Convenient one-pot synthesis of 2,2-bis-(4-hydroxyphenyl)-cyclopentanone

Article abstract of DOI:10.1021/jo701850u

(Chemical Equation Presented) 2,2-Bis-(4-hydroxyphenyl)-cyclopentanone (3a) was unexpectedly obtained in 76% yield from a reductive coupling reaction of 4,4′-dihydroxybenzophenone (1a) and cyclobutanone with TiCl₄ and Zn. Further optimization showed that catechol as an external ligand and a hydroxy group on benzophenone facilitated the generation of a quinonemethide (intermediate II) that is involved in the pinacol-type rearrangement of intermediate I to give the rearranged product.

Full text of DOI:10.1021/jo701850u

SCHEME 1
Convenient One-Pot Synthesis of
2,2-Bis-(4-hydroxyphenyl)-cyclopentanone
Jai Woong Seo,† Hee Jun Kim,† Byoung Se Lee,†
John A. Katzenellenbogen,*,‡ and Dae Yoon Chi*,†
Department of Chemistry, Inha UniVersity, 253 Yonghyundong
Namgu, Inchon 402-751, Korea, and Department of Chemistry,
UniVersity of Illinois, Urbana, Illinois 61801
jkatzene@uiuc.edu; dychi@inha.ac.kr
ReceiVed August 23, 2007
product was identified as a 2,2-bis-(4-hydroxyphenyl)-cyclo-
1
pentanone (3a) by analysis of its H and 13C NMR and mass
spectra.
As far as we are aware, this interesting side reaction has
heretofore not been reported. It is also of note that this 2,2-
diarylcyclopentanone 3a is an analogue of 2,2-diphenylcyclo-
pentanone (6), a synthetically important precursor of 2,2-
diarylcyclopentanol (7, Figure 1), a chiral auxiliary3 that is used
in various stereoselective syntheses: [4 + 2] cycloadditions,4
tandem inter-[4 + 2]/intra-[3 + 2] cycloadditions,5 and hydro-
genations of â-acetoamidocrotonates.6 Although phenolic hy-
droxyl groups are present in compound 3a, the analogue of
compound 7 that could be produced from it might also be useful
as a chiral auxiliary, or these hydroxyl groups could be masked
or removed. Synthetic methods to obtain sterically bulky R,R-
diaryl substituted cyclopentanones have been investigated by
several groups.7 We performed a number of experiments to
elucidate the mechanistic basis for the dramatic change in
formation of olefinic products (2a, 4, and 5) versus 2,2-
diarylcyclopentanone 3a with differing cyclic ketone ring sizes.
It is generally recognized that McMurry-type carbonyl
coupling reactions between arylcarbonyl and alkylcarbonyl
compounds proceed by a two-step mechanism. Generation of a
stabilized dianion derived from the diaryl ketone8 is followed
by nucleophilic addition of this species to the alkyl ketone to
form a pinacol complex with titanium (step 1, Figure 2).9 This
pinacol intermediate is quite stable and may undergo one-
2,2-Bis-(4-hydroxyphenyl)-cyclopentanone (3a) was unex-
pectedly obtained in 76% yield from a reductive coupling
reaction of 4,4′-dihydroxybenzophenone (1a) and cyclobu-
tanone with TiCl4 and Zn. Further optimization showed that
catechol as an external ligand and a hydroxy group on
benzophenone facilitated the generation of a quinonemethide
(intermediate II) that is involved in the pinacol-type rear-
rangement of intermediate I to give the rearranged product.
The McMurry reaction is a powerful tool to synthesize alkene
compounds via reductive dimerization of ketones in the presence
of low-valent titanium activated by several reducing reagents
such as LiAlH4, LiBH4, Zn, and Mg.1 While performing
McMurry reactions with several cyclic ketones and 4,4′-
dihydroxybenzophenone using titanium(0) generated by zinc
from titanium tetrachloride (Mukaiyama method),2 a protocol
that gave us good yields of the expected alkene products with
cyclopentanone and cyclohexanone, we interestingly isolated
only 8% of the expected olefinic product 2a from the reaction
with cyclobutanone, an unexpected material 3a being obtained
as the major product (76%) (Scheme 1). This unexpected major
(3) (a) Dumas, F.; Mezrhab, B.; d’Angelo, J.; Riche, C.; Chiaroni, A. J.
Org. Chem. 1996, 61, 2293-2304. (b) McEvoy, M. A.; Halterman, R. L.
J. Am. Chem. Soc. 1990, 112, 6690-6695.
(4) Denmark, S. E.; Schnute, M. E. J. Org. Chem. 1994, 59, 4576-
4595.
(5) Denmark, S. E.; Guagnano, V.; Dixon, J. A.; Stolle, A. J. Org. Chem.
1997, 62, 4610-4628.
* Corresponding authors. (J.A.K.) Tel.: (217) 333-6310; fax: (217) 333-
7325. (D.Y.C.) Tel.: +82-32-860-7686; fax: +82-32-867-5604.
† Inha University.
(6) Potin, D.; Dumas, F.; d’Angelo, J. J. Am. Chem. Soc. 1990, 112,
3483-3486.
‡ University of Illinois.
(7) (a) Chen, K.; Koser, G. F. J. Org. Chem. 1991, 56, 5764-5767. (b)
Stang, P. J.; Ryan, J. H. Tetrahedron Lett. 1997, 38, 5061-5064. (c) Estieu,
K.; Ollivier, J.; Salau¨n, J. Tetrahedron 1998, 54, 8075-8090. (d) Denmark,
S. E.; Marcin, L. R.; Schnute, M. E.; Thorarensen, A. Organic Synthesis of
Colloids; Vol. 9, p 362.
(1) For review: (a) McMurry, J. E. Chem. ReV. 1989, 89, 1513-1524.
(b) McMurry, J. E. Acc. Chem. Res. 1983, 16, 405-411. (c) Welzel, P.
Nachr. Chem., Tech. Lab. 1983, 31, 814-816. (d) Lai, Y.-H. Org. Prep.
Proced. Int. 1980, 12, 361-391.
(2) Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 2, 1041-1044.
(8) McMurry, J. E.; Krepski, L. R. J. Org. Chem. 1976, 41, 3929-3930.
10.1021/jo701850u CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/19/2007
J. Org. Chem. 2008, 73, 715-718
715

TABLE 1. Product Ratios in the McMurry Reaction of
4,4′-Dihydroxybenzophenone and Various Equivalents of
Cyclobutanonea
FIGURE 1. (R)-2,2-Diarylcyclopentanol (7), chiral auxiliary, and its
precursor.
yield (%)b
Equiv of
entry
cyclobutanone
2a
3a
2a + 3a
1
2
3
1.0
1.5
2.0
11
12
10
64
69
76
75
81
86
a Reactions were carried out in a 1.0 mmol scale, and the reaction time
indicated was after the addition of ketones in THF. b Isolated yield, based
on 1a.
TABLE 2. Rearrangement Reactions in McMurry Reactions of
Different 4-Substituted Benzophenones and Cyclobutanone under
Various Conditionsa
FIGURE 2. Classical mechanism of reductive coupling reaction and
proposed two-electron transfer rearrangement.
electron transfer deoxygenation to form the expected McMurry
coupling alkene product, diarylmethylenecyclobutane (step 2
with blue arrows, Figure 2). In our case, however, it appears
that a two-electron transfer reaction resulting in a pinacol-type
rearrangement is the preferred mode of reaction because of the
cyclobutane ring strain (step 2 with red arrows, Figure 2).
While most McMurry reactions have been homo couplings
with a single ketone, our unexpected product was obtained by
unsymmetrical reductive carbonyl addition with mixed carbonyl
compounds.8 Therefore, the effect of differing amounts of
cyclobutanone (1.0, 1.5, and 2.0 equiv) was examined to obtain
an optimal yield of unsymmetrical reductive coupling products.
As shown in Table 1, 1 molar equiv of cyclobutanone was
sufficient to obtain a good yield of products. Total product yields
(2a + 3a), however, did increase with additional equivalents
of cyclobutanone.
Further reactions examined two different titanium reducing
agents, magnesium and zinc, which form complexes with
titanium after reducing titanium(IV) to titanium(0), as well as
three derivatives of benzophenone (4,4′-dihydroxybenzophenone
(1a), originally studied, 4-hydroxy-4′-methoxy-benzophenone
(1b), and 4,4′-dimethoxybenzophenone (1c)), to determine how
the course of the reaction was influenced by the presence of
the para-hydroxyl groups. In addition, catechol was employed
to see whether an external ligand of the titanium complex would
affect the rearrangement.9
yield (%)b
additive
R2 reagent (M) time (h) (3 equiv) 2a-c 3a-c
entry R1
1c
2c
3
Me Me
Me Me
H
Mg/HgCl2
Mg/HgCl2
Mg/HgCl2
Mg/HgCl2
Zn
Zn
Zn
Zn
Zn
4
20
4
4
3
2
2
2
3
-
13
87
18
32
34
18
10
5
trace
trace
74
-
H
-
4
5
Me Me
Me Me
catechol
-
Me
49
6
Me
H
Me Me
H
H
-
-
57c
76
7
8d
9
catechol
catechol
66
92
H
H
-
a Reactions were carried out in a 1.0 mmol scale with a molar ratio of
benzophenone (1.0 equiv), cyclobutanone (2.0 equiv), TiCl4 (3.1 equiv),
Zn (6.2 equiv), and Mg (6.2 equiv). b Isolated yields based on benzophenone.
c Enantiomeric mixture. d Reactions were performed in duplicate, and the
yields, which were similar, were averaged.
was performed in the presence of a low-valent titanium (LVT)
complex formed by the reduction of TiCl4 with magnesium,
according to a published method.10 This LVT complex was
relatively unreactive, and little reaction took place by 4 h (Table
2, entry 1). After 20 h, however, the olefinic compound 2c was
obtained in 87% yield (Table 2, entry 2). With the original
ketone, 4,4′-dihydroxybenzophenone, this LVT gave the typical
Initially, the coupling reaction of 4,4′-dimethoxybenzophe-
none (note, not 4,4′-dihydroxybenzophenone) and cyclobutanone
(9) Balu, N.; Nayak, S. K.; Banerji, A. J. Am. Chem. Soc. 1996, 118,
5932-5937.
(10) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S. J. Org. Chem.
1976, 41, 260-265.
716 J. Org. Chem., Vol. 73, No. 2, 2008

FIGURE 3. Proposed mechanism for the pinacol-type rearrangement.
ratios of alkene (2a) and cyclic ketone (3a) (Table 2, entry 3)
as shown in Table 1. When titanium(IV) chloride was reduced
by zinc (Table 2, entry 5), the LVT complex that formed
appeared to be more reactive; the reaction time was shortened,
and product ratios were altered, so by 3 h, both the alkene 2c
(34%) and the ring expanded ketone 3c (49%) were produced
from the dimethoxybenzophenone. Considering the outer shell
electrons of Zn versus Mg, Zn(II), being 3d-block metal, is
relatively rich in electrons. Thus, the titanium-zinc complex
might be less tightly bound to the pinacol at intermediate (Figure
2), with the result that with this metal there is an increasing
chance of rearrangement via the two-electron transfer mecha-
nism shown in Figure 1.
To elucidate effects of the functional groups of starting
materials, 4,4′-dihydroxybenzophenone (1a), 4-hydroxy-4′-
methoxybenzophenone (1b), and 4,4′-dimethoxybenzophenone
(1c) were used to compare the yields of the olefinic coupling
products (2a-c) versus the rearranged cyclopentanone products
(3a-c). In the reaction using LVT reduced by zinc, yields of
cyclopentanones (3c, 3b, and 3a) gradually increased to 49, 56,
and 76%, respectively, as the number of hydroxy groups
increased in the order 1c, 1b, to 1a (Table 2, entries 5-7). As
additional examples, when reactions were performed with the
LVT formed by reduction with magnesium, the same trend was
observed, with the yields of the rearrangement cyclopentanone
products, 3c and 3a, increasing from trace to 74%, respectively,
as hydroxy groups replace methoxy groups (Table 2, entries 2
and 3). Other substituted or unsubstituted benzophenones were
investigated (4-nitrobenzophenone, benzophenone, and 4-fluo-
robenzophenone), but they failed to produce the corresponding
2,2-diarylcyclopentanones, even in minor amounts. These
observations led us to consider that the pinacol-type rearrange-
ment might be occurring by an initial deoxygenation or 1,6-
elimination step that could lead to the formation of a stable
para-quinonemethide (intermediate II, Figure 3). This deoxy-
genation would also be facilitated by the relatively weak
benzyl-oxygen bond.11
assist in the rearrangement leading to the 2,2-diarylcyclopen-
tanones (3a-c). Chelation of the LVT complex with catechol
was performed for 30 min at room temperature after reduction
of Ti(IV) by Mg or Zn. When the color of the reaction mixture
turned to dark red, the ketones were added.
In the presence of catechol, the rearrangement reaction was,
indeed, facilitated, so that even with the less reactive 4,4′-
dimethoxybenzophenone, the 2,2-bis-(4-methoxyphenyl)-cyclo-
pentanone rearrangement product 3c was produced in 31% yield
with the Mg-LVT complex (Table 2, entry 4) and in 66% yield
with the Zn-LVT complex (Table 2, entry 8). The effect of
catechol can be appreciated by noting the increment in the yields
of 3c of 31% (compare entry 2 with entry 4 in Table 2) and
17% (compare entry 5 with entry 8 in Table 2) that occurs with
the addition of this chelator under both conditions. With the
original ketone, 4,4′-dihydroxybenzophenone, catechol addition
also boosted the yield of the rearrangement product, 2,2-bis-
(4-hydroxyphenyl)-cyclopentanone (3a), from 76% (Table 2,
entry 7) to 92% (Table 2, entry 9). Thus, this interesting product
can be produced in one step, by the reaction of 4,4′-dihydroxy-
benzophenone and cyclobutanone upon treatment of titanium-
(IV) chloride with Zn and catechol (Table 2, entry 9).
In summary, we have developed a one-pot synthesis of 2,2-
bis-(4-hydroxyphenyl)-cyclopentanone (3a) by coupling in situ
a pinacol-type rearrangement with a McMurry reaction with
LVT. Through several reactions performed to elucidate the
mechanism of this transformation, we identified that the ring
strain of cyclobutane, as well as other factors (such as hydroxy
or methoxyl groups on the benzophenone and external catechol)
presumed to generate a quinonemethide intermediate, facilitate
this rearrangement (Figure 3). This is the first report of a one-
pot synthesis of 2,2-diarylcyclopentanones and an investigation
of factors that modulate the balance of product formation
between diarylcyclopentanone and diarylmethylenecyclobutane
in this McMurry reaction.
Experimental Section
Because the reactivity or oxidation state of the LVT complex
can be influenced by steric and electronic factors,9,12 the
possibility of chelation of the LVT complex by the hydroxy
groups of benzophenone was examined by adding catechol to
reaction media as an additional external ligand (Figure 3). We
thought that external chelation of the LVT by catechol might
General Procedure of McMurry Reaction: Titanium Tetra-
chloride with Mg/HgCl2. A two-necked round-bottomed flask fitted
with a reflux condenser was flame dried under vacuum, and Mg
(150 mg, 6.2 mmol) and HgCl2 (14 mg, 50 µmol) were added.
After additional drying under high vacuum (0.5 mmHg) for 30-
60 min, the flask was charged with argon. THF (5 mL) was added,
and the resulting mixture was stirred at room temperature for 15
min. The turbid solution was removed by syringe, and the metal
species was washed 2 times with additional portions of THF (5
mL × 2). THF (10-15 mL) was added, and the mixture was cooled
(11) McMurry, J. E.; Silvestri, M. G.; Fleming, M. P.; Hoz, T.; Grayston,
M. W. J. Org. Chem. 1978, 43, 3249-3255.
(12) Hegedus, L. S. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon: Oxford, 1995; Vol. 12, pp 1-7.
J. Org. Chem, Vol. 73, No. 2, 2008 717

to -10 °C. TiCl4 (581 mg, 3.1 mmol) was slowly added dropwise,
and the reaction mixture showed yellow fumes and turned green.
After removal of the cooling bath, the reaction mixture was refluxed
for 2 h. (In those experiments to investigate the affect of additional
chelation, catechol was added at this point and stirred for 30 min
at r oom temperature). Diarylketone (1.0 mmol) and 2 equiv of
cyclobutanone (2.0 mmol) dissolved in THF (5-10 mL) were added
slowly, and the mixture was refluxed for the time noted. After
cooling down, the reaction mixture was slowly poured into saturated
aqueous NaHCO3 (150 mL), and Et2O (100 mL) was added with
stirring. The mixture was filtered through Celite, and the ether layer
was decanted. The aqueous layer was extracted with additional Et2O
or EtOAc. The combined ether extracts were dried over Na2SO4
and evaporated. Flash column chromatography (EtOAc/hexane) was
performed to obtain each product.
8.8 Hz, 4H), 6.75(d, J ) 8.8 Hz, 4H), 2.63 (t, J ) 6.8 Hz, 2H),
2.36 (t, J ) 7.6 Hz, 2H), 1.87 (quintet, J ) 6.8 Hz, 2H); 13C NMR
(100 MHz, acetone-d6) δ 217.9, 156.7, 134.5, 130.0, 115.7, 61.6,
39.0, 38.3, 19.4; IR (KBr): 3347, 1709, 1611, 1594, 1513, 1237,
1178, 836 cm-1; MS (EI) m/z 268 (M+), 240, 212 (100), 197.
HRMS (EI) m/z calcd for C17H16O3, 268.1099; found, 268.1097.
2-(4-Hydroxyphenyl)-2-(4-methoxyphenyl)-cyclopentanone (3b).
1
Off-white solid; mp 109-110 °C; H NMR (400 MHz, CDCl3) δ
7.12 (d, J ) 8.8 Hz, 2H), 7.03 (d, J ) 8.8 Hz, 2H), 6.83 (d, J )
9.2 Hz, 2H), 6.73 (d, J ) 8.0 Hz, 2H), 3.77 (s, 3H), 2.63 (t, J )
6.8 Hz, 2H), 2.43 (t, J ) 7.6 Hz, 2H), 1.91 (quintet, J ) 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 219.8, 158.1, 154.7, 134.1,
133.6, 129.14, 129.04, 115.3, 113.7, 61.4, 55.2, 38.30, 37.99, 18.7;
IR (KBr): 3364. 1702, 1610, 1513, 1438, 1255, 1182, 836 cm-1
;
MS (EI) m/z 282 (M+), 254, 226 (100), 211. HRMS (EI) m/z cacld
General Procedure of McMurry Reaction: Titanium Tetra-
chloride with Zn. A two-necked round-bottomed flask fitted with
a reflux condenser was flame dried under vacuum, and Zn powder
(405 mg, 6.2 mmol) was added. After additional drying under high
vacuum (0.5 mmHg) for 30-60 min, the flask was charged with
argon. THF (10-15 mL) was added, and the mixture was cooled
to -10 °C. TiCl4 (581 mg, 3.1 mmol) was slowly added dropwise,
and the reaction mixture showed yellow fumes and turned green.
The rest of the procedure is same as the one stated previously.
Bis-(4-hydroxyphenyl)-methylenecyclobutane (2a). White solid;
1H NMR (400 MHz, acetone-d6) δ 6.97 (d, J ) 8.8 Hz, 4H), 6.76
(d, J ) 8.8 Hz, 4H), 2.86 (t, J ) 8.0 Hz, 4H), 1.99 (quintet, J )
8.0 Hz, 2H); 13C NMR (100 MHz, acetone-d6) δ 156.6, 137.7,
133.4, 133.1, 130.7, 115.6, 32.5, 17.7; MS (EI) m/z 252 (M+, 100),
223, 107. HRMS (EI) m/z calcd for C17H16O2, 252.1150; found,
252.1152. Registry No.: 66422--09-1.
for C18H18O3, 282.1256; found, 282.1258.
2,2-Bis-(4-methoxyphenyl)-cyclopentanone (3c). Off-white solid;
1H NMR (400 MHz, CDCl3) δ 7.15 (d, J ) 9.2 Hz, 2H), 6.85 (d,
J ) 9.2 Hz, 2H), 3.78 (s, 3H), 2.66 (t, J ) 6.8 Hz, 2H), 2.44 (t, J
) 7.6 Hz, 2H), 1.93 (quintet, J ) 7.2 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 218.2, 158.2, 134.1, 129.0, 113.6, 61.1, 55.1, 38.2,
37.9, 18.7; MS (EI) m/z 296 (M+), 268, 240 (100), 209, 164.
Registry No.: 5383--22-2.
Bis-(4-hydroxyphenyl)-methylenecyclopentane (4). White solid;
1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J ) 8.4 Hz, 4H), 6.66
(d, J ) 8.4 Hz, 4H), 2.26 (bt, J ) 6.4 Hz, 4H), 1.60 (bt, J ) 6.4
Hz, 4H); 13C NMR (100 MHz, DMSO-d6) δ 155.4, 139.9, 134.2,
132.2, 129.9, 114.7, 32.7, 26.5; MS (EI) m/z 266 (M+, 100), 223,
168, 141, 115. Registry No.: 66422--10-4.
Bis-(4-hydroxyphenyl)-methylenecyclohexanone (5). White
solid; 1H NMR (400 MHz, DMSO-d6) δ 6.83 (d, J ) 8.4 Hz, 4H),
6.66 (d, J ) 8.8 Hz, 4H), 2.10-2.21 (m, 4H), 1.42-1.60 (m, 6H);
13C NMR (100 MHz, DMSO-d6) δ 155.6, 136.3, 133.9, 133.7,
130.4, 114.7, 31.9, 28.2, 26.3; MS (EI) m/z 280 (M+), 199 (100),
107. Registry No.: 5189--40-2.
1-(4-Hydroxyphenyl)-1-(4-methoxyphenyl)methylenecyclob-
1
utane (2b). Off-white solid; mp 94-95 °C; H NMR (400 MHz,
CDCl3) δ 7.08 (d, J ) 8.8 Hz, 2H), 7.02 (d, J ) 8.8 Hz, 2H), 6.82
(d, J ) 8.8 Hz, 2H), 6.74 (d, J ) 8.8 Hz, 2H), 3.78 (s, 3H), 2.87
(t, J ) 8.0 Hz, 4H), 2.01 (quintet, J ) 8.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 157.7, 153.9, 138.8, 133.48, 133.45, 131.8, 130.1,
129.9, 114.9, 113.4, 55.2, 32.1, 17.3; IR (KBr): 3357, 2951, 1606,
1508, 1452, 1234, 1174, 1037, 837 cm-1; MS (EI) m/z 266 (M+,
100), 238, 167. HRMS (EI) m/z calcd for C18H18O2, 266.1307;
found, 266.1308.
Acknowledgment. This work was supported by a Korea
Science and Engineering Foundation (KOSEF) grant funded by
the Korean government (MOST) (2006-03770 to D.Y.C.) and
a grant from the National Institutes of Health (PHS 5R37
DK15556 to J.A.K.). High-resolution mass spectra were carried
out at the Korea Basic Science Institute (Daegu, Korea).
Bis-(4-methoxyphenyl)-methylenecyclobutane (2c). White solid;
1H NMR (400 MHz, CDCl3) δ 7.10 (d, J ) 8.8 Hz, 4H), 6.84 (d,
J ) 8.8 Hz, 4H), 3.81 (s, 6H), 2.91 (t, J ) 8.0 Hz, 4H), 2.04
(quintet, J ) 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 157.8,
138.8, 133.4, 131.8, 129.9, 113.4, 55.2, 32.1, 17.3. MS (EI) m/z
280 (M+, 100), 249, 165, 121. Registry No.: 5289--37-2.
2,2-Bis-(4-hydroxyphenyl)-cyclopentanone (3a). Off-white solid;
Supporting Information Available: 1H and 13C NMR spectra
of all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
mp 139-140 °C; H NMR (400 MHz, acetone-d6) δ 7.04 (d, J )
JO701850U
718 J. Org. Chem., Vol. 73, No. 2, 2008