Reaction of 1-substituted 2,2-dimethyl-3-phenylpropane with t-BuOK in DMSO. An unexpected formation of a cyclopropane ring

Full text of DOI:10.1021/jo9905165

J . Org. Chem. 1999, 64, 6115-6118
6115
When we performed this reaction with 2 with an excess
of t-BuOK, besides the reduction product 3, 1,1-dimethyl-
2-phenylcyclopropane 5 was formed (eq 3).
Rea ction of 1-Su bstitu ted
2,2-Dim eth yl-3-p h en ylp r op a n e w ith t-Bu OK
in DMSO. An Un exp ected F or m a tion of a
Cyclop r op a n e Rin g
J uan E. Argu¨ello, Alicia B. Pen˜e´n˜ory,* and
Roberto A. Rossi*
INFIQC, Departamento de Quı´mica Orga´nica, Facultad de
Ciencias Quı´micas, Universidad Nacional de Co´rdoba,
5000 Co´rdoba, Argentina
The ring-closure product 5 was not observed in the
reaction with ketone enolate ions without t-BuOK in
excess. The pKa of t-BuOH is 32.2 in DMSO,5 much
higher than acetone (26.5)5 and acetophenone (24.7);5
meanwhile, the value for a benzylic or R-iodoalkyl is
around 40.5 In the reaction of 6-iodo-5,5-dimethyl-1-
hexene with the strong base LDA, the formation of a
carbene intermediate has been reported, yielding C-H
insertion and addition to the double-bond products. This
reaction occurred simultaneously with an ET pathway.6
Product 5 can proceed from two possible competitive
mechanisms:7 (i) deprotonation of the R hydrogen of
carbon 1 and subsequent loss of halide ion leads to the
carbene 6, which affords the insertion products 5 and 7
(eq 4); (ii) deprotonation of the benzylic carbon gives the
carbanion 8, which, by an intramolecular nucleophilic
substitution, gives product 5 (eq 5).
Received March 23, 1999
Neopentyl derivatives, which are very unreactive
substrates in polar nucleophilic substitution,1 have been
proposed to react with different nucleophiles by an ET
process in a cage collapse2 or a chain mechanism (or SRN1)
giving the substitution products.3
Several carbanions failed to react in liquid ammonia.
In DMSO, neopentyl iodide reacts with carbanions such
as the enolate anion of acetophenone, anthrone, and
nitromethane anion with good yields of substitution (eq
1).4
With the enolate ion of acetone, neopentyl iodide gives
only 100% of dehalogenation, and no substitution prod-
ucts were found. In the photostimulated reaction of
1-iodo-2,2-dimethyl-3-phenylpropane (1) with the enolate
ion of acetone (2), only reduction 3 (50%) or dimerization
4 (20%) products of the radical intermediate are observed
(eq 2).This was ascribed to the lower reactivity of the
nucleophile in the coupling reaction with the neopentyl
radical.
To establish the mechanism of the formation of 5, we
studied the reaction of 1-substituted 2,2-dimethyl-3-
phenylpropane with t-BuOK in DMSO.
Effect of th e Lea vin g Gr ou p . The reaction of 1-iodo-
2,2-dimethyl-3-phenylpropane (1) with t-BuOK in a 1:3
ratio gives 52% of dehalogenation and 46% of 5 after 30
min. The formation of 5 was 87% after 2 h of reaction at
50 °C (Table 1, entries 1 and 2). In these reactions, two
minor products 9 and 10 are formed, presumably coming
from an SN2 reaction of 1 with t-BuOK and dimsyl anion.
With the chloride derivative 11, 6 h were needed to
yield 5 in 63% yield (Table 1, entry 3). When the leaving
group was tosylate (12) and the reaction mixture after
30 min quenched with methyl iodide, only 2% of 5 was
* To whom correspondence should be addressed. Fax: 54-351-433-
3030. E-mail: rossi@dqo.fcq.unc.edu.ar.
(1) March, J . Advanced Organic Chemistry, 4th ed.; J ohn Wiley &
Sons: New York, 1992.
(2) (a) Ashby, E. C.; Argyropoulus J . N. J . Org. Chem. 1985, 50,
3274. (b) Ashby, E. C.; Gurumurthy, R.; Ridlehuber, R. W. J . Org.
Chem. 1993, 58, 5832.
(3) (a) Pierini, A. B.; Pen˜e´n˜ory, A. B.; Rossi, R. A. J . Org. Chem.
1985, 50, 2739. (b) Bornancini, E. R. N.; Palacios, S. M.; Pen˜e´n˜ory, A.
B.; Rossi, R. A. J . Phys. Org. Chem. 1989, 2, 255.
(5) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(6) Ashby, E. C.; Park, B.; Patil, G. S.; Gadru, K.; Gurumurthy, R.
J . Org. Chem. 1993, 58, 424.
(7) It is known that cyclizations to small rings have an entropy
advantage. Ab initio calculations demonstrate that although three-
membered rings have high ring strain, the enthalpic barrier to forming
them can be very small. Gronert, S.; Azizian, K.; Friedman, M. A. J .
Am. Chem. Soc. 1998, 120, 3220 and references therein.
(4) Pen˜e´n˜ory, A. B.; Rossi, R. A. Gazz. Chim. Ital. 1995, 125, 1.
10.1021/jo9905165 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/16/1999

6116 J . Org. Chem., Vol. 64, No. 16, 1999
Notes
Ta ble 1. Rea ction s of Neop en tyl Der iva tives w ith
Ta ble 2. Effect of th e Tr a p p in g Agen t on th e Rea ction s
t-Bu OK in DMSOa
of 1 w ith t-Bu OK in DMSOa
entry substrate time, h convnb (%)
productsc (%)
productsc (%)
reaction conditions
entry [1]/[t-BuOK]/[trapping agent]
convnb
(%)
5
9
10
1
2
3
4
5
6
7
8
1
1
0.5
2.0
6.0
0.5d
0.5
j
52.1
95.2
64.0
e
64.2
0
5 (46.1), 9 (3.4), 10 (4.0)
5 (87.2), 9 (5.9), 10 (3.0)
5 (63.0)
1
2
3
4
5
[1]/[t-BuOK], 1:5
76.8
71.4
31.4
d
69.5 4.6
5
11
12
13
13
14a
14b
[1]/[t-BuOK]/[t-BuNH2], 1:5:5
[1]/[t-BuOK]/[t-BuOH], 1:5:5
[1]/[t-BuOK], 1:3, DMSO-d6
[1]/[t-BuOK]/[t-BuOD], 1:3:3,
DMSO-d6
65.9 4.3 4.3
30.9 3.1
5 (2.0)f,g
5 (10.0)h, 9i
e, f
e
e
d
6.7g
72.0
0.5
0
28.6
16 (16.1), 17 (10.5)
a
Performed under nitrogen atmosphere and protected from
a
Performed under nitrogen atmosphere and protected from
b
incident light, reaction time 30 min. Conversion determined by
quantification of the halide ions by potentiometric titration with
AgNO3 (0.1 M). c The reaction products 5, 9, and 10 were quanti-
fied by gas-liquid chromatography, using the internal standard
incident light; 0.04 M solutions of substrate and 0.12 M of t-BuOK
were used. b Conversion determined by quantification of the halide
ions by potentiometric titration with AgNO3 (0.1 M) or quantifica-
tion of unreacted substrate by gas-liquid chromatography. c The
reaction products 5, 9, 10, 16, and 17 were quantified by gas-
liquid chromatography using the internal standard method, error
d
method, error 5%. The reactions were performed in 1.0 mL of
DMSO-d6, and the halide ions were not quantified. e Not quanti-
fied. f No incorporation of deuterium was detected in 1 and 5 by
d
5%. Quenched with methyl iodide. e Undetermined. f The reac-
g
GC-mass spectrometry. 11% of deuterium incorporation was
determined in the substrate by GC-mass spectrometry.
g
tion develops a dark green color. Together with neopentyl p-
h
ethylbenzenesulfonate derivative. Together with 53.8% of 2,2-
i
j
dimethyl-3-phenylpropan-1-ol. Not quantified. A solution of
substrate, without t-BuOK, was treated with diethyl ether and
water and extracted. The substrate was recovered unchanged.
When a mixture of 1-chloro-2-methyl-2-phenylpropane
(neophyl chloride, 14a , X ) Cl) and t-BuOK was stirred
during 3 days, no products were found. With the iodide
derivative (14b, X ) I), only products coming from a
classical nucleophilic substitution with t-BuOK and
dimsyl anion were observed (Table 1, entries 7 and 8).
quantified together with products coming from methy-
lation on the methyl group of the phenyl ring (Table 1,
entry 4). To avoid deprotonation of the methyl group,
benzenesulfonate 13 was used as leaving group instead
of tosylate. Thus, the reaction 13 gives 10% of 5 with
53.8% of 2,2-dimethyl-3-phenylpropan-1-ol. As control
experiments, a solution of the sulfonate 13 in DMSO was
treated with diethyl ether and water the same as during
the workup of the reactions. After the extraction, sul-
fonate 13 was recovered without changes (Table 1, entries
5 and 6).
Not even traces of the cyclopropane derivative (15)
were detected in these two reactions; however, the
formation of a carbene intermediate is more probable in
the chloride derivative due to the higher inductive effect
of the chloride than the iodide ion.
The carbene intermediate 6 was generated by an
alternative pathway, that is, thermal decomposition of
the corresponding tosylhydrazone 18 derived from the
2,2-dimethyl-3-phenylpropanal.10 In this reaction, 5 and
7 are observed as minor products, with a complex mixture
of alkenes, coming from migration of the methyl or benzyl
group in the carbene intermediate (eq 9). Similar results
were reported by Kirmse et al. under almost identical
reaction conditions.10
The effect of the leaving group I > SO3C6H5 > Cl on
the reactivity for this series of substrates is expected for
a polar reaction.8 The sulfonates showed a lower reactiv-
ity than the iodide, probably due to a competitive
hydrolysis reaction in the presence of t-BuOK.9
Effect of th e Su bstr a te Str u ctu r e. To test which
methylenic hydrogen is involved in the formation of the
cyclopropane, we studied the reactivity of the neophyl
derivatives. For these substrates with no benzylic hy-
drogen, the mechanism of eq 5 is not possible, and the
cyclopropane derivative 15 would be formed if a carbene
were an intermediate (eq 7).
Both results (reactivity of 14 and the products coming
from the carbene intermediate generated from 18) al-
lowed us to discard the intermediacy of a carbene in the
formation of 5 (eq 4).
Effects of La beled Solven t a n d Tr a p p in g Agen ts.
The reaction of 1 with t-BuOK in a 1:5 ratio gives after
30 min 77% of dehalogenation and the products 5 (69.5%),
9 (4.6%), and 10 (5.0%) (Table 2, entry 1). To test the
intermediacy of a carbanion, this reaction was conducted
in the presence of tert-butylamine, a well-known trapping
agent for these intermediates,11 in a 1:5:5 ratio (1/t-
BuOK/t-BuNH2). The product distribution and yields
(10) Kirmse, W.; Schladetsch, H. J .; Bu¨cking, H-W. Chem. Ber. 1966,
99, 2579.
(11) Smith, G. F.; Kuivila, H. G.; Simon, R.; Sultan, L. J . Am. Chem.
Soc. 1981, 103, 833.
(8) March, J . Advanced Organic Chemistry, 4th ed.; J ohn Wiley &
Sons: New York, 1992; Table 10.10, p 357.
(9) Bunnett, J . F.; Basset, J . Y. J . Am. Chem. Soc. 1959, 81, 2104.

Notes
J . Org. Chem., Vol. 64, No. 16, 1999 6117
filtered and recrystallized from ethanol/water (50:50): 1.645 g,
observed were almost the same (Table 2, entry 2). When
the more acidic t-BuOH (pKa 32.2) was used (1:5:5 ratio),
the yield of 5 was significantly depressed to 30.9% (Table
2, entry 3).
When the reaction of 1 with t-BuOK was performed in
DMSO-d6 for 30 min and the anions neutralized with
D2O, no incorporation of deuterium was detected in 1 and
5 by GC-mass spectrometry. The only products observed
were 5, 9, and 10. In the presence of t-BuOK and an
equimolar amount of t-BuOD, the yield of 5 decreased to
6.7%, and 11% deuterium incorporation was observed for
the substrate, affording 1-d . No other products were
detected (Table 2, entries 4 and 5).
1
34% yield; mp 136-137 °C (lit.10 mp 137 °C); H NMR (CDCl3)
δ 1.0 (6H, s), 2.4 (3H, s), 2.6 (2H, s), 6.85-6.95 (2H, m), 7.0 (1H,
s), 7.1-7.2 (3H, m), 7.2-7.8 (4H, dd); 13C NMR (CDCl3) δ 21.6,
24.9, 39.0, 46.9, 126.1, 127.8, 127.9, 129.4, 130.2, 135.1, 137.3,
143.9. MS (EI+) 240 (49.6), 239 (61.8), 92 (44.2), 91 (100.0).
Decom p osition of th e Tosylh yd r a zon e 18 w ith Sod iu m
Meth oxid e. The tosylhydrazone of 18 (0.59 g, 1.8 mmol) was
dissolved in 25 mL of diglime, sodium methoxide (0.49 g, 7.2
mmol) was added to this solution, and the flask was gradually
heated in an oil bath. At 150 °C, decomposition of tosylhydrazone
was observed, developing a yellow color. After 2 h, the reaction
was quenched with addition of an excess of ammonium nitrate
and 50 mL of water, and then the reaction mixture was extracted
with diethyl ether. The mixture of the reaction was chromato-
graphed over silica gel and eluted with petroleum ether. The
less polar fraction was analyzed by GC-MS, giving a complex
mixture of products with molecular weight of 146.
Gen er a l P r oced u r es for th e Rea ction of 1 w ith t-Bu OK.
The reaction was carried out in a 20 mL, three-necked Schlenk
tube, equipped with nitrogen gas inlet, a condenser with a
cooling jacket, and a magnetic stirrer. The tube was charged
with nitrogen and then with 10 mL of dried DMSO and 1.2 mmol
of t-BuOK, and the substrate was added. After varying deter-
mined times, the reaction was quenched with an excess of
ammonium nitrate and 10 mL of water, and then the mixture
was extracted with diethyl ether. The products were quantified
by GC by the internal standard method, immediately after
extraction.
1,1-Dim eth yl-2-p h en ylcyclop r op a n e (5).10 Compound 5
was isolated from the reaction of 1 with t-BuOK by silica gel
chromatography with petroleum ether and further purified by
distillation: 1H NMR (CDCl3) δ 0.79 (3H, s), 0.66-0.91 (2H, m),
1.22 (3H, s), 1.84-1.91 (1H, m) 7.13-7.29 (5H, m); 13C NMR
(CDCl3) δ18.4, 19.0, 20.3, 27.5, 29.8, 125.5, 127.8, 128.9, 140.3;
MS (EI+) 146 (31.1), 131 (100.0), 116 (17.6), 91 (34.3).
These results can be rationalized as follows. The very
weak acids t-BuNH2 (pKa above 35)5 and DMSO (pKa )
35)5 are not able to protonate the carbanion intermediate
8, whereas when t-BuOH is used, 8 is quenched and the
yield of 5 decreases (thus, the pKa for the benzylic
hydrogen should be intermediate between the pKa of
t-BuOH (32.2) and DMSO (35)). The intermediacy of a
carbanion in the formation of 5 (eq 5) is confirmed by
the incorporation of deuterium in the substrate (11% d1)
in the reaction carried out in the presence of the labeled
t-BuOD and DMSO-d6.
2,2-Dim eth yl-3-p h en ylp r op yl t-Bu tyl Eth er (9). Com-
pound 9 was isolated from the reaction of 1 with t-BuOK by silica
gel chromatography with petroleum ether: 1H NMR (CDCl3) δ
0.8(6H, s), 1.2 (9H, s), 2.5 (2H,s), 2.9 (2H, s), 7.1-7.3 (5H, m);
13C NMR (CDCl3) δ 24.7, 27.6, 35.2, 44.9, 69.1, 72.0, 125.6, 127.5,
130.7, 139.5; MS (EI+) 164 (1.77), 146 (6.72), 92 (14.70), 91
(70.97), 57 (100.00), 43 (4.60), 41 (27.80).
Exp er im en ta l Section
Ma ter ia ls. 1-Iodo-2,2-dimethyl-3-phenylpropane12 (1) and
1-chloro-2,2-dimethyl-3-phenylpropane13 (11) were synthesized
by reaction of the corresponding tosylate with KI or LiCl in DMF.
The tosylate (12) and the benzenesulfonate (13) were prepared
by standard procedures. p-Toluensulfonylhydrazide was obtained
from reaction of hydrazine hydrate (Carlo Erba) with p-toluen-
sulfonyl chloride (Fluka) in THF.14 1-Iodo-2-methyl-2-phenyl-
propane15 (14b) was obtained by reaction of the corresponding
tosylate with KI in DMF. 1-Chloro-2-methyl-2-phenylpropane
(14a , Aldrich) and t-BuOK (Fluka) were commercially available
and used as received. DMSO (Carlo Erba) was distilled under
vacuum and stored over molecular sieves (4A).
3,3-Dim eth yl-4-p h en ylbu tyl Meth yl Su lfoxid e (10). Com-
pound 10 was isolated from the reaction of 1 with t-BuOK by
silica gel chromatography with diethyl ether: 1H NMR (CDCl3)
δ 1.0 (6H, s), 1.5-1.8 (2H, m), 2.60 (3H,s), 2.61 (2H, s), 2.7-2.9
(2H, m), 7.1-7.3 (5H, m); 13C NMR (CDCl3) δ 26.1, 26.2, 33.7,
33.8, 38.2, 48.1, 50.0, 125.9, 127.6, 130.2, 137.9; IR (KBr) cm-1
1055.8; GC-MS analysis: this compound decomposes in the
injector giving the product that has lost CH3S(O)H with MS (EI+)
160 (5.2), 92 (38.0), 91 (81.8), 69 (100.0), 68 (12.4) and the peak
of the giving compound with MS (EI+) 208 (14.4), 117 (31.6),
116 (12.9), 91 (41.2), 61 (100.0).
2-Meth yl-2-p h en ylp r op yl ter t-Bu tyl Eth er (16).18 Com-
pound 16 was isolated from the reaction of 14b with t-BuOK by
silica gel chromatography with petroleum ether: 1H NMR
(CDCl3) δ 1.1 (9H, s), 1.3 (6H, s), 3.3 (2H, s), 7.1-7.4 (5H, m);
13C NMR (CDCl3) δ 25.8, 27.4, 38.7, 71.2, 72.2, 125.6, 126.2,
127.8, 148.3; MS (EI+) 150 (1.4), 120 (8.5), 92 (17.4), 91 (57.1),
57 (72.3), 43 (92.1), 41 (100).
2,2-Dim et h yl-3-p h en ylp r op en -1-a l.16
2,2-Dimethyl-3-
phenylpropen-1-al was prepared by oxidation of 2,2-dimethyl-
3-phenylpropan-1-ol (7.8 g, 47.5 mmol) with pyridinium chloro-
chromate (PCC)17 (15.4 g, 71.5 mmol) in anhydrous CH2Cl2. The
reaction mixture was kept at room temperature for 2 h. Diethyl
ether was added, and the supernatant solution was decanted
from the black gum. Evaporation of the solution produced crude
aldehyde that was purified by distillation under vacuum.
Tosylh yd r a zon e of 2,2-Dim et h yl-3-p h en ylp r op en -1-a l
(18). A solution of 2.7 g (14.5 mmol) of p-toluensulfonylhydrazine
in 45 mL of ethanol and 2.2 mL of acetic acid was treated with
2.34 g (14.4 mmol) of the aldehyde dissolved in 2.9 mL of ethanol.
The reaction mixture was kept at room temperature for 2 h and
later cooled to 0 °C. Then ice-cooled water was added and the
tosylhydrazone 18 precipitated after a while. The solid was
3-Meth yl-3-p h en ylbu tyl Meth yl Su lfoxid e (17). Com-
pound 17 was isolated from the reaction of 14b with t-BuOK,
by silica gel chromatography with diethyl ether: 1H NMR (CDCl3)
δ 1.4 (6H, s), 1.9-2.2 (2H, m), 2.3-2.5 (2H,m), 2.4 (3H, s), 7.1-
7.3 (5H, m); 13C NMR (CDCl3) δ 29.1, 29.5, 36.8, 37.9, 38.9, 50.9,
126.1, 126.5, 128.5, 147.7; IR (KBr) cm-1 1055.8. GC-MS
analysis: this compound decomposes in the injector giving the
product that has lost CH3S(O)H with MS (EI+) 146 (8.0), 131
(45.1), 91 (41.0), 39 (100), and the peak of the giving compound
with MS (EI+) 194 (9.1), 119 (51.7), 91 (74.0), 75 (74.8), 61 (40.9),
41 (100).
(12) Yuan, K.; Scott, W. J . J . Org. Chem. 1990, 55, 6188.
(13) Duca, J . S.; Gallego, M. H.; Pierini, A. B.; Rossi, R. A. J . Org.
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(14) Friedman, L.; Litle, R. L.; Reichle, W. R. Organic Syntheses;
Wiley: New York, 1973; Collect. Vol. V, p 1055.
(15) Collman, J . P.; Brauman, J . I.; Madonik, A. M. Organometallics
1986, 5, 310.
(16) Stork, G.; Dowed, S. R. J . Am. Chem. Soc. 1963, 85, 2178.
(17) Vogel’s Textbook of Practical Organic Chemistry, 5th ed.;
Longman Scientific & Technical: Essex, 1989; p 426.
(18) Zimmerman, H. E.; Carpenter, C. W. J . Org. Chem. 1988, 53,
3298.

6118 J . Org. Chem., Vol. 64, No. 16, 1999
Additions and Corrections
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and mass spectra of compounds 5, 9, 10, and 16-18. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This work was supported in part
by the Consejo de Investigaciones de la Provincia de
Co´rdoba (CONICOR) and the Consejo Nacional de
Investigaciones Cient´ıficas y Te´cnicas (CONICET), Ar-
gentina. J .E.A. gratefully acknowledges receipt of a
fellowship from the Consejo Nacional de Investigaciones
Cient´ıficas y Te´cnicas (CONICET).
J O9905165
Additions and Corrections
Vol. 63, 1998
Ma r tin G. Ba n w ell, Ber n a r d L. F lyn n , a n d Scott G.
Stew a r tSelective Cleavage of Isopropyl Aryl Ethers by Alu-
minium Trichloride
Page 9139. Professor C. Sza´ntay (Technical University
of Budapest) has previously reported three examples of
the title reaction: Sza´ntay, C. Acta Chim. Hung. 1957,
12, 83. We thank Professor Sza´ntay for drawing our
attention to his work.
J O994003+
10.1021/jo994003+
Published on Web 07/20/1999