Highly efficient and enantioselective α-arylation of cycloalkanones by scandium-catalyzed diazoalkane-carbonyl homologation

Article abstract of DOI:10.1055/s-0031-1289650

Functionalized α-tertiary and -quaternary 2-arylcycloalkanones are rapidly accessed by scandium(III) triflate-catalyzed diazo-alkane-carbonyl homologations. Recent developments have allowed for carbon insertion reactions to be performed with catalyst loadings as low as 0.5 mol% on scales up to 5 mmol. Pairing readily available bis- and tris(oxazoline) based ligands with scandium triflate allows access to arylated medium ring carbocycles with enantioselectivities up to 98:2 er and >98% yield. The formal C-C insertion of aryldiazo-methanes into unsubstituted cycloalkanones provides a single-step solution to the ongoing challenge of α-arylation. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289650

686
PRACTICAL SYNTHETIC PROCEDURES
Highly Efficient and Enantioselective a-Arylation of Cycloalkanones by
Scandium-Catalyzed Diazoalkane–Carbonyl Homologation
Victor L. Rendina, Hilan Z. Kaplan, Jason S. Kingsbury*
Eugene F. Merkert Chemistry Center, Boston College, 2609 Beacon St.,
Chestnut Hill, MA 02467, USA
Fax +1(617)5522705; E-mail: jason.kingsbury@bc.edu
Received 31 October 2011
PSP
No216
Abstract: Functionalized a-tertiary and -quaternary 2-arylcycloalkanones are rapidly accessed by scandium(III) triflate-catalyzed diazo-
alkane-carbonyl homologations. Recent developments have allowed for carbon insertion reactions to be performed with catalyst loadings
as low as 0.5 mol% on scales up to 5 mmol. Pairing readily available bis- and tris(oxazoline) based ligands with scandium triflate allows
access to arylated medium ring carbocycles with enantioselectivities up to 98:2 er and >98% yield. The formal C–C insertion of aryldiazo-
methanes into unsubstituted cycloalkanones provides a single-step solution to the ongoing challenge of a-arylation.
Key words: diazo compounds, scandium, asymmetric catalysis, ring expansion, arylation
procedure 1:
O
O
ligands:
Sc(OTf)3 (5 mol%)
N2
+
+
+
toluene, –78 → 0 °C
1b
2b
3i
15 min
O
O
(1.2 equiv)
(1.0 equiv)
92% yield
N
N
procedure 2:
O
O
5
Sc(OTf)3 (10 mol%)
ligand 5 (11 mol%)
N2
toluene, –78 °C
14 h
1c
2f
4i
O
O
(1.0 equiv)
(1.4 equiv)
97% yield, 93.5:6.5 er
N
N
N
O
procedure 3:
O
O
Sc(OTf)3 (5.0 mol%)
ligand 6 (5.5 mol%)
N2
6
toluene, –78 °C
6 h
1c
2b
4e
(1.0 equiv)
(1.2 equiv)
94% yield, 97:3 er
Scheme 1 Racemic and enantioselective a-arylation of cycloalkanones
basic reaction conditions. Thus far, direct access to tertia-
ry aryl ketones in enantiopure form5 has been precluded
Introduction
Efficient and selective strategies for the preparation of a- by the problem of facile racemization due to enhanced
substituted carbonyl compounds remain an ongoing chal- acidity of the a-proton. We recently developed a new mild
lenge in modern chemical synthesis.1 Traditional and catalytic entry to a-arylalkanones based on formal
approaches2 based on enolate alkylation rely on costly sto- carbon insertion into the a-C–C (or C–H) bonds of ke-
ichiometric preformation of the nucleophile and must be tones and aldehydes.6 The transformations take place by
carried out in an iterative fashion when an a-quaternary 1,2-rearrangement in Sc-complexed diazonium betaine
carbon atom is desired. In addition, the more specialized intermediates, cleanly affording a-tertiary and -quaterna-
methods of a-vinylation3 and -arylation4 require harsh and ry carbonyls in one step with dinitrogen as the only by-
product (Scheme 2).7 With mild reagents now available
for hydrazone oxidation,8 along with a safe and conve-
SYNTHESIS 2012, 44, 686–693
Advanced online publication: 20.12.2011
DOI: 10.1055/s-0031-1289650; Art ID: Z102711SS
x
x
.x
x
.2
0
1
1
nient procedure for titrating stock solutions of nonstabi-
lized diazoalkanes,9 large scale homologations are now
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Catalytic a-Arylation of Cycloalkanones
687
safer and more practical. Herein, we report improved pro-
cedures (Scheme 1, Procedures 1–3) for the preparation of
racemic and optically active a-arylcycloalkanones on
scales up to 5 mmol and with catalyst loadings as low as
0.5 mol%.
N2
[Sc]
N2
O
R2
R1
O
N2
O
R1
R3
+
R4
R1
R2
R3
R4
R4
R3
R2
donor–acceptor atom
two new C–C bonds
Scheme 2 Pathway for diazoalkane insertion reactions
Table 1 Catalytic Ring Expansion of Cycloalkanones with Aryldiazomethanesa
Entry Cycloalkanone
Aryldiazoalkane
Catalyst loading Product
Yield (%)b
O
O
O
1
1a
2a
1 mol%
3a
>98
N2
N2
G
G
2
3
4
5
6
1a
1a
1a
1a
1a
2b
2c
2d
2e
2f
G = H
1 mol%
1 mol%
1 mol%
1 mol%
1 mol%
3b
3c
3d
3e
3f
G = H
>98
95
G = 2-Br
G = 2-Br
G = 4-CF3
G = 3-OMe
G = 2-Me
G = 4-CF3
92
G = 3-OMe
G = 2-Me
88
93
O
7
8
1a
1b
2g
2a
1 mol%
1 mol%
3g
3h
95
N2
O
O
>98
N2
O
N2
9
1b
1c
2b
2b
0.5 mol%
1 mol%
3i
3j
92
89
O
O
N2
10
O
O
11
1d
2a
7 mol%
3k
84
N2
a Conditions: 0.2–1.0 M in toluene or CH2Cl2; 1.0 equiv of diazoalkane 2 for reactions with 1a,b; 1.1 equiv of 2 for reactions with 1c,d; <1 h
in every case.
b Isolated yield of analytically pure product as determined by 1H NMR spectroscopy.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 686–693

688
V. L. Rendina et al.
PRACTICAL SYNTHETIC PROCEDURES
complex mixture derived from overhomologation. Not
surprisingly, strongly Lewis basic functionality such as
Scope and Limitations
Table 1 illustrates the results of our recent efforts to re- free alcohols and amines are not well tolerated, and by-
duce catalyst loadings and improve the efficiency of a- products from O–H insertion have been observed for sub-
arylation reactions. A variety of substitution patterns and strates containing hydroxy groups.10
electronic modifications of the diazoalkane nucleophile
are readily tolerated. Even sterically congested ortho-sub-
stituted nucleophiles (Table 1, entries 3, 6, and 7) afford
Catalyst loadings of 1 mol% and lower were achieved by
the rigorous exclusion of moisture from all reagents and
the removal of any trace of Lewis basic impurities intro-
the homologation products in excellent yields. Addition-
duced during preparation of the diazoalkane solutions. By
ally, a-quaternary carbon centers are readily prepared by
vacuum drying Sc(OTf)3 at 200 °C and storing diazo-
insertion of disubstituted diazomethanes (entries 1, 8, and
alkane solutions over 3 Å molecular sieves, dramatic im-
11). By careful tuning of reaction stoichiometry, ring ex-
provements in reaction rate and chemical yield are
pansion products for 4-, 6-, 7-, and 12-membered electro-
observed. Applying these practices, we are able to extend
philes are all obtained in high yield. Noticeably absent
the methodology to include asymmetric reactions with
from Table 1 is the homologation of cyclopentanone; the
monosubstituted aryldiazomethanes.
cyclohexanone product from insertion of phenyldiazo-
After extensive optimization of reaction conditions with
regard to solvent, temperature, ligand, and catalyst load-
methane (2b) is considerably more reactive towards ring
expansion than the starting cyclopentanone, leading to a
Table 2 Asymmetric Arylation by Diazoalkane Ring Expansiona
Entry Cycloalkanone
Aryldiazoalkane
Product
Yield (%)b erc
O
O
N2
1
1a
1b
2b
4a
>98
85.5:14.5
O
O
N2
G
G
2
3
4
1b
1b
1b
2b
2h
2i
G = H
G = 4-Me
G = 3-Br
4b
4c
4d
G = H
G = 4-Me
G = 3-Br
94
96
>98
95:5
94:6
94.5:5.5
O
O
N2
1c
G
G
5
1c
1c
1c
1c
1c
1c
2b
2c
2d
2e
2f
G = H
G = 2-Br
G = 4-CF3
G = 3-OMe
G = 2-Me
G = 4-Me
4e
4f
4g
4h
4i
G = H
94
85
78
>98
97
>98
97:3
92.5:7.5
98:2
97:3
93.5:6.5
98.5:1.5
6d
7
G = 2-Br
G = 4-CF3
G = 3-OMe
G = 2-Me
G = 4-Me
8
9d
10
2h
4j
O
11d
12e
1c
1e
2g
2b
4k
4l
94
93:7
93:7
N2
O
O
N2
>98
a Reaction conditions: 0.1–0.2 M in toluene, Sc(OTf)3 (5–10 mol%), ligand 6 (5.5–11 mol%), 1.5–14 h.
b Isolated yield of analytically pure product as determined by 1H NMR spectroscopy.
c By chiral SFC analysis.
d Run with ligand 5.
e Run at -45 °C.
Synthesis 2012, 44, 686–693
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Catalytic a-Arylation of Cycloalkanones
689
ings, we arrived at pseudo C3-symmetric11 6 (Scheme 1)
as the premier ligand for the arylation of medium ring cy-
cloalkanones. As previously mentioned, the introduction
of Lewis basic functionality to the catalyst significantly
slows reaction rates. Thus, when coordinated to an oxazo-
line-based ligand, catalyst loadings of 5–10 mol% are re-
quired to maintain productive reaction efficiencies. At
lower loadings, Lewis acid catalyzed decomposition of
the nucleophile6a becomes more problematic. Gratifying-
ly, the functional group tolerance of the asymmetric reac-
tion is comparable to the racemic variant. With regard to
substrate scope, higher levels of enantioselectivity are ob-
served for insertion reactions with cycloheptanone com-
pared to the other ring sizes evaluated (Table 2, entries 1,
2, 5, and 12). More sterically demanding ortho-substituted
substrates are tolerated when the parent bis(oxazoline)
ligand 5 (Scheme 1) is utilized (entries 6, 9, and 11). To
demonstrate scalability, (S)-2-phenylcyclooctanone has
been produced on a 250 mg scale in 94% yield and 97:3 er
with a 5 mol% catalyst loading.
(2b; 2.10 mL, 2.52 mmol, 1.20 M in toluene, 1.00 equiv) was added
and the reaction mixture was warmed to 0 °C. An 18 gauge exit nee-
dle was used to relieve excess pressure generated by the copious
amounts of N2 gas evolved. After 15 min, the pale yellow solution
was diluted with Et2O (30 mL), washed with H2O (20 mL), brine
(20 mL), dried (Na2SO4), filtered, and concentrated. Purification by
column chromatography (8% EtOAc in hexanes v/v) afforded the
desired compound 3i as a colorless oil (436 mg, 92%) that solidified
just below r.t.; Rf = 0.20 (10% EtOAc in hexanes).
IR (neat): 3028 (w), 2929 (m), 2855 (w), 1702 (s), 1495 (w), 1452
(m), 719 (w), 698 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.35–7.29 (m, 2 H), 7.27–7.21 (m,
3 H), 3.73 (dd, J = 11.3, 4.1 Hz, 1 H), 2.70 (ddd, J = 13.3, 13.3, 3.1
Hz, 1 H), 2.57–2.49 (m, 1 H), 2.20–2.11 (m, 1 H), 2.10–1.91 (m, 4
H), 1.72–1.58 (m, 1 H), 1.54–1.40 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 213.6, 140.5, 128.6, 128.0, 127.0,
58.9, 42.8, 32.1, 30.1, 28.7, 25.4.
HRMS (ESI+): m/z calcd for C13H17O [M + H]+: 189.1279; found:
189.1277.
2-Methyl-2-phenylcyclopentanone (3a)
Prepared according to Typical Procedure 1 using Sc(OTf)3 (24.6
mg, 0.050 mmol, 1.00 mol%) suspended in CH2Cl2 (16.1 mL), cy-
In summary, we have demonstrated that the formal carbon
insertion of aryldiazomethane carbon nucleophiles into clobutanone (411 mL, 5.50 mmol, 1.10 equiv), and 2a (11.4 mL, 5.0
mmol, 0.44 M in toluene, 1.0 equiv). Purification by column chro-
matography afforded 3a as a colorless oil (857 mg, 98%); Rf = 0.33
(10% EtOAc in hexanes).
the a-C–C bond of naked cycloalkanones is efficient, scal-
able, and amenable to asymmetric synthesis with simple
bis- and tris(oxazoline) chiral ligands. Work is currently
underway to expand the scope of the enantioselective pro-
cess to include a-quaternary products and to generate the
diazoalkane reagents for use in situ.
IR (neat): 2965 (br m), 2870 (br w), 1735 (s), 1496 (m), 1445 (m),
1156 (m), 1056 (m), 760 (m), 670 (m), 545 cm–1 (br m).
1H NMR (500 MHz, CDCl3): d = 7.37–7.30 (m, 4 H), 7.25–7.21 (m,
1 H), 2.58–2.53 (m, 1 H), 2.37–2.33 (m, 2 H), 2.05–1.84 (m, 3 H),
1.39 (s, 3 H).
Unless stated otherwise, all reactions were carried out in flame-
dried glassware under an atmosphere of N2. Toluene and CH2Cl2
were dispensed under argon from a Glass Contour solvent purifica-
tion system custom manufactured by SG Waters, LLC (Nashua,
13C NMR (125 MHz, CDCl3): d = 220.77, 142.75, 128.69, 126.78,
126.41, 53.23, 38.22, 37.76, 25.16, 18.86.
HRMS (ESI+): m/z calcd for C12H15O [M + H]+: 175.1123; found:
175.1128.
NH). Sc(OTf)3 (99%) was purchased from Aldrich and then finely
powdered and dried at 200 °C over P2O5 for 24 h under high vacuum
(0.1 mm Hg) before being taken directly into a glove box under inert
atmosphere. Diazoalkanes and ligands were prepared according to
the previously reported literature procedures.6c,12 Unsubstituted cy-
cloalkanones were obtained from commercial sources and purified
by distillation according to the literature procedures before use.13
Silica gel chromatography was performed with ZEOPrep 60 Eco
40–63 mm silica gel. Analytical TLC was performed using 0.25 mm
silica gel 60 F254 plates purchased from EMD Chemicals. TLC
plates were visualized by exposure to ultraviolet light and/or expo-
sure to ceric ammonium molybdate, p-anisaldehyde, or KMnO4
stains. 1H NMR spectra were recorded on a 400 or 500 MHz instru-
ment and referenced using the residual solvent as an internal stan-
dard (CHCl3: d = 7.26 ppm). 13C NMR spectra were recorded on a
100 or 125 MHz instrument and referenced using the solvent as an
internal standard (CDCl3: d = 77.16 ppm). High-resolution mass
spectra were obtained at the Boston College Mass Spectrometry fa-
cility. Supercritical fluid chromatography (SFC) data were obtained
on a Berger Instruments system using Daicel CHIRALPAK AS-H
or AD-H columns (j 4.6 mm, 25 cm length).
2-Phenylcyclopentanone (3b)
Prepared according to Typical Procedure 1 using Sc(OTf)3 (24.6
mg, 0.0500 mmol, 1.00 mol%) suspended in CH2Cl2 (6.2 mL), cy-
clobutanone (392 mL, 5.25 mmol, 1.05 equiv), and 2b (3.76 mL, 5.0
mmol, 1.33 M in toluene, 1.0 equiv). Purification by column chro-
matography afforded 3b as a white solid (794 mg, 99%); mp 37–
39 °C; Rf = 0.33 (20% EtOAc in hexanes).
IR (neat): 2961 (br w), 1737 (s), 1495 (m), 1452 (m), 1269 (br w),
1141 (m), 756 (m), 698 (s), 535 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 7.36–7.31 (m, 2 H), 7.27–7.23 (m,
1 H), 7.21–7.18 (m, 2 H), 3.33 (dd, J = 11.7, 8.8 Hz, 1 H), 2.55–
2.44 (m, 2 H), 2.30 (ddd, J = 19.5, 10.7, 8.8 Hz, 1 H), 2.21–2.08 (m,
2 H), 1.99–1.89 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 218.20, 138.57, 128.73, 128.27,
127.03, 55.45, 38.58, 31.89, 21.00.
HRMS (ESI+): m/z calcd for C11H13O [M + H]+: 161.0966; found:
161.0960.
2-(2-Bromophenyl)cyclopentanone (3c)
2-Phenylcycloheptanone (3i); Typical Procedure 1 for Racemic
Homologations
In an inert atmosphere glovebox, Sc(OTf)3 (6.2 mg, 0.012 mmol,
0.48 mol%) was suspended in toluene (0.4 mL). The suspension
was moved to a N2 manifold and cyclohexanone (311 mL, 3.00
mmol, 1.19 equiv) was added in a single portion. The solution was
stirred for 5 min at r.t., then cooled to –78 °C. Phenyldiazomethane
Prepared according to Typical Procedure 1 using Sc(OTf)3 (4.9 mg,
0.010 mmol, 1.0 mol%) suspended in CH2Cl2 (0.4 mL), cyclobu-
tanone (82 mL, 1.1 mmol, 1.1 equiv), and 2c (1.6 mL, 1.0 mmol,
0.64 M in toluene, 1.0 equiv). Purification by column chromatogra-
phy afforded 3c as a white solid (228 mg, 95%); mp 50–53 °C;
Rf = 0.35 (20% EtOAc in hexanes).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 686–693

690
V. L. Rendina et al.
PRACTICAL SYNTHETIC PROCEDURES
IR (neat): 2964 (br m), 2879 (br w), 1740 (s), 1474 (m), 1438 (m),
1163 (m), 1146 (m), 1022 (m), 825 (w), 754 cm–1 (m).
J = 19.5, 10.8, 8.9 Hz, 1 H), 2.32 (s, 3 H), 2.22–2.15 (m, 1 H), 2.09–
1.91 (m, 2 H).
1H NMR (500 MHz, CDCl3): d = 7.57 (dd, J = 8.0, 1.5 Hz, 1 H),
7.27 (ddd, J = 7.6, 7.6, 1.5 Hz, 1 H), 7.11 (ddd, J = 7.6, 7.6, 1.7 Hz,
1 H), 7.07 (dd, J = 7.6, 1.7 Hz, 1 H), 3.80–3.74 (m, 1 H), 2.60–2.49
(m, 2 H), 2.41–2.32 (m, 1 H), 2.22–2.15 (m, 1 H), 2.08–1.92 (m, 2
H).
13C NMR (125 MHz, CDCl3): d = 218.81, 137.68, 136.90, 130.67,
127.46, 127.01, 126.40, 53.12, 38.82, 31.82, 21.17, 20.04.
HRMS (ESI+): m/z calcd for C12H15O [M + H]+: 175.1123; found
175.1122.
13C NMR (125 MHz, CDCl3): d = 217.54, 138.90, 133.20, 129.80,
2-(Napthalen-1-yl)cyclopentanone (3g)
128.67, 127.89, 125.23, 56.32, 38.74, 31.92, 21.03.
Prepared according to Typical Procedure 1 using Sc(OTf)3 (4.9 mg,
0.010 mmol, 1.0 mol%) suspended in CH2Cl2 (0.3 mL), cyclobu-
tanone (82 mL, 1.1 mmol, 1.1 equiv), and 2g (1.7 mL, 1.0 mmol,
0.58 M in toluene, 1.0 equiv). Purification by column chromatogra-
phy afforded 3g as a white solid (200 mg, 95%); mp 93–95 °C;
Rf = 0.27 (20% EtOAc in hexanes).
HRMS (ESI+): m/z calcd for C11H12BrO [M + H]+: 239.0072;
found: 239.0079.
2-(4-Trifluoromethylphenyl)cyclopentanone (3d)
Prepared according to Typical Procedure 1 using Sc(OTf)3 (4.9 mg,
0.010 mmol, 1.0 mol%) suspended in CH2Cl2 (1.1 mL), cyclobu-
tanone (82 mL, 1.1 mmol, 1.1 equiv), and 2d (943 mL, 1.0 mmol,
1.06 M in toluene, 1.0 equiv). Purification by column chromatogra-
phy afforded 3d as a white solid (209 mg, 92%); mp 33–35 °C;
Rf = 0.30 (20% EtOAc in hexanes).
IR (neat): 2964 (br w), 1738 (s), 1510 (w), 1400 (m), 1142 (m),
1114 (m), 798 (m), 778 cm–1 (s).
1H NMR (500 MHz, CDCl3): d = 7.91–7.85 (m, 2 H), 7.77 (d,
J = 8.3 Hz, 1 H), 7.53–7.47 (m, 2 H), 7.43 (dd, J = 8.3, 7.3 Hz, 1 H),
7.25 (dd, J = 7.3, 1.0 Hz, 1 H), 4.08 (dd, J = 8.8, 8.8 Hz, 1 H), 2.68–
2.56 (m, 2 H), 2.52–2.43 (m, 1 H), 2.28–2.17 (m, 2 H), 2.13–2.02
(m, 1 H).
IR (neat): 2967 (br w), 2883 (br w), 1743 (m), 1619 (w), 1326 (s),
1163 (m), 1120 (br s), 1069 (m), 840 cm–1 (w).
1H NMR (500 MHz, CDCl3): d = 7.59 (d, J = 8.3 Hz, 1 H), 7.32 (d,
J = 8.1 Hz, 1 H), 3.39 (dd, J = 12.0, 8.8 Hz, 1 H), 2.58–2.47 (m, 2
H), 2.31 (ddd, J = 19.3, 10.5, 8.5 Hz, 1 H), 2.24–2.08 (m, 2 H),
2.02–1.92 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 216.98, 142.41, 129.35 (q,
JC,F = 32.2 Hz), 128.64, 125.63 (q, JC,F = 4.1 Hz), 124.31 (q,
JC,F = 272.0 Hz), 55.19, 38.44, 31.57, 20.94.
13C NMR (125 MHz, CDCl3): d = 218.73, 135.58, 134.23, 132.20,
129.10, 127.78, 126.20, 125.78, 125.62, 125.18, 123.75, 52.44,
39.13, 32.56, 21.30.
HRMS (ESI+): m/z calcd for C15H15O [M + H]+: 211.1123; found:
211.1129.
2-Methyl-2-phenylcycloheptanone (3h)
Prepared according to Typical Procedure 1 using Sc(OTf)3 (4.9 mg,
0.010 mmol, 1.0 mol%), cyclohexanone (114 mL, 1.10 mmol, 1.10
equiv), and 2a (2.3 mL, 1.0 mmol, 0.44 M in toluene, 1.0 equiv). Pu-
rification by column chromatography afforded 3h as a colorless oil
(206 mg, quant); Rf = 0.43 (10% EtOAc in hexanes).
HRMS (ESI+): m/z calcd for C12H12F3O [M + H]+: 229.0840;
found: 229.0848.
2-(3-Methoxyphenyl)cyclopentanone (3e)
Prepared according to Typical Procedure 1 using Sc(OTf)3 (4.9 mg,
0.010 mmol, 1.0 mol%) suspended in CH2Cl2 (1.1 mL), cyclobu-
tanone (82 mL, 1.1 mmol, 1.1 equiv), and 2e (943 mL, 1.0 mmol,
1.06 M in toluene, 1.0 equiv). Purification by column chromatogra-
phy afforded 3e as a colorless oil (167 mg, 88%); Rf = 0.24 (20%
EtOAc in hexanes).
IR (neat): 2930 (br m), 2858 (br w), 1702 (s), 1495 (w), 1458 (m),
764 (m), 700 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 7.34–7.30 (m, 2 H), 7.25–7.20 (m,
3 H), 2.55 (ddd, J = 13.7, 11.2, 2.7 Hz, 1 H), 2.34–2.28 (m, 1 H),
2.22–2.17 (m, 2 H), 1.99–1.91 (m, 1 H), 1.88–1.80 (m, 2 H), 1.57–
1.39 (m, 2 H), 1.35 (s, 3 H), 1.33–1.24 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 215.16, 145.09, 128.83, 126.74,
126.09, 55.97, 41.05, 36.77, 30.78, 27.10, 26.68, 24.49.
HRMS (ESI+): m/z calcd for C14H19O [M + H]+: 203.1436; found:
203.1443.
IR (neat): 2961 (br m), 2875 (br w), 1739 (s), 1601 (m), 1583 (m),
1490 (m), 1245 (br m), 1159 (m), 1041 (br m), 779 (br m), 695
cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 7.25 (dd, J = 7.8, 7.8 Hz, 1 H),
6.81–6.77 (m, 2 H), 6.75 (dd, J = 2.2, 2.2 Hz, 1 H), 3.80 (s, 3 H),
3.30 (dd, J = 11.7, 9.0 Hz, 1 H), 2.54–2.43 (m, 2 H), 2.30 (ddd,
J = 19.5, 11.0, 9.0 Hz, 1 H), 2.20–2.07 (m, 2 H), 1.98–1.87 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 217.95, 159.85, 140.10, 129.68,
120.58, 114.30, 112.26, 55.39, 55.32, 38.57, 31.85, 20.98.
HRMS (ESI+): m/z calcd for C12H15O2 [M + H]+: 191.1072; found:
191.1081.
2-Phenylcyclooctanone (3j)
Prepared according to Typical Procedure 1 using Sc(OTf)3 (24.6
mg, 0.050 mmol, 1.0 mol%) suspended in toluene (5.8 mL), cyclo-
heptanone (710 mL, 6.00 mmol, 1.2 equiv), and 2b (4.17 mL, 5.0
mmol, 1.2 M in toluene, 1.0 equiv). Purification by column chroma-
tography afforded 3j as a white solid (903 mg, 89%); mp 36–38 °C;
Rf = 0.33 (10% EtOAc in hexanes).
2-(2-Methylphenyl)cyclopentanone (3f)
Prepared according to Typical Procedure 1 using Sc(OTf)3 (4.9 mg,
0.010 mmol, 1.0 mol%) suspended in CH2Cl2 (1.2 mL), cyclobu-
tanone (82 mL, 1.1 mmol, 1.1 equiv), and 2f (769 mL, 1.00 mmol,
1.30 M in toluene, 1.0 equiv). Purification by column chromatogra-
phy afforded 3f as a colorless oil (162 mg, 93%); Rf = 0.36 (20%
EtOAc in hexanes).
IR (neat): 2927 (s), 2855 (w), 1698 (s), 1494 (w), 1449 (m), 700
cm–1 (m).
1H NMR (CDCl3, 400 MHz): d = 7.36–7.28 (m, 4 H), 7.26–7.20 (m,
1 H), 3.79 (dd, J = 12.3, 2.7 Hz, 1 H), 2.61 (ddd, J = 12.5, 12.5, 4.3
Hz, 1 H), 2.42–2.30 (m, 1 H), 2.29–2.22 (m, 1 H), 2.04–1.86 (m, 3
H), 1.83–1.70 (m, 2 H), 1.65–1.55 (m, 2 H), 1.53–1.37 (m, 2 H).
IR (neat): 2963 (br m), 2879 (br w), 1740 (s), 1493 (w), 1461 (br w),
1146 (m), 756 (m), 727 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 7.20–7.13 (m, 3 H), 7.01–6.99 (m,
1 H), 3.53 (dd, J = 11.7, 8.0 Hz, 1 H), 2.54–2.45 (m, 2 H), 2.33 (ddd,
13C NMR (100 MHz, CDCl3): d = 216.57, 139.49, 128.64, 127.91,
127.12, 57.53, 40.40, 31.67, 26.98, 26.88, 26.85, 24.76.
HRMS (ESI+): m/z calcd for C14H19O [M + H]+: 203.1436; found:
203.1439.
Synthesis 2012, 44, 686–693
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Catalytic a-Arylation of Cycloalkanones
691
2-Methyl-2-phenylcyclotridecanone (3k)
mmol, 11 mol%), toluene (1.5 mL), cyclohexanone (19 mL, 0.18
mmol, 1.2 equiv), and 2b (203 mL, 0.15 mmol, 0.74 M in toluene,
1.0 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4b as a colorless oil (26.5 mg, 94%)
with 95:5 er [AS-H, 50 °C, 150 psi, 3.0 mL/min, 2% MeOH,
l = 220 nm; tR = 2.35 min (minor), 2.70 min (major)]. Character-
ization data were in agreement with those tabulated above for the ra-
cemic compound; [a]D20 –138.2 (c 0.80, CHCl3).
Prepared according to Typical Procedure 1 using Sc(OTf)3 (24.6
mg, 0.050 mmol, 7.00 mol%), however, rather than suspending the
Sc(OTf)3 in solvent, cyclododecanone (145 mg, 0.715 mmol, 1.00
equiv) was introduced to the Sc(OTf)3 as a solution in CH2Cl2 (1.8
mL). The rest of the procedure was carried out as usual with 2a (1.8
mL, 0.79 mmol, 0.44 M in toluene, 1.1 equiv). Purification by col-
umn chromatography afforded 3k as a colorless semi-solid (191
mg, 84%); Rf = 0.43 (10% EtOAc in hexanes).
(S)-2-(4-Methylphenyl)cycloheptanone (4c)
IR (neat): 2930 (br s), 2860 (br m), 1706 (s), 1495 (m), 1463 (m),
1445 (m), 763 (m), 700 cm–1 (m).
Run for 1.5 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cyclohexanone (19 mL, 0.18
mmol, 1.2 equiv), and 2h (227 mL, 0.15 mmol, 0.66 M in toluene,
1.0 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4c as a colorless oil (29.2 mg, 96%)
with 94:6 er [AS-H, 50 °C, 150 psi, 3.0 mL/min, 2%
MeOH, l = 220 nm; tR = 2.49 min (minor), 2.90 min (major)];
[a]D20 –154.5 (c 0.47, CHCl3); Rf = 0.18 (10% EtOAc in hexanes).
1H NMR (500 MHz, CDCl3): d = 7.34–7.29 (m, 2 H), 7.27–7.20 (m,
3 H), 2.37 (ddd, J = 18.3, 9.0, 4.2 Hz, 1 H), 2.24 (ddd, J = 12.9,
12.9, 3.2 Hz, 1 H), 1.98 (dddd, J = 18.3, 4.6, 4.6, 4.6 Hz, 1 H), 1.90
(ddd, J = 13.2, 13.2, 5.6 Hz, 1 H), 1.84–1.76 (m, 1 H), 1.61–1.54
(m, 1 H), 1.51–1.39 (m, 2 H), 1.38–1.22 (m, 11 H), 1.36 (s, 3 H),
1.21–1.14 (m, 1 H), 1.14–1.03 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 213.65, 145.55, 128.73, 126.79,
126.50, 56.04, 36.86, 36.13, 27.56, 26.92, 26.64, 25.84, 25.72,
25.22, 24.75, 24.24, 22.26, 22.13.
IR (neat): 3022 (br w), 2927 (br m), 2856 (w), 1702 (s), 1513 (m),
1454 (br m), 1163 (w), 1129 (w), 825 (w), 789 (w) cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.16–7.10 (m, 4 H), 3.69
(dd, J = 11.3, 4.1 Hz, 1 H), 2.73–2.64 (m, 1 H), 2.55–2.47 (m, 1 H),
2.32 (s, 3 H), 2.18–2.08 (m, 1 H), 2.08–1.89 (m, 4 H), 1.70–1.56 (m,
1 H), 1.52–1.40 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 213.77, 137.46, 136.61, 129.35,
127.80, 58.56, 42.71, 32.04, 30.18, 28.63, 25.51.
HRMS (ESI+): m/z calcd for C14H19O [M + H]+: 203.1436; found:
203.1445.
HRMS (ESI+): m/z calcd for C20H31O [M + H]+: 287.2375; found:
287.2376.
(S)-2-Phenylcyclooctanone (4e); Typical Procedures 2 and 3 for
Asymmetric Homologation
In an inert atmosphere glove box, Sc(OTf)3 (30.4 mg, 0.0618 mmol,
5.00 mol%) was weighed into a 25 mL scintillation vial. Ligand 6
(35.0 mg, 0.0679 mmol, 5.50 mol%) was transferred to the vial con-
taining Sc(OTf)3 with toluene (6.2 mL). The suspension was sealed
with a rubber septum and stirred for 1.5 h, then removed from the
glove box and to a N2 manifold. Cycloheptanone (146 mL, 1.24
mmol, 1.00 equiv) was added to the cloudy gray suspension and
stirred for 15 min at which point the reaction mixture became clear
and homogeneous. The mixture was cooled to –78 °C and phenyl-
diazomethane (2b; 1.20 mL, 1.48 mmol, 1.20 M in toluene, 1.20
equiv) was added in a single portion. After 6 h, the cold reaction
mixture was quickly poured into H2O (20 mL) and diluted with
Et2O (30 mL). The organic layer was washed with H2O (20 mL),
brine (20 mL), dried (Na2SO4), and concentrated to a crude yellow
oil. Purification by column chromatography (10% EtOAc in hex-
anes) yielded 4f as a white solid (235 mg, 94%) with 97:3 er [AS-
H, 50 °C, 150 psi, 3.0 mL/min, 4% MeOH, l = 220 nm; tR = 1.85
min (minor), 2.07 min (major)]. Characterization data were in
agreement with those tabulated above for the racemic compound;
[a]D20 –138.8 (c 1.26, CHCl3).
(S)-2-(3-Bromophenyl)cycloheptanone (4d)
Run for 3 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cyclohexanone (19 mL, 0.18
mmol, 1.2 equiv), and 2i (125 mL, 0.15 mmol, 1.20 M in toluene, 1.0
equiv). The crude reaction mixture was directly purified by column
chromatography to afford 4d as a colorless oil (41.1 mg, quant) with
94.5:5.5 er [AS-H, 50 °C, 150 psi, 3.0 mL/min, 3% MeOH, l = 220
nm; tR = 3.02 min (minor), 3.58 min (major)]; [a]D20 –102.7 (c 1.05,
CHCl3); Rf = 0.27 (10% EtOAc in hexanes).
IR (neat): 2928 (m), 2855 (w), 1702 (s), 1593 (w), 1566 (w), 1475
(w), 1454 (w), 1129 (w), 1074 (w), 937 (w), 779 (w), 690 cm–1 (w).
1H NMR (CDCl3, 400 MHz): d = 7.38–7.34 (m, 2 H), 7.20–7.12 (m,
2 H), 3.70 (dd, J = 11.2, 3.7 Hz, 1 H), 2.69–2.60 (m, 1 H), 2.59–
2.51 (m, 1 H), 2.14–1.86 (m, 5 H), 1.72–1.59 (m, 1 H), 1.54–1.38
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 212.67, 142.80, 131.11, 130.10,
130.07, 126.83, 122.63, 58.57, 43.06, 32.19, 29.87, 28.82, 25.10.
HRMS (ESI+): m/z calcd for C13H16BrO [M + H]+: 269.0364;
found: 269.0401.
(S)-2-Phenylcyclopentanone (4a)
Run for 1.5 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cyclobutanone (16 mL, 0.18
mmol, 1.2 equiv), and 2b (203 mL, 0.15 mmol, 0.74 M in toluene,
1.0 equiv). The crude reaction mixture was not purified by column
chromatography,14 but instead poured into pentane (15 mL) and fil-
tered through a cotton plug. The organics were washed with H2O
(10 mL), brine (10 mL), and dried (Na2SO4). Concentration under
high vacuum afforded a crude yellow oil that was taken up in hex-
anes (1.5 mL) and again filtered through a cotton plug. Concentra-
tion afforded 4a as a pale yellow oil (26.2 mg, quant) with 85.5:14.5
er [AS-H, 50 °C, 150 psi, 1.5 mL/min, 2% MeOH, l = 220 nm;
tR = 4.02 min (minor), 4.67 min (major)]. Characterization data
were in agreement with those tabulated above for the racemic com-
pound.
(S)-2-(2-Bromophenyl)cyclooctanone (4f)
Run for 14 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 5 (5.9 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cycloheptanone (18 mL, 0.15
mmol, 1.0 equiv), and 2c (370 mL, 0.21 mmol, 0.57 M in toluene,
1.4 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4f as a colorless oil (35.9 mg, 85%)
with 92.5:7.5 er [AS-H, 50 °C, 150 psi, 2.0 mL/min, 2%
MeOH, l = 220 nm; tR = 4.65 min (major), 5.09 min (minor)];
[a]D20 –1.9 (c 0.99, CHCl3); Rf = 0.21 (10% EtOAc in hexanes).
IR (neat): 3063 (br w), 2927 (br m), 2856 (br w), 1705 (s), 1467 (m),
1440 (m), 1326 (w), 1157 (w), 1021 (m), 743 cm–1 (m).
(S)-2-Phenylcycloheptanone (4b)
Run for 1.5 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
© Thieme Stuttgart · New York
Synthesis 2012, 44, 686–693

692
V. L. Rendina et al.
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (CDCl3, 400 MHz): d = 7.54–7.48 (m, 2 H), 7.34–7.28 (m,
1 H), 7.12–7.05 (m, 1 H), 4.67 (dd, J = 11.5, 3.3 Hz, 1 H), 2.74
(ddd, J = 14.9, 7.4, 3.1 Hz, 1 H), 2.49–2.40 (m, 1 H), 2.39–2.25 (m,
1 H), 2.15–2.04 (m, 1 H), 2.03–1.88 (m, 2 H), 1.86–1.66 (m, 3 H),
1.65–1.52 (m, 2 H), 1.37–1.24 (m, 1 H).
1.4 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4i as a colorless oil (31.3 mg, 97%
yield) with 93.5:6.5 er [AS-H, 50 °C, 150 psi, 2.5 mL/min, 2%
MeOH, l = 220 nm; tR = 2.74 min (minor), 3.11 min (major)];
[a]D20 –98.1 (c 1.26, CHCl3); Rf = 0.21 (10% EtOAc in hexanes).
13C NMR (100 MHz, CDCl3): d = 215.99, 139.78, 132.55, 130.04,
128.33, 127.68, 124.54, 52.89, 44.67, 35.56, 28.61, 25.74, 25.08,
23.87.
IR (neat): 3096 (w), 3020 (w), 2927 (br s), 2856 (w), 1697 (s), 1488
(w), 1464 (m), 1446 (m), 1325 (m), 1160 (w), 1123 (w), 845 (w),
755 (br m), 730 cm–1 (m).
HRMS (ESI+): m/z calcd for C14H18BrO [M + H]+: 281.0541;
found: 281.0571.
1H NMR (CDCl3, 400 MHz): d = 7.45–7.41 (m, 1 H), 7.23–7.17 (m,
1 H), 7.16–7.10 (m, 2 H), 4.06 (dd, J = 12.1, 2.7 Hz, 1 H), 2.72
(ddd, J = 13.1, 11.7, 4.3 Hz, 1 H), 2.46–2.35 (m, 1 H), 2.40 (s, 3 H),
2.33–2.23 (m, 1 H), 2.01–1.87 (m, 3 H), 1.84–1.71 (m, 2 H), 1.67–
1.46 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 216.22, 138.06, 136.47, 130.63,
127.04, 126.83, 126.33, 53.04, 40.77, 32.02, 27.21, 27.15, 27.04,
24.91, 20.21.
(S)-2-(4-Trifluromethylphenyl)cyclooctanone (4g)
Run for 14 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cycloheptanone (18 mL, 0.15
mmol, 1.0 equiv), and 2d (320 mL, 0.21 mmol, 0.66 M in toluene,
1.4 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4g as a colorless oil (31.7 mg, 78%)
with 98:2 er [AD-H, 50 °C, 150 psi, 1.0 mL/min, 3%
MeOH, l = 220 nm; tR = 8.69 min (minor), 9.44 min (major)];
[a]D20 –93.52 (c 0.88, CHCl3); Rf = 0.18 (10% EtOAc in hexanes).
HRMS (ESI+): m/z calcd for C15H21O [M + H]+: 217.1591; found:
217.1592.
(S)-2-(4-Methylphenyl)cyclooctanone (4j)
Run for 3 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cycloheptanone (18 mL, 0.15
mmol, 1.0 equiv), and 2h (320 mL, 0.21 mmol, 0.66 M in toluene,
1.4 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4j as a colorless oil (32.5 mg, quant)
with 98.5:1.5 er [AS-H, 50 °C, 150 psi, 3.0 mL/min, 4%
MeOH, l = 220 nm; tR = 1.90 min (minor), 2.13 min (major)];
[a]D20 –148.9 (c 0.98, CHCl3); Rf = 0.37(10% EtOAc in hexanes).
IR (neat): 2935 (br w), 2860 (br w), 1703 (m), 1617 (w), 1466 (w),
1447 (w), 1419 (w), 1325 (s), 1163 (m), 1122 (m), 1069 (m), 1019
(m), 838 cm–1 (br w).
1H NMR (CDCl3, 400 MHz): d = 7.56 (d, J = 8.0 Hz, 1 H), 7.46
(d, J = 8.0 Hz, 1 H), 3.92 (dd, J = 12.1, 2.9 Hz, 1 H), 2.55
(ddd, J = 12.5, 12.5, 3.7 Hz, 1 H), 2.38–2.22 (m, 2 H), 2.10–1.97
(m, 2 H), 1.96–1.86 (m, 1 H), 1.84–1.69 (m, 2 H), 1.64–1.46 (m, 4
H).
13C NMR (100 MHz, CDCl3): d = 215.72, 143.67 (q, JC,F = 1.5 Hz),
129.40 (q, JC,F = 32.2 Hz), 128.44, 125.50 (q, JC,F = 3.7 Hz), 124.30
(q, JC,F = 271.5 Hz), 56.73, 41.40, 32.97, 27.22, 26.44, 26.18, 24.75.
HRMS (ESI+): m/z calcd for C15H18F3O [M + H]+: 271.1310; found:
271.1341.
IR (neat): 3021 (br w), 2926 (br s), 2856 (br m), 1698 (s), 1513 (m),
1465 (w), 1446 (w), 1159 (w), 818 cm–1 (m).
1H NMR (CDCl3, 400 MHz): d = 7.22 (d, J = 8.2 Hz, 2 H), 7.11
(d, J = 8.0 Hz, 2 H), 3.74 (dd, J = 12.3, 2.7 Hz, 1 H), 2.61
(ddd, J = 12.7, 11.7, 4.5 Hz, 1 H), 2.42–2.29 (m, 1 H), 2.31 (s, 3 H),
2.26–2.20 (m, 1 H), 2.00–1.85 (m, 3 H), 1.81–1.70 (m, 2 H), 1.63–
1.54 (m, 2 H), 1.53–1.36 (m, 2 H).
(S)-2-(3-Methoxyphenyl)cyclooctanone (4h)
Run for 3 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cycloheptanone (18 mL, 0.15
mmol, 1.0 equiv), and 2e (200 mL, 0.21 mmol, 1.05 M in toluene,
1.4 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4h as a colorless oil (35.1 mg, quant)
with 97:3 er [AS-H, 50 °C, 150 psi, 2.0 mL/min, 2%
MeOH, l = 220 nm; tR = 2.05 min (minor), 2.26 min (major)];
[a]D20 –116.3 (c 0.99, CHCl3); Rf = 0.16 (10% EtOAc in hexanes).
13C NMR (100 MHz, CDCl3): d = 216.75, 136.78, 136.44, 129.37,
127.76, 57.26, 40.16, 31.46, 27.13, 26.92, 26.82, 24.78, 21.13.
HRMS (ESI+): m/z calcd for C15H21O [M + H]+: 217.1592; found:
217.1599.
(S)-2-(Napthalen-1-yl)cyclooctanone (4k)
Run for 14 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 5 (5.9 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cycloheptanone (18 mL, 0.15
mmol, 1.0 equiv), and 2g (396 mL, 0.21 mmol, 0.53 M in toluene,
1.4 equiv). The crude reaction mixture was directly purified by col-
umn chromatography to afford 4k as a pale yellow solid (35.5 mg,
94%) with 93:7 er [AD-H, 50 °C, 150 psi, 2.0 mL/min, 3%
MeOH, l = 220 nm; tR = 21.52 min (major), 25.15 min (minor)];
mp 97–100 °C; [a]D20 +48.3 (c 0.82, CHCl3); Rf = 0.20 (10%
EtOAc in hexanes).
IR (neat): 2929 (s), 2856 (w), 1697 (s), 1598 (m), 1583 (m), 1491
(m), 1465 (m), 1286 (s), 1048 (m), 767 (w), 696 cm–1 (w).
1H NMR (CDCl3, 400 MHz): d = 7.24–7.18 (m, 1 H), 6.94–6.88 (m,
2 H), 6.80–6.75 (m, 1 H), 3.80 (s, 3 H), 3.75 (dd, J = 12.5, 2.7 Hz,
1 H), 2.62 (ddd, J = 11.7, 4.7 Hz, 1 H), 2.41–2.29 (m, 1 H), 2.29–
2.21 (m, 1 H), 2.03–1.84 (m, 3 H), 1.82–1.69 (m, 2 H), 1.64–1.53
(m, 2 H), 1.53–1.34 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 216.41, 159.79, 140.98, 129.53,
120.21, 113.81, 112.41, 57.60, 55.31, 40.25, 31.44, 27.10, 26.87,
26.80, 24.74.
HRMS (ESI+): m/z calcd for C15H21O2 [M + H]+: 233.1542; found:
233.1560.
IR (neat): 3042 (w), 2924 (br m), 2898 (br w), 1689 (s), 1510 (w),
1397 (w), 1117 (m), 800 (m), 780 cm–1 (br s).
1H NMR (CDCl3, 400 MHz): d = 8.33–8.28 (m, 1 H), 7.87–7.83 (m,
1 H), 7.79–7.74 (m, 1 H), 7.64–7.60 (m, 1 H), 7.60–7.54 (m, 1 H),
7.51–7.45 (m, 2 H), 4.65 (dd, J = 12.1, 2.6 Hz, 1 H), 2.82
(ddd, J = 12.3, 12.3, 3.9 Hz, 1 H), 2.68–2.55 (m, 1 H), 2.30
(ddd, J = 12.9, 5.7, 3.7 Hz, 1 H), 2.11–1.94 (m, 3 H), 1.90–1.79 (m,
2 H), 1.78–1.63 (m, 2 H), 1.61–1.49 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 215.91, 135.62, 134.07, 131.86,
129.01, 127.75, 126.46, 125.70, 125.59, 124.63, 123.68, 52.49,
39.88, 31.66, 27.41, 27.30, 26.91, 24.92.
(S)-2-(2-Methylphenyl)cyclooctanone (4i)
Run for 14 h at –78 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 5 (5.9 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cycloheptanone (18 mL, 0.15
mmol, 1.0 equiv), and 2f (180 mL, 0.21 mmol, 1.18 M in toluene,
Synthesis 2012, 44, 686–693
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Catalytic a-Arylation of Cycloalkanones
693
HRMS (ESI+): m/z calcd for C18H21O [M + H]+: 253.1592; found:
253.1622.
(2) (a) Meyers, A. I.; Williams, D. R.; Druelinger, M. J. Am.
Chem. Soc. 1976, 98, 3032. (b) Job, A.; Janeck, C. F.;
Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253.
(S)-2-(4-Phenyl)cyclononanone (4l)
Run for 14 h at –45 °C according to the general procedure with
Sc(OTf)3 (7.4 mg, 0.015 mmol, 10 mol%), ligand 6 (8.5 mg, 0.016
mmol, 11 mol%), toluene (1.5 mL), cyclooctanone (18.9 mg, 0.15
mmol, 1.0 equiv) in toluene (0.15 mL), and 2b (284 mL, 0.21 mmol,
0.74 M in toluene, 1.4 equiv). The crude reaction mixture was di-
rectly purified by column chromatography to afford 4l as a colorless
oil (33.0 mg, quant) with 93:7 er [AD-H, 50 °C, 150 psi, 2.0
mL/min, 2% MeOH, l = 220 nm; tR = 9.04 min (minor), 9.82 min
(major)]; [a]D20 –43.9 (c 0.94, CHCl3); Rf = 0.25 (10% EtOAc in
hexanes).
(3) (a) Alexander, M.; Altman, R. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2009, 131, 9900. (b) Chieffi, A.; Kamikawa, K.;
Åhman, J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001, 3,
1897.
(4) (a) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918.
(b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 1261. (c) Chae, J.; Yun, J.;
Buchwald, S. L. Org. Lett. 2004, 6, 4809. (d) Liao, X.;
Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195.
(5) (a) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H.
J. Am. Chem. Soc. 1996, 118, 12854. (b) Yanagisawa, A.;
Inanami, H.; Yamamoto, H. Chem. Commun. 1998, 1573.
(c) Nakamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto, H.
J. Am. Chem. Soc. 2002, 122, 8120. (d) Ishihara, K.;
Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am. Chem.
Soc. 2003, 125, 24. (e) Cheon, C. H.; Yamamoto, H. J. Am.
Chem. Soc. 2008, 130, 9246. (f) Yanagisawa, A.; Touge, T.;
Arai, T. Angew. Chem. Int. Ed. 2005, 44, 1546.
(6) (a) Moebius, D. C.; Kingsbury, J. S. J. Am. Chem. Soc. 2009,
131, 878. (b) Wommack, A. J.; Moebius, D. C.; Travis, A.
L.; Kingsbury, J. S. Org. Lett. 2009, 11, 3202. (c) Rendina,
V. L.; Moebius, D. C.; Kingsbury, J. S. Org. Lett. 2011, 13,
2004.
(7) (a) Gutsche, C. D. Org. React. 1954, 8, 364. (b) Gutsche, C.
D.; Redmore, D. In Carbocyclic Ring Expansion Reactions;
Hart, H.; Karabatsos, G. J., Eds.; Academic Press: New
York, 1968, 81–98.
(8) (a) Javed, M. I.; Brewer, M. Org. Lett. 2007, 9, 1789.
(b) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004,
126, 12222. (c) Holton, T. L.; Shechter, H. J. Org. Chem.
1995, 60, 4725.
IR (neat): 3061 (br w), 3026 (br w), 2926 (br m), 1702 (s), 1495 (w),
1451 (m), 698 cm–1 (s).
1H NMR (CDCl3, 400 MHz): d = 7.29–7.14 (m, 5 H), 3.88 (dd,
J = 11.9, 2.7 Hz, 1 H), 2.46–2.34 (m, 1 H), 2.34–2.24 (m, 2 H),
1.95–1.34 (m, 11 H).
13C NMR (100 MHz, CDCl3): d = 216.28, 139.72, 128.68, 128.02,
127.12, 58.94, 41.80, 31.78, 25.97, 25.68, 25.49, 24.22, 24.02.
HRMS (ESI+): m/z calcd for C15H21O [M + H]+: 217.1592; found:
217.1589.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. 1H and
13C NMR data are included.
Acknowledgment
We wish to thank Boston College for their generous support of this
work. Mass spectrometry facilities in the department are supported
by the NSF (DBI-0619576).
(9) Rendina V. L.; Kingsbury, J. S. Submitted to J. Org. Chem.
for publication.
References
(10) Though not studied in the context of cycloalkanone ring
expansions, heteroaromatic substrates are well tolerated in
the Sc-catalyzed homologation of aldehydes. See reference
6b.
(11) (a) Tang, Y.; Zhou, J. J. Am. Chem. Soc. 2002, 124, 9030.
(b) Zhou, J.; Tang, Y. Chem. Soc. Rev. 2005, 34, 664.
(12) Davies, I. W.; Gerena, L.; Castonguay, L.; Senanayake, C.
H.; Larsen, R. D.; Verhoevena, T. R.; Reidera, P. J. Chem.
Commun. 1996, 1753.
(13) Armarego, W. L. F.; Chai, C. L. L. Purification of
Laboratory Chemicals, 5th ed.; Butterworth-Heinemann:
Oxford, 2003.
(14) Tertiary 2-arylcyclopentanones are known to racemize on
silica gel. See: Shen, Y.-M.; Wang, B.; Shi, Y. Angew.
Chem. Int. Ed. 2006, 45, 1429.
(1) (a) Dolling, U. F.; Davis, P.; Grabowski, E. J. J. J. Am.
Chem. Soc. 1984, 106, 446. (b) Corey, E. J.; Xu, F.; Noe, M.
C. J. Am. Chem. Soc. 1997, 119, 12414. (c) Behenna, D. C.;
Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
(d) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 62. (e) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005,
127, 2846. (f) Braun, M.; Meier, T. Synlett 2005, 2968.
(g) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
17192. (h) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe,
K.; Koga, K. J. Am. Chem. Soc. 1994, 116, 8829. For
unrelated catalytic entries to such products, see:
(i) Luchaco-Cullis, C.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 8192. (j) Shen, Y.-M.; Wang, B.; Shi, Y.
Tetrahedron Lett. 2006, 47, 5455. For a lead reference on
the a-derivatization of aldehydes by organocatalysis, see:
(k) Mastracchio, A.; Warkentin, A. A.; Walji, A. M.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 20648.
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Synthesis 2012, 44, 686–693