Catalytic asymmetric intermolecular C-H insertion of 1,4-cyclohexadiene with α-alkyl-α-diazoesters using chiral dirhodium(II) carboxylates

Article abstract of DOI:10.3987/COM-12-S(N)120

The first example of dirhodium(II) complex-catalyzed asymmetric intermolecular C-H insertion with α-alkyl-α-diazoesters is described. The reaction of 1,4-cyclohexadiene with 2,4-dimethyl-3-pentyl α-alkyl-α-diazoacetates under catalysis by dirhodium(II) te

Full text of DOI:10.3987/COM-12-S(N)120

HETEROCYCLES, Vol. 86, No. 2, 2012
1647
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1647 - 1659. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 6th September, 2012, Accepted, 24th September, 2012, Published online, 5th October, 2012
DOI: 10.3987/COM-12-S(N)120
CATALYTIC ASYMMETRIC INTERMOLECULAR C–H INSERTION
OF 1,4-CYCLOHEXADIENE WITH !-ALKYL-!-DIAZOESTERS USING
†
CHIRAL DIRHODIUM(II) CARBOXYLATES
Takayuki Goto,a,b Tomohiro Onozuka,a Yuhei Kosaka,a Masahiro Anada,a
Koji Takeda,a and Shunichi Hashimotoa
*
aFaculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,
Japanꢀ
ꢀDevelopment Research Laboratories, Kyorin Pharmaceutical Co., Ltdꢁ 1848,
Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329–0114, Japan
E-mail: hsmt@pharm.hokudai.ac.jp
Abstract – The first example of dirhodium(II) complex-catalyzed asymmetric
intermolecular C–H insertion with !-alkyl-!-diazoesters is described. The
reaction
of
1,4-cyclohexadiene
under
with
catalysis
Rh2(S-PTTL)4,
2,4-dimethyl-3-pentyl
!-alkyl-!-diazoacetates
by
dirhodium(II)
dirhodium(II)
tetrakis[N-phthaloyl-(S)-tert-leucinate],
or
tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh2(S-TFPTTL)4, gave the
corresponding C–H insertion products with enantioselectivities of up to 86% ee,
albeit in low to modest yields.
Catalytic functionalization of unactivated C–H bonds represents one of the most powerful strategies for
C–C bond formation, and the development of asymmetric variants would be one of the ultimate goals in
organic synthesis.1 In this context,†C–H insertion of diazo compounds catalyzed by chiral dirhodium(II)
complexes has been recognized as an efficient means for enantioselective functionalization of C(sp3)–H
bonds.2 In 1997, Davies and Hansen made a major breakthrough in this field when they achieved
intermolecular C–H insertion reactions with high yield and excellent enantiocontrol.3a Donor/acceptor
rhodium carbenes derived from the combination of aryldiazoacetates or arylvinyldiazoacetates with
Rh2(S-DOSP)4 (2) as a chiral catalyst are capable of effective asymmetric C–H insertions with a diverse
array of substrates, including alkanes (up to 96% ee),3a,c tetrahydrofuran (up to 60% de and 98% ee),3a,c
†
Dedicated to Professor Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
N-Boc-protected amines (up to 94% de and 97% ee),3b allylic alkenes (up to 88% de and 95% ee),3c,e silyl
ethers (up to >90% de and 95% ee),3d silyl enol ethers (up to >90% de and 97% ee),3f ethylbenzenes (up to
68% de and 94% ee),3g and N,N-dimethylanilines (up to 95% ee).3h The power of this strategy3–10 has been
verified by the synthesis of a variety of natural products and pharmaceutical agents.4a–c,11–13 However,
catalytic asymmetric intermolecular C–H insertion with !-alkyl-!-diazoesters14,15 remains a significant
challenge because of the propensity to form !,"-unsaturated esters via a 1,2-hydride shift in
metal-carbene intermediates.16 A notable exception is the recent work of Katsuki and Suematsu in which
highly diastereo- and enantioselective C–H insertions with tert-butyl !-diazopropionate were achieved by
using Ir(III)-salen complexes 4.7
O
O
R
N
N
O
C12H25
S
H
H
O
O
O
O
O
N
O
N
O
Rh Rh
Rh Rh
Ir
L
N
N
N
N
Me
Ir
R = tBu: Rh2(S-PTTL)4 (1a)
R = iPr: Rh2(S-PTV)4 (1b)
R = Me: Rh2(S-PTA)4 (1c)
Ar Ar
Rh2(S-DOSP)4 (2)
L
X
O
X
H
O
L = 4-CH3C6H4
N
X
Ir(III)-salen complex
H
O
N
X
O
O
O
O
4a: Ar = C6H5
4b: Ar = H
Rh Rh
L = EtOH
Ir(III)-porphyrin complex (5)
Rh Rh
Rh2(4S,R-MenthAZ)4 (3)
X = F: Rh2(S-TFPTTL)4 (1d)
X = Cl: Rh2(S-TCPTTL)4 (1e)
The intermolecular C–H insertion reaction of 1,4-cyclohexadiene with diazocarbonyl compounds under
the influence of chiral catalysts represents the bench mark reaction in this area.4–8,13,17 In 1999, Davies and
co-workers were the first to demonstrate asymmetric induction (up to 95% ee) in the reaction with
aryldiazoacetates using Rh2(S-DOSP)4 (2).4,5 Thereafter, Doyle and co-workers reported the reaction with
vinyldiazolactone, in which Rh2(4S,R-MenthAZ)4 (3) provided the corresponding C–H insertion product
in up to 80% ee.6 As touched on above, Katsuki and Suematsu recently disclosed that Ir(III)-salen catalyst
4a is highly exceptional for reactions with aryldiazoacetates (up to 99% ee) or tert-butyl
!-diazopropionate (up to >99% ee).7 More recently, Che and co-workers explored the reaction with
aryldiazoacetates in the presence of iridium(III)-porphyrin catalyst 5, in which high levels of asymmetric
induction (up to 98% ee) were achieved.8
In recent years, we have achieved high levels of enantiocontrol in a range of catalytic metal carbene
transformations of !-alkyl-!-diazoesters, including intramolecular C–H insertion,18 cyclopropenation,19
cyclopropanation,20 and C–H functionalization of indole,21 by using dirhodium(II) carboxylate catalysts,

HETEROCYCLES, Vol. 86, No. 2, 2012
1649
which incorporate N-phthaloyl- or N-tetrahalophthaloyl-(S)-amino acids as bridging ligands. In a
continuation of our work, we addressed the issue of enantiocontrol in intermolecular C–H insertion
reactions of 1,4-cyclohexadiene with !-alkyl-!-diazoesters.
At the outset, we explored the reaction of 2,4-dimethyl-3-pentyl !-diazopropionate (7a) with 4 equiv of
1,4-cyclohexadiene (6) in dichloromethane at room temperature using 1 mol % of Rh2(S-PTTL)4
(1a),15d,18,22 the most generally efficient catalyst of our dirhodium(II) carboxylate catalysts (Table 1, entry
1). The reaction proceeded to completion within 0.5 h and gave the C–H insertion product 8a in 61%
yield with no signs of the formation of !,"-unsaturated ester 10a. In order to determine the sense and
23
extent of asymmetric induction, 8a {[!]D +25.5 (c 1.36, CHCl3)} was converted by reduction with
LiAlH4 and subsequent oxidation with DDQ into the known 2-phenyl-1-propanol (9a).23 The
enantiomeric excess of 9a was determined to be 62% by HPLC using a Daicel Chiralcel OB-H column.
The absolute stereochemistry of 9a was established as R by comparison of the sign of optical rotation
23
23
{[!]D +9.1 (c 0.77, CHCl3) for 62% ee; lit.,23 [!]D +14.3 (c 1.65, CHCl3) for 95% ee of
Table 1. Enantioselective C–H Insertion of 1,4-Cyclohexadiene (6) with 2,4-Dimethyl-3-
pentyl !-Diazopropionate (7a) Catalyzed by Chiral Dirhodium(II) Carboxylatesa
O
Me
O
Rh(II) catalyst
(1 mol %)
Me
OH
OCHiPr2
1. LiAlH4, THF
Me
+
OCHiPr2
CH2Cl2, 23 °C
0.5 h
N2
2. DDQ, CH2Cl2
76–85%
6
7a
9a
8a
C–H Insertion product 8a
O
Yield (%)b
Ee (%)c
OCHiPr2
Entry
Rh(II) catalyst
1
2d
61
63
66
72
72
73
62
61
25
3
Rh2(S-PTTL)4 (1a)
Rh2(S-PTTL)4 (1a)
Rh2(S-PTV)4 (1b)
Rh2(S-PTA)4 (1c)
Rh2(S-TFPTTL)4 (1d)
Rh2(S-TCPTTL)4 (1e)
10a
not detected
3
4
5
71
61
6
a All reactions were carried out as follows: Rh(II) catalyst (1 mol %) was added in one portion to a solution
b
c
of 6 (2 mmol) and 7a (0.5 mmol) in CH2Cl2 (1.5 mL). Isolated yield. Determined by HPLC after
transformation of 8a to (R)-2-phenyl-1-propanol (9a). d 10 equiv of 6 was used.
(R)-enantiomer}. The reaction with 10 equiv of 6 showed little variation in either yield or
enantioselectivity (entry 2). Although Rh2(S-PTV)4 (1b) and Rh2(S-PTA)4 (1c) provided 8a in good yieldsꢀ
with the same sense of asymmetric induction as that observed with 1a, poor enantioselectivities were

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HETEROCYCLES, Vol. 86, No. 2, 2012
obtained (25% and 3% ee, entries 3 and 4). We then evaluated the performance of Rh2(S-TFPTTL)4
(1d)24and Rh2(S-TCPTTL)4 (1e),25,26 fluorinated and chlorinated analogues of Rh2(S-PTTL)4 (1a).
Catalysis with Rh2(S-TFPTTL)4 was found to provide 8a in 72% yield with 71% ee (entry 5), while
Rh2(S-TCPTTL)4 displayed modest enantioselectivity (61% ee, entry 6).
Using Rh2(S-TFPTTL)4 (1d) as a catalyst, the effects of solvents on the enantioselectivity were examined
(Table 2, entries 1–4). The use of !,!,!-trifluorotoluene, hexanes, and 2,2-dimethylbutane in place of
CH2Cl2 produced good levels of asymmetric induction, in which 2,2-dimethylbutane exhibited the highest
enantioselectivity (80% ee, entry 4). The effect of the ester moiety was also evaluated. Reactions with
tert-butyl ester 7b and ethyl ester 7c resulted in only modest enantioselectivity (45% ee, entries 5 and 6).
These results clearly show that the use of 2,4-dimethyl-3-pentyl ester moiety19,21,27 is crucial for a good
degree of enantioselection. An examination of the temperature profile demonstrated that lowering the
reaction temperature to 0 or !20 °C had only a marginal effect on the enantioselectivity (82% and 80%
ee), though a sharp drop in product yield was observed (50% and 48%, entries 7 and 8).
Table 2. Enantioselective C–H Insertion of 1,4-Cyclohexadiene (6) with !-Diazopropionates 7
Catalyzed by Rh2(S-TFPTTL)4 (1d)a
O
Me
Rh2(S-TFPTTL)4 (1d)
(1 mol %)
O
Me
OH
1. LiAlH4, THF
OR
Me
+
OR
0.5 h
2. DDQ, CH2Cl2
79–84%
N2
6
7
9a
8
C–H Insertion product 8
Yield (%)b
Ee (%)c
Temp, °C
23
Entry
R
Solvent
1
2
3
4
5
6
7
8
7a
7a
7a
7a
iPr2CH
iPr2CH
iPr2CH
iPr2CH
8a
72
63
60
66
55
73
50
48
71
77
79
80
45
45
82
80
CH2Cl2
8a
8a
8a
8b
8c
8a
8a
CF3C6H5
23
23
hexanes
2,2-dimethylbutane
2,2-dimethylbutane
2,2-dimethylbutane
2,2-dimethylbutane
2,2-dimethylbutane
23
23
7b tBu
7c
Et
23
0
7a
7a
iPr2CH
iPr2CH
–20
a All reactions were performed on 0.5 mmol scale with 4 equiv of 6. b Isolated yield. c Determined by HPLC
after transformation of 8 to (R)-2-phenyl-1-propanol (9a).
We next turned our attention to C–H insertion with 2,4-dimethyl-3-pentyl !-diazobutanoate (7d) bearing
more reactive "-C–H bonds than the methyl C–H bonds of !-diazopropionates (Table 3). The reaction

HETEROCYCLES, Vol. 86, No. 2, 2012
1651
with 7d using 1 mol % of Rh2(S-TFPTTL)4 (1d) or Rh2(S-PTTL)4 (1a) resulted in complete conversion
within 0.5 h at room temperature, but formation of the desired C–H insertion product 8d was not
observed by 1H-NMR analysis of the crude reaction mixture (entries 1 and 2). Instead (Z)-alkene 10d via
a 1,2-hydride shift was isolated in 76% and 71% yields, respectively. It has been shown that low reaction
temperatures are the key to suppression of the 1,2-hydride shift.15b–g,18 Thus, we conducted the reaction at
!60 °C. Although Rh2(S-TFPTTL)4 produced almost none of 8d (entry 3), catalysis with Rh2(S-PTTL)4
furnished 8d with 83% ee, albeit in 12% yield (entry 4).28 These results are consistent with Taber’s
speculation that a rhodium carbene intermediate bearing more electron-withdrawing ligands is more
strongly positive at the carbene carbon and favors the less entropically demanding 1,2-hydride shift via an
early transition state.15a,g,16b,d,19 Under the same conditions, the reaction with !-diazopentanoate 7e gave
the C–H insertion product 8e in 20% yield with 86% ee, along with 22% of (Z)-alkene 10e (entry 5).29
Table 3. Enantioselective C–H Insertion of 1,4-Cyclohexadiene (6) with !-Alkyl-!-diazoesters 7 Catalyzed by Chiral
Dirhodium(II) Carboxylatesa
O
Rh(II) catalyst
(1 mol %)
O
R
O
R
OCHiPr2
OCHiPr2
+
+
R
OCHiPr2
10
2,2-dimethylbutane
N2
6
7
8
C–H Insertion product 8
Yield (%)b Ee (%)
Alkene 10
Yield (%)b
Entry
Rh(II) catalyst
Time (h)
R
Temp (°C)
–
–
1
2
3
4
5
Rh2(S-TFPTTL)4 (1d)
Rh2(S-PTTL)4 (1a)
Rh2(S-TFPTTL)4 (1d)
Rh2(S-PTTL)4 (1a)
Rh2(S-PTTL)4 (1a)
76
71
38
26
22
7d
7d
7d
7d
7e
8d
8d
8d
8d
8e
10d
10d
10d
10d
10e
Me
Me
Me
Me
Et
23
23
0.5
0.5
6
–
–
–
–
–60
–60
–60
8
12
20
83c
86d
12
a
b
All reactions were performed on 1 mmol scale with 4 equiv of 6. Isolated yield. Determined by HPLC after
c
d
transformation of 8d to (R)-2-Phenyl-1-butanol.
(R)-2-Phenyl-1-pentanol.
Determined by HPLC after transformation of 8e to
In summary, we have reported that chiral dirhodium(II) carboxylate catalysts, Rh2(S-PTTL)4 and
Rh2(S-TFPTTL)4, display a reasonable level of catalytic performance in intermolecular C–H insertion
reactions of 1,4-cyclohexadiene (6) with 2,4-dimethyl-3-pentyl !-alkyl-!-diazoacetates 7. This represents
the first example of intermolecular C–H insertion with !-alkyl-!-diazocarbonyl compounds bearing
longer-chain alkyl groups than a methyl substituent, though there is considerable room for improvement
in terms of chemo- and enantioselectivity as well as product yield.ꢀEfforts toward such improvement are
currently underway.

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HETEROCYCLES, Vol. 86, No. 2, 2012
EXPERIMENTAL
General. IR spectra were recorded on a JASCO FT/IR-5300 spectrometer and absorbance bands are
1
reported in wavenumber (cm!1). H NMR spectra were recorded on a JEOL JNM-AL 400 (400 MHz)
spectrometer. Chemical shifts are reported relative to an internal standard (tetramethylsilane at #H 0.00 or
CDCl3 at #H 7.26). Data are presented as follows: chemical shift (#, ppm), multiplicity (s = singlet, d =
doublet, t = triplet, m = multiplet), coupling constant and integration. 13C NMR spectra were recorded on
a JEOL JNM-AL 400 (100 MHz) spectrometer. Chemical shifts are reported relative to an internal
standard (CDCl3 at # 77.00). Optical rotations were measured on a JASCO P-1030 digital polarimeter at
the sodium D line (589 nm). ESI-MS spectra were obtained on a JEOL JMS-T100LP or Thermo
Scientific Exactive. Column chromatography was carried out on Kanto silica gel 60 N (63–210 mesh).
Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F254 plates with
visualization by ultraviolet, anisaldehyde stain solution or phosphomolybdic acid stain solution.
Analytical high-performance liquid chromatography (HPLC) was performed on a JASCO PU-1580
intelligent HPLC pump with a JASCO UV-1575 intelligent UV/VIS detector. Detection was performed at
254 nm. Chiralpak AD-H, Chiralpak IA, or Chiralcel OB-H columns (0.46 cm $ 25 cm) from Daicel were
used. Retention times (tR) and peak ratios were determined with a JASCO-Borwin analysis system. All
non-aqueous reactions were carried out in flame-dried glassware under an Ar atmosphere unless
otherwise noted. Reagents and solvents were purified by standard means. Dehydrated CH2Cl2 was
purchased from Kanto Chemical Co., Inc. 2,2-Dimethylbutane and !,!,!-trifluorotoluene were distilled
from calcium hydride prior to use. 1,4-Cyclohexadiene (6) and hexanes were purchased from Aldrich, Inc.
Chiral dirhodium(II) carboxylates 1a!e22c,24a,25a and !-alkyl-!-diazoesters 719 were prepared according to
the literature procedures.
General procedure for enantioselective intermolecular C–H insertion (Table 1, entry 1):
(R)-2,4-Dimethyl-3-pentyl 2-(2,5-cyclohexadienyl)propionate (8a). Rh2(S-PTTL)4!2AcOEt (1a) (7.1
mg, 0.005 mmol) was added in one portion to a solution of 6 (160.3 mg, 2.0 mmol) and 7a19 (99.1 mg,
0.50 mmol) in CH2Cl2 (1.5 mL) at room temperature. After stirring for 0.5 h at this temperature, the
mixture was concentrated in vacuo. The ratio of 8a/10a was determined to be >99:1 by 1H NMR analysis
of the crude reaction mixture. The crude product was purified by column chromatography (silica gel, 25:1
hexane/EtOAc) to provide 8a (76.5 mg, 61%) as a colorless oil; TLC Rf = 0.39 (10:1 hexane/EtOAc);
[!]D23 +25.5 (c 1.36, CHCl3) for 62% ee; IR (neat) % 2934, 2877, 1730, 1464, 1387, 1176 cm–1; 1H NMR
(400 MHz, CDCl3) # 0.86!0.90 (m, 12H, CH(CH3)2), 1.09 (d, J = 6.9 Hz, 3H, CHCH3), 1.87!1.94 (m, 2H,
CH(CH3)2), 2.52!2.57 (m, 1H, CHCO), 2.64 (m, 2H, CH2CH=CH), 3.28 (m, 1H, CHCH=CH), 4.63 (t, J
13
= 6.0 Hz, 1H, OCH), 5.56!5.64 (m, 2H, CH2CH=CH), 5.80!5.85 (m, 2H, CH2CH=CH); C NMR (100

HETEROCYCLES, Vol. 86, No. 2, 2012
1653
MHz, CDCl3) # 12.0 (CH3), 17.3 (CH3), 17.4 (CH3), 19.4 (CH3), 19.5 (CH3), 26.4 (CH2), 29.3 (CH), 29.4
(CH), 37.4 (CH), 52.5 (CH), 83.8 (CH), 127.7 (CH), 129.3 (CH), 133.9 (CH), 133.9 (CH), 175.9 (C=O);
HRMS (EI) calcd for C16H27O2 (M + H)+ 251.2006, found 251.2005. The absolute configuration of 8a was
determined to be R by chemical correlation (vide infra).
General procedure for reduction with LiAlH4 and oxidation with DDQ (Table 1, entry 1):
(R)-2-Phenyl-1-propanol (9a). A solution of 8a (62.6 mg, 0.25 mmol) in THF (0.5 mL) was added
dropwise to a stirred suspension of LiAlH4 (19.0 mg, 0.50 mmol) in THF (0.5 mL) at 0 °C. After stirring
for 1 h, 1 M hydrochloric acid (1 mL) was added at 0 °C and the whole mixture was extracted with
EtOAc (15 mL). The organic layer was washed with water (2 mL) and brine (2 mL) and then dried over
anhydrous
Na2SO4.
Filtration
and
evaporation
in
vacuo
furnished
crude
2-(2,5-cyclohexadienyl)-1-propanol (35.1 mg) as a colorless oil, which was used without purification.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (113.5 mg, 0.50 mmol) was added to a stirred
solution of 2-(2,5-cyclohexadienyl)-1-propanol in CH2Cl2 (2 mL) at room temperature. After stirring for 1
h at this temperature, the reaction mixture was quenched with saturated aqueous Na2CO3 (2 mL). The
mixture was extracted with EtOAc (15 mL). The organic layer was washed with water (2 mL) and brine
(2 mL) and then dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude
product (35 mg), which was purified by column chromatography on silica gel (7:3 hexane/Et2O) to afford
23
9a (28.3 mg, 83%) as a colorless oil; TLC Rf = 0.35 (3:1 hexane/EtOAc); [!]D +9.1 (c 0.77, CHCl3)
[lit.,23 [!]D23 +14.3 (c 1.65, CHCl3) for 95% ee of (R)-enantiomer]; 1H NMR (400 MHz, CDCl3) # 1.28 (d,
J = 7.2 Hz, 3H, CHCH3), 2.94!3.00 (m, 1H, CHCH3), 3.71 (d, J = 6.8 Hz, 2H, CH2OH), 7.22!7.26 (m,
3H, Ar), 7.32!7.36 (m, 2H, Ar). The enantiomeric excess of 9a was determined to be 62% by HPLC with
a Chiralpak OB-H column (100:1 hexane/iPrOH, 1.0 mL/min): tR (minor) = 16.5 min; tR (major) = 17.7
min.
(R)-tert-Butyl 2-(2,5-cyclohexadienyl)propionate (8b).7 According to the general procedure for
intermolecular C–H insertion, 8b was prepared from 6 (160.3 mg, 2.0 mmol) and 7b (78.1 mg, 0.50
mmol) using Rh2(S-TFPTTL)4!2AcOEt (1d) (8.6 mg, 0.005 mmol). The crude product was purified by
column chromatography (silica gel, 25:1 hexane/EtOAc) to provide 8b (57.3 mg, 55%) as a colorless oil;
25
21
TLC Rf = 0.39 (10:1 hexane/EtOAc); [!]D +13.0 (c 1.41, CHCl3) for 45% ee [lit.,7 [!]D +29.1 (c 1.1,
CHCl3) for >99% ee of (R)-enantiomer]; 1H NMR (400 MHz, CDCl3) # 1.02 (d, J = 7.0 Hz, 3H, CHCH3),
1.45 (s, 9H, C(CH3)3), 2.33!2.44 (m, 1H, CHCO), 2.62 (m, 2H, CH2CH=CH), 3.19 (m, 1H, CHCH=CH),
5.49!5.59 (m, 2H, CH2CH=CH), 5.73!5.84 (m, 2H, CH2CH=CH). The enantiomeric excess of 8b was
determined to be 45% after conversion to 9a.

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HETEROCYCLES, Vol. 86, No. 2, 2012
(R)-Ethyl 2-(2,5-cyclohexadienyl)propionate (8c).7 According to the general procedure for
intermolecular C–H insertion, 8c was prepared from 6 (160.3 mg, 2.0 mmol) and 7c (64.1 mg, 0.50
mmol) using Rh2(S-TFPTTL)4!2AcOEt (1d) (8.6 mg, 0.005 mmol). The crude product was purified by
column chromatography (silica gel, 25:1 hexane/EtOAc) to provide 8c (65.9 mg, 73%) as a colorless oil;
25
23
TLC Rf = 0.36 (10:1 hexane/EtOAc); [!]D +15.8 (c 1.28, CHCl3) for 45% ee [lit.,7 [!]D +27.4 (c 1.1,
CHCl3) for 83% ee of (R)-enantiomer]; 1H NMR (400 MHz, CDCl3) # 1.07 (d, J = 6.8 Hz, 3H, CHCH3),
1.26 (t, J = 6.9 Hz, 3H, OCH2CH3), 2.50 (m, 1H, CHCO), 2.66 (m, 2H, CH2CH=CH), 3.16!3.27 (m, 1H,
CHCH=CH), 4.04!4.22 (m, 2H, OCH2CH3), 5.51!5.64 (m, 2H, CH2CH=CH), 5.77!5.88 (m, 2H,
CH2CH=CH). The enantiomeric excess of 8c was determined to be 45% after conversion to 9a.
(R)-2,4-Dimethyl-3-pentyl 2-(2,5-cyclohexadienyl)butanoate (8d). According to the general procedure
for intermolecular C–H insertion, 8d was prepared from 6 (320.1 mg, 4.0 mmol) and 7d19 (212.3 mg, 1.0
mmol) using Rh2(S-PTTL)4!2AcOEt (1a) (14.2 mg, 0.01 mmol). The crude product was purified by
column chromatography (silica gel, 9:1 hexane/benzene) to give 8d (31.7 mg, 12%) as a colorless oil and
10d19 (47.9 mg, 26%) as a colorless oil; Data for 8d: TLC Rf = 0.38 (15:1 hexane/EtOAc); [!]D25 +23.3 (c
1
0.67, CHCl3) for 83% ee; IR (neat) % 2965, 2876, 1730, 1464, 1388, 1177 cm–1; H NMR (400 MHz,
CDCl3) # 0.87 (d, J = 6.7 Hz, 6H, CH(CH3)2), 0.89 (d, J = 6.7 Hz, 6H, CH(CH3)2), 0.91 (t, J = 7.4 Hz, 3H,
CH2CH3), 1.48 (m, 1H, CHCH2), 1.66 (m, 1H, CHCH2), 1.85-1.95 (m, 2H, CH(CH3)2), 2.35 (dt, J = 3.8,
10.5 Hz, 1H, CHCO), 2.64 (m, 2H, CH2CH=CH), 3.28 (m, 1H, CHCH=CH), 4.64 (t, J = 6.1 Hz, 1H,
OCH), 5.59!5.67 (m, 2H, CH2CH=CH), 5.76!5.82 (m, 2H, CH2CH=CH); 13C NMR (100 MHz, CDCl3) #
12.6 (CH3), 17.2 (CH3), 17.5 (CH3), 19.6 (CH3), 19.7 (CH3), 20.7 (CH2), 26.3 (CH2), 29.4 (CH), 29.4
(CH), 37.4 (CH), 52.5 (CH), 82.4 (CH), 125.7 (CH), 125.9 (CH), 125.9 (CH), 127.5 (CH), 174.4 (C=O);
HRMS (ESI) calcd for C17H28O2Na (M+Na)+ 287.1987, found 287.1987. Data for 10d: TLC Rf = 0.41
(15:1 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) # 0.88 (d, J = 6.8 Hz, 6H, CH(CH3)2), 0.89 (d, J = 7.2
Hz, 6H, CH(CH3)2), 1.88–1.96 (m, 2H, CH(CH3)2), 2.14 (dd, J = 1.8, 7.2 Hz, 3H, CH3CH=CH), 4.65 (t, J
= 6.3 Hz, 1H, OCH), 5.83 (dq, J = 1.8, 11.3 Hz, 1H, CH3CH=CH), 6.32 (dq, J = 7.2, 11.8 Hz, 1H,
CH3CH=CH). The absolute configuration of 8d was determined to be R by chemical correlation (vide
infra).
(R)-2-Phenyl-1-butanol.28 According to the general procedure for preparation of 9a, 2-phenyl-1-butanol
was prepared from 8d (26.4 mg, 0.10 mmol). The crude product was purified by column chromatography
on silica gel (7:3 hexane/Et2O) to afford 2-phenyl-1-butanol (11.9 mg, 79%) as a colorless oil; TLC Rf =
23
25
0.35 (3:1 hexane/EtOAc); [!]D –15.3 (c 0.35, CHCl3) [lit.,28 [!]D –21.1 (c 1.00, CHCl3) for
(R)-enantiomer]; 1H NMR (400 MHz, CDCl3) # 0.77 (t, J = 7.5 Hz, 3H, CH2CH3), 1.52 (m, 1H, CHCH2),

HETEROCYCLES, Vol. 86, No. 2, 2012
1655
1.68 (m, 1H, CHCH2), 2.62 (m, 1H, CHCH2), 3.64!3.71 (m, 2H, CH2OH), 7.10!7.20 (m, 3H, Ar),
7.22–7.39 (m, 2H, Ar). The enantiomeric excess of 2-phenyl-1-butanol was determined to be 83% by
HPLC with a Chiralpak AD-H column (300:1 hexane/iPrOH, 1.0 mL/min): tR (minor) = 54.6 min; tR
(major) = 59.0 min.
(R)-2,4-Dimethyl-3-pentyl 2-(2,5-cyclohexadienyl)pentanoate (8e). According to the general procedure
for intermolecular C–H insertion, 8e was prepared from 6 (320.6 mg, 4.0 mmol) and 7e19 (226.3 mg, 1.0
mmol) using Rh2(S-PTTL)4!2AcOEt (1a) (14.2 mg, 0.01 mmol). The crude product was purified by
column chromatography (silica gel, 9:1 hexane/benzene) to provide 8e (55.7 mg, 20%) as a colorless oil
23
and 10e19 (43.6 mg, 22%) as a colorless oil; Data for 8e: TLC Rf = 0.39 (15:1 hexane/EtOAc); [!]D
1
+24.7 (c 1.10, CHCl3) for 86% ee; IR (neat) % 2962, 2874, 1730, 1465, 1388, 1176 cm–1; H NMR (400
MHz, CDCl3) # 0.87 (d, J = 6.7 Hz, 6H, CH(CH3)2), 0.88 (d, J = 6.7 Hz, 6H, CH(CH3)2), 0.90 (t, J = 7.4
Hz, 3H, CH2CH3), 1.19!1.41 (m, 3H, CH2), 1.60!1.69 (m, 1H, CHCH2), 1.85!1.95 (m, 2H, CH(CH3)2),
2.42!2.45 (m, 1H, CHCO), 2.63!2.65 (m, 2H, CH2CH=CH), 3.16!3.20 (m, 1H, CHCH=CH), 4.63 (t, J =
13
6.1 Hz, 1H, OCH), 5.58!5.67 (m, 2H, CH2CH=CH), 5.78!5.82 (m, 2H, CH2CH=CH); C NMR (100
MHz, CDCl3) # 14.1 (CH3), 17.2 (CH3), 17.5 (CH3), 19.6 (CH3), 19.7 (CH3), 21.2 (CH2), 26.3 (CH2), 29.4
(CH2), 29.4 (CH), 29.6 (CH2), 37.5 (CH), 50.4 (CH), 82.4 (CH), 125.7 (CH), 126.0 (CH), 126.0 (CH),
127.5 (CH), 174.6 (C=O); HRMS (ESI) calcd for C18H30O2Na (M+Na)+ 301.2138, found 301.2136. Data
1
for 10e: TLC Rf = 0.42 (15:1 hexane/EtOAc); H NMR (400 MHz, CDCl3) # 0.87 (d, J = 6.8 Hz, 6H,
CH(CH3)2), 0.89 (d, J = 6.8 Hz, 6H, CH(CH3)2), 1.07 (t, J = 7.7 Hz, 3H, CH2CH3), 1.87!1.96 (m, 2H,
CH(CH3)2), 2.66 (dd, J = 7.7, 7.7 Hz, 2H, CH2CH3), 4.65 (t, J = 6.3 Hz, 1H, OCH), 5.78 (dt, J = 1.8, 11.3
Hz, 1H, CH2CH=CH), 6.21 (dt, J = 7.2, 11.3 Hz, 1H, CH2CH=CH). The absolute configuration of 8e was
determined to be R by chemical correlation (vide infra).
(R)-2-Phenyl-1-pentanol.29 According to the general procedure for preparation of 9a,
2-phenyl-1-pentanol was prepared from 8e (50.1 mg, 0.18 mmol). The crude product was purified by
column chromatography on silica gel (7:3 hexane/Et2O) to give 2-phenyl-1-pentanol (23.7 mg, 80%) as a
colorless oil; TLC Rf = 0.35 (3:1 hexane/EtOAc); [!]D23 –9.9 (c 0.71, MeOH) for 86% ee [lit.,29 [!]D23 –12
1
(c 3.76, MeOH) for (R)-enantiomer]; H NMR (400 MHz, CDCl3) # 0.86 (t, J = 7.2 Hz, 3H, CH2CH3),
1.15!1.26 (m, 2H, CH2CH3), 1.53!1.67 (m, 2H, CHCH2), 2.73 (m, 1H, CHCH2), 3.65!3.76 (m, 2H,
CH2OH), 7.19!7.33 (m, 5H, Ar). The enantiomeric excess of 2-phenyl-1-pentanol was determined to be
86% by HPLC with a Chiralpak IA column (300:1 hexane/iPrOH, 1.0 mL/min): tR (minor) = 23.4 min; tR
(major) = 26.6 min.

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ACKNOWLEDGEMENTS
This research was supported, in part, by a Grant-in-Aid for Scientific Research from the Japan Society for
the Promotion of Science and also by a Grant-in-Aid for Scientific Research on Innovative Areas
"Organic Synthesis Based on Reaction Integration" (No. 2105) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We thank S. Oka and M. Kiuchi from the Center for Instrumental
Analysis at Hokkaido University for technical assistance with mass spectrometry.
REFERENCES AND NOTES
1. For a book and reviews, see: (a) 'Handbook of C–H Transformation,' Vols 1 and 2, ed. by G. Dyker,
Wiley-VCH, Weinheim, 2005; (b) K. Godula and D. Sames, Science, 2006, 312, 67; (c) R. Giri, B.-F.
Shi, K. M. Engle, N. Maugel, and J.-Q. Yu, Chem. Soc. Rev., 2009, 38, 3242; (d) D. A. Colby, R. G.
Bergman, and J. A. Ellman, Chem. Rev., 2010, 110, 624; (e) J.-Q. Yu and Z. Shi, Top. Curr. Chem.,
2010, 292, 1; (f) T. Newhouse and P. S. Baran, Angew. Chem. Int. Ed., 2011, 50, 3362; (g) J.
Wencel-Delord, T. Dröge, F. Liu, and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; (h) H. Lu and X.
P. Zhang, Chem. Soc. Rev., 2011, 40, 1899; (i) C.-M. Che, V. K.-Y. Lo, C.-Y. Zhou, and J.-S. Huang,
Chem. Soc. Rev., 2011, 40, 1950; (j) K. M. Engle, T.-S. Mei, M. Wasa, andꢀJ.-Q. Yu, Acc. Chem.
Res., 2012, 45, 788; (k) L. Yang and H. Huang, Catal. Sci. Technol., 2012, 2, 1099; (l) J. Yamaguchi,
A. D. Yamaguchi, and K. Itami, Angew. Chem. Int. Ed., 2012, 51, 8960.
2. For books and reviews, see: (a) M. P. Doyle, M. A. McKervey, and T. Ye, 'Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds,' Wiley-Interscience, New York, 1998; (b)
M. P. Doyle and D. C. Forbes, Chem. Rev., 1998, 98, 911; (c) C. A. Merlic and A. L. Zechman,
Synthesis, 2003, 1137; (d) H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103, 2861; (e)
P. M. P. Gois and C. A. M. Afonso, Eur. J. Org. Chem., 2004, 3773; (f) Z. Zhang and J. Wang,
Tetrahedron, 2008, 64, 6577; (g) H. M. L. Davies and J. R. Manning, Nature, 2008, 451, 417; (h) H.
M. L. Davies and J. R. Denton, Chem. Soc. Rev., 2009, 38, 3061; (i) H. M. L. Davies and J. Hansen,
'Catalytic Asymmetric Synthesis,' 3rd ed, ed. by I. Ojima, Wiley-VCH, New York, 2010, chap. 4; (j)
C. N. Slattery, A. Ford, and A. R. Maguire, Tetrahedron, 2010, 66, 6681; (k) M. P. Doyle, R. Duffy,
M. Ratnikov, and L. Zhou, Chem. Rev., 2010, 110, 704; (l) M. P. Doyle, M. Ratnikov, and Y. Liu,
Org. Biomol. Chem., 2011, 9, 4007; (m) H. M. L. Davies and D. Morton, Chem. Soc. Rev., 2011, 40,
1857.
3. (a) H. M. L. Davies and T. Hansen, J. Am. Chem. Soc., 1997, 119, 9075; (b) H. M. L. Davies, T.
Hansen, D. W. Hopper, and S. A. Panaro, J. Am. Chem. Soc., 1999, 121, 6509; (c) H. M. L. Davies,
T. Hansen, and M. R. Churchill, J. Am. Chem. Soc., 2000, 122, 3063; (d) H. M. L. Davies and E. G.
Antoulinakis, Org. Lett., 2000, 2, 4153; (e) H. M. L. Davies, P. Ren, and Q. Jin, Org. Lett., 2001, 3,

HETEROCYCLES, Vol. 86, No. 2, 2012
1657
3587; (f) H. M. L. Davies and P. Ren, J. Am. Chem. Soc., 2001, 123, 2070; (g) H. M. L. Davies, Q.
Jin, P. Ren, and A. Y. Kovalevsky, J. Org. Chem., 2002, 67, 4165; (h) H. M. L. Davies and Q. Jin,
Org. Lett., 2004, 6, 1769; (i) H. M. L. Davies and Q. Jin, J. Am. Chem. Soc., 2004, 126, 10862ꢀ
4. (a) H. M. L. Davies, D. G. Stafford, and T. Hansen, Org. Lett., 1999, 1, 233; (b) H. M. L. Davies and
T. M. Gregg, Tetrahedron Lett., 2002, 43, 4951; (c) H. M. L. Davies, A. M. Walji, and R. J.
Townsend, Tetrahedron Lett., 2002, 43, 4981; (d) H. M. L. Davies and A. M. Walji, Org. Lett., 2003,
5, 479; (e) H. M. L. Davies and J. Nikolai, Org. Biomol. Chem., 2005, 3, 4176; (f) A. Ni, J. E.
France, and H. M. L. Davies, J. Org. Chem., 2006, 71, 5594; (g) P. Pelphrey, J. Hansen, and H. M. L.
Davies, Chem. Sci., 2010, 1, 254.
5. P. Müller and S. Tohill, Tetrahedron, 2000, 56, 1725.
6. D. Bykowski, K.-H. Wu, and M. P. Doyle, J. Am. Chem. Soc., 2006, 128, 16038.
7. H. Suematsu and T. Katsuki, J. Am. Chem. Soc., 2009, 131, 14218.
8. J.-C. Wang, Z.-J. Xu, Z. Guo, Q.-H. Deng, C.-Y. Zhou, X.-L. Wan, and C.-M. Che, Chem. Commun.,
2012, 48, 4299.
9. Fokin and co-workers recently reported highly enantioselective intermolecular C–H insertion
reactions of alkanes with 1-sulfonyl triazoles using Rh2(S-NTTL)4 or Rh2(S-PTAD)4 (up to 97% ee).
S. Chuprakov, J. A. Malik, M. Zibinsky, and V. V. Fokin, J. Am. Chem. Soc., 2011, 133, 10352.
10. For other examples of catalytic asymmetric intermolecular C–H insertions, see: (a) J. M. Fraile, J. I.
García, J. A. Mayoral, and M. Roldán, Org. Lett., 2007, 9, 731; (b) H.-Y. Thu, G. S.-M. Tong, J.-S.
Huang, S. L.-F. Chan, Q.-H. Deng, and C.-M. Che, Angew. Chem. Int. Ed., 2008, 47, 9747; (c) J. M.
Fraile, P. López-Ram-de-Viu, J. A. Mayoral, M. Roldán, and J. Santafé-Valero, Org. Biomol. Chem.,
2011, 9, 6075.
11. J. M. Axten, R. Ivy, L. Krim, and J. D. Winkler, J. Am. Chem. Soc., 1999, 121, 6511.
12. (a) H. M. L. Davies and Q. Jin, Tetrahedron: Asymmetry, 2003, 14, 941; (b) H. M. L. Davies and A.
Ni, Chem. Commun., 2006, 3110.
13. For intermolecular C–H insertion of 1,4-cyclohexadiene using the combination of piperidinyl
mandelate chiral auxiliary and Rh2(S-DOSP)4 (2) and it application to the stereocontrolled synthesis
of kainoids. T. Higashi, Y. Isobe, H. Ouchi, H. Suzuki, Y. Okazaki, T. Asakawa, T. Furuta, T.
Wakimoto, and T. Kan, Org. Lett., 2011, 13, 1089.
14. (a) P. Panne and J. M. Fox, J. Am. Chem. Soc., 2007, 129, 22; (b) P. Müller and C. Gränicher, Helv.
Chim. Acta, 1995, 78, 129; (c) A. Padwa, J. M. Kassir, and S. L. Xu, J. Org. Chem., 1997, 62, 1642.
15. For other examples of dirhodium(II) complex-catalyzed intermolecular transformation of
!-alkyl-!-diazoesters without alkene formation, see: (a) G. G. Cox, D. Haigh, R. M. Hindley, D. J.
Miller, and C. J. Moody, Tetrahedron Lett., 1994, 35, 3139; (b) A. DeAngelis, P. Panne, G. P. A.

1658
HETEROCYCLES, Vol. 86, No. 2, 2012
Yap, and J. M. Fox, J. Org. Chem., 2008, 73, 1435; (c) P. Panne, A. DeAngelis, and J. M. Fox, Org.
Lett., 2008, 10, 2987; (d) A. DeAngelis, O. Dmitrenko, G. P. A. Yap, and J. M. Fox, J. Am. Chem.
Soc., 2009, 131, 7230; (e) A. DeAngelis, V. W. Shurtleff, O. Dmitrenko, and J. M. Fox, J. Am. Chem.
Soc., 2011, 133, 1650; (f) D. T. Boruta, O. Dmitrenko, G. P. A. Yap, and J. M. Fox, Chem. Sci.,
2012, 3, 1589; (g) A. DeAngelis, O. Dmitrenko, and J. M. Fox, J. Am. Chem. Soc., 2012, 134,
11035.
16. (a) N. Ikota, N. Takamura, S. D. Young, and B. Ganem, Tetrahedron Lett., 1981, 22, 4163; (b) D. F.
Taber, M. J. Hennessy, and J. P. Louey, J. Org. Chem., 1992, 57, 436; (c) D. F. Taber, R. J. Herr, S.
K. Pack, and J. M. Geremia, J. Org. Chem., 1996, 61, 2908; (d) D. F. Taber and P. V. Joshi, J. Org.
Chem., 2004, 69, 4276.
17. Hilt and co-workers reported intermolecular C–H insertion reactions of diazocarbonyl compounds
with various polysubstituted and functionalized 1,4-dienes using Rh2(OAc)4. (a) G. Hilt and F.
Galbiati, Org. Lett., 2006, 8, 2195; (b) G. Hilt and F. Galbiati, Synthesis, 2006, 3589.
18. K. Minami, H. Saito, H. Tsutsui, H. Nambu, M. Anada, and S. Hashimoto, Adv. Synth. Catal., 2005,
347, 1483.
19. T. Goto, K. Takeda, N. Shimada, H. Nambu, M. Anada, M. Shiro, K. Ando, and S. Hashimoto,
Angew. Chem. Int. Ed., 2011, 50, 6803.
20. T. Goto, K. Takeda, M. Anada, K. Ando, and S. Hashimoto, Tetrahedron Lett., 2011, 52, 4200.
21. T. Goto, Y. Natori, K. Takeda, H. Nambu, and S. Hashimoto, Tetrahedron: Asymmetry, 2011, 22,
907.
22. (a) N. Watanabe, T. Ogawa, Y. Ohtake, S. Ikegami, and S. Hashimoto, Synlett, 1996, 85; (b) H.
Saito, H. Oishi, S. Kitagaki, S. Nakamura, M. Anada, and S. Hashimoto, Org. Lett., 2002, 4, 3887;
(c) H. Tsutsui, T. Abe, S. Nakamura, M. Anada, and S. Hashimoto, Chem. Pharm. Bull., 2005, 53,
1366; (d) K. Takeda, T. Oohara, M. Anada, H. Nambu, and S. Hashimoto, Angew. Chem. Int. Ed.,
2010, 49, 6979.
23. C. Spino and C. Beaulieu, J. Am. Chem. Soc., 1998, 120, 11832.
24. (a) H. Tsutsui, Y. Yamaguchi, S. Kitagaki, S. Nakamura, M. Anada, and S. Hashimoto,
Tetrahedron: Asymmetry, 2003, 14, 817; (b) M. Anada, M. Tanaka, T. Washio, M. Yamawaki, T.
Abe, and S. Hashimoto, Org. Lett., 2007, 9, 4559; (c) N. Shimada, S. Nakamura, M. Anada, M.
Shiro, and S. Hashimoto, Chem. Lett., 2009, 38, 488.
25. (a) M. Yamawaki, H. Tsutsui, S. Kitagaki, M. Anada, and S. Hashimoto, Tetrahedron Lett., 2002, 43,
9561; (b) N. Shimada, M. Anada, S. Nakamura, H. Nambu, H. Tsutsui, and S. Hashimoto, Org. Lett.,
2008, 10, 3603; (c) N. Shimada, T. Oohara, J. Krishnamurthi, H. Nambu, and S. Hashimoto, Org.
Lett., 2011, 13, 6284.

HETEROCYCLES, Vol. 86, No. 2, 2012
1659
26. (a) V. N. G. Lindsay, W. Lin, and A. B. Charette, J. Am. Chem. Soc., 2009, 131, 16383; (b) V. N. G.
Lindsay, C. Nicolas, and A. B. Charette, J. Am. Chem. Soc., 2011, 133, 8972; (c) V. N. G. Lindsay
and A. B. Charette, ACS Catal., 2012, 2, 1221.
27. (a) S. Hashimoto, N. Watanabe, T. Sato, M. Shiro, and S. Ikegami, Tetrahedron Lett., 1993, 34,
5109; (b) S. Hashimoto, N. Watanabe, and S. Ikegami, Synlett, 1994, 353; (c) S. Kitagaki, H.
Matsuda, N. Watanabe, and S. Hashimoto, Synlett, 1997, 1171.
28. The enantioselectivity was determined by HPLC after transformation of 8d to
(R)-2-phenyl-1-butanol. C. H. Senanayake, R. D. Larsen, T. J. Bill, J. Liu, E. G. Corley, and P. J.
Reider, Synlett, 1994, 199.
29. The enantioselectivity was determined by HPLC after transformation of 8e to
(R)-2-phenyl-1-pentanol. K. Kawazu, T. Fujita, and T. Mitsui, J. Am. Chem. Soc., 1959, 81, 932.