. Bis-spirochroman-4(1H)-one 3a (Table 2, entry 1)
White solid; mp 184–185 °C; IR (neat): 2940, 2853, 1701, 1641,
1605, 1561, 1482, 1429, 1362, 1338, 1210, 1070, 1022, 938, 914,
879 cmꢁ1 lH NMR (200 MHz, CDCl3): d = 1.44–1.79 (m, 20H),
;
858 cmꢁ1 lH NMR (200 MHz, CDCl3): d = 1.43–1.74 (m, 16H),
;
2.01–2.13 (m, 4H), 2.70 (br s, 4H), 6.44 (s, 1H, aromatic), 8.44 (s,
1H, aromatic); l3C NMR (50 MHz, CDCl3): d = 190.7, 165.3,127.6,
115.6, 105.5, 85.5, 48.7, 38.5, 29.3, 21.9; ESI-MS: m/z = 383
[M+H]+, 301, 275; Anal. Calcd for C24H30O4: C, 75.36; H, 7.91.
Found: C, 75.61; H, 7.72.
1.94–2.01 (m, 4H), 2.68 (br s, 4H), 6.50 (s, 1H, aromatic), 8.46 (s,
1H, aromatic); l3C NMR (50 MHz, CDCl3): d = 190.4, 164.9, 127.4,
115.5, 105.3, 81.0, 47.8, 34.8, 24.9, 21.3; ESI-MS: m/z = 355
[M+H]+, 301, 183; Anal. Calcd for C22H26O4: C, 74.55; H, 7.39.
Found: C, 74.87; H, 7.14.
3.1.8. Bis-chroman-4(1H)-one 3i (Table 2, entry 9)
3.1.2. Bis-spirochroman-4(1H)-one 3b (Table 2, entry 2)
White solid; mp 100–101 °C; IR (neat): 3778, 3620, 3468,
3019, 2876, 2400, 1685, 1608, 1521, 1470, 1424, 1246, 1215,
White solid; mp 123–124 °C; IR (neat): 3342, 2978, 1704, 1606,
1552, 1469, 1378, 1296, 1260, 1222, 1168, 1042, 1023, 911, 882,
836 cmꢁ1 lH NMR (200 MHz, CDCl3): d = 0.97 (t, J = 4.0, 2.0 Hz,
;
1026, 966, 859 cmꢁ1 lH NMR (200 MHz, CDCl3): d = 1.68–1.83
;
6H), 1.69–1.84 (m, 4H), 2.61 (d, J = 6.0 Hz, 2H), 2.73 (d, J = 6.0 Hz,
2H), 6.39 (s, 1H, aromatic). 8.45 (s, 1H, aromatic); l3C NMR
(50 MHz, CDCl3): d = 190.7, 165.4, 127.6, 115.3, 105.3, 82.6, 46.8,
32.4, 23.6, 7.8; HRMS (ESI): m/z calcd for C18H22O4 [M]+:
302.1518; found: 302.1360.
(m, 4H), 1.98–2.04 (m, 4H), 2.38–2.49 (m, 4H), 2.61–2.65 (m,
4H), 2.69 (br s, 4H), 3.54 (s, 4H), 6.56 (s, 1H, aromatic), 7.31
(m, 10H, aromatic), 8.46 (s, 1H, aromatic); l3C NMR (50 MHz,
CDCl3): d = 190.0, 164.7, 138.1, 129.0, 128.2, 127.1, 115.8,
105.6, 79.2, 62.9, 48.6, 47.7, 34.5; ESI-MS: m/z = 537 [M+H]+,
379, 263; Anal. Calcd for C34H36N2O4: C, 76.09; H, 6.76; N,
5.22. Found: C, 75.78; H, 7.05; N, 5.28.
3.1.9. Bis-chroman-4(1H)-one 3j (Table 2, entry 10)
White solid; mp 125–126 °C; IR (neat): 2978, 1704, 1606, 1561,
1469, 1378, 1296, 1260, 1222, 1168, 1082, 1023, 930, 889,
3.1.3. Bis-spirochroman-4(1H)-one 3c (Table 2, entry 3)
White solid; mp 216–217 °C; IR (neat): 3019, 2978, 1687, 1608,
1559, 1470, 1368, 1343, 1247, 1215, 1158, 1027, 966, 860 cmꢁ1; lH
NMR (200 MHz, CDCl3): d = 1.46 (s, 18H), 1.62 (m, 4H), 1.97–2.05
(m, 4H), 2.71 (br s, 4H), 3.14–3.26 (m, 4H), 3.86–3.93 (m, 4H),
6.55 (s, 1H, aromatic), 8.50 (s, 1H, aromatic); l3C NMR (50 MHz,
CDCl3): d = 189.4, 164.5, 154.6, 128.0, 115.9, 105.6, 79.9, 79.2,
63.3, 47.7, 34.2, 28.3; ESI-MS: m/z = 357 [MꢁBoc+H]+; Anal. Calcd
for C30H40N2O8: C, 64.73; H, 7.24; N, 5.03. Found: C, 64.79; H,
6.95; N, 4.98.
856.cmꢁ1 lH NMR (200 MHz, CDCl3): d = 0.98 (d, J = 4 Hz, 6H),
;
1.01 (d, J = 4 Hz, 6H), 1.31 (s, 6H), 2.09 (m, 2H), 2.59 (d, J = 16 Hz,
2H), 2.82 (d, J = 16 Hz, 2H), 6.41 (s, 1H, aromatic), 8.46 (s, 1H, aro-
matic); l3C NMR (50 MHz, CDCl3): d = 190.8, 165.3, 127.3, 115.2,
105.3, 85.1, 44.8, 35.7, 19.8, 17.2, 16.6; ESI-MS: m/z = 331
[M+H]+; Anal. Calcd for C20H26O4: C, 72.70; H, 7.93. Found: C,
72.94; H, 7.63.
Acknowledgements
3.1.4. Bis-spirochroman-4(1H)-one 3d (Table 2, entry 4)
M.M.K. is thankful to the Department of Science and Technol-
ogy, Govt. of India for generous funding of the project (Grant SR/
FTP/CS-25/2007). The authors are grateful to Dr. Ganesh Pandey,
Head, Organic Chemistry division for his constant encouragement
and support.
Semisolid; IR (neat): 3678, 3425, 3119, 2467, 2128, 1665,
1642, 1525, 1440, 1424, 1222, 1215, 1028, 966, 860 cmꢁ1 lH
;
NMR (200 MHz, CDCl3): d = 0.92 (t, J = 8 Hz, 6H), 1.31–1.54 (m,
8H), 1.94–2.04 (m, 8H), 2.51–2.65 (m, 8H), 2.71 (br s, 4H), 3.11
(m, 4H), 6.48 (s, 1H, aromatic), 8.38 (s, 1H, aromatic); l3C NMR
(50 MHz, CDCl3): d = 190.5, 165.8, 129.2, 115.7, 105.6, 79.1,
56.2, 48.6, 47.2, 34.8, 30.2, 20.9, 13.1; Anal. Calcd for
C28H40N2O4: C, 71.76; H, 8.60; N, 5.98. Found: C, 72.08; H,
8.21; N, 6.18.
References and notes
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Heterocyclic Compounds; Wiley: New York, 1977; Vol. 31, pp 11–139; (b)
Hepworth, J.. In Comprehensive Heterocyclic Chemistry; Katrizky, A. R., Rees, C.
W., Eds.; Pergamon: Oxford, UK, 1984; Vol. 3, pp 737–883.
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Butcher, J. W.; Habecker, C. N.; King, S. W.; Lynch, J. J.; Phillips, B. T.; Ponticello,
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3.1.5. Bis-spirochroman-4(1H)-one 3e (Table 2, entry 5)
White solid; mp 239–240 °C; IR (neat): 2949, 2867, 1699, 1606,
1557, 1469, 1366, 1299, 1241, 1185, 1138, 1009, 985, 936, 878,
l
855 cmꢁ1; H NMR (200 MHz, CDCl3): d = 0.87 (s, 18H), 1.60–1.79
(m, 14H), 2.06–2.12 (m, 4H), 2.83 (s, 4H), 6.39 (s, 1H, aromatic),
8.44 (s, 1H, aromatic); l3C NMR (50 MHz, CDCl3): d = 190.7, 164.9,
127.6, 115.7, 105.4, 80.4, 48.8, 46.9, 35.2, 32.37, 27.5, 21.9; ESI-
MS: m/z = 467 [M+H]+, 381, 300; Anal. Calcd for C30H42O4: C,
77.21; H, 9.07. Found: C, 76.85; H, 9.22.
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Ka) = 0.71073 Å at T = 293 (2) K. All the data were corrected for Lorentzian,
polarization, and absorption effects using Bruker’s SAINT and SADABS programs.
The crystal structure was solved by direct methods using SHELXS-97 and the
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Hydrogen atoms were included in the refinement as per the riding model.; (b)
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University of Göttingen: Germany, 1997.
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12 union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk].
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