Enantioselective baeyer-villiger oxidation catalyzed by palladium(II) complexes with chiral P,N-ligands

Article abstract of DOI:10.1021/jo800246g

(Chemical Equation Presented) Asymmetric Baeyer-Villiger reaction of symmetrical cyclobutanones 1a-j with urea-hydrogen peroxide (UHP) can be catalyzed by a complex of Pd(II) and the new terpene-derived P,N-ligand 7. The resulting lactones 2a-j were obtained in high yields and with good enantioselectivity (≤81% ee).

Full text of DOI:10.1021/jo800246g

Enantioselective Baeyer–Villiger Oxidation Catalyzed by
Palladium(II) Complexes with Chiral P,N-Ligands|
Andrei V. Malkov,*,† Frédéric Friscourt,† Mark Bell,†,‡ Martin E. Swarbrick,§ and
Pavel Kocˇovský*,†
Department of Chemistry, WestChem, Joseph Black Building, UniVersity of Glasgow,
Glasgow G12 8QQ, U.K., and Neurology Centre of Excellence for Drug DiscoVery, GlaxoSmithKline,
Harlow CM19 5AW, U.K.
amalkoV@chem.gla.ac.uk; paVelk@chem.gla.ac.uk
ReceiVed January 30, 2008
Asymmetric Baeyer–Villiger reaction of symmetrical cyclobutanones 1a-j with urea-hydrogen peroxide
(UHP) can be catalyzed by a complex of Pd(II) and the new terpene-derived P,N-ligand 7. The resulting
lactones 2a-j were obtained in high yields and with good enantioselectivity (e81% ee).
SCHEME 1. Baeyer-Villiger Oxidation of Prochiral
Cyclobutanones
Introduction
The Baeyer–Villiger conversion of aldehydes and ketones
into the corresponding esters by insertion of an oxygen atom
into the C-C bond1 is an established, regioselective, and
stereospecific synthetic tool.2 In the case of symmetrical cyclic
ketones, such as 3-substituted cyclobutanones (1), 4-substituted
cyclohexanones, etc., the Baeyer–Villiger reaction results in the
formation of a chiral lactone, e.g., 2 (Scheme 1). Preferential
formation of one of its enantiomers requires a chiral reagent or
auxiliary. While a successful use of stoichiometric amounts of
chiral peroxy acids has not been reported, the application of
chiral stoichiometric auxiliaries proved quite effective3 and
particularly high enantioselectivities were attained in specific
cases by application of enzymes.4 Catalytic processes, using
| Dedicated to the memory of Professor Otto Exner.
† University of Glasgow.
‡ Present address: Department of Chemistry and Chemical Engineering,
Queens University, Stranmillis Road, Belfast, BT9 5AG, UK.
§ GlaxoSmithKline.
(1) Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625.
(2) For reviews see: (a) Hassall, C. H. Org. React. 1957, 9, 73. (b) Krow,
G. C. Org. React. 1993, 43, 251. (c) Strukul, G. Angew. Chem., Int. Ed. 1998,
37, 1198. (d) Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 737. (e) Le Paith,
J.; Frison, J.-C.; Bolm, C. In Modern Oxidation Methods; Bäckvall, J.-E., Ed.;
Wiley-VCH: Weinheim, Germany, 2004; p 267. (f) Bolm, C.; Palazzi, C.;
Beckmann, O. In Transition Metals for Organic Synthesis, 2nd ed.; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, p 267.
atransition metal coordinated to a chiral ligand with a hydro-
peroxide as the stoichiometric oxidant, represent an attractive
(3) For the reactions of cyclic ketal, prepared from the corresponding ketone
and enantiopure pentane-1,3-diol, see: (a) Sugimura, T.; Fujiwara, Y.; Tai, A.
Tetrahedron Lett. 1997, 38, 6019. (b) Aoki, M.; Seebach, D. HelV. Chim. Acta
2001, 84, 187. (c) Miyake, Y.; Nishibayashi, Y.; Uemura, S. Bull. Chem. Soc.
Jpn. 2002, 75, 2233.
3996 J. Org. Chem. 2008, 73, 3996–4003
10.1021/jo800246g CCC: $40.75 2008 American Chemical Society
Published on Web 05/01/2008

Baeyer–Villiger Reaction of Symmetrical Cyclobutanones
alternative2 but further development is required as the enantio-
selectivities do not reach the level attained by enzymatic
systems.
CHART 1. P,N-Ligands
Nonenantioselective transition metal-catalyzed Baeyer–Vil-
liger oxidation reactions, which laid the foundations to further
development, included Mo,5 W,6 Re,7 Pt,8 Ni,9 and Fe10 as
catalysts with H2O25–8 or the Mukaiyama O2-aldehyde systems
as stoichiometric oxidizing reagents.9,10
The first examples of asymmetric transition metal-catalyzed
Baeyer–Villiger oxidation were reported by Strukul (e58% ee)11
and Bolm (e69% ee),12 who utilized this approach for the
resolution of racemic R-substituted cyloalkanones. While Strukul
employed a Pt-BINAP complex with 2-vaniline as an additional
ligand and H2O2 as oxidant,11 Bolm used a Cu-oxazoline
complex and the Mukaiyama system (O2 with a sacrificial
aldehyde).12 Lopp13 was the first to report on the oxidation of
prochiral cyclobutanone 1 (R ) CH2OH) to afford (R)-2 (40%
ee) using (i-PrO)4Ti, (+)-diethyl tartrate, and tert-butyl hydro-
peroxide, a system originally developed by Sharpless for
epoxidation of allylic alcohols. Bolm14 extended the scope of
his Cu(II) catalyst to the oxidation of prochiral cyclobutanones
but the enantioselectivity remained moderate (e47% ee). His
new complex of Zr(IV) with BINOL had to be used in
stoichiometric amounts and gave 21–31% ee for 3-substituted
cyclobutanones and 12–84% ee for 2,3-substituted cyclobu-
tanones.15 Kotsuki16 reported on oxidation of cyclobutanones
with O2, using a complex generated from Et2Zn and a chiral
amino alcohol, but the reaction required high catalyst loading
and the enantioselectivities remained moderate (e39% ee). Bolm
then improved his BINOL system by replacing Zr(IV) with
Mg(II): using cumene hydroperoxide and 50 mol % catalyst
loading, he obtained lactones 2 in 52–65% ee.17 A combination
of the Lewis-acidic Me2AlCl and BINOL or vaulted BINOL
(VANOL) as chiral ligands resulted in further improvement in
enantioselectivity (37–84% ee) and lowering of the catalyst
loading to 20 mol %.18 A slightly increased level of asymmetric
induction for 1 (60–87% ee) was attained by Katsuki, who
developed several new salen-type complexes of Co(III), Zr(IV),
and Hf(IV), which proved efficient in combination with the
urea-H2O2 complex (percarbamide) as the stoichiometric
oxidant.19 The Pd(II) complex with the phosphinopyridine ligand
3 (Chart 1) gave lactone 2 in 60–80% ee20(Table 1, entries 1–3).
Herein, we report on the application of the terpene-derived P,N-
ligands 4-7 (Chart 1) in the Pd(II)-catalyzed oxidation of 1a-j
to produce chiral lactones 2a-j.
Results and Discussion
Synthesis of Ligands. Being inspired by the Katsuki P,N-
ligand 3, we have now studied the role of the analogous terpene-
derived P,N-ligands 4–7. The synthesis of (-)-4 from (+)-∆2-
carene in five steps was described by us recently in connection
with our studies on asymmetric Heck reaction21 and Pd(0)-
catalyzed allylic substitution.22,23 In the same paper we have
also reported on the synthesis of the enantiomeric (-)-6 from
(-)-ꢀ-pinene or (-)-R-pinene, both in 4 steps.21 Using an
analogous procedure and (+)-R-pinene as starting material, we
have now prepared (+)-5, (+)-6, and (-)-7 as follows (Scheme
2). (+)-R-Pinene was first converted into (-)-pinocarvone (-)-8
via an ene reaction with singlet oxygen21,24 and the latter terpene
was submitted to Kröhnke annulation21,25,26 with the pyridinium
salt 9,21 derived from o-fluoro acetophenone (9, AcONH4,
AcOH, reflux, 6 h), to afford the pyridine derivative (+)-10
(67%). Deprotonation of 10 in the “benzylic” position (n-BuLi,
THF, –40 °C, 1 h),21,26 followed by alkylation with MeI (-40
°C to rt, overnight), afforded (+)-11 (59%) in the same highly
diastereoselective manner as that reported by us previously21
for its enantiomer. In analogy, alkylation of (+)-10 with i-PrI
afforded the new isopropyl derivative (+)-12 (67%). Aromatic
nucleophilic substitution of the fluorine in 10-12 with Ph2PK
(Ph2PH, t-BuOK, 18-crown-6, THF, rt, 48 h)27 furnished the
required phosphines (+)-5, (+)-6, and (-)-7 in 42%, 50%, and
52% yields, respectively.28
(4) For reviews see: (a) Mihovilovic, M. D.; Müller, B.; Stanetty, P. Eur. J.
Org. Chem. 2002, 3711. (b) Alphand, V.; Furstoss, R. In Enzymes Catalysis in
Organic Synthesis; Drauz, K., Waldmann, H., Eds.; VCH: Weinheim, Germany,
1995; p 754. For a biomimetic approach, see the following: (c) Murahashi, S.-
I.; Ono, S.; Imada, Y. Angew. Chem., Int. Ed. 2002, 41, 2366.
(5) (a) Jacobson, S. E.; Tang, R.; Mares, F. J. Chem. Soc., Chem. Commun.
1978, 888. (b) Campestrini, S.; Di Furia, F. J. Mol. Catal. 1993, 79, 13.
(6) Yoshida, A.; Yoshimura, M.; Uehara, K.; Hikichi, S.; Mizuno, M. Angew.
Chem., Int. Ed. 2006, 45, 1956.
(7) (a) Hermann, W. A. J. Organomet. Chem. 1995, 500, 149. (b) Phillips,
A. M. F.; Romão, C. Eur. J. Org. Chem. 1999, 1767.
(8) (a) Del Todesco Frisone, M.; Pinna, F.; Strukul, G. Organometallics 1993,
12, 148. (b) Baccin, C.; Gusso, A.; Pinna, F.; Strukul, G. Organometallics 1995,
14, 1161.
(9) Yamada, T.; Takahashi, K.; Kato, K.; Takai, T.; Inoki, S.; Mukaiyama,
T. Chem. Lett. 1991, 641.
(10) Murahashi, S.-I.; Oda, Y.; Naota, T. Tetrahedron Lett. 1992, 33, 7557.
(11) Gusso, A.; Baccin, C.; Pinna, F.; Strukul, G. Organometallics 1994,
13, 3442.
(12) Bolm, C.; Schlingloff, G.; Weickhardt, K. Angew. Chem., Int. Ed. Engl.
1994, 33, 1848.
(13) (a) Lopp, M.; Paju, A.; Kanger, T.; Pehk, T. Tetrahedron Lett. 1996,
37, 7583. (b) Kanger, T.; Kriis, K.; Paju, A.; Pehk, T.; Lopp, M. Tetrahedron:
Asymmetry 1998, 9, 4475.
(14) (a) Bolm, C.; Schlingloff, G. J. Chem. Soc., Chem. Commun. 1995,
1247. (b) Bolm, C.; Luong, T. K. K.; Schlingloff, G. Synlett 1997, 1151. (c)
Bolm, C.; Schlingloff, G.; Bienewald, F. J. Mol. Catal. A 1997, 117, 347.
(15) Bolm, C.; Beckmann, O. Chirality 2000, 12, 523.
(16) Shinohara, T.; Fujioka, S.; Kotsuki, H. Heterocycles 2001, 55, 237.
(17) Bolm, C.; Beckmann, O.; Cosp, A.; Palazzi, C. Synlett 2001, 9, 1461.
(18) (a) Bolm, C.; Beckmann, O.; Palazzi, C. Can. J. Chem. 2001, 79, 1593.
(b) Bolm, C.; Beckmann, O.; Kühn, T.; Palazzi, C.; Adam, W.; Rao, P. B.; Saha-
Möller, C. R. Tetrahedron: Asymmetry 2001, 12, 2441. (c) Bolm, C.; Frison,
J.-C.; Zhang, Y.; Wulff, W. D. Synlett 2004, 9, 1619. (d) Frison, J.-C.; Palazzi,
C.; Bolm, C. Tetrahedron 2006, 62, 6700.
Synthesis of Cyclobutanones. The required cyclobutanones
1a-j were synthesized in two steps via [2 + 2] cycloaddition
(19) (a) Uchida, T.; Katsuki, T. Tetrahedron Lett. 2001, 42, 6911. (b) Uchida,
T.; Katsuki, T. HelV. Chim. Acta 2002, 85, 3078. (c) Watanabe, A.; Uchida, T.;
Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481. (d) Matsumoto, K.;
Watanabe, A.; Uchida, T.; Ogi, K.; Katsuki, T. Tetrahedron Lett. 2004, 45, 2385.
(20) Ito, K.; Ishii, A.; Kuroda, T.; Katsuki, T. Synlett 2003, 5, 643.
(21) Malkov, A. V.; Bella, M.; Stará, I. G.; Kocˇovský, P. Tetrahedron Lett.
2001, 42, 3045.
(22) Kocˇovský, P. J. Organomet. Chem. 2003, 687, 256.
(23) Chelucci, G.; Saba, A.; Soccolini, F. Tetrahedron Lett. 2001, 57, 9989.
(24) Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48, 4135.
J. Org. Chem. Vol. 73, No. 11, 2008 3997

Malkov et al.
TABLE 1. Baeyer-Villiger Oxidation of Ketones 1a-j with Urea-H2O2, Catalyzed by the Pd(II) Complexes with P,N-Ligands 3–7a
entry
ligand
ketone
R
temp (°C)
solvent
yield (%)b
2c (% ee)
1
2
3
4
5
6
7
8
3
3
3
4
5
6
7
7
7
7
7
7
7
7
7
7
7
7
7
1a
1a
1j
Ph
Ph
n-octyl
Ph
Ph
Ph
Ph
Ph
Ph
rt
THF
THF
THF
THF
THF
THF
THF
MeCN
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
92
100
65
g99
g99
g99
g99
98
g99
97
93
96
94
95
92
83
91
89
83
59 (R)d
78 (R)d
60 (R)d
22 (S)e
4 (S)e
-40
-60
rt
rt
rt
rt
rt
rt
-40
-40
-40
-40
-40
-40
-40
-40
-40
-40
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
17 (S)e
64 (S)e
46 (S)e
36 (S)e
81 (S)e
75 (S)e
72 (+)e
73 (S)e
76 (+)f
70 (+)f
71 (+)f
58 (R)g, h
65 (-)f
55 (R)f
9
10
11
12
13
14
15
16
17
18
19
Ph
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
2-Br-C6H4
2-Naphth
4-MeO-C6H4CH2
cyclohexyl
n-octyl
1g
1h
1i
1j
a The reaction was carried out at 0.5 mmol scale with 1.3 equiv of urea-H2O2 and 5 mol % of the Pd(II) catalysts overnight, unless stated otherwise.
b Isolated yield. c The absolute configuration was established from the optical rotation (measured in CHCl3) by comparison with the literature data (see
the Experimental Section). Lactones 2a, 2b, and 2d were (S)-configured; the configuration of 2c and 2e-g is assumed to be (S) in analogy with the rest
of the series. d Reference 20. e Determined by chiral GC. f Determined by chiral HPLC (Chiralpak IB) after conversion into the corresponding hydroxy
benzylamide derivative.32 g Determined by optical rotation.33 h Note the change in the substituent priorities in the Cahn-Ingold-Prelog system.
SCHEME 2. Synthesis of P,N-ligands from r-pinene;
N+C5H5 ) pyridinium
of the catalyst thus generated, i.e., (Ligand)Pd(SbF6)2, was used
in the individual oxidation reactions.
The oxidation of the respective cyclobutanone derivatives
1a-j was carried out with the urea-H2O2 complex as the
stoichiometric oxidant, either at room temperature or at -40
°C, in the presence of a catalytic amount of (Ligand)Pd(SbF6)2
(5 mol %),31 where Ligand ) 4, 5, 6, and 7, respectively
(Scheme 1 and Table 1). Oxidation of 3-phenylcyclobutanone
(1a), catalyzed by the 4/Pd complex, afforded lactone 2a in
quantitative yield but with only 22% ee (entry 4). Similarly
inferior results were obtained with ligands 5 and 6 (entries 5
and 6). On the other hand, ligand 7 (FredPhos) turned out to be
substantially more effective, with 64% ee at room temperature
(entry 7). Variation of the solvent proved detrimental to
enantioselectivity (entries 8 and 9) but lowering the temperature
to -40 °C resulted in an increase to 81% ee (entry 10). Since
(26) For the construction of pyridine derivatives from terpenes, see the
following: (a) Hayoz, P.; von Zelewsky, A. Tetrahedron Lett. 1992, 33, 5165.
(b) Fletcher, N. C.; Keene, F. R.; Ziegler, M.; Stoeckli-Evans, H.; Viebrock, H.;
von Zelewsky, A. HelV. Chim. Acta 1996, 79, 1192. (c) Gianini, M.; von
Zelewsky, A. Synthesis 1996, 702. (d) Mamula, O.; von Zelewsky, A.; Bark,
T.; Bernardinelli, G. Angew. Chem., Int. Ed. Engl. 1999, 38, 2945. (e) Lötscher,
D.; Rupprecht, S.; Stoeckli-Evans, H.; von Zelewsky, A. Tetrahedron: Asymmetry
2000, 11, 4341. (f) Kolp, B.; Abeln, D.; Stoeckli-Evans, H.; von Zelewsky, A.
Eur. J. Inorg. Chem. 2001, 1207. (g) Lötscher, D.; Rupprecht, S.; Collomb, P.;
Belser, P.; Viebrock, H.; von Zelewsky, A.; Burger, P. Inorg. Chem. 2001, 40,
5675. (h) Chelucci, G.; Pinna, G. A.; Saba, A. Tetrahedron: Asymmetry 1997,
8, 2571. (i) Chelucci, G.; Cabras, A. Tetrahedron: Asymmetry 1996, 7, 965. (j)
Chelucci, G.; Pinna, G. A.; Saba, A. Tetrahedron: Asymmetry 1997, 8, 2571.
(k) Chelucci, G.; Berta, D.; Saba, A. Tetrahedron 1997, 53, 3843. (l) Malkov,
A. V.; Bella, M.; Langer, V.; Kocˇovský, P. Org. Lett. 2000, 2, 3047. (m) Malkov,
A. V.; Baxendale, I. R.; Fawcett, J.; Russel, D. R.; Langer, V.; Mansfield, D. J.;
Valko, M.; Kocˇovský, P. Organometallics 2001, 20, 673. (n) Malkov, A. V.;
Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.; Kocˇovský, P.
Org. Lett. 2002, 4, 1047. (o) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.;
Massa, A.; Teplý, F.; Meghani, P.; Kocˇovský, P. J. Org. Chem. 2003, 68, 4727.
(p) Malkov, A. V.; Bell, M.; Orsini, M.; Pernazza, D.; Massa, A.; Herrmann,
P.; Meghani, P.; Kocˇovský, P. J. Org. Chem. 2003, 68, 9659. (q) Malkov, A. V.;
Bell, M.; Vassieu, M.; Bugatti, V.; Kocˇovský, P. J. Mol. Catal. A 2003, 196,
179. (r) Seymour, J. L.; Turecˇek, F.; Malkov, A. V.; Kocˇovský, P. J. Mass
Spectrom. 2004, 39, 1044. (s) Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kocˇovský,
P. Org. Lett. 2005, 7, 3219. For reviews, see: (t) Knof, U.; von Zelewsky, A.
Angew. Chem., Int. Ed. 1999, 38, 303. (u) Chelucci, G.; Thummel, R. P. Chem.
ReV. 2002, 102, 3129. (v) Malkov, A. V.; Kocˇovský, P. Curr. Org. Chem. 2003,
7, 1737. (w) Malkov, A. V.; Kocˇovský, P. Eur. J. Org. Chem. 2007, 29.
SCHEME 3. Synthesis of 3-Substituted Cyclobutanones (for
a-j, See Scheme 1)
of dichloro ketene (generated in situ from trichloroacetyl
chloride, Zn-Cu couple, and POCl3) to the vinyl derivative
13a-j, followed by reduction of the resulting dichloro ketones
14a-j with zinc in AcOH (Scheme 3).29,30
Asymmetric Baeyer–Villiger Oxidation. The precatalysts
for the oxidation were generated in situ from (PhCN)2PdCl2
and the respective ligand (4-7) in THF at room temperature.
Each of the resulting complexes was then treated with AgSbF6,
the insoluble AgCl was removed by filtration, and the solution
(25) For the methodology, see: (a) Kröhnke, F. Chem. Ber. 1937, 70, 864.
For an overview, see: (b) Kröhnke, F. Synthesis 1976, 1.
3998 J. Org. Chem. Vol. 73, No. 11, 2008

Baeyer–Villiger Reaction of Symmetrical Cyclobutanones
1595 (s, Ar), 1440 (s, Ar), 1225 (m, C-H methyl), 1108 (s, C-F),
752 (m, Ar-H) cm-1; 1H NMR (400 MHz, CDCl3) δ 0.69 (s, 3H,
CH3), 1.32 (d, J ) 9.6 Hz, 1H, 9-H), 1.41 (s, 3H, CH3), 2.39 (tt,
J ) 5.8, 2.9 Hz, 1H, 8-H), 2.71 (dt, J ) 9.6, 5.8 Hz, 1H, 9-H′),
2.79 (t, J ) 5.8 Hz, 1H, 10-H), 3.18 (d, J ) 2.9 Hz, 2H, 7-H),
7.12 (ddd, J ) 11.3, 8.1, 1.2 Hz, 1H, 3′-H), 7.23 (td, J ) 7.9, 1.3
Hz, 1H, 5′-H), 7.25 (d, J ) 7.8 Hz, 1H, 4-H), 7.31 (m, 1H, 4′-H),
7.46 (dd, J ) 7.8, 2.4 Hz, 1H, 3-H), 7.96 (td, J ) 7.9, 1.9 Hz, 1H,
6′-H); 13C NMR (100 MHz, CDCl3) δ 21.3 (CH3), 26.0 (CH3), 31.9
(CH2-9), 36.7 (CH2-7), 39.5 (C-11), 40.2 (CH-8), 46.3 (CH-10),
116.0 (d, J ) 23 Hz, CH-3′), 121.1 (d, J ) 9 Hz, CH-3), 124.4 (d,
J ) 4 Hz, CH-5′), 127.9 (d, J ) 12 Hz, C-1′), 129.6 (d, J ) 8 Hz,
CH-4′), 130.9 (d, J ) 3 Hz, CH-6′), 133.1 (CH-4), 140.7 (C-5),
150.3 (d, J ) 2 Hz, C-2), 156.9 (C-6), 160.3 (d, J ) 249 Hz, C-2′);
19F NMR (376 MHz, CDCl3) δ –117.4 (s); MS (EI) m/z (%) 267
(M•+, 68), 252 (M•+ - CH3, 52), 224 (100), 83 (38); HRMS (EI)
267.1427 (C18H18FN requires 267.1423).
General Procedure for the Alkylation of (+)-10. A solution
of n-butyllithium in hexane (2.5 M; 0.6 mL, 1.5 mmol, 1 equiv)
was added dropwise to a solution of (+)-10 (400 mg, 1.5 mmol, 1
equiv) in anhydrous THF (2 mL) under argon at –40 °C. The
solution was stirred at that temperature for 1 h, then the respective
electrophile, iodomethane (0.1 mL, 1.5 mmol, 1 equiv) or 2-io-
dopropane (0.15 mL, 1.5 mmol, 1 equiv), was added dropwise at
–40 °C. The solution was then gradually warmed to room
temperature and stirred overnight. The reaction was quenched by
addition of water (15 mL). The aqueous phase was extracted with
CH2Cl2 (3 × 20 mL) and the combined organic extracts were
washed with brine (20 mL) and dried over MgSO4. The solvent
was removed under vacuum and the residue was purified by
chromatography on a column of silica gel (15 g) with a mixture of
petroleum ether and AcOEt (97:3) to give respectively pure (+)-
11 (246 mg, 59%) as a colorless oil or pure (+)-12 (309 mg, 67%).
(7R,8S,10S)-(+)-2-(2′-Fluorophenyl)-7,11,11-trimethyl-1-
azatricyclo[7.1.1.05,6]undeca-2,4,6-triene (+)-11. [R]20D +38.4 (c
1.0, CHCl3) [the enantiomer21 had [R]D –39.5 (c 1.3, CHCl3)]; IR
(NaCl) ν 2945 (s, C-H), 1586 (m, Ar), 1488 (m, Ar), 1437 (m,
Ar), 1206 (m, CH3), 1031 (s, C-F), 754 (m, Ar-H) cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.65 (s, 3H, CH3), 1.31 (d, J ) 9.8 Hz, 1H,
9-H), 1.38 (s, 3H, CH3), 1.44 (d, J ) 7.1 Hz, 3H, CH3C(7)), 2.13
(td, J ) 5.8, 2.5 Hz, 1H, 8-H), 2.53 (dt, J ) 9.8, 5.8 Hz, 1H, 9-H′),
2.74 (t, J ) 5.8 Hz, 1H, 10-H), 3.24 (qd, J ) 7.1, 2.5 Hz, 1H,
7-H), 7.09 (ddd, J ) 11.5, 8.1, 1.3 Hz, 1H, 3′-H), 7.18 (d, J ) 7.8
Hz, 1H, 4-H), 7.20 (td, J ) 7.6, 1.3 Hz, 1H, 5′-H), 7.24–7.29 (m,
1H, 4′-H), 7.48 (dd, J ) 7.8, 2.0 Hz, 1H, 3-H), 7.96 (td, J ) 7.9,
1.9 Hz, 1H, 6′-H); 13C NMR (100 MHz, CDCl3) δ 18.2 (CH3C(7)),
20.8 (CH3), 26.2 (CH3), 28.5 (CH2-9), 38.8 (CH-7), 41.3 (C-11),
46.7 (CH-8), 46.9 (CH-10), 115.9 (d, J ) 23 Hz, CH-3′), 121.0 (d,
J ) 9 Hz, CH-3), 124.2 (d, J ) 4 Hz, CH-5′), 127.8 (d, J ) 12
Hz, C-1′), 129.5 (d, J ) 9 Hz, CH-4′), 130.9 (d, J ) 4 Hz, CH-6′),
132.8 (CH-4), 140.4 (C-5), 149.9 (d, J ) 3 Hz, C-2), 160.4 (d, J
) 249 Hz, C-2′), 160.6 (C-6); 19F NMR (376 MHz, CDCl3) δ
–116.9 (s); MS (EI) m/z (%) 281 (M•+, 19), 266 (M•+ - CH3, 50),
238 (62), 224 (12), 83 (100); HRMS (EI) 281.1583 (C19H20FN
requires 281.1580).
the reaction at even lower temperatures proved to be imprac-
tically slow, the latter conditions (entry 10) were accepted as
optimized.
Variation of the substitution pattern in the 4-position of the
cyclobutanone (1b-j) showed reduction in enantioselectivity
to 70–75% ee for the aromatics with electron-withdrawing or
neutral groups 1b-g (entries 11–16) and to 58% ee for the
p-methoxybenzyl derivative 1h (entry 17). The asymmetric
induction observed for the cyclohexyl derivative 1i was in the
middle between the two groups (entry 18), whereas n-octylcy-
clobutanone 1j leaned toward the lower end of the spectrum
(entry 19).
Conclusion
We have developed a series of new terpene-derived pyridine-
phosphine ligands 4–7, whose complexes with Pd(II) proved
to catalyze Baeyer–Villiger oxidation of prochiral cyclobu-
tanones 1a-j with the urea-H2O2 complex as the stoichiometric
oxidant. Low temperature (-40 °C), THF as the solvent, and 5
mol % catalyst loading31 were identified as optimal conditions.
Ligand 7 (FredPhos) exhibited the highest enantioselectivities
(e81% ee; Table 1, entry 10), which brings it into the same
category as the most successful ligand reported to date (3 with
78% ee;20 entry 2).
Experimental Section
(8S,10S)-(+)-2-(2′-Fluorophenyl)-11,11-dimethyl-1-azatricyclo-
[7.1.1.05,6]undeca-2,4,6-triene (+)-10. A solution of pinocarvone
(-)-821,24 (1.05 g, 7.0 mmol), with the Kröhnke salt 921 (2.41 g,
7.0 mmol) and ammonium acetate (9.25 g) in acetic acid (12 mL)
was refluxed for 6 h. The mixture was then diluted with water (25
mL), made neutral by addition of an aqueous solution of sodium
hydroxide (2 M), and extracted with ethyl acetate (3 × 50 mL).
The organic phase was washed successively with water (3 × 50
mL) and brine (50 mL) and dried over MgSO4. The solvent was
removed under vacuum to afford pure (+)-10 (1.25 g, 67%) as a
red oil: [R]19 +68.8 (c 1.0, CHCl3) [the enantiomer21 had [R]D
D
–75.2 (c 0.8, CHCl3)]; IR (NaCl) ν 2939 (s, C-H), 1588 (s, Ar),
(27) For the method, see, e.g.: Kündig, E. P.; Meier, P. HelV. Chim. Acta
1999, 82, 1360.
(28) While the synthesis of 5 was straightforward, the preparation of 6 and
7 was complicated by the difficulties associated with the isolation of the pure
product from the crude mixture. Since phosphines 6 and 7 could not be fully
separated from the unreacted, respective fluorides 11 and 12 and traces of Ph2PH,
the crude mixture was oxidized (H2O2, Me2CO, rt, 10 min) to convert the
phosphines into the corresponding phosphine oxides, which were then readily
separated from the fluorides 11 and 12 by column chromatography. However,
the phosphine oxides were still contaminated by Ph2P(O)H, generated from
Ph2PH. Therefore, the mixture was treated with KOH in EtOH (reflux, 4 h),
which generated the water-soluble Ph2PO2K (presumably via air oxidation),
whose separation from the respective phosphine oxides was carried out by
partitioning between the aqueous and organnic phase (for the method, see:
Tsvetkov, E. N.; Bondarenko, N. A.; Malakhova, I. G.; Kabachnik, M. I. Synthesis
1986, 198). The pure phosphine oxides were then reduced [Cl3SiH, Et3N, toluene,
reflux, 24 h; for the method, see: (a) Kurz, L.; Lee, G.; Morgans, D., Jr.; Waldyke,
(7R,8S,10S)-(+)-2-(2′-Fluorophenyl)-7-isopropyl-11,11-dimethyl-
1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene (+)-12. [R]25D +15.8
(c 1.0, CHCl3); IR (NaCl) ν 2942 (s, C-H), 1587 (m, Ar), 1483
(m, Ar), 1432 (m, Ar), 1213 (m, C-H methyl), 1056 (s, C-F),
752 (m, Ar-H) cm-1; 1H NMR (400 MHz, CDCl3) δ 0.59 (s, 3H,
CH3), 0.81 (d, J ) 7.0 Hz, 3H, CH3CH), 1.17 (d, J ) 7.0 Hz, 3H,
CH3’CH)), 1.35 (d, J ) 9.7 Hz, 1H, 9-H), 1.36 (s, 3H, CH3), 2.32
(td, J ) 5.7, 2.0 Hz, 1H, 8-H), 2.52 (dt, J ) 9.7, 5.7 Hz, 1H, 9-H′),
2.68 (t, J ) 5.7 Hz, 1H, 10-H), 2.83 (spd, J ) 7.0, 4.7 Hz, 1H,
(CH3)2CH), 2.93 (dd, J ) 4.7, 2.0 Hz, 1H, 7-H), 7.06 (ddd, J )
11.5, 8.1, 1.3 Hz, 1H, 3′-H), 7.17 (d, J ) 7.8 Hz, 1H, 4-H), 7.18
(td, J ) 7.5, 1.4 Hz, 1H, 5′-H), 7.22–7.27 (m, 1H, 4′-H), 7.47 (dd,
J ) 7.8, 2.0 Hz, 1H, 3-H), 8.04 (td, J ) 7.9, 2.0 Hz, 1H, 6′-H);
13C NMR (100 MHz, CDCl3) δ 20.0 (CH3CH), 21.0 (CH3), 22.2
ˇ
M. J.; Wars, T. Tetrahedron Lett. 1990, 31, 6321. (b) Vyskocˇil, S.; Smrcˇina,
M.; Hanusˇ, V.; Polásˇek, M.; Kocˇovský, P. J. Org. Chem. 1998, 63, 7738.] to
afford the respective phosphines (+)-6 and (-)-7. The yields (50% and 52%,
respectively) correspond to the overall procedure.
(29) For the method, see the following: (a) Krepski, L. R.; Hassner, A. J.
Org. Chem. 1978, 43, 2879. (b) Hassner, A.; Dillon, J. L. J. Org. Chem. 1983,
48, 3382.
(30) Most of the cyclobutanones 1a-j were obtained in good yields.
However, we failed to prepare p-methoxyphenylcyclobutanone due to the
polymerization of the starting p-methoxystyrene under the reaction conditions.
(31) Lower catalyst loading was not explored.
(32) (a) Uchida, T.; Katsuki, T. Tetrahedron Lett. 2001, 42, 6911. (b) Uchida,
T.; Katsuki, T. HelV. Chim. Acta 2002, 85, 3078.
(33) Koul, S.; Singh, B.; Taneja, S. C.; Qazi, G. N. Tetrahedron 2003, 59,
3487.
J. Org. Chem. Vol. 73, No. 11, 2008 3999

Malkov et al.
(C’H3CH), 26.3 (CH3), 29.4 (CH2-9), 30.3 (CH3CHCH3), 41.2 (CH-
8), 41.9 (C-11), 46.5 (CH-10), 49.1 (CH-7), 116.0 (d, J ) 23 Hz,
CH-3′), 121.0 (d, J ) 10 Hz, CH-3), 124.3 (d, J ) 4 Hz, CH-5′),
127.9 (d, J ) 12 Hz, C-1′), 129.5 (d, J ) 9 Hz, CH-4′), 130.9 (d,
J ) 3 Hz, CH-6′), 132.9 (CH-4), 141.1 (C-5), 149.6 (d, J ) 3 Hz,
C-2), 159.2 (C-6), 160.5 (d, J ) 249 Hz, C-2′); 19F NMR (376
MHz, CDCl3) δ –116.9 (s); MS (EI) m/z (%) 309 (M•+, 17), 294
(M•+ - CH3, 15), 266 (M•+ - CH(CH3)2, 84), 224 (100), 83 (78);
HRMS (EI) 309.1897 (C21H24FN requires 309.1893).
J ) 24 Hz, C-2′), 155.6 (C-6), 155.8 (d, J ) 2 Hz, C-2); 31P NMR
(162.0 MHz, CDCl3) δ -9.3 (s); MS (EI) m/z (%) 433 (M•+, 10),
356 (M•+ - C6H5, 100), 248 (M•+ - PPh2, 5), 91 (12), 44 (76);
HRMS (EI) 433.1953 (C30H28NP requires 433.1959).
(7R,8S,10S)-(+)-2-[2′-(Diphenylphosphino)phenyl]-7,11,11-tri-
methyl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene (+)-6. [R]26
D
+3.4 (c 1.0, CHCl3) [the enantiomer21 had [R]D –10.1 (c 2.00,
CHCl3)]; IR (KBr) ν 2942 (m, C-H), 1573 (m, Ar), 1452 (m, Ar),
1431 (m, Ar), 1217 (m), 755 (s, Ar-H) cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.51 (s, 3H, CH3), 0.90 (d, J ) 7.0 Hz, 3H, CH3C(7)),
1.17 (d, J ) 9.9 Hz, 1H, 9-H), 1.31 (s, 3H, CH3), 1.97 (td, J ) 5.7,
2.4 Hz, 1H, 8-H), 2.41 (dt, J ) 9.9, 5.7 Hz, 1H, 9-H′), 2.63 (t, J
) 5.7 Hz, 1H, 10-H), 2.90 (qd, J ) 7.0, 2.4 Hz, 1H, 7-H), 6.96
(dd, J ) 7.5, 3.8 Hz, 1H, 3′-H), 7.06 (d, J ) 7.7 Hz, 1H, 4-H),
7.11 (d, J ) 7.7 Hz, 1H, 3-H), 7.15–7.25 (m, 11H, aromH), 7.34
(td, J ) 7.5, 1.0 Hz, 1H, 5′-H), 7.55 (ddd, J ) 7.5, 4.3, 1.1 Hz,
1H, 6′-H); 13C NMR (100 MHz, CDCl3) δ 17.7 (CH3C(7)), 20.9
(CH3), 26.2 (CH3), 28.5 (CH2-9), 38.7 (CH-7), 41.3 (C-11), 46.8
(CH-8), 46.9 (CH-10), 120.2 (d, J ) 3.0 Hz, CH-3), 127.7, (CH-
4′), 128.0–128.2 (6 × aromCH), 128.4 (CH-5′), 129.4 (d, J ) 4.2
Hz, CH-6′), 132.5 (CH-4), 133.7 (d, J ) 15.1 Hz, 2 × aromCH),
134.9 (d, J ) 14.8 Hz, 2 × aromCH), 134.4 (d, J ) 21.4 Hz, CH-
3′), 136.1 (d, J ) 18 Hz, C-1′), 139.0 (d, J ) 11 Hz, CPAr2), 139.2
(d, J ) 11 Hz, C’PAr2), 139.5 (C-5), 146.4 (d, J ) 23 Hz, C-2′),
156.0 (d, J ) 2 Hz, C-2), 159.6 (C-6); 31P NMR (162.0 MHz,
General Procedure for the Reaction of Fluoro Derivatives
10–12 with Ph2PK. Diphenylphosphine (0.32 mL, 1.86 mmol, 2
equiv) was added to a suspension of potassium tert-butoxide (210
mg, 1.86 mmol, 2 equiv) and 18-crown-6 (490 mg, 1.86 mmol) in
THF (10 mL) at 0 °C and the resulting deep red solution was stirred
at this temperature for 1 h. A solution of the respective fluoro
derivative 10 (250 mg, 0.93 mmol, 1 equiv), 11 (262 mg, 0.93
mmol, 1 equiv), and 12 (287 mg, 0.93 mmol) in THF (2 mL) was
then added dropwise and the mixture was stirred at room temper-
ature for 48 h. Methanol (2 mL) was then added and the solvent
was removed in vacuo to afford an oil that was purified via flash
chromatography on silica gel (25 g) with use of petroleum ether
followed by a 9:1 mixture of petroleum ether and ethyl acetate to
give pure (+)-5 (167 mg, 42%) as a white solid. In the case of
(+)-6 and (-)-7,28 after evaporation of the solvent, the residue was
dissolved in acetone (20 mL) and a 30% aqueous solution of
hydrogen peroxide (3 mL) was then added. The resulting mixture
was stirred at room temperature for 10 min and then partitioned
between water and CH2Cl2. The layers were separated, the aqueous
phase was extracted with CH2Cl2 (3 × 10 mL), and the combined
organic extracts were washed with water (20 mL) and brine (20
mL), dried over MgSO4, and concentrated under vacuum. The crude
mixture was then purified via flash chromatography on silica gel
(17 g) with a 1:1 mixture of petroleum ether and ethyl acetate,
followed by pure methanol. The methanolic fraction was concen-
trated in vacuo and the residue was dissolved in ethanol (1.5 mL).
Potassium hydroxide (1.3 mmol, 56.1 mg, 1.3 equiv) was added to
the ethanolic solution and the reaction mixture was refluxed for
4 h. The latter mixture was then cooled to room temperature and
diluted with water (20 mL). The aqueous phase was extracted with
ethyl acetate (3 × 20 mL) and the combined organic extracts were
then washed with a saturated aqueous solution of NaHCO3 (3 ×
20 mL), dried over MgSO4, and concentrated under vacuum.
Finally, the residue was dissolved in toluene (10 mL), triethylamine
(2.1 mL, 15 mmol, 15 equiv) and trichlorosilane (1 mL, 10 mmol,
10 equiv) were added, and the resulting reaction mixture was
refluxed for 24 h. The mixture was then diluted with an aqueous
solution of sodium hydroxide (2 M, 10 mL) and the aqueous phase
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were washed with water (20 mL) and brine (20 mL) and
dried over MgSO4 and concentrated under vacuum to afford pure
(+)-6 (208 mg, 50%) and (-)-7 (230 mg, 52%), respectively.
(8S,10S)-(+)-2-[2′-(Diphenylphosphino)phenyl]-11,11-dimeth-
yl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene (+)-5. [R]19D +58.5
(c 1.0, CHCl3); IR (KBr) ν 2936 (m, C-H), 1576 (m, Ar), 1445
CDCl3) δ -9.9 (s); MS (EI) m/z (%) 447 (M•+, 14), 370 (M•+
-
C6H5, 100); HRMS (EI) 447.2118 (C31H30NP requires 447.2116).
(7R,8S,10S)-(-)-2-[2′-(Diphenylphosphino)phenyl]-7-isopro-
pyl-11,11-dimethyl-1-azatricyclo[7.1.1.05,6]undeca-2,4,6-triene (-)-
7. [R]26D -15.0 (c 1.0, CHCl3); IR (KBr) ν 2951 (m, C-H), 1571
(m, Ar), 1449 (m, Ar), 1433 (m, Ar), 1215 (m), 752 (s, Ar-H)
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.49 (s, 3H, CH3), 0.53 (d,
J ) 7.0 Hz, 3H, CH3CH), 0.73 (d, J ) 7.0 Hz, 3H, CH3’CH), 1.30
(d, J ) 9.9 Hz, 1H, 9-H), 1.31 (s, 3H, CH3), 2.15–2.25 (m, 2H,
8-H, CH3CHCH3), 2.44 (dt, J ) 9.9, 5.6 Hz, 1H, 9-H′), 2.60 (t, J
) 5.6 Hz, 1H, 10-H), 2.63–2.67 (m, 1H, 7-H), 6.99 (dd, J ) 7.2,
3.8 Hz, 1H, 3′-H), 7.09 (d, J ) 7.7 Hz, 1H, 4-H), 7.12 (d, J ) 7.7
Hz, 1H, 3-H), 7.14–7.26 (m, 11H, aromH), 7.33 (t, J ) 7.2 Hz,
1H, 5′-H), 7.54 (dd, J ) 7.2, 4.4 Hz, 1H, 6′-H); 13C NMR (100
MHz, CDCl3) δ 19.7 (CH3CH), 21.1 (CH3), 22.0 (C’H3CH), 26.3
(CH3), 29.1 (CH(CH3)2), 29.5 (CH2-9), 40.4 (CH-8), 41.9 (C-11),
46.6 (CH-10), 48.9 (CH-7), 120.4 (d, J ) 3.1 Hz, CH-3),
127.7–128.2 (7 × aromCH), 128.6 (CH-5′), 129.6 (d, J ) 5.0 Hz,
CH-6′), 132.5 (CH-4), 133.6 (d, J ) 18.8 Hz, 2 × aromCH), 133.8
(d, J ) 18.8 Hz, 2 × aromCH), 135.2 (d, J ) 22.2 Hz, CH-3′),
135.8 (d, J ) 18 Hz, C-1′), 139.0 (d, J ) 12.8 Hz, CPAr2), 139.3
(d, J ) 12.6 Hz, C’PAr2), 140.3 (C-5), 147.4 (d, J ) 25.7 Hz,
C-2′), 156.2 (d, J ) 2.7 Hz, C-2), 158.2 (C-6); 31P NMR (162.0
MHz, CDCl3) δ -11.2 (s); MS (EI) m/z (%) 475 (M•+, 39), 398
(M•+ - C6H5, 100), 355 (M•+ - C6H5 - (CH3)2CH, 32), 194 (60);
HRMS (EI) 475.2428 (C33H34NP requires 475.2429).
Zinc-Copper Couple Preparation. A solution of copper sulfate
(CuSO4 ·5H2O, 0.76 g) in water (5 mL) was added in two portions
at 30-s intervals to a stirred mixture of zinc dust (6.5 g, 0.1 mol)
in water (10 mL). After 1 min the mixture was filtered through a
sintered-glass Büchner funnel and the zinc-copper couple was
washed with water (2 × 5 mL), acetone (2 × 5 mL), and ether (5
mL). The resulting dark-gray powder was dried at 100 °C under
vacuum for 6 h and then stored under argon.
General Procedure for the Formation of 2,2-Dichlorocy-
clobutanones 14a-j. A solution of trichloroacetyl chloride (1.12
mL, 10.0 mmol, 2.0 equiv) and phosphorus oxychloride (0.51 mL,
5.5 mmol, 1.1 equiv) in ether (5 mL) was added dropwise to a
solution of the vinyl derivative 13a-j (5.0 mmol, 1.0 equiv) and
zinc-copper couple (0.98 g, 15.0 mmol, 3.0 equiv) in ether (10
mL). The resulting solution was heated at 40 °C for 2 h and then
stirred at room temperature overnight. The resulting mixture was
filtered over Celite and the Celite was washed with ether (12 mL).
Hexane (40 mL) was added to the filtrate, which was then gently
1
(m, Ar), 1432 (m, Ar), 1213 (m), 757 (s, Ar-H) cm-1; H NMR
(400 MHz, CDCl3) δ 0.46 (s, 3H, CH3), 1.13 (d, J ) 9.4 Hz, 1H,
9-H), 1.27 (s, 3H, CH3), 2.18 (tt, J ) 5.7, 2.9 Hz, 1H, 8-H), 2.52
(dt, J ) 9.4, 5.7 Hz, 1H, 9-H′), 2.60 (t, J ) 5.7 Hz, 1H, 10-H),
2.75 (d, J ) 2.9 Hz, 2H, 7-H), 6.92 (ddd, J ) 7.7, 4.1, 1.1 Hz, 1H,
3′-H), 7.02 (d, J ) 7.7 Hz, 1H, 4-H), 7.08 (d, J ) 7.7 Hz, 1H,
5-H), 7.12–7.22 (m, 11H, aromH), 7.31 (td, J ) 7.6, 1.3 Hz, 1H,
5′-H), 7.51 (ddd, J ) 7.6, 4.2, 1.2 Hz, 1H, 6′-H); 13C NMR (100
MHz, CDCl3) δ 21.3 (CH3), 26.0 (CH3), 31.7 (CH2-9), 36.0 (CH2-
7), 39.4 (C-11), 40.1 (CH-8), 46.2 (CH-10), 120.14 (d, J ) 3.7
Hz, CH-3), 127.7, (CH-4′), 128.0–128.2 (6 × aromCH), 128.5 (CH-
5′), 129.3 (d, J ) 4 Hz, CH-6′), 132.6 (CH-4), 133.9 (d, J ) 6.4
Hz, 2 × aromCH), 134.1 (d, J ) 6.4 Hz, 2 × aromCH), 134.2 (d,
J ) 30.5 Hz, CH-3′), 136.6 (d, J ) 18 Hz, C-1′), 138.6 (d, J ) 11
Hz, CPAr2), 138.7 (d, J ) 11 Hz, C’PAr2), 139.7 (C-5), 145.9 (d,
4000 J. Org. Chem. Vol. 73, No. 11, 2008

Baeyer–Villiger Reaction of Symmetrical Cyclobutanones
stirred to help zinc dichloride to precipitate. The supernatant solution
was successively washed with water (20 mL), a saturated aqueous
solution of NaHCO3 (20 mL), and brine (20 mL) and dried over
Na2SO4, then concentrated under vacuum to afford pure 14a-j,
which were used directly in the next step (i.e., conversion into 1a–j)
without further purification.
2,2-Dichloro-3-phenylcyclobutanone (14a). Yield 1.042 g, 97%;
1H NMR (400 MHz, CDCl3) δ 3.55 (dd, J ) 17.6, 10.3 Hz, 1H,
4-H), 3.73 (dd, J ) 17.6, 10.3 Hz, 1H, 4-H′), 4.26 (t, J ) 10.3 Hz,
1H, 3-H), 7.33 (d, J ) 7.2 Hz, 2H, 2′-H, 6′-H), 7.40 (t, J ) 7.2
Hz, 1H, 4′-H), 7.45 (t, J ) 7.2 Hz, 2H, 3′-H, 5′-H); 13C NMR (100
MHz, CDCl3) δ 45.7 (CH2-4), 50.5 (CH-3), 89.5 (C-2), 128.0 (2
× CH-2′,6′), 128.3 (CH-4′), 128.6 (2 × CH-3′,5′), 134.4 (C-1′),
191.9 (CdO) in agreement with the literature data.29
organic phase was washed successively with a saturated solution
of aqueous NaHCO3 (3 × 20 mL), water (30 mL), and brine (30
mL), then dried over MgSO4 and concentrated under vacuum. The
crude material was then purified by flash chromatography on silica
gel (20 g) with a mixture of petroleum ether and ethyl acetate (5:
1) to afford 1a-j as colorless oils.
3-Phenylcyclobutanone (1a). Yield 612 mg, 86%; 1H NMR (400
MHz, CDCl3) δ 3.18 (ddt, J ) 19.9, 8.2, 3.7 Hz, 2H, 2-H, 4-H),
3.42 (ddt, J ) 19.9, 8.2, 3.7 Hz, 2H, 2-H′, 4-H′), 3.57 (pent, J )
8.2 Hz, 1H, 3-H), 7.16 (t, J ) 7.1 Hz, 1H, 4′-H), 7.20 (d, J ) 7.1
Hz, 2H, 2′-H, 6′-H), 7.26 (t, J ) 7.1 Hz, 2H, 3′-H, 5′-H); 13C NMR
(100 MHz, CDCl3) δ 28.3 (CH-3), 54.6 (2 × CH2-2,4), 126.4 (2
× CH-2′,6′), 126.5 (CH-4′), 128.6 (2 × CH-3′,5′), 143.5 (C-1′),
206.5 (CdO) in agreement with the literature data.29
2,2-Dichloro-3-(4′-toluyl)cyclobutanone (14b). Yield 1.040 g,
91%; H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H, CH3), 3.41 (dd,
3-(4′-Toluyl)cyclobutanone (1b). Yield 232 mg, 32%; IR (NaCl)
ν 2922 (w, C-H), 1783 (s, CdO), 1608 (m, Ar), 1570 (m, Ar),
1515 (m, Ar), 1161 (m), 1019 (m), 813 (s, Ar-H) cm-1; 1H NMR
(400 MHz, CDCl3) δ 2.28 (s, 3H, CH3), 3.17 (ddt, J ) 20.0, 8.6,
3.1 Hz, 2H, 2-H, 4-H), 3.42 (ddt, J ) 20.0, 8.6, 3.1 Hz, 2H, 2-H′,
4-H′), 3.54 (pent, J ) 8.6 Hz, 1H, 3-H), 7.09 (d, J ) 8.4 Hz, 2H,
3′-H, 5′-H), 7.12 (dd, J ) 8.4 Hz, 2H, 2′-H, 6′-H); 13C NMR (100
MHz, CDCl3) δ 20.7 (CH3), 27.7 (CH-3), 54.4 (2 × CH2-2,4), 126.1
(2 × CH-2′,6′), 129.0 (2 × CH-3′,5′), 135.8 (C-4′), 140.3 (C-1′),
1
J ) 17.7, 10.3 Hz, 1H, 4-H), 3.59 (dd, J ) 17.7, 10.3 Hz, 1H,
4-H′), 4.13 (t, J ) 10.3 Hz, 1H, 3-H), 7.14 (d, J ) 8.2 Hz, 2H,
3′-H, 5′-H), 7.18 (dd, J ) 8.2 Hz, 2H, 2′-H, 6′-H).
2,2-Dichloro-3-(4′-fluorophenyl)cyclobutanone (14c). Yield
1
1.092 g, 94%; H NMR (400 MHz, CDCl3) δ 2.75 (dd, J ) 17.7,
10.3 Hz, 1H, 4-H), 3.55 (dd, J ) 17.7, 10.3 Hz, 1H, 4-H′), 4.10 (t,
J ) 10.3 Hz, 1H, 3-H), 6.97 (t, J ) 8.7 Hz, 2H, 3′-H, 5′-H), 7.17
(dd, J ) 8.7, 5.2 Hz, 2H, 2′-H, 6′-H); 13C NMR (100 MHz, CDCl3)
δ 45.8 (CH2-4), 49.8 (CH-3), 89.4 (C-2), 115.5 (d, J ) 21.6 Hz, 2
× CH-3′,5′), 129.7 (d, J ) 8.2 Hz, 2 × CH-2′,6′), 130.2 (d, J )
3.3 Hz, C-1′), 162.4 (d, J ) 247.4 Hz, CF-4′), 191.5 (CdO); 19F
NMR (376 MHz, CDCl3) δ –113.2 (s).
206.5 (CdO); MS (EI) m/z (%) 160 (M•+, 12), 118 (M•+
-
CH2CdO, 100), 91 (M•+ - C3H5CdO, 26), 83 (32); HRMS (EI)
160.0889 (C11H12O requires 160.0888).
3-(4′-Fluorophenyl)cyclobutanone (1c). Yield 409 mg, 56%;
IR (NaCl) ν 2977 (w, C-H), 1785 (s, CdO), 1604 (m, Ar), 1511
(m, Ar), 1431 (m, Ar), 1226 (s), 1103 (m, C-F), 829 (s, Ar-H)
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.11 (ddt, J ) 20.0, 8.3, 3.0
Hz, 2H, 2-H, 4-H), 3.40 (ddt, J ) 20.0, 8.3, 3.0 Hz, 2H, 2-H′,
4-H′), 3.58 (pent, J ) 8.3 Hz, 1H, 3-H), 6.95 (t, J ) 8.6 Hz, 2H,
3′-H, 5′-H), 7.19 (dd, J ) 8.6, 5.4 Hz, 2H, 2′-H, 6′-H); 13C NMR
(100 MHz, CDCl3) δ 27.5 (CH-3), 54.5 (2 × CH2-2,4), 115.2 (d,
J ) 21.3 Hz, 2 × CH-3′,5′), 127.8 (d, J ) 8.0 Hz, 2 × CH-2′,6′),
139.1 (d, J ) 3.1 Hz, C-1′), 161.3 (d, J ) 244.7 Hz, CF-4′), 206.0
(CdO);19F NMR (376 MHz, CDCl3) δ –116.3 (s); MS (EI) m/z
(%) 164 (M•+, 4), 122 (M•+ - CH2CdO, 100), 84 (61), 49 (86);
HRMS (EI) 164.0638 (C10H9FO requires 164.0637).
2,2-Dichloro-3-(4′-chlorophenyl)cyclobutanone (14d). Yield
1
1.121 g, 90%; H NMR (400 MHz, CDCl3) δ 3.49 (dd, J ) 17.7,
10.3 Hz, 1H, 4-H), 3.61 (dd, J ) 17.7, 10.3 Hz, 1H, 4-H′), 4.14 (t,
J ) 10.3 Hz, 1H, 3-H), 7.18 (d, J ) 8.9 Hz, 2H, 3′-H, 5′-H), 7.34
(dd, J ) 8.9 Hz, 2H, 2′-H, 6′-H).
2,2-Dichloro-3-(4′-bromophenyl)cyclobutanone (14e). Yield
1
1.352 g, 92%; H NMR (400 MHz, CDCl3) δ 3.55 (dd, J ) 17.6,
10.3 Hz, 1H, 4-H), 3.67 (dd, J ) 17.6, 10.3 Hz, 1H, 4-H′), 4.19 (t,
J ) 10.3 Hz, 1H, 3-H), 7.19 (d, J ) 8.5 Hz, 2H, 3′-H, 5′-H), 7.56
(dd, J ) 8.5 Hz, 2H, 2′-H, 6′-H).
2,2-Dichloro-3-(2′-bromophenyl)cyclobutanone (14f). Yield
1.314 g, 94%; 1H NMR (400 MHz, CDCl3) δ 3.60 (d, J ) 9.8 Hz,
2H, 4H), 4.67 (t, J ) 9.8 Hz, 1H, 3-H), 7.13 (td, J ) 7.7, 1,5 Hz,
1H, 4′-H), 7.17 (dd, J ) 7.7, 1,5 Hz, 1H, 6′-H), 7.28 (td, J ) 7.7,
1.1 Hz, 1H, 5′-H), 7.58 (dd, J ) 7.7, 1.1 Hz, 1H, 3′-H).
2,2-Dichloro-3-(2′-naphthyl)cyclobutanone (14g). Yield 547
mg, 41%; 1H NMR (400 MHz, CDCl3) δ 3.35 (dd, J ) 17.7, 10.3
Hz, 1H, 4-H), 3.63 (dd, J ) 17.7, 10.3 Hz, 1H, 4-H′), 4.17 (t, J )
10.3 Hz, 1H, 3-H), 7.33 (dd, J ) 8.5, 1.8 Hz, 1H, 3′-H), 7.37–7.45
(m, 2H, 6′-H, 7′-H), 7.63–7.67 (m, 1H, 1′-H), 7.72–7.80 (m, 3H,
4′-H, 8′-H, 5′-H).
3-(4′-Chlorophenyl)cyclobutanone (1d). Yield 371 mg, 46%;
IR (NaCl) ν 2974 (w, C-H), 1786 (s, CdO), 1593 (m, Ar), 1493
1
(m, Ar), 1092 (s, C-Cl), 1013 (m), 821 (s, Ar) cm-1; H NMR
(400 MHz, CDCl3) δ 3.17 (ddt, J ) 20.2, 8.3, 3.1 Hz, 2H, 2-H,
4-H), 3.47 (ddt, J ) 20.2, 8.3, 3.1 Hz, 2H, 2-H′, 4-H′), 3.63 (pent,
J ) 8.3 Hz, 1H, 3-H), 7.21 (d, J ) 8.4 Hz, 2H, 2′-H, 6′-H), 7.29
(d, J ) 8.4 Hz, 2H, 3′-H, 5′-H); 13C NMR (100 MHz, CDCl3) δ
27.7 (CH-3), 54.5 (2 × CH2-2,4), 127.7 (2 × CH-3′,5′), 128.5 (2
× CH-2′,6′), 132.1 (C-4′), 141.9 (C-1), 205.8 (CdO) in agreement
with the literature data.34
2,2-Dichloro-3-(4′-methoxybenzyl)cyclobutanone (14 h). Yield
1.287 g, 99%; H NMR (400 MHz, CDCl3) δ 2.75 (dd, J ) 14.0,
8.7 Hz, 1H, 4-H), 3.03 (dd, J ) 16.7, 8.0 Hz, 1H, 4-H′), 3.10–3.30
(m, 3H, CH2CH), 3.77 (s, 3H, CH3O), 6.86 (d, J ) 8.7 Hz, 2H,
3′-H, 5′-H), 7.15 (dd, J ) 8.7, 2H, 2′-H, 6′-H).
3-(4′-Bromophenyl)cyclobutanone (1e). Yield 459 mg, 51%;
1
IR (NaCl) ν 2976 (w, C-H), 1786 (s, CdO), 1589 (m, Ar), 1489
1
(m, Ar), 1073 (s), 1009 (m), 817 (s, Ar-H) cm-1; H NMR (400
MHz, CDCl3) δ 3.20 (ddt, J ) 20.1, 8.3, 3.7 Hz, 2H, 2-H, 4-H),
3.50 (ddt, J ) 20.1, 8.3, 3.7 Hz, 2H, 2-H′, 4-H′), 3.64 (pent, J )
8.4 Hz, 1H, 3-H), 7.17 (d, J ) 8.3 Hz, 2H, 2′-H, 6′-H), 7.47 (d, J
) 8.3 Hz, 2H, 3′-H, 5′-H); 13C NMR (100 MHz, CDCl3) δ 28.0
(CH-3), 54.6 (2 × CH2-2,4), 120.4 (C-4′), 128.2 (2 × CH-2′,6′),
131.7 (2 × CH-3′,5′), 142.5 (C-1′), 206.0 (CdO); MS (EI) m/z
(%) 225 (d, M•+, 7), 183 (d, M•+ - CH2CdO, 100), 115 (17), 103
(M•+ - CH2CdO-Br, 60), 77 (42); HRMS (EI) 223.9835 (C10H9-
BrO requires 223.9837).
2,2-Dichloro-3-(cyclohexyl)cyclobutanone (14i). Yield 1.062
g, 96%; 1H NMR (400 MHz, CDCl3) δ 0.92–1.35 (m, 5H),
1.51–1.79 (m, 5H), 2.00–2.12 (m, 1H, 1′-H), 2.54 (q, J ) 10.3 Hz,
1H, 3-H), 3.03 (dd, J ) 17.4, 10.3 Hz, 1H, 4-H), 3.13 (dd, J )
17.4, 10.3 Hz, 1H, 4-H′).
2,2-Dichloro-3-octylcyclobutanone (14j). Yield 1.062 g, 85%;
1H NMR (400 MHz, CDCl3) δ 0.83 (t, J ) 6.8 Hz, 3H, CH3CH2),
1.16–1.46 (m, 12H, 6 × CH2), 1.50–1.62 (m, 1H, CH2CH2CH),
1.80–1.90 (m, 1H, CH2CH2’CH), 2.78–2.87 (m, 1H, 3-H), 2.91 (dd,
J ) 17.1, 9.2 Hz, 1H, 4-H), 3.30 (dd, J ) 17.1, 9.2 Hz, 1H, 4-H′).
General Procedure for the Formation of Cyclobutanones
1a-j. A mixture of dichloro ketone 14a-j (1 equiv) and zinc dust
(4 equiv) in acetic acid (15 mL) was stirred at room temperature
for 2 h and then refluxed for 5 h. The resulting mixture was diluted
with water (20 mL) and extracted with ether (2 × 30 mL). The
3-(2′-Bromophenyl)cyclobutanone (1f). Yield 468 mg, 52%;
IR (NaCl) ν 2981 (w, C-H), 1786 (s, CdO), 1590 (m, Ar), 1566
(m, Ar), 1472 (m, Ar), 1102 (s), 1026 (s), 754 (s, Ar-H) cm-1; 1H
NMR (400 MHz, CDCl3) δ 3.23 (ddt, J ) 20.2, 8.3, 3.2 Hz, 2H,
2-H, 4-H), 3.53 (ddt, J ) 20.2, 8.3, 3.2 Hz, 2H, 2-H′, 4-H′), 3.95
(34) Resende, P.; Almeida, W. P.; Coelho, F. Tetrahedron: Asymmetry 1999,
10, 2113.
J. Org. Chem. Vol. 73, No. 11, 2008 4001

Malkov et al.
(pent, J ) 8.3 Hz, 1H, 3-H), 7.14 (ddd, J ) 8.4, 6.1, 3.0 Hz, 1H,
4′-H), 7.32–7.38 (m, 2H, 5′-H, 6′-H), 7.61 (d, J ) 8.4 Hz, 1H,
3′-H); 13C NMR (100 MHz, CDCl3) δ 28.9 (CH-3), 52.9 (2 × CH2-
2,4), 124.7 (C-2′), 126.4 (CH-5′), 127.5 (CH-4′), 128.2 (CH-6′),
133.0 (CH-3′), 141.5 (C-1′), 205.9 (CdO); MS (EI) m/z (%) 225
gel (15 g), using a mixture of petroleum ether and ethyl acetate
(9:1), afforded pure γ-butyrolactones 2a-j.
(S)-(+)-3-Phenyl-γ-butyrolactone (S)-(+)-(2a). Yield 78.6 mg,
97%; [R]24D +38.4 (c 1.0, CHCl3, 81% ee), [lit.35 gives [R]D +46.0
1
(c 0.95, CHCl3, 96% ee)]; H NMR (400 MHz, CDCl3) δ 2.58
(M•+, 100), 183 (M•+ - CH2CdO, 30), 147 (28), 103 (M•+
-
(dd, J ) 17.5, 8.9 Hz, 1H, 2-H), 2.83 (dd, J ) 17.5, 8.9 Hz, 1H,
2-H′), 3.70 (pent, J ) 8.9 Hz, 1H, 3-H), 4.18 (dd, J ) 8.9, 8.1 Hz,
1H, 4-H), 4.57 (dd, J ) 8.9, 8.1 Hz, 1H, 4-H′), 7.14 (d, J ) 7.3
Hz, 2H, 2′-H, 6′-H), 7.21 (t, J ) 7.3 Hz, 1H, 4′-H), 7.28 (t, J )
7.3 Hz, 2H, 3′-H, 5′-H); 13C NMR (100 MHz, CDCl3) δ 35.6 (CH2-
2), 41.0 (CH-3), 74.0 (CH2-4), 126.6 (2 × CH-2′,6′), 127.6 (CH-
4′), 129.1 (2 × CH-3′,5′), 139.3 (C-1′), 176.3 (CdO) in agreement
with the literature data;36 Chiral GC (Supelco R-DEX), carrier gas
He (flow 2 mL ·min-1), injection temp 200 °C, initial column temp
110 °C for 3 min, rate 1 deg ·min-1, final temp 220 °C, tR ) 56.11
min, tS ) 56.58 min.
CH2CdO-Br, 25); HRMS (CI-isobutane) 224.9912 (C10H10BrO
(MH+) requires 224.9915).
3-(2′-Naphthyl)cyclobutanone (1g). Yield 60.8 mg, 15%; IR
(NaCl) ν 3050 (w, Car-H), 1781 (s, CdO), 1623 (m, Ar), 1511
1
(m, Ar), 1430 (m, Ar), 1226 (s), 817 (s, Ar-H) cm-1; H NMR
(400 MHz, CDCl3) δ 3.26 (ddt, J ) 20.0, 8.3, 3.4 Hz, 2H, 2a-H,
4a-H), 3.47 (ddt, J ) 20.0, 8.3, 3.4 Hz, 2H, 2-H′, 4-H′), 3.74 (pent,
J ) 8.3 Hz, 1H, 3-H), 7.33 (dd, J ) 8.5, 1.8 Hz, 1H, 3′-H),
7.37–7.45 (m, 2H, 6′-H, 7′-H), 7.64 (br s, 1H, 1′-H), 7.72–7.80
(m, 3H, 4′-H, 8′-H, 5′-H); 13C NMR (100 MHz, CDCl3) δ 28.5
(CH-3), 54.5 (2 × CH2-2,4), 124.7 (CH-1′), 124.8 (CH-3′), 125.7
(CH-6′), 126.3 (CH-7′), 127.48 (CH-4′), 127.54 (CH-8′), 128.5 (CH-
5′), 132.1 (C-8a′), 133.2 (C-4a′), 140.7 (C-2′), 206.6 (CdO); MS
(CI-isobutane) m/z (%) 197 (MH•+, 95), 154 (M•+ - CH2CdO,
12), 85 (72), 69 (100); HRMS (CI-isobutane) 197.0967 (C14H13O
(MH+) requires 197.0966).
(S)-(+)-3-(4′-Toluyl)-γ-butyrolactone (S)-(+)-(2b). Yield 81.9
1
mg, 93%; [R]24 +36.9 (c 1.0, CHCl3, 75% ee); H NMR (400
D
MHz, CDCl3) δ 2.34 (s, 3H, CH3), 2.65 (dd, J ) 17.5, 8.9 Hz, 1H,
2-H), 2.90 (dd, J ) 17.5, 8.9 Hz, 1H, 2-H′), 3.75 (pent, J ) 8.9
Hz, 1H, 3-H), 4.23 (dd, J ) 8.9, 8.0 Hz, 1H, 4-H), 4.64 (dd, J )
8.9, 8.0 Hz, 1H, 4-H′), 7.11 (d, J ) 8.1 Hz, 2H, 3′-H, 5′-H), 7.17
(dd, J ) 8.1 Hz, 2H, 2′-H, 6′-H); 13C NMR (100 MHz, CDCl3) δ
21.0 (CH3), 35.7 (CH2-2), 40.8 (CH-3), 74.1 (CH2-4), 126.5 (2 ×
CH-3′,5′), 129.7 (2 × CH-2′,6′), 136.3 (C-1′), 137.4 (C-4′), 176.4
(CdO) in agreement with the literature data;37 Chiral GC (Supelco
R-DEX), carrier gas, He (flow 2 mL ·min-1), injection temp 200
°C, initial column temp 110 °C for 3 min, rate 1 deg ·min-1, final
temp 220 °C, tR ) 66.18 min, tS ) 66.67 min.
3-(4′-Methoxybenzyl)cyclobutanone (1h). Yield 400 mg, 43%;
IR (NaCl) ν 2957 (w, Car-H), 1777 (s, CdO), 1612 (m, Ar), 1590
1
(m, Ar), 1512 (m, Ar), 1247 (s, C-O), 836 (s, Ar-H) cm-1; H
NMR (400 MHz, CDCl3) δ 2.51–2.61 (m, 1H, 3-H), 2.6 (ddt, J )
20.3, 7.1, 2.7 Hz, 2H, 2-H, 4-H), 2.75 (d, J ) 7.5 Hz, 2H, CH2CH),
2.99 (ddt, J ) 20.3, 7.1, 2.7 Hz, 2H, 2-H′, 4-H′), 3.70 (s, 3H,
CH3O), 6.80 (d, J ) 8.6 Hz, 2H, 3′-H, 5′-H), 7.05 (d, J ) 8.6 Hz,
2H, 2′-H, 6′-H); 13C NMR (100 MHz, CDCl3) δ 24.7 (CH-3), 40.4
(CH2CH), 51.6 (2 × CH2-2,4), 54.7 (CH3), 113.5 (2 × CH-3′,5′),
129.0 (2 × CH-2′,6′), 131.6 (C-1′), 157.7 (C-4′), 207.1 (CdO);
MS (EI) m/z (%) 190 (M•+, 56), 148 (M•+ - CH2CdO, 96), 121
(M•+ - C3H5CdO, 100), 77 (32); HRMS (EI) 190.0997 (C12H14O2
requires 190.0994).
(+)-3-(4′-Fluorophenyl)-γ-butyrolactone (+)-(2c). Yield 86.5
1
mg, 96%; [R]24 +29.8 (c 1.0, CHCl3, 72% ee); H NMR (400
D
MHz, CDCl3) δ 2.61 (dd, J ) 17.5, 8.9 Hz, 1H, 2-H), 2.90 (dd, J
) 17.5, 8.9 Hz, 1H, 2-H), 3.77 (pent, J ) 8.9 Hz, 1H, 3-H), 4.21
(t, J ) 8.9 Hz, 1H, 4-H′), 4.64 (t, J ) 8.9 Hz, 1H, 4-H′), 7.04 (t,
J ) 8.6 Hz, 2H, 3′-H, 5′-H), 7.20 (dd, J ) 8.6, 5.2 Hz, 2H, 2′-H,
6′-H); 13C NMR (100 MHz, CDCl3) δ 35.6 (CH2-2), 40.2 (CH-3),
73.8 (CH2-4), 115.9 (d, J ) 21.5 Hz, 2 × CH-3′,5′), 128.2 (d, J )
8.1 Hz, 2 × CH-2′,6′), 135.1 (d, J ) 3.2 Hz, C-1′), 161.9 (d, J )
246.4 Hz, C-4′), 176.1 (CdO); 19F NMR (376 MHz, CDCl3) δ
–114.5 (s) in agreement with the literature data;36 Chiral GC
(Supelco R-DEX), carrier gas, He (flow 2 mL ·min-1), injection
temp 200 °C, initial column temp 110 °C for 3 min, rate 1
deg·min-1, final temp 220 °C, tminor ) 58.06 min, tmajor ) 58.64
min.
3-(Cyclohexyl)cyclobutanone (1i). Yield 371 mg, 51%; IR
(NaCl) ν 2923 (s, C-H), 2851 (s, C-H), 1786 (s, CdO), 1448
(m, CH2), 1108 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 0.78–0.92
(m, 2H), 1.02–1.22 (m, 4H), 1.54–1.74 (m, 5H), 1.90–2.03 (m, 1H,
3-H), 2.60–2.70 (m, 2H, 2-H, 4-H), 2.89–3.00 (m, 2H, 2-H′, 4-H′);
13C NMR (100 MHz, CDCl3) δ 25.7 (2 × CH2), 25.9 (CH2-4′),
29.6 (CH-3), 30.6 (2 × CH2), 43.4 (CH-1′), 50.5 (2 × CH2-2,4),
207.9 (CdO); MS (CI-isobutane) m/z (%) 153 (MH•+, 100), 135
(MH•+ - O, 15), 71 (10); HRMS (CI-isobutane) 153.1281 (C10H17O
(MH+) requires 153.1279).
(S)-(+)-3-(4′-Chlorophenyl)-γ-butyrolactone (S)-(+)-(2d).
24
1
3-Octylcyclobutanone (1j). Yield 354 mg, 46%; IR (NaCl) ν
Yield 92.6 mg, 94%; [R]D +36.5 (c 1.0, CHCl3, 73% ee); H
NMR (400 MHz, CDCl3) δ 2.62 (dd, J ) 17.5, 8.8 Hz, 1H, 2-H),
2.93 (dd, J ) 17.5, 8.8 Hz, 1H, 2-H′), 3.77 (pent, J ) 8.8 Hz, 1H,
3-H), 4.23 (dd, J ) 8.8, 7.8 Hz, 1H, 4-H), 4.65 (dd, J ) 8.8, 7.8
Hz, 1H, 4-H′), 7.17 (d, J ) 8.3 Hz, 2H, 2′-H, 6′-H), 7.34 (d, J )
8.3 Hz, 2H, 3′-H, 5′-H); 13C NMR (100 MHz, CDCl3) δ 35.6 (CH2-
2), 40.5 (CH-3), 73.7 (CH2-4), 128.0 (2 × CH-2′,6′), 129.2 (2 ×
CH-3′,5′), 133.5 (C-4′), 137.9 (C-1′), 175.8 (C)O); in agreement
with the literature data;36 Chiral GC (Supelco R-DEX), carrier gas,
He (flow 2 mL.min-1), injection temp 200 °C, initial column temp
110 °C for 3 min, rate 1 °C.min-1, final temp 220 °C, tminor ) 81.43
min, tmajor ) 81.90 min.
2923 (s, C-H), 2854 (m, C-H), 1785 (s, CdO), 1461 (w), 1380
1
(w), 1095 (w) cm-1; H NMR (400 MHz, CDCl3) δ 0.83 (t, J )
6.8 Hz, 3H, CH3CH2), 1.16–1.31 (m, 12H, 6 × CH2), 1.48–1.56
(m, 2H, CH2CH), 2.29 (pent, J ) 7.5, 1.2 Hz, 1H, 3-H), 2.59 (ddt,
J ) 20.4, 7.5, 3.2 Hz, 2H, 2-H, 4-H), 3.06 (ddt, J ) 20.4, 7.5, 3.2
Hz, 2H, 2-H′, 4-H′); 13C NMR (100 MHz, CDCl3) δ 13.9
(CH3CH2), 22.5 (CH2), 23.7 (CH-3), 28.1 (CH2), 29.1 (CH2), 29.3
(CH2), 29.4 (CH2), 31.7 (CH2), 36.2 (CH2CH), 52.3 (2 × CH2-
2,4), 208.1 (CdO); MS (CI-isobutane) m/z (%) 183 (MH•+, 100),
165 (MH•+ - H2O, 9), 71 (18); HRMS (CI-isobutane) 183.1747
(C12H23O (MH+) requires 183.1749).
(+)-3-(4′-Bromophenyl)-γ-butyrolactone (+)-(2e). Yield 114.5
General Procedure for the Formation of γ-Butyrolactones
2a-j via the Baeyer–Villiger Reaction. A mixture of dichloro-
bis(benzonitrile)palladium(II) (9.5 mg, 0.025 mmol, 5.0 mol%) and
ligand (-)-7 (13 mg, 0.0275 mmol, 5.5 mol%) in THF (2 mL)
was stirred at room temperature for 1 h. Silver hexafluoroantimonate
(17 mg, 0.05 mmol, 10 mol %) was then added and the reaction
mixture was stirred for an additional 1 h. The mixture was then
filtered over a Celite pad, cyclobutanone 1a-j (0.5 mmol, 1 equiv)
was then added to the filtrate, and the solution was cooled to –40
°C. Urea-hydrogen peroxide (61 mg, 0.65 mmol, 1.3 equiv) was
then added and the mixture was then stirred at –40 °C overnight.
Concentration in vacuo, followed by flash chromatography on silica
mg, 95%; mp 61 °C (hexane); [R]25 +28.6 (c 1.0, CHCl3, 76%
D
1
ee); H NMR (400 MHz, CDCl3) δ 2.61 (dd, J ) 17.5, 8.8 Hz,
1H, 2-H), 2.92 (dd, J ) 17.5, 8.8 Hz, 1H, 2-H′), 3.75 (pent, J )
8.8 Hz, 1H, 3-H), 4.22 (dd, J ) 8.8, 7.7 Hz, 1H, 4-H), 4.65 (dd, J
) 8.8, 7.7 Hz, 1H, 4-H′), 7.11 (d, J ) 8.3 Hz, 2H, 2′-H, 6′-H),
7.48 (d, J ) 8.3 Hz, 2H, 3′-H, 5′-H); 13C NMR (100 MHz, CDCl3)
(35) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi, T.
Tetrahedron: Asymmetry 1999, 10, 4047.
(36) Imada, Y.; Iida, H.; Murahashi, S.-I.; Naota, T. Angew. Chem., Int. Ed.
2005, 44, 1704.
(37) Lawston, I. W.; Inch, T. D. J. Chem. Soc., Perkin Trans. 1983, 11, 2629.
4002 J. Org. Chem. Vol. 73, No. 11, 2008

Baeyer–Villiger Reaction of Symmetrical Cyclobutanones
δ 35.5 (CH2-2), 40.5 (CH-3), 73.6 (CH2-4), 121.5 (C-4′), 128.3 (2
× CH-2′,6′), 132.1 (2 × CH-3′,5′), 138.4 (C-1′), 175.8 (CdO);
MS (EI) m/z (%) 241 (M•+, 31), 183 (M•+ - CH2CO2, 100), 103
(M•+ - CH2CO2-Br, 40); HRMS (EI) 239.9792 (C10H9BrO2
6.5 Hz, 1H, 4-H), 4.30 (dd, J ) 9.1, 6.5 Hz, 1H, 4-H′), 6.84 (d, J
) 8.6 Hz, 2H, 3′-H, 5′-H), 7.06 (d, J ) 8.6 Hz, 2H, 2′-H, 6′-H);
13C NMR (100 MHz, CDCl3) δ 34.1 (CH2-2), 37.2 (CH-3), 37.9
(CH2CH), 55.2 (CH3), 72.5 (CH2-4), 114.0 (2 × CH-3′,5′), 129.5
(2 × CH-2′,6′), 130.1 (C-1′), 158.3 (C-4′), 176.8 (CdO) in
agreement with the literature data.33
requires 239.9786); Chiral HPLC (Chiracel IB, 0.75 mL ·min-1
,
hexane/2-propanol, 92:8) tmajor ) 33.4 min, tminor ) 39.1 min after
derivatization into the hydroxyl benzylamide derivative.32
(+)-3-(2′-Bromophenyl)-γ-butyrolactone (+)-(2f). Yield 110.9
(-)-3-Cyclohexyl-γ-butyrolactone (-)-(2i). Yield 74.8 mg,
1
89%; [R]24 -6.8 (c 0.5, CHCl3, 65% ee); H NMR (400 MHz,
D
mg, 92%; mp 42 °C (hexane); [R]25 +26.6 (c 1.0, CHCl3, 70%
D
CDCl3) δ 0.89–1.02 (m, 2H), 1.09–1.35 (m, 4H), 1.56–1.77 (m,
5H), 2.20 (dd, J ) 16.6, 8.0 Hz, 1H, 2-H), 2.30 (pent, J ) 9.8 Hz,
1H, 3-H), 2.53 (dd, J ) 16.6, 8.0 Hz, 1H, 2-H′), 3.96 (dd, J ) 8.9,
8.0 Hz, 1H, 4-H), 4.39 (dd, J ) 8.9, 8.0 Hz, 1H, 4-H′); 13C NMR
(100 MHz, CDCl3) δ 25.7 (CH2), 25.8 (CH2), 26.1 (CH2), 30.4
(CH2), 31.1 (CH2), 32.7 (CH2-2), 41.3 (CH-1′), 41.6 (CH-3), 72.1
(CH2-4), 177.3 (CdO); MS (EI) m/z (%) 168 (M•+, 49), 150 (21),
137 (66), 86 (100), 83 (95); HRMS (EI) 168.1153 (C10H16O2
1
ee); H NMR (400 MHz, CDCl3) δ 2.67 (dd, J ) 17.6, 8.7 Hz,
1H, 2-H), 2.98 (dd, J ) 17.6, 8.7 Hz, 1H, 2-H′), 4.23 (pent, J )
8.7 Hz, 1H, 3-H), 4.31 (dd, J ) 8.7, 6.7 Hz, 1H, 4-H), 4.71 (dd, J
) 8.7, 6.7 Hz, 1H, 4-H′), 7.17 (td, J ) 7.7, 1.7 Hz, 1H, 4′-H), 7.28
(dd, J ) 7.7, 1.7 Hz, 1H, 6′-H), 7.35 (td, J ) 7.7, 1.2 Hz, 1H,
5′-H), 7.61 (dd, J ) 7.7, 1.2 Hz, 1H, 3′-H); 13C NMR (100 MHz,
CDCl3) δ 34.6 (CH2-2), 40.0 (CH-3), 72.8 (CH2-4), 124.3 (C-2′),
126.6 (CH-6′), 128.2 (CH-5′), 129.1 (CH-4′), 133.4 (CH-3′), 138.6
requires 168.1150); Chiral HPLC (Chiracel IB, 0.75 mL ·min-1
,
(C-1′), 176.0 (CdO); MS (EI) m/z (%) 241 (M•+, 29), 183 (M•+
-
hexane/2-propanol, 90:10) tmajor ) 14.0 min, tminor ) 17.5 min after
CH2CO2, 100), 103 (M•+ - CH2CO2-Br, 67); HRMS (EI)
239.9787 (C10H9BrO2 requires 239.9786); Chiral HPLC (Chiracel
OJ-H, 0.75 mL ·min-1, hexane/2-propanol, 75:25) tminor ) 9.1 min,
tmajor ) 10.4 min after derivatization into the hydroxyl benzylamide
derivative.32
derivatization into the hydroxyl benzylamide derivative.32
(R)-(+)-3-Octyl-γ-butyrolactone (R)-(+)-(2j). Yield 82.5 mg,
1
83%; [R]24 +0.6 (c 1.0, CHCl3, 55% ee); H NMR (400 MHz,
D
CDCl3) δ 0.85 (t, J ) 6.9 Hz, 3H, CH3CH2), 1.19–1.30 (m, 12H,
6 × CH2), 1.40–1.48 (m, 2H, CH2CH), 2.14 (dd, J ) 16.7, 7.7 Hz,
1H, 2-H), 2.46–2.56 (m, 1H, 3-H), 2.58 (dd, J ) 16.7, 8.3 Hz, 1H,
2-H′), 3.89 (dd, J ) 8.9, 7.1 Hz, 1H, 4-H), 4.38 (dd, J ) 8.9, 7.4
Hz, 1H, 4-H′); 13C NMR (100 MHz, CDCl3) δ 13.9 (CH3CH2),
22.5 (CH2), 27.2 (CH2), 29.0 (CH2), 29.2 (CH2), 29.3 (CH2), 31.6
(CH2), 32.9 (CH2CH), 34.4 (CH2-2), 35.5 (CH-3), 73.3 (CH2-4),
177.2 (CdO) in agreement with the literature data;36 Chiral HPLC
(Chiracel IB, hexane/2-propanol 95:5, 0.75 mL·min-1) tR ) 30.12
min, tS ) 33.66 min after derivatization into hydroxyl the hydroxyl
benzylamide derivative.32
(+)-3-(2′-Naphthyl)-γ-butyrolactone (+)-(2g). Yield 88.1 mg,
1
83%; [R]24 +43.6 (c 1.0, CHCl3, 71% ee); H NMR (400 MHz,
D
CDCl3) δ 2.79 (dd, J ) 17.5, 8.9 Hz, 1H, 2-H), 3.00 (dd, J )
17.5, 8.9 Hz, 1H, 2-H), 3.95 (pent, J ) 8.9 Hz, 1H, 3-H), 4.37 (dd,
J ) 8.9, 7.9 Hz, 1H, 4-H′), 4.74 (dd, J ) 8.9, 7.9 Hz, 1H, 4-H′),
7.34 (dd, J ) 8.5, 1.8 Hz, 1H, 3′-H), 7.47–7.55 (m, 2H, 7′-H, 6′-
H), 7.67 (br s, 1H, 1′-H), 7.80–7.90 (m, 3H, 4′-H, 8′-H, 5′-H); 13
C
NMR (100 MHz, CDCl3) δ 35.6 (CH2-2), 41.1 (CH-3), 73.9 (CH2-
4), 124.4 (CH-3′), 125.4 (CH-1′), 126.2 (CH-6′), 126.6 (CH-7′),
127.60 (CH-4′), 127.63 (CH-8′), 129.0 (CH-5′), 132.6 (C-8a′), 133.3
(C-4a′), 136.6 (C-2′), 176.4 (CdO) in agreement with the literature
data;36 Chiral HPLC (Chiracel IB, 0.75 mL ·min-1, hexane/2-
propanol, 90:10) tmajor ) 31.5 min, tminor ) 34.7 min after
derivatization into the hydroxyl benzylamide derivative.32
Acknowledgment. We thank the GSK and EPSRC for an
industrial CASE award to F.F.
Supporting Information Available: Additional experimental
(R)-(+)-3-(4′-Methoxybenzyl)-γ-butyrolactone (R)-(+)-(2h).
Yield 93.8 mg, 91%; [R]23 +3.2 (c 0.5, CHCl3, 58% ee), [lit.33
1
procedures, H and 13C NMR spectra of key compounds, and
D
1
gives [R]D +5.4 (c 6.8, CHCl3, 98% ee)]; H NMR (400 MHz,
chiral GC and HPLC traces for lactones 2a-j. This material is
available free of charge via the Internet at http://pubs.acs.org.
CDCl3) 2.56 (dd, J ) 17.5, 8.0 Hz, 1H, 2-H), 2.57 (dd, J ) 17.5,
8.0 Hz, 1H, 2-H′), 2.70 (dd, J ) 7.6, 3.3 Hz, 2H, CH2CH),
2.72–2.86 (m, 1H, 3-H), 3.78 (s, 3H, CH3O), 4.00 (dd, J ) 9.1,
JO800246G
J. Org. Chem. Vol. 73, No. 11, 2008 4003