Synthesis and reactions of functionalized spirocyclopropanes by cyclization?of dilithiated β-ketosulfones, α-cyanoacetone and diethyl 2-oxopropylphosphonate with 1,1-diacetylcyclopropane

Article abstract of DOI:10.1016/j.tet.2008.01.066

The cyclization of β-ketosulfone, β-ketonitrile and β-ketophosphonate dianions with 1,1-diacetylcyclopropane afforded 1-hydroxyspiro[5.2]cyclooct-4-en-3-ones, which were transformed, by reaction with tetrabutylammonium halides, into functionalized phenols

Full text of DOI:10.1016/j.tet.2008.01.066

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3246e3252
www.elsevier.com/locate/tet
Synthesis and reactions of functionalized spirocyclopropanes by
cyclization of dilithiated b-ketosulfones, a-cyanoacetone and diethyl
2-oxopropylphosphonate with 1,1-diacetylcyclopropane
Nasir Rasool a, Muhammad A. Rashid a, Helmut Reinke a, Christine Fischer b, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
Received 21 September 2007; received in revised form 12 January 2008; accepted 14 January 2008
Available online 19 January 2008
Abstract
The cyclization of b-ketosulfone, b-ketonitrile and b-ketophosphonate dianions with 1,1-diacetylcyclopropane afforded 1-hydroxyspiro[5.2]-
cyclooct-4-en-3-ones, which were transformed, by reaction with tetrabutylammonium halides, into functionalized phenols containing a remote
halide function.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
of mitosis (taxol, vinblastine). The illudins belong to the group
of alkylating agents: The reaction of a nucleophile (such as glu-
tathione) with the unsaturated ketone moiety results in formation
of a cyclohexadiene, which rapidly undergoes an aromatization
with concurrent ring opening of the cyclopropane moiety and
alkylation of the DNA (Chart 1).3
In their pioneering work, Baird and Winstein studied the
synthesis of spiro[2.5]cycloocta-4,7-dien-6-ones and their reac-
tion with various nucleophiles.5 Padwa and co-workers reported
interesting cyclization reactions of diazo compounds, which
allow a convenient synthesis of illudins.6 We reported7 the syn-
thesis of ester-substituted 1-hydroxyspiro[5.2]cyclooct-4-en-3-
ones based on cyclization reactions of 1,3-dicarbonyl dianions.
Noteworthy, the products showed a considerable antiprolifera-
tive activity against human leukaemia HL60 cells. Herein, we
report the synthesis and reactions of novel spirocyclopropanes
Cytotoxic natural products are important lead structures for
the synthesis of new anticancer agents.1 Notably, the search for
new cytotoxic compounds is of ongoing importance since tu-
mours, similar to bacteria, may become resistant to known
chemotherapeutics.2 In addition, several types of tumours have
not yet been efficiently addressed by chemotherapeutic methods.
Spiro[2.5]cycloocta-4,7-dien-6-ones and related spirocyclopro-
panes constitute an important structural motif of cytotoxic and
cancerostatic natural and non-natural products. This includes,
for example, the illudins S and M (Fig. 1), which possess a 1-hy-
droxyspiro[5.2]cyclooct-4-en-2-one skeleton.3 The cytotoxic
natural products CC-1065 and duocarmycin SA contain a
spiro[2.5]cycloocta-4,7-dien-6-one moiety containing aromatic
rings fused to a heterocyclic ring system.4 Most of the chemo-
therapeutic agents used today belong to alkylating compounds
(chlorambucil, melphalan, thiotepa and busulfan), platinum
derivatives (cisplatin, carboplatin), inhibitors of topoisomerases
(camptothecin, etoposide, doxorubicin), antimetabolic com-
pounds (5-fluoruracil, methotrexate, hydroxyurea) or inhibitors
Me
O
Me
OH
Me
Illudin M
Chart 1. Natural cancerostatic spirocyclopropanes.
H
N
O
H
N
O
MeO2C
OMe
OMe
N
Me
HO
OMe
Duocarmyin SA
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.066

N. Rasool et al. / Tetrahedron 64 (2008) 3246e3252
3247
based on cyclizations of b-ketosulfone, b-ketonitrile and b-ke-
tophosphonate dianions with 1,1-diacetylcyclopropane. These
reactions provide a convenient access to functionalized phenols,
which are not readily available by other methods.
The BF3$OEt2-mediated reaction of pure 3a,b with tetrabu-
tylammonium halides afforded the sulfonyl-substituted phenols
4aef containing a remote chloride, bromide, and iodide group
(Scheme 2, Table 2). Alternatively, the crude material could
be successfully employed (vide supra). Products 4aef were pre-
sumably formed by Lewis acid mediated elimination of water to
giveahighly reactivespiro[2.5]cycloocta-4,7-dien-6-one (inter-
mediate A). The cyclopropane moiety is subsequently cleaved
by Lewis acid mediated attack of the halide ion to give a pheno-
late (intermediate B), which is protonated upon addition of
water (aqueous work-up). The structure of 4f was independently
confirmed by X-ray crystal structure analysis (Fig. 2).
2. Results and discussion
2.1. b-Ketosulfones
Dianions of b-ketosulfones are useful synthetic building
blocks, which have been previously used in cyclization
reactions. This includes, for example, the synthesis of 2-(sulfo-
nylmethylidene)tetrahydrofurans8 and 7-sulfonyl-2,3,3a,4,5,6-
hexahydrobenzofurans9 by cyclization of b-ketosulfone dianions
with cyclic sulfates and 1,4-dibromobut-2-ene, respectively. The
cyclization of the dianions of b-ketosulfones 1a,b, generated by
means of LDA (2.0 equiv), with 1,1-diacetylcyclopropane (2) af-
forded the 1-hydroxyspiro[5.2]cyclooct-4-en-3-ones 3a,b
(Scheme 1, Table 1). The relatively low isolated yields can be ex-
plained by the fact that the products are, due to their high reactiv-
ity, rather unstable and readily decompose during the
chromatographic purification. However, it proved possible to di-
rectly use the crude spirocyclopropane for the next synthetic step
(vide infra) without chromatographic purification.
OH
O
SO2Ar
SO2Ar
Me
N(nBu)4X
HO
Me
Me
Me
X
i
4a-f
3a,b
.
BF3 OEt2
H2O
_
+
+
N(nBu)
O N(nBu)4
O
4
SO2Ar
SO2Ar
.
BF3 OEt2
Me
Me
X
Me
Me
Despite its unstable nature, it proved to be possible to grow
a single crystal of spirocyclopropane 3b and to independently
confirmitsstructurebyX-raycrystalstructureanalysis(Fig. 1).10
_
X
B
A
Scheme 2. Synthesis of 4aef, (i): BF3$OEt2, CH2Cl2, ꢁ78/20 ꢀC, 6 h, then
20 ꢀC, 6 h.
O
SO2Ar
Table 2
Reaction of 3a,b with N(n-Bu)4X
O
SO2Ar
1a,b
i
4
Ar
X
Yielda (%)
O
O
HO
Me
Me
+
a
b
c
d
e
f
Ph
Ph
Cl
Br
I
80
75
81
78
68
84
Me
Me
Ph
3a,b
2
4-MeC6H4
4-MeC6H4
4-MeC6H4
Cl
Br
I
Scheme 1. Synthesis of 3a,b, (i): (1) LDA (2.0 equiv), 1a,b (1.0 equiv), THF,
1 h 0 ꢀC; (2) 2 (1.0 equiv), ꢁ78/20 ꢀC, 14 h.
a
Yields of isolated products.
Table 1
Synthesis of 3a,b
3
Ar
Yielda (%)
a
Ph
4-MeC6H4
30
32
b
a
Yields of isolated products.
Figure 1. Ortep plot of 3b.
Figure 2. Ortep plot of 4f.

3248
N. Rasool et al. / Tetrahedron 64 (2008) 3246e3252
O
2.2. a-Cyanoacetone
O
PO(OEt)2
8
The cyclization of 2 with the dianion of a-cyanoacetone,
generated by treatment of 5-methylisoxazole (5) with LDA,11
afforded 1-hydroxyspiro[5.2]cyclooct-4-en-3-one 6 (Scheme
3). The BF3$OEt2-mediated reaction of 6 with tetrabutylammo-
nium halides gave the 2-cyanophenols 7aec containing a re-
mote halide group (Scheme 3, Table 3). The formation of
7aec can be explained by a similar mechanism as discussed
for 4aef. The structure of 7b was independently confirmed
by X-ray crystal structure analysis (Fig. 3).10
i
O
O
HO
Me
Me
+
Me
Me
9 (30%)
H2O
2
O
O
PO(OEt)2
LiO
Me
OLi
Me
LiO
Me
Me
2.3. Diethyl 2-oxopropylphosphonate
_
LiOPO(OEt)2
D
C
The cyclization of 2 with the dianion of diethyl 2-oxopropyl-
phosphonate (8), generated by means of LDA, afforded the
novel unsubstituted 1-hydroxyspiro[5.2]cyclooct-4-en-3-one 9
Scheme 4. Synthesis of spirocyclopropane 9, (i): (1) LDA (2.0 equiv), 8
(1.0 equiv), THF, 1 h, 0 ꢀC; (2) 2 (1.0 equiv), ꢁ78/20 ꢀC, 14 h.
(Scheme 4). The formation of 9 can be explained by cyclization
(intermediate C), elimination of lithium diethylphosphate
(intermediateD)andsubsequentprotonationuponadditionofwa-
ter. Alternatively, the reaction can be regarded as a domino ‘aldol/
HornereWadswortheEmmons(HWE)’reaction. TheBF3$OEt2-
mediatedreactionof 9with tetrabutylammoniumhalides afforded
the functionalized phenols 10aec (Scheme 5, Table 4).
O
H3C
N
O
CN
Me
5
i
O
O
HO
Me
+
Me
Me
6 (41%)
2
OH
ii
N(nBu)4X
CN
O
OH
Me
Me
X
N(nBu)4X
HO
Me
Me
Me
Me
X
i
7a-c
10a-c
9
Scheme 3. Synthesis of 7aec, (i): (1) LDA (2.0 equiv), 5 (1.0 equiv), THF, 1 h,
0 ꢀC; (2)
BF3$OEt2 (0.5 equiv), ꢁ78/20 ꢀC, 12 h.
2
(1.0 equiv), ꢁ78/20 ꢀC, 14 h; (ii): n-Bu4NX (1.0 equiv),
Scheme 5. Reaction of 9 with n-Bu4NX, (i): n-Bu4NX (1.0 equiv), BF3$OEt2
(0.5 equiv), ꢁ78/20 ꢀC, 12 h.
Table 4
Products and yields
Table 3
Products and yields
10
X
Yielda (%)
7
X
Yielda (%)
a
b
c
a
Cl
Br
I
73
68
63
a
b
c
Cl
Br
I
64
67
75
Yields of isolated products.
a
Yields of isolated products.
3. Conclusion
In conclusion, 1-hydroxyspiro[5.2]cyclooct-4-en-3-ones were
prepared bycyclization of b-ketosulfone, b-ketonitrile andb-keto-
phosphonatedianionswith1,1-diacetylcyclopropane.Theseprod-
ucts were transformed into functionalized phenols by Lewis acid
mediated reaction with tetrabutylammonium halides. The reac-
tions reported provide a convenienttwo-step approach to function-
alized phenols, which are not readily available by other methods.
4. Experimental section
4.1. General comments
All solvents were dried by standard methods and all reac-
1
tions were carried out under an inert atmosphere. For H and
Figure 3. Ortep plot of 7b.

N. Rasool et al. / Tetrahedron 64 (2008) 3246e3252
3249
13C NMR spectra the deuterated solvents indicated were used.
Mass spectrometric data (MS) were obtained by electron ioni-
zation (EI, 70 eV), chemical ionization (CI, H2O) or electro-
spray ionization (ESI). For preparative scale chromatography,
silica gel (60e200 mesh) was used. Melting points are
uncorrected.
(m), 1373 (m), 1301 (s), 1186 (s), 1086 (s), 981 (s), 815 (m),
543 (s) cmꢁ1; MS (CI, 70 eV): m/z (%): 321 ([Mþ1]þ) (100),
303 (10.21), 253 (11), 213 (9); HRMS (CI): calcd for
C17H21SO4 ([Mþ1]þ): 321.11521, found: 321.11551.
4.3. Typical procedure for the reaction of 8-hydroxy-4,8-
dimethyl-5-(phenylsulfonyl)spiro[2.5]oct-4-en-6-ones with
tetraalkylammonium halides
4.2. Typical procedure for the cyclization of b-ketosulfone
dianions with 1,1-diacetylcyclopropane
To a CH2Cl2 solution (12.4 mL) of 3a (500 mg, 1.63 mmol)
and of n-Bu4NCl (526 mg, 1.6 mmol) was dropwise added
BF3$OEt2 (0.10 mL, 0.8 mmol) at ꢁ78 ꢀC under argon atmo-
sphere. The solution was allowed to warm to 20 ꢀC over 6 h
and was stirred for additional 6 h at 20 ꢀC. The solution was fil-
tered and the filtrate was poured into an aqueous solution of HCl
(1.0 M). The organic and the aqueous layers were separated and
the latter was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried (Na2SO4), filtered, and
the filtrate was concentrated in vacuo. The residue was purified
by chromatography (silica gel, hexane/EtOAc) to give 4a as
a yellow solid (435 mg, 75%).
ATHF solution (8.5 mL) of LDAwas prepared by addition of
n-BuLi (3.10 mL, 7.7 mmol, 2.5 M solution in hexane) to a THF
solution of diisopropylamine (1.0 mL, 7.76 mmol) at 0 ꢀC.
After stirring for 1 h, b-ketosulfone 1 (768 mg, 3.88 mmol)
was added at ꢁ78 ꢀC and the solution was stirred for 1 h. To
the solution was added 1,1-diacetylcyclopropane (2) (490 mg,
3.88 mmol) at ꢁ78 ꢀC and the solution was allowed to warm
to 20 ꢀC for 14 h. To the reaction mixture was added an aqueous
solution of HCl (1 M) and the organic and aqueous layers were
extracted with CH2Cl2 and the combined organic layers were
washed with brine, dried (Na2SO4), filtered, and the filtrate
was concentrated in vacuo. The residue was purified by chroma-
tography (silica gel, hexane/EtOAc) to give 3a as a yellow solid
(230 mg, 30%).
4.3.1. 4-(2-Chloroethyl)-3,5-dimethyl-2-(phenylsulfonyl)-
phenol (4a)
Starting with 3a (300 mg, 1.0 mmol), n-Bu4NCl (272 mg,
1.0 mmol), CH2Cl2 (7.4 mL) and BF3$OEt2 (0.06 mL,
0.5 mmol), 4a was isolated (355 mg, 80%) as a colourless solid.
Mp¼192e196 ꢀC; 1H NMR (300 MHz, CDCl3): d¼2.27(s, 3H,
CH3), 2.33 (s, 3H, CH3), 2.89 (t, 2H, J¼7.6 Hz, CH2), 3.40 (t,
2H, J¼6.9 Hz, CH2), 6.79 (s, 1H, CH), 7.50e7.54 (m, 2H,
ArH), 7.60e7.65 (m, 1H, ArH), 7.83e7.87 (m, 1H, ArH),
10.45 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼16.5, 20.8
(CH3), 32.6, 41.7 (CH2), 118.6 (C), 119.1 (CH), 126.4 (2C,
CH), 128.3 (C), 129.2 (2C, CH), 133.5 (CH), 137.2, 142.1,
145.6, 157.1 (C); IR (KBr): ~n ¼ 3265ðsÞ, 2957 (w), 2920 (w),
1601 (s), 1445 (s), 1342 (s), 1295 (m), 1109 (s), 1157 (m),
762 (m), 691 (s), 649 (s), 568 (s) cmꢁ1; GCeMS (EI, 70 eV):
m/z (%): 324 (Mþ, 35Cl, 22), 275 (100), 133 (19), 91 (12), 77
(15); HRMS (EI): calcd for C16H17O3ClS [Mþ, 35Cl]:
324.05814, found: 324.057851.
4.2.1. 8-Hydroxy-4,8-dimethyl-5-(phenylsulfonyl)spiro-
[2.5]oct-4-en-6-one (3a)
1
Mp¼165e167 ꢀC; H NMR (300 MHz, CDCl3): d¼0.93e
0.97 (m, 1H, CH2), 1.13 (s, 3H, CH3), 1.28e1.32 (m, 1H,
CH2), 1.50e1.54 (m, 1H, CH2), 2.22 (s, 3H, CH3), 2.45 (d,
1H, J¼15.8 Hz, CH2), 2.55 (d, 1H, J¼15.8 Hz, CH2), 7.40e
7.49 (m, 3H, ArH), 7.83e7.87 (dd, 2H, J¼8.4, 3.6 Hz, ArH);
13C NMR (75 MHz, CDCl3): d¼11.5, 13.6 (CH2), 16.5, 25.8
(CH3), 38.8 (C), 52.4 (CH2), 69.7 (C), 128.0 (2C, CH), 128.9
(2C, CH), 133.3 (CH), 136.5, 149.0, 173.8, 191.4 (C); IR
(KBr): ~n ¼ 3407ðsÞ, 2967 (w), 2924 (w), 1664 (m), 1544 (s),
1447 (m), 1375 (m), 1334 (s), 1301 (s), 1088 (s), 732
(s) cmꢁ1; MS (CI): m/z (%): 307 ([Mþ1]þ) (100), 289
(11.21), 247 (6.07), 199 (2.82); HRMS (CI): calcd for
C16H19SO4 ([Mþ1]þ) 307.0996, found 307.1001.
4.2.2. 8-Hydroxy-4,8-dimethyl-5-(4-methylphenylsulfonyl)-
spiro[2.5]oct-4-en-6-one (3b)
4.3.2. 4-(2-Bromoethyl)-3,5-dimethyl-2-(phenylsulfonyl)-
phenol (4b)
Starting with n-BuLi (31 mL, 78.4 mmol, 2.5 M solution in
hexane), diisopropylamine (11 mL, 78.4 mmol), 1,1-diacetyl-
cyclopropane (2) (5.00 g, 39.7 mmol), and p-tolylsulfonylace-
tone (8.41 g, 39.7 mmol) in THF (86 mL), 3b was isolated as
a colourless solid. Mp¼160e163 ꢀC; 1H NMR (300 MHz,
CDCl3): d¼1.06e1.10 (m, 1H, CH2), 1.29 (s, 3H, CH3),
1.32e1.36 (m, 1H, CH2), 1.42e1.46 (m, 1H, CH2), 1.66e
1.70 (m, 1H, CH2), 2.37 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.66
(d, 1H, J¼13.4 Hz, CH2), 2.72 (d, 1H, J¼16.4 Hz, CH2), 7.38
(d, 2H, J¼8.0 Hz, ArH), 7.94 (d, 2H, J¼8.0 Hz, ArH); 13C
NMR (75 MHz, CDCl3): d¼11.3, 13.5 (CH2), 16.6, 22.0, 25.8
(CH3), 37.1 (C), 52.5 (CH2), 71.6 (C), 128.2 (2C, CH), 129.6
(2C, CH), 136.8, 140.0, 144.2, 173.8, 191.5 (C); IR (KBr):
~n ¼ 3489ðmÞ, 2974 (m), 2929 (m), 1718 (m), 1679 (s), 1597
Starting with 3a (500 mg, 1.6 mmol), n-Bu4NBr (526 mg,
1.63 mmol), CH2Cl2 (12.4 mL) and BF3$OEt2 (0.1 mL,
0.8 mmol), 4b was isolated (435 mg, 75%) as a colourless solid.
1
Mp¼144e146 ꢀC; H NMR (300 MHz, CDCl3): d¼2.31 (s,
3H, CH3), 2.52 (s, 3H, CH3), 3.05 (t, 2H, J¼7.7 Hz, CH2),
3.23 (t, 2H, J¼6.9 Hz, CH2), 6.79 (s, 1H, CH), 7.50e7.55 (m,
2H, ArH), 7.60e7.65 (m, 1H, ArH), 7.83e7.87 (m, 1H,
ArH), 10.62 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼16.9, 21.2 (CH3), 29.5, 33.4 (CH2), 119.1 (C), 119.7 (CH),
127.1 (2C, CH), 129.6 (2C, CH), 129.9 (C), 133.9 (CH),
137.5, 142.5, 146.1, 157.5 (C); IR (KBr): ~n ¼ 3264ðsÞ, 2955
(w), 1601 (s), 1558 (s), 1445 (s), 1342 (s), 1278 (m), 1126
(s), 1083 (s), 865 (w), 761 (m), 730 (s), 642 (m) cmꢁ1; GCe
MS (EI, 70 eV): m/z (%): 368 (Mþ, 79Br, 22), 289 (22), 275

3250
N. Rasool et al. / Tetrahedron 64 (2008) 3246e3252
(100), 133 (19), 91 (10), 77 (17); HRMS (EI): calcd for
C16H17O3BrS [Mþ, 79Br]: 368.00763, found: 368.007146.
MS (EI, 70 eV): m/z (%): 382 (Mþ, 79Br, 29), 303 (25),
289 (100), 197 (12), 133 (27), 91 (13), 65 (10); HRMS (EI):
calcd for C17H19O3BrS [Mþ, 79Br]: 382.02328, found:
382.02340.
4.3.3. 4-(2-Iodoethyl)-3,5-dimethyl-2-(phenylsulfonyl)-
phenol (4c)
Starting with 3a (500 mg, 1.6 mmol), n-Bu4NI (603 mg,
1.6 mmol), CH2Cl2 (12.4 mL) and BF3$OEt2 (0.1 mL,
0.8 mmol), 4c was isolated (425 mg, 81%) as a colourless solid.
4.3.6. 4-(2-Iodoethyl)-3,5-dimethyl-2-[(4-methylphenyl)-
sulfonyl]phenol (4f)
Starting with 3b (400 mg, 1.3 mmol), n-Bu4NI (461 mg,
1.3 mmol), CH2Cl2 (9.5 mL) and BF3$OEt2 (0.08 mL,
0.6 mmol), 4f was isolated (520 mg, 84%) as a colourless solid.
Mp¼136e139 ꢀC; 1H NMR (300 MHz, CDCl3): d¼2.23 (s, 3H,
CH3), 2.29 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.94e2.98 (m, 2H,
CH2), 3.03e3.07 (m, 2H, CH2), 6.75 (s, 1H, CH), 7.30 (d, 2H,
J¼7.8 Hz, ArH), 7.70 (d, 2H, J¼8.4 Hz, ArH), 10.47 (s, 1H,
OH); 13C NMR (75 MHz, CDCl3): d¼0.0 (CH2I), 15.6, 19.9,
20.7 (CH3), 33.4 (CH2), 118.1 (C), 118.4 (CH), 126.7 (2C,
CH), 128.9 (2C, CH), 130.8, 135.9, 138.3, 143.7, 144.2. 155.0
(C); IR (KBr): ~n ¼ 3206ðmÞ, 2900 (s), 1597 (s), 1562 (s),
1493 (m), 1348 (m), 1259 (m), 1166 (w), 1125 (s), 709 (s),
696 (s), 648 (w), 523 (m) cmꢁ1; GCeMS (EI, 70 eV): m/z
(%): 430 (Mþ, 7), 303 (100), 289 (10), 209 (7), 133 (10), 91
(18), 77 (8); HRMS (EI): calcd for C17H19O3IS [Mþ]:
430.00872, found 430.00864.
1
Mp¼170e171 ꢀC; H NMR (300 MHz, CDCl3): d¼2.24 (s,
3H, CH3), 2.30 (s, 3H, CH3), 2.94e2.98 (m, 2H, CH2), 3.05e
3.10 (m, 2H, CH2), 6.78 (s, 1H, CH), 7.50e7.54 (m, 2H,
ArH), 7.58e7.62 (m, 1H, ArH), 7.83e7.87 (m, 1H, ArH),
10.54 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼0.0
(CH2), 15.8, 20.0 (CH3), 33.5 (CH2), 117.9 (C), 118.4 (CH),
125.7 (2C, CH), 128.4 (2C, CH), 131.0 (C), 132.7 (CH),
136.0, 141.3, 144.5, 156.2 (C); IR (KBr): ~n ¼ 3262ðsÞ, 2950
(w), 1598 (s), 1559 (s), 1445 (s), 1341 (s), 1291 (s), 1207
(m), 1125 (s), 1082 (s), 866 (m), 727 (s), 690 (s), 667 (m),
548 (s) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 416 (Mþ, 6),
289 (100), 275 (7), 196 (5), 148 (11), 91 (10), 77 (15);
HRMS (EI): calcd for C16H17O3IS [Mþ]: 415.99376, found:
415.99368.
4.3.4. 4-(2-Chloroethyl)-3,5-dimethyl-2-[(4-methylphenyl)-
sulfonyl]phenol (4d)
4.3.7. 8-Hydroxy-4,8-dimethyl-5-cyanospiro[2.5]oct-4-en-
6-one (6)
Starting with 3b (300 mg, 0.9 mmol), n-Bu4NCl (260 mg,
0.9 mmol), CH2Cl2 (7.0 mL) and BF3$OEt2 (0.06 mL,
0.5 mmol), 4d was isolated (248 mg, 78%) as a colourless solid.
Starting with n-BuLi (48.8 mL, 122.0 mmol, 2.5 M solution
in hexane), diisopropylamine (17.2 mL, 122.0 mmol), 1,1-diac-
etylcyclopropane (2) (7.70 g, 61.4 mmol), and 5-methylisoxa-
zole (5) (5.00 g, 61.4 mmol) in THF (134 mL), 6 was isolated
1
Mp¼118e121 ꢀC; H NMR (300 MHz, CDCl3): d¼2.40 (s,
3H, CH3), 2.46 (s, 3H, CH3), 2.55 (s, 3H, CH3), 3.11 (t, 2H,
J¼8.0 Hz, CH2), 3.53 (t, 2H, J¼6.6 Hz, CH2), 6.96 (s, 1H,
CH), 7.43 (d, 2H, J¼8.0 Hz, ArH), 8.37 (d, 2H, J¼8.0 Hz,
ArH), 10.74 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼16.9, 21.3, 22.0 (CH3), 33.0, 42.1 (CH2), 119.4 (C), 119.5
(CH), 126.5 (2C, CH), 129.7 (C), 130.2 (2C, CH), 137.7,
139.4, 144.9, 145.8, 157.8 (C); IR (KBr): ~n ¼ 3193ðmÞ, 2960
(w), 2854 (w), 1605 (m), 1566 (m), 1463 (m), 1240 (s), 1124
(s), 1085 (s), 811 (w), 684 (s), 548 (m), 555 (s) cmꢁ1; GCe
MS (EI, 70 eV): m/z (%): 338 (Mþ, 35Cl, 28), 289 (100), 197
(11), 133 (23), 91 (14), 77 (10); HRMS (EI): calcd for
C17H19O3ClS [Mþ, 35Cl]þ: 338.07379, found: 338.07326.
1
as yellow oil (4.80 g, 41%); H NMR (300 MHz, CDCl3):
d¼0.94e1.07 (m, 2H, CH2), 1.25e1.32 (m, 1H, CH2), 1.22
(s, 3H, CH3), 1.61e1.68 (m, 1H, CH2), 2.03 (s, 3H, CH2),
2.69 (d, 2H, J¼5.7 Hz, CH2); 13C NMR (62 MHz, CDCl3):
d¼12.1, 13.7 (CH2), 19.6, 25.4 (CH3), 34.2 (C), 51.0 (CH2),
70.1 (C), 114.1 (CN), 128.7, 171.9, 191 (C); IR (neat): ~n ¼
3488ðmÞ, 2969 (w), 2931 (w), 2228 (m), 1678 (s), 1573 (m),
1383 (s), 1295 (s), 1164 (w), 1089 (m), 965 (w), 740
(w) cmꢁ1; GCeMS (CI, 70 eV): m/z (%) 191 ([Mþ1]þ)
(100), 148 (11), 125 (7), 74 (6); HRMS (CI): calcd for
C11H13O2N ([Mþ1]þ): 191.09408, found: 191.093758.
4.3.5. 4-(2-Bromoethyl)-3,5-dimethyl-2-[(4-methylphenyl)-
sulfonyl]phenol (4e)
4.3.8. 4-(2-Chloroethyl)-3,5-dimethyl-2-cyanophenol (7a)
Starting with 6 (300 mg, 1.6 mmol), n-Bu4NCl (436 mg,
1.6 mmol), CH2Cl2 (11.9 mL) and BF3$OEt2 (0.10 mL,
0.8 mmol), 7a was isolated (205 mg, 64%) as a colourless solid.
Starting with 3b (500 mg, 1.5 mmol), n-Bu4NBr (503 mg,
1.5 mmol), CH2Cl2 (11.8 mL) and BF3$OEt2 (0.10 mL,
0.8 mmol), 4e was isolated (395 mg, 68%) as a colourless solid.
1
1
Mp¼135e137 ꢀC; H NMR (300 MHz, CDCl3): d¼2.46 (s,
Mp¼124e126 ꢀC; H NMR (300 MHz, acetone-d6): d¼2.40
3H, CH3), 2.51 (s, 3H, CH3), 2.61 (s, 3H, CH3), 3.24 (t, 2H,
J¼7.8 Hz, CH2), 3.66 (t, 2H, J¼6.1 Hz, CH2), 6.97 (s, 1H,
CH), 7.49 (d, 2H, J¼8.0 Hz, ArH), 8.37 (d, 2H, J¼8.4 Hz,
ArH), 10.76 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼16.5, 18.9, 20.8 (CH3), 34.2, 41.8 (CH2), 119.1 (C), 119.7
(CH), 126.5 (2C, CH), 128.2 (C), 129.8 (2C, CH), 139.2,
141.3,144.5, 145.5, 160.0 (C); IR (KBr): ~n ¼ 3194ðmÞ, 2955
(w), 2853 (w), 1605 (m), 1565 (m), 1462 (m), 1239 (s), 1124
(s), 1085 (s), 811 (m), 685 (s), 548 (m), 555 (s) cmꢁ1; GCe
(s, 3H, CH3), 2.54 (s, 3H, CH3), 3.20e3.25 (m, 2H, CH2),
3.64e3.68 (m, 2H, CH2), 6.92 (s, 1H, CH), 9.90 (s, 1H, OH);
13C NMR (62 MHz, CDCl3): d¼18.2, 20.7 (CH3), 29.7, 43.1
(CH2), 100.0 (C), 116.2 (CH), 116.6, 129.0, 142.1, 146.6,
159.3 (C); IR (KBr): ~n ¼ 3194ðsÞ, 2961 (w), 1605 (s), 1566
(m), 1463 (s), 1350 (m), 1240 (m), 1224 (s), 684 (s), 555
(m) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 209 (Mþ, 35Cl, 13),
160 (100), 77 (5); HRMS (EI): calcd for C11H12ONCl [Mþ,
35Cl]: 209.06019, found: 209.06040.

N. Rasool et al. / Tetrahedron 64 (2008) 3246e3252
3251
4.3.9. 4-(2-Bromoethyl)-3,5-dimethyl-2-cyanophenol (7b)
Starting with 6 (400 mg, 2.0 mmol), n-Bu4NBr (674 mg,
2.0 mmol), CH2Cl2 (15.2 mL) and BF3$OEt2 (0.13 mL,
1.0 mmol), 7b was isolated (142 mg, 67%) as a colourless solid;
1H NMR (300 MHz, acetone-d6): d¼2.57 (s, 3H, CH3), 2.71 (s,
3H, CH3), 3.40 (t, 2H, J¼7.6 Hz, CH2), 3.72 (t, 2H, J¼7.4 Hz,
CH2), 6.98 (s, 1H, CH), 9.82 (s, 1H, OH); 13C NMR (62 MHz,
CDCl3): d¼18.1, 20.6 (CH2), 30.7, 33.4 (CH3), 100.4 (C), 116.2
(CH), 116.6, 129.0, 142.0, 144.6, 159.3 (C); IR (KBr): ~n ¼
2958ðmÞ, 2928 (m), 2858 (m), 1728 (s), 1464 (m), 1286 (s),
1124 (m), 1073 (w), 742 (m), 704 (w) cmꢁ1; GCeMS (EI,
70 eV): m/z (%): 253 (Mþ, 79Br, 16), 174 (49), 160 (100),
77 (6); HRMS (EI): calcd for C11H12ONBr [Mþ, 79Br]:
253.00968, found: 253.00949.
(m), 1621 (s), 1582 (m), 1449 (s), 1315 (m), 1180 (m), 1161
(s), 1112 (w), 834 (m) cmꢁ1; GCeMS (EI, 70 eV): m/z (%):
184 (Mþ, 35Cl, 13), 148 (6), 135 (100), 105 (10), 91 (14), 77
(9); HRMS (EI): calcd for C10H13OCl [Mþ, 35Cl]: 184.05432,
found: 184.05631.
4.3.13. 4-(2-Bromoethyl)-3,5-dimethylphenol (10b)
Starting with 8-hydroxy-4,8-dimethylspiro[2.5]oct-4-en-6-
one (9) (180 mg, 1.0 mmol), n-Bu4NBr (322 mg, 1.0 mmol),
CH2Cl2 (7.6 mL) and BF3$OEt2 (0.074 mL, 1.0 mmol), 10b
was isolated (170 mg, 68%) as a colourless solid. Mp¼76e
79 ꢀC;1H NMR (300 MHz, CDCl3): d¼2.21 (s, 6H, CH3),
3.12 (t, 2H, J¼6.3 Hz, CH2), 3.34 (t, 2H, J¼6.5 Hz, CH2),
6.40 (s, 2ꢂ1H, CH); 13C NMR (62 MHz, CDCl3): d¼19.2
(2C, CH3), 30.0, 32.7 (CH2), 115.2 (2C, CH), 126.9 (C),
138.2 (2C, C), 153.8 (C); IR (KBr): ~n ¼ 3314ðsÞ, 2966 (S),
2855 (w), 1596 (s), 1475 (s), 1318 (m), 1213 (w), 1191 (m),
1138 (s), 1025 (s), 852 (m), 633 (s) cmꢁ1; GCeMS (EI,
70 eV): m/z (%): 228 (Mþ, 79Br, 19), 149 (60), 135 (100),
105 (10), 91 (16), 77 (10); HRMS (EI): calcd for
C10H13OBr [Mþ, 79Br]þ: 228.01444, found: 228.01429.
4.3.10. 4-(2-Iodoethyl)-3,5-dimethyl-2-cyanophenol (7c)
Starting with 6 (400 mg, 2.0 mmol), n-Bu4NI (738 mg,
2.0 mmol), CH2Cl2 (15.2 mL) and BF3$OEt2 (0.13 mL,
1.0 mmol), 7c was isolated (475 mg, 75%) as a colourless solid.
1
Mp¼185e188 ꢀC; H NMR (300 MHz, acetone-d6): d¼2.50
(s, 3H, CH3), 2.64 (s, 3H, CH3), 3.34e3.38 (m, 2H, CH2),
3.43e3.47 (m, 2H, CH2), 6.89 (s, 1H, CH), 9.85 (s, 1H, OH);
13C NMR (75 MHz, CDCl3): d¼2.7 (CH2), 18.5, 20.9 (CH3),
35.1 (CH2), 100.0 (C), 116.6 (CH), 117.6, 131.6, 141.9,
144.5, 159.6 (C); IR (KBr): ~n ¼ 3223ðsÞ, 2923 (w), 2232 (s),
1598 (s), 1443 (m), 1312 (m), 1168 (m), 1090 (w), 867 (m),
705 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 300 (Mþ, 5),
174 (100), 160 (18), 77 (5); HRMS (EI): calcd for
C11H12ONI [Mþ]: 300.99581, found: 300.995296.
4.3.14. 4-(2-Iodoethyl)-3,5-dimethylphenol (10c)
Starting with 9 (135 mg, 0.8 mmol), n-Bu4NI (298 mg,
0.8 mmol), CH2Cl2 (6.1 mL) and BF3$OEt2 (0.10 mL,
0.8 mmol), 10c was isolated (170 mg, 68%) as a colourless
1
solid. Mp¼69e72 ꢀC; H NMR (250 MHz, CDCl3): d¼2.23
(s, 6H, CH3), 3.01 (t, 2H, J¼4.7 Hz, CH2), 3.06 (t, 2H,
J¼4.7 Hz, CH2), 6.40 (s, 2H, CH); 13C NMR (62 MHz,
CDCl3): d¼0.00 (CH2) 17.7 (2C, CH3), 32.1 (CH2), 112.6
(2C, CH), 128,1 (C), 135.8 (2C, C), 151.1 (C); IR (KBr): ~n ¼
3362ðsÞ, 3402 (S), 2960 (w), 1705 (m), 1606 (s), 1595 (m),
1460 (s), 1312 (s), 1190 (m), 1166 (s), 1133 (s), 1024 (s), 850
(m) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 276 (Mþ, 8), 149
(100), 135 (21), 105 (10), 91 (13), 77 (9); HRMS (EI): calcd
for C1oH13OI [Mþ]þ: 276.00056, found: 276.07548.
4.3.11. 8-Hydroxy-4,8-dimethylspiro[2.5]oct-4-en-6-one (9)
Starting with n-BuLi (28.6 mL, 57.2 mmol, 2.5 M solution
in hexane), diisopropylamine (8.6 mL, 57.2 mmol), 1,1-diace-
tylcyclopropane (2) (7.70 g, 61.4 mmol), and diethyl 2-oxo-
phosphonate 8 (5.55 g, 28.6 mmol) in THF (62 mL), 9 was
isolated as gummy compound (2.20 g, 29%); 1H NMR
(300 MHz, CDCl3): d¼0.76e0.80 (m, 1H, CH2), 0.97e1.02
(m, 2H, CH2), 1.22 (s, 3H, CH3), 1.34e1.38 (m, 1H, CH2),
1.68 (s, 3H, CH3), 2.54 (d, 2H, J¼15.8 Hz, CH2), 2.65 (d,
2H, J¼15.8 Hz, CH2); 13C NMR (62 MHz, CDCl3): d¼9.0,
10.2 (CH2), 19.9, 25.3 (CH3), 32.1 (C), 51.8 (CH2), 72.5 (C),
126.5 (CH), 161.5, 198.4 (C); IR (neat): ~n ¼ 3403ðsÞ, 2975
(m), 1648 (s), 1604 (s), 1444 (m), 1387 (m), 1286 (m), 1144
(m), 1028 (m), 963 (m), 860 (m), 641 (w) cmꢁ1; GCeMS
(EI, 70 eV): m/z (%): 166 (Mþ, 41), 148 (50), 138 (40), 123
(38), 107 (85), 79 (100), 43 (85); HRMS (EI): calcd for
C10H14O2 [Mþ]þ: 166.09883, found: 166.09916.
Acknowledgements
Financial support from the state of Pakistan (HEC scholar-
ships for N.R. and M.A.R.) is gratefully acknowledged.
References and notes
1. (a) Zips, D.; Thames, H. D.; Baumann, M. In Vivo 2005, 19, 1; (b) Kim, R.
Cancer 2005, 103, 1551; (c) Kim, J.; Park, E. J. Curr. Med. Chem.
Anti-Cancer Agents 2002, 2, 485.
2. (a) Filipits, M. Drug Discov. Today 2004, 1, 229; (b) Righetti, S. C.; Gatti,
L.; Beretta, G. L.; Zunino, F.; Perego, P. Rec. Res. Dev. Mol. Pharmacol.
2002, 1, 167.
4.3.12. 4-(2-Chloroethyl)-3,5-dimethylphenol (10a)
Starting with 9 (334 mg, 2.0 mmol), n-Bu4NCl (554 mg,
2.0 mmol), CH2Cl2 (16 mL) and BF3$OEt2 (0.25 mL,
2.0 mmol), 10a was isolated (170 mg, 68%) as a colourless
solid; 1H NMR (300 MHz, CDCl3): d¼2.22 (s, 6H, CH3),
2.98e3.02 (m, 2H, CH2), 3.38e3.43 (m, 2H, CH2), 6.43 (s,
2H, CH); 13C NMR (75 MHz, CDCl3): d¼19.2 (2C, CH3),
30.1, 42.4 (CH2), 115.0 (2C, CH), 126.9 (C), 138.2 (2C, C),
153.8 (C); IR (KBr): ~n ¼ 3355ðmÞ, 3423 (s), 2920 (m), 1712
3. (a) Saever, F. J. J. New York Bot. Gard. 1938, 263; (b) Seaver, F. J. J. New
York Bot. Gard. 1939, 236; (c) Nakanishi, K.; Tada, M.; Yamada, Y.;
Ohashi, M.; Komatsu, N.; Terekawa, H. Nature 1963, 197, 292; (d)
Anchel, M.; Hervey, A.; Robbins, W. J. Proc. Natl. Acad. Sci. U.S.A.
1950, 36, 300; (e) McMorris, T. C.; Anchel, M. J. Am. Chem. Soc.
1963, 85, 831; (f) McMorris, T. C.; Anchel, M. J. Am. Chem. Soc. 1965,
87, 1594; (g) Ayer, W. A.; Browne, L. M. Tetrahedron 1981, 37, 2199;
(h) McMorris, T. C.; Kelner, M. J.; Wang, W.; Estes, L. A.; Montoya,

3252
N. Rasool et al. / Tetrahedron 64 (2008) 3246e3252
M. A.; Taetle, R. J. Org. Chem. 1992, 57, 6876; For the synthesis of an
illudinoid library, see: (i) Pirrung, M. C.; Liu, H. Org. Lett. 2003,
5, 1983.
Toder, B. H. J. Am. Chem. Soc. 1982, 104, 4244; (h) Schultz, A. G.;
Taveras, A. G. Tetrahedron Lett. 1996, 37, 5853.
6. Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1996, 61, 73.
7. (a) Langer, P.; Bose, G. Angew. Chem. 2003, 115, 4165; Angew. Chem.,
Int. Ed. 2003, 42, 4033; (b) Bose, G.; Nguyen, V. T. H.; Ullah, E.; Lahiri,
4. (a) Bryson, T. A.; Roth, G. A. Tetrahedron Lett. 1988, 29, 2167; (b) Boger,
D. L.; Johnson, D. S. J. Am. Chem. Soc. 1990, 112, 5832; (c) Boger, D. L.;
Garbaccio, R. M.; Jin, Q. J. Org. Chem. 1997, 62, 8875; (d) Boger, D. L.;
Boyce, C. W.; Carpaccio, R. M.; Goldberg, J. A. Chem. Rev. 1997, 97,
S.; Gorls, H.; Langer, P. J. Org. Chem. 2004, 69, 9128; (c) Bose, G.;
¨
Langer, P. Tetrahedron Lett. 2004, 3861; (d) Bose, G.; Bracht, K.;
Bednarski, P. J.; Lalk, M.; Langer, P. Bioorg. Med. Chem. 2006, 14, 4694.
8. Pound, M. K.; Davies, D. L.; Pilkington, M.; Sousa, M. M.; Wallis, J. D.
Tetrahedron Lett. 2002, 43, 1915.
787; (e) Tietze, L. F.; Hannemann, R.; Buhr, W.; Logers, M.; Menningen,
¨
¨
P.; Lieb, M.; Starck, D.; Grote, T.; Doring, A.; Schuberth, I. Angew. Chem.
1996, 108, 2840; Angew. Chem., Int. Ed. 1996, 35, 2674; (f) Tietze, L. F.;
Buhr, W.; Looft, J.; Grote, T. Chem.dEur. J. 1998, 4, 1554.
9. Langer, P.; Holtz, E.; Saleh, N. N. R. Chem.dEur. J. 2002, 8, 917.
10. CCDC-674698 (3b), CCDC-674699 (4f) and CCDC-674700 (7b) contain all
crystallographic details of this publication and are available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.htmlorcanbeorderedfromthefollow-
ing address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB21EZ; fax: (þ44)1223 336 033; or deposit@ccdc.cam.ac.uk.
11. Vinick, F. J.; Pan, Y.; Gschwend, H. W. Tetrahedron Lett. 1978, 44,
4221.
5. (a) Baird, R.; Winstein, S. J. Am. Chem. Soc. 1957, 79, 4238; (b) Baird,
R.; Winstein, S. J. Am. Chem. Soc. 1963, 85, 574; (c) Woolhouse, A. D.
Aust. J. Chem. 1977, 30, 1145; (d) Schuster, D. I.; Polowczyk, C. J.
J. Am. Chem. Soc. 1966, 88, 1722; (e) Phillips, J. P.; Gillmore, J. G.;
Schwartz, P.; Brammern, L. E., Jr.; Berger, D. J.; Tanko, J. M. J. Am.
Chem. Soc. 1998, 120, 195; (f) Ward, R. S.; Thatcher, K. S. Tetrahedron
Lett. 1981, 22, 4831; (g) Kende, A. S.; Hebeisen, P.; Sanfilippo, P. J.;