Palladium-catalyzed ligand-directed oxidative functionalization of cyclopropanes

Article abstract of DOI:10.1055/s-0030-1260087

This report describes the palladium-catalyzed functionalization of cyclopropanes containing oxazoline, oxime ether, and pyridine directing groups. Three different oxidants were examined in these studies: IOAc, PhI(OAc) ₂, and benzoquinone. The reactions yielded products derived from 2° sp³ C-H functionalization and/or C-C activation of the cyclopropane ring. The outcome and the product distributions were highly dependent on the structure of the substrate and the nature of the oxidant. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260087

SPECIAL TOPIC
2579
Palladium-Catalyzed Ligand-Directed Oxidative Functionalization of
Cyclopropanes
Cyclopropane
Oxi
s
dative Fun
a
c
tionalizat
kion o Kubota, Melanie S. Sanford*
University of Michigan, Department of Chemistry, 930 N. University Ave, Ann Arbor, MI 48109, USA
Fax +1(734)6474865; E-mail: mssanfor@umich.edu
Received 15 March 2011
stituted cyclopropanes. Interestingly, the C–H bonds of
cyclopropanes are not particularly activated towards ei-
ther homolytic nor heterolytic cleavage (BDE = 106 kcal/
mol; pKa = 46).11 Nonetheless, in many of these exam-
Abstract: This report describes the palladium-catalyzed function-
alization of cyclopropanes containing oxazoline, oxime ether, and
pyridine directing groups. Three different oxidants were examined
in these studies: IOAc, PhI(OAc)2, and benzoquinone. The reac-
tions yielded products derived from 2° sp3 C–H functionalization ples, the cyclopropane C–H bonds are cleaved selectively
in lieu of adjacent sp2 and/or 1° sp3 C–H bonds.
and/or C–C activation of the cyclopropane ring. The outcome and
the product distributions were highly dependent on the structure of
the substrate and the nature of the oxidant.
Pd(OAc)2 (5 mol%)
OAc
PhI(OAc)2 (1.1 equiv)
Key words: cyclopropane, C–H functionalization, palladium,
(i)
cleavage, homogeneous catalysis
N
O
A
N
O
AcOH–Ac2O (1:1)
44%
Transition-metal-catalyzed reactions for the direct func-
tionalization of C–H bonds serve as atom economical
methods for the synthesis of diverse organic molecules.1
Research in this area has expanded dramatically over the
past decade, and palladium-catalyzed ligand-directed C–
H functionalization has become a particularly active sub-
field.2 Numerous palladium-catalyzed methods have been
developed for transforming C–H bonds into C–O, C–halo-
gen, C–S, C–N, and C–C linkages.2 Furthermore, these re-
actions have been applied to the functionalization of
diverse aromatic, olefinic, and 1° sp3 C–H bonds.2
Pd(OAc)2 (5 mol%)
[Ph2I]BF4 (1.2 equiv)
(ii)
N
N
N
AcOH–Ac2O (1:1)
60%
B
Ph
Ph
H
Ph
MeO
MeO
N
OAc
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (1.1 equiv)
H
H
(iii)
(iv)
AcOH–Ac2O (1:1)
81%
H
C
In marked contrast, the palladium-catalyzed functional-
ization at 2° sp3 C–H sites remains a significant challenge.
Sporadic examples of this type of reactivity have been re-
ported. However, as shown in Scheme 1, the vast majority
of these require the presence of an electronically and/or
sterically biasing element within the substrate. For exam-
ple, substrates A and B are activated by the presence of a-
heteroatoms and a-aryl groups adjacent to the site of 2°
C–H functionalization (Scheme 1, i and ii).3,4 The rigid
structure of substrate C provides a conformational bias for
2° sp3 C–H functionalization (Scheme 1, iii).3 Finally,
substrate D can participate in two-point binding to the pal-
ladium catalyst (through the quinoline and amide nitro-
gens), and this facilitates cleavage of an unactivated 2° sp3
C–H bond (Scheme 1, iv).5
Pd(OAc)2 (5 mol%)
aryl–I (4 equiv)
N
N
Ag(OAc)2 (1.1 equiv)
92%
NH
aryl
NH
O
O
D
[aryl = 4-MeOC6H4]
Scheme 1 Examples of 2° sp3 C–H activation/acetoxylation
The reactions in Scheme 2 are of particular interest be-
cause substituted cyclopropanes serve as versatile inter-
mediates for further synthetic manipulations.12 In
addition, studies of the scope and limitations of such
transformations could provide valuable insights for the
development of more general palladium-catalyzed reac-
tions for 2° sp3 C–H functionalization. However, to date,
these cyclopropane C–H functionalization reactions re-
main isolated examples, and have not been subject to sys-
tematic investigation.
Cyclopropanes have also been successfully utilized as
substrates for palladium-catalyzed 2° sp3 C–H functional-
ization. For example, recent reports have described the
palladium-catalyzed ligand-directed C–H halogenation,6
arylation,7 alkylation,8 and olefination9,10 of various sub-
To address this gap in knowledge, we have conducted a
detailed study of the palladium-catalyzed ligand-directed
oxidation of cyclopropane derivatives. This paper de-
scribes the palladium-catalyzed reactions of cyclopropyl
oxazolines, oxime ethers, and pyridines with three differ-
SYNTHESIS 2011, No. 16, pp 2579–2589
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.07.2011
DOI: 10.1055/s-0030-1260087; Art ID: C00711SS
© Georg Thieme Verlag Stuttgart · New York

2580
A. Kubota, M. S. Sanford
SPECIAL TOPIC
ent oxidants: IOAc, PhI(OAc)2, and benzoquinone (BQ).
We demonstrate that these reactions are remarkably sen-
sitive to subtle changes in the directing group and reaction
conditions. Minor perturbations of both variables often
lead to competing C–C bond activation of the cyclopro-
pane to afford ring opened products.
O
O
R
R
Pd(OAc)2 (10 mol%)
N
N
I2/
+
PhI(OAc)2
CH2Cl2
24 °C, 96 h
I
1 R = Me
2 R = H
1a R = Me 65%
2a R = H not detected
Three different oxidants were utilized for all of the sub-
strates discussed in this manuscript. First, the oxidant
IOAc [generated in situ from PhI(OAc)2 and I2] was ex-
amined, since this reagent was shown to be effective for
Scheme 3 Oxazoline-directed C–H iodination
The palladium-catalyzed oxidation of 1 and 2 was next
examined using PhI(OAc)2. Under standard conditions for
palladium-catalyzed sp3 C–H acetoxylation [10 mol%
Pd(OAc)2, 2 equiv PhI(OAc)2 in AcOH at 100 °C],3,13,14
the major observable products were oxazolium acetate
salts 1b (19%) and 2b (29%) (Scheme 4). C–H acetoxyla-
tion products were not detected by 1H NMR spectroscopy
or by mass spectrometric analysis. The protonated oxazo-
lines 1b and 2b were also formed (in 59% and 62% yield)
when 1 and 2 were heated in acetic acid at 100 °C for six
hours in the absence of palladium and oxidant.
the C–H iodination of cyclopropyl oxazoline
1
(Scheme 2, i).6 Second, PhI(OAc)2 was used as an oxi-
dant, since our group13 and others14 have demonstrated
that this is a highly effective reagent for the palladium(II/
IV)-catalyzed C–H acetoxylation of diverse substrates.
Finally, benzoquinone was employed in conjunction with
acetic acid as an external nucleophile. Benzoquinone is a
much weaker oxidant than PhI(OAc)2, and is frequently
used to mediate palladium(II/0) catalytic cycles. Most rel-
evant to the current manuscript, Yudin has demonstrated
the PdCl2-catalyzed oxidative C–C activation of arylcy-
clopropanes using benzoquinone as a terminal oxidant.15
OAc
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
O
O
R
R
N
N
AcOH
100 °C, 6 h
H
O
O
Pd(OAc)2 (10 mol%)
N
I2/
N
1 R = Me
2 R = H
1b R = Me
2b R = H
+
(i)
PhI(OAc)2
CH2Cl2, 24 °C, 96 h
65%
I
Scheme 4 Oxazolium acetate salt formation
Pd(OAc)2 (10 mol%)
In an effort to limit this undesired acid/base chemistry, we
switched the solvent for this reaction from acetic acid to
dichloroethane (DCE). Under these conditions, substrate
1 underwent cyclopropane C–C bond activation to gener-
ate olefin 1c in modest 29% yield as a mixture of E- and
Z-isomers (Scheme 5). Notably, similar reactivity was ob-
served at room temperature (with 1c formed in 12%
yield). In contrast, substrate 2 did not yield any detectable
acetoxylated products under any conditions examined.
benzoquinone (0.5 equiv)
Ag2CO3 (1 equiv)
Ph
B
HO2C
HO2C
Ph
K2HPO4 (1.5 equiv)
O
O
+
(ii)
t-BuOH, 100 °C, 3 h
20%
Pd(OAc)2 (10 mol%)
Cu(OAc)2 (1.1 equiv)
AgOAc (1.1 equiv)
LiCl (2 equiv)
O
O
C6F5
Ph
(iii)
C6F5
Ph
+
N
N
CO2Bn
H
DMF, 120 °C
12 h
OAc
O
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
O
71%
CO2Bn
R
N
N
DCE
100 °C, 6 h
Scheme 2 Examples of ligand-directed C–H functionalization of
cyclopropane derivatives
R
1 R = Me
2 R = H
1c R = CH3 29%
2c R = H not detected
Oxazoline Substrates
Scheme 5 Oxazoline-directed acetoxylation
Our initial studies focused on the oxazoline substrates 1
and 2. These were selected based on Yu’s report that 1
participates in 2° sp3 C–H iodination at room temperature
using IOAc.6 However, interestingly, under analogous
conditions compound 2 was completely unreactive to-
wards C–H iodination (Scheme 3). After 96 hours at 25
°C, the starting material remained in nearly quantitative
Finally, oxazolines 1 and 2 were subjected to benzoqui-
none in acetic acid [10 mol% Pd(OAc)2, 2 equiv BQ in
AcOH at 100 °C]. The major observable products under
these conditions were also the oxazolium acetate salts [1b
(<10%) and 2b (25%), respectively], and no acetoxylated
products were observed upon analysis of the crude reac-
tion mixtures by NMR or electrospray mass spectrometry.
1
yield (99%), as determined by H NMR spectroscopic
analysis of the crude reaction mixture. This result demon-
strates that the C–H iodination reaction is extremely sen-
sitive to the steric/electronic environment around the
directing group.
Oxime Ether Substrates
Several reports by our group have shown that oxime de-
rivatives are versatile directing groups for palladium-cat-
Synthesis 2011, No. 16, 2579–2589 © Thieme Stuttgart · New York

SPECIAL TOPIC
Cyclopropane Oxidative Functionalization
2581
alyzed sp3 C–H functionalization.3,13c,f As such, oxime genation. Consistent with this proposal, subjecting an
ether derivatives 3–5 were examined next. These sub- isolated sample of 4a to the reaction conditions led to for-
strates were prepared by oximation of the corresponding mation of 4b in 43% yield (Scheme 8, ii). Notably, similar
ketones and isolated in 68–91% yields as clear oils. Sub- palladium-catalyzed olefin dioxygenation reactions have
jecting 3–5 to Yu’s conditions6 for palladium-catalyzed been reported in the literature.16
C–H iodination [10 mol% Pd(OAc)2, 1 equiv PhI(OAc)2,
1 equiv I2 in CH2Cl2 at r.t.] did not produce the desired io-
(i)
dinated products (Scheme 6). In all cases, 1H NMR spec-
troscopic analysis of the crude reaction mixtures showed
that significant quantities of starting material remained af-
ter 96 hours (22–68%). Complex mixtures of minor prod-
ucts were also observed; however, electrospray mass
spectrometry did not show any signals associated with the
expected monoiodinated cyclopropane.
MeO
OAc MeO
+
OAc
OAc
MeO
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
N
N
N
AcOH
100 °C, 6 h
OH
4
4a
4b
4a 19%
4b 24%
(ii)
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
AcOH
MeO
R2
MeO
R2
100 °C, 6 h
N
N
43%
R1
R1
Scheme 8 Acetoxylation of 4 with Pd(OAc)2/PhI(OAc)2
Pd(OAc)2 (10 mol%)
I2/
I
3,4
+
PhI(OAc)2
I
CH2Cl2
MeO
R
MeO
R
Treatment of substrate 5 with Pd(OAc)2/PhI(OAc)2 result-
ed in cyclopropane ring opening to form diacetoxylated
branched products 5a and 5b along with linear product 5c
(Scheme 9). The ratio of these three isomers was highly
temperature dependent. At 60 °C, 5a was the major prod-
uct (45% yield) and 5b was not detected (Table 1, entry
1). In contrast, at 120 °C, the yield of 5a was only 9% and
5b was formed in 10% yield (Table 1, entry 4).
24 °C, 96 h
N
N
5
(not observed)
MeO
MeO
MeO
N
N
N
H
Ph
3
4
5
We reasoned that the strong temperature dependence of
the 5a/5b ratio might indicate that 5a is kinetically fa-
vored, while 5b is the thermodynamic product. Indeed,
Scheme 6 Attempted iodination of oxime ether derivatives
The palladium-catalyzed reactions of oxime ethers 3–5
with 2 equivalents of PhI(OAc)2 in the presence of 10
mol% of Pd(OAc)2 in acetic acid at 100 °C were studied
next. With all three substrates, C–C activation and ring
opening of the cyclopropane ring were observed. As
shown in Scheme 7, substrate 3 formed the a,b-unsaturat-
ed allylic acetate 3a in low (14%) yield. The mass balance
was poor in this reaction; the starting material was com-
pletely consumed, and a complex and undecipherable
mixture of other by-products was formed. This suggested
to us that the product might be unstable under the reaction
conditions. Indeed, resubjecting an isolated sample of 3a
to Pd(OAc)2/PhI(OAc)2/AcOH showed that only 6% of
3a remained after six hours at 100 °C.
MeO
OAc
N
N
N
OAc
5a 26%
OAc
R
+
+
MeO
MeO
R
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
N
OAc
R
AcOH
100 °C, 6 h
5b 16%
5
MeO
OAc
R
OAc
5c 8%
Scheme 9 Acetoxylation of 5 with Pd(OAc)2/PhI(OAc)2
Table 1 Product Distribution as a Function of Temperature
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
MeO
MeO
N
N
H
OAc
AcOH
100 °C, 6 h
C5H12
C5H12
3a 14%
3
Entry
Temp
(°C)
Yield (%) Yield (%) Yield (%) Yield (%)
of 5a
of 5b
n.d.a
n.d.a
16
of 5c
of 5
Scheme 7 Acetoxylation of 3 with Pd(OAc)2/PhI(OAc)2
1
2
3
4
60
80
45
7
8
8
9
3
Substrate 4 showed somewhat different reactivity with
Pd(OAc)2/PhI(OAc)2. Under analogous conditions, it
formed a mixture of monoacetoxylated product 4a and tri-
oxygenated 4b in 19% and 24% yield, respectively
(Scheme 8, i). We hypothesized that 4b might be generat-
ed from 4a via in situ palladium-catalyzed olefin dioxy-
44
6
100
120
26
3
9
10
3
a n.d. = not detected.
Synthesis 2011, No. 16, 2579–2589 © Thieme Stuttgart · New York

2582
A. Kubota, M. S. Sanford
SPECIAL TOPIC
heating a pure sample of 5a in CD3CO2D for six hours at 3). The 3-ethyl- and 3-methoxy-substituted derivatives
120 °C produced a 1.0:1.1 mixture of 5a/5b, implicating showed similar modest reactivity towards C–H iodination
isomerization under the reaction conditions (Scheme 10). (entries 4 and 5). Notably, attempts to further optimize
Collectively these results suggest that isomerization of 5a these reactions by varying the reaction time, temperature,
is likely a major pathway to 5b.
and screening iodine salt additives did not lead to signifi-
cant improvements in yield for any of these transforma-
tions.
MeO
R
OAc
OAc
CD3CO2D
N
5a + 5b
120 °C, 6 h
Table 2 C–H Iodination of 2-Cyclopropylpyridines with Pd(OAc)2/
IOAc
5a
1.0:1.1
Pd(OAc)2 (10 mol%)
Scheme 10 Isomerization of 5a at 120 °C in CD3CO2D
I2/
R
R
+
I
CH2Cl2
24 °C, 96 h
PhI(OAc)2
N
N
Finally, the use of benzoquinone in acetic acid for the pal-
ladium-catalyzed oxime ether directed functionalization
of 3–5 was examined. As shown in Scheme 11, substrates
3 and 4 underwent ring opening to generate 3a and 4a, re-
spectively. In contrast, no acetoxylated products were de-
tected when substrate 5 was subjected to benzoquinone in
acetic acid.
6–10
6a–10a
Yield (%)
n.d.
Entry
R
1
2
3
4
5
4-Me (6)
6-Me (7)
3-Me (8)
3-Et (9)
n.d.
19
MeO
MeO
Pd(OAc)2 (10 mol%)
BQ (2 equiv)
21
N
N
H
OAc
3-MeO (10)
19
C5H12
C5H12
AcOH
100 °C, 6 h
3
3a
82%
The reactions of 2-cyclopropylpyridines with Pd(OAc)2/
PhI(OAc)2 were similarly sensitive to pyridine substitu-
tion patterns (Table 3). The 4- and 6-methyl substrates did
not yield detectable acetoxylated products (Table 3, en-
tries 1 and 2). However, the 3-substituted derivatives 8–10
all underwent ring opening triacetoxylation to afford
moderate yields (21–34%) of 8b–10b as mixtures of dia-
stereomers (entries 3–5).
MeO
Pd(OAc)2 (10 mol%)
BQ (2 equiv)
MeO
OAc
N
N
AcOH
100 °C, 6 h
4a
4
24%
MeO
R
Pd(OAc)2 (10 mol%)
BQ (2 equiv)
N
Table 3 C–C Activation of 2-Cyclopropylpyridines with Pd(OAc)2/
PhI(OAc)2
no acetoxylation
detected
AcOH
100 °C, 6 h
5
OAc
Pd(OAc)2 (10 mol%)
R
R
Scheme 11 Reaction of substrates 3–5 with benzoquinone/acetic
OAc
PhI(OAc)2
+
AcOH
N
N
acid
100 °C, 6 h
OAc
6–10
6b–10b
Pyridine Substrates
Entry
R
Yield (%)
Pyridine derivatives have proven to be highly effective di-
recting groups for palladium-catalyzed ligand-directed C–
H functionalization reactions.3,4,13d As such, our final set
of studies focused on evaluating 2-cyclopropylpyridines
6–10 as substrates for the palladium-catalyzed oxidation
of cyclopropanes. Compounds 6–10 were prepared via
Suzuki coupling between cyclopropyl boronic acid and
the appropriate 2-bromopyridines.17
1
2
3
4
5
4-Me (6)
6-Me (7)
3-Me (8)
3-Et (9)
n.d.
n.d.
29
21
3-MeO (10)
34
In general, the reactivity of substrates 6–10 was extremely
sensitive to the substitution pattern on the pyridine ring.
For example, the Pd(OAc)2-catalyzed reactions of 6 and 7
with IOAc did not yield any monoiodinated products, as
The trioxygenated products 8b–10b are structurally simi-
lar to oxime ether 4b. As such, we hypothesized that they
likely derive from a similar pathway involving initial cy-
clopropane ring opening followed by palladium-catalyzed
dioxygenation of allylic acetate intermediates 8c–10c
(Scheme 12).16 Consistent with this possibility, when an
independently synthesized sample of 8c was subjected to
1
determined by H NMR and electrospray mass spectro-
metric analysis of the crude reaction mixtures (Table 2,
entries 1 and 2). In contrast, when the pyridine methyl
substituent was moved to the 3-position (substrate 8), the
cis-iodinated product 8a was formed in 19% yield (entry
Synthesis 2011, No. 16, 2579–2589 © Thieme Stuttgart · New York

SPECIAL TOPIC
Cyclopropane Oxidative Functionalization
2583
R
extrapolate the reactivity of cyclopropanes to the func-
tionalization of other substrates containing 2° sp3 C–H
sites. Furthermore, future efforts to achieve palladium-
catalyzed C–H and/or C–C activation of cyclopropane de-
rivatives should take into account the possibility of gener-
ating products derived from these two different pathways.
R
OAc
Pd(OAc)2 (10 mol%)
PhI(OAc)2
+
OAc
AcOH
100 °C, 6 h
N
N
OAc
8b–10b
8–10
R
NMR spectra were obtained on a Varian Inova 500 (499.90 MHz for
1H; 125.70 MHz for 13C), a Varian Inova 400 (399.96 MHz for 1H;
OAc
N
1
8c–10c
100.57 MHz for 13C), or a MR400 (400.53 MHz for H; 100.71
MHz for 13C) spectrometer. 1H and 13C NMR chemical shifts are re-
ported in parts per million (ppm) relative to TMS, with the residual
solvent peak used as an internal reference. Standard abbreviations
are used to describe the signal multiplicity. Flash chromatography
was performed on EM Science silica gel 60 (0.040–0.063 mm par-
ticle size, 230–400 mesh) and TLC was performed on Merck TLC
plates precoated with silica gel 60 F254. HPLC was performed on a
Varian ProStar 210 HPLC using Waters SunFire Prep Silica 5 mm
(19 × 150 mm) column. IR spectra were obtained on a Perkin-Elmer
Spectrum BX FT-IR spectrometer. HRMS were obtained on a
Micromass AutoSpec Ultima Magnetic sector mass spectrometer.
Scheme 12 Plausible pathway to triacetoxylated product
Pd(OAc)2/PhI(OAc)2, product 8b was observed, albeit in
modest (17%) yield.
Finally, cyclopropyl pyridines 8–10 were subjected to 10
mol% Pd(OAc)2 and 2 equivalents of benzoquinone at
100 °C in acetic acid. Interestingly, these substrates did
not undergo ring opening or C–H acetoxylation under
these conditions. In all cases, the major organic compound
at the end of the reaction was the starting material (55–
All reagents mentioned below were obtained from commercial
sources and used as received unless noted otherwise. Petroleum
ether (PE) used refers to the fraction boiling in the range 36–60 °C.
Benzoquinone (BQ) was obtained from Acros and sublimed prior to
use. The parent ketone of 3 was synthesized from oct-1-en-3-ol via
Simmons–Smith cyclopropanation followed by oxidation of the al-
cohol.19 The parent ketone of 5 was synthesized by the addition of
allylmagnesium bromide to 4-phenylbutanal, Simmons–Smith cy-
clopropanation, and oxidation of the alcohol.19,20
1
81%). Furthermore, H NMR spectroscopic analysis and
electrospray mass spectrometric analysis of the crude re-
action mixtures did not show detectable quantities of
monoacetoxylated products.
The results reported herein show that cyclopropanes are
not very general substrates for ligand-directed 2° sp3 C–H
activation/functionalization. Under certain conditions, cy-
clopropane C–H functionalization was observed. For ex-
ample, iodinated cyclopropyl oxazolines and pyridines
could be isolated using IOAc as the oxidant. However, the
yields of these transformations were typically modest, and
the reactions were extremely sensitive to the substitution
patterns of the substrate.
Substrates 1 and 2
Substrates 1 and 2 were synthesized according to the reported
procedure6 by converting cyclopropanecarboxylic acid into its acid
chloride and coupling with (S)-tert-leucinol. The coupled product
was then cyclized using Ph3P.
4-tert-Butyl-2-(1-methylcyclopropyl)-4,5-dihydrooxazole (1)
The three-step synthesis6 from 1-methylcyclopropanecarboxylic
acid (320 mg, 3.2 mmol, 1.0 equiv) afforded substrate 1 as a clear
oil after purification by chromatography on silica gel using PE–
Et2O (80:20); yield: 349 mg (60% yield over 3 steps); Rf = 0.31
(hexanes–EtOAc, 85:15).
Under most conditions that are commonly used for palla-
dium-catalyzed C–H functionalization, C–C activation of
the cyclopropane was observed. These ring-opening reac-
tions proceeded with concomitant incorporation of an
acetate nucleophile derived from the solvent and/or the
oxidant. While the detailed mechanism of cyclopropane
ring opening has not been elucidated in the current sys-
tems, it is likely to be initiated by nucleopalladation of the
cyclopropane. Such reactions have significant precedent
in the organopalladium(II) literature. For example, Back-
vall has shown the stoichiometric acetoxypalladation and
methoxypalladation of vinylcyclopropanes in acetic acid
and methanol solvent, respectively.18 A similar mecha-
nism has also been proposed by Yudin in the catalytic
conversion of substituted cyclopropanes into heterocy-
cles.15
IR (film): 3008, 1663 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.06 (dd, J = 9.6, 8.8 Hz, 1 H),
3.99 (dd, J = 8.8, 6.8 Hz, 1 H), 3.78 (dd, J = 9.6, 6.8 Hz, 1 H), 1.34
(s, 3 H), 1.12 (m, 1 H), 1.06 (m, 1 H), 0.86 (s, 9 H), 0.59 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 170.00, 75.68, 68.52, 33.82,
25.64, 20.94, 14.80, 14.58, 14.01.
HRMS (ESI): m/z [M + H]+ calcd for C11H20NO: 182.1539; found:
182.1536.
4-tert-Butyl-2-cyclopropyl-4,5-dihydrooxazole (2)
The three-step synthesis6 from cyclopropanecarboxylic acid (2.0 g,
23.2 mmol, 1.0 equiv) afforded substrate 2 as a clear oil after puri-
fication by chromatography on silica gel using PE–Et2O (80:20);
yield: 1.7 g (43% yield over 3 steps); Rf = 0.24 (hexanes–EtOAc,
80:20).
In summary, this paper describes studies of the ligand-
directed oxidative functionalization of cyclopropane de-
rivatives. In certain cases, these substrates undergo 2° sp3
C–H oxidation reactions. However, relatively minor per-
turbations of the substrate structure, oxidant, and/or reac-
tion conditions can lead to oxidative ring opening of the
cyclopropane moiety. As a result, it is likely to be hard to
IR (film): 3015, 1669 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.06 (dd, J = 8.0, 6.8 Hz, 1 H),
3.94 (dd, J = 6.8, 6.0 Hz, 1 H), 3.75 (dd, J = 8.0, 6.0 Hz, 1 H), 1.62
(dddd, J = 6.8, 6.8, 4.0, 4.0 Hz, 1 H), 0.90 (m, 1 H), 0.87 (m, 1 H),
0.87 (s, 9 H), 0.79 (m, 1 H), 0.78 (m, 1 H).
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A. Kubota, M. S. Sanford
SPECIAL TOPIC
13C NMR (100 MHz, CDCl3): d = 168.01, 75.57, 68.28, 33.60,
25.71, 8.43, 6.75, 6.34.
Oxime Isomer 1
Rf = 0.52 (hexanes–EtOAc, 90:10).
HRMS (ESI): m/z [M + H]+ calcd for C10H18NO: 168.1383; found:
168.1377.
1H NMR (400 MHz, CDCl3): d = 7.28 (m, 2 H), 7.20–7.16 (multiple
peaks, 3 H), 3.81 (s, 3 H), 2.65 (dd, J = 7.6, 7.6 Hz, 2 H), 2.30 (dd,
J = 8.0, 7.6 Hz, 2 H), 2.20 (d, J = 6.8 Hz, 2 H), 1.86 (m, 2 H), 0.84
(m, 1 H), 0.45 (m, 2 H), 0.10 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 160.58, 142.01, 128.43, 128.28,
125.77, 61.04, 35.53, 33.53, 32.27, 28.39, 7.68, 4.70.
Oxime Substrates 3–5; Representative Procedure (for Sub-
strate 3)
The corresponding ketone (7.6 mmol, 1.0 equiv) and NH2OMe·HCl
(10.3 mmol, 1.35 equiv) were combined in pyridine (2.7 M). The re-
sulting solution was stirred at 80 °C for 15 min and then at r.t. over-
night. The reaction mixture was diluted with Et2O (10 mL) and
washed with H2O containing a few drops of glacial AcOH (5 × 20
mL), H2O (20 mL), sat. aq NaHCO3 (20 mL), and brine (20 mL).
The organic layer was dried over MgSO4, filtered, and concentrated
under vacuum.
Oxime Isomer 2
Rf = 0.48 (hexanes–EtOAc, 90:10).
1H NMR (400 MHz, CDCl3): d = 7.29 (m, 2 H), 7.20–7.17 (multiple
peaks, 3 H), 3.81 (s, 3 H), 2.64 (dd, J = 7.6, 7.6 Hz, 2 H), 2.41 (dd,
J = 8.0, 8.0 Hz, 2 H), 2.04 (d, J = 7.2 Hz, 2 H), 1.83 (m, 2 H), 0.81
(m, 1 H), 0.46 (m, 2 H), 0.11 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 161.01, 141.90, 128.36, 128.28,
1-Cyclopropylhexan-1-one O-Methyl Oxime (3)
Substrate 3 was obtained as a 2.3:1 mixture of oxime isomers as a
clear oil (1.18 g, 91%). Purification by column chromatography was
not necessary.
125.82, 61.01, 38.84, 36.03, 27.56, 27.51, 8.55, 4.63.
Pyridine Substrates 6–8 and 10; Representative Procedure (for
Substrate 6)
IR (film, mixture of oxime isomers): 3088, 1621 cm–1.
The corresponding 2-bromopyridine (5.8 mmol, 1.0 equiv) and cy-
clopropylboronic acid (2.0 equiv) were reacted via a modification
of a literature procedure.17 The reaction was run overnight and then
cooled to r.t. A 3 M aq solution of HCl (10 mL) was added, and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The EtOAc
extracts were discarded, the aqueous layer was made basic with 3 M
aq NaOH, and the product was extracted with Et2O (3 × 20 mL). The
Et2O extracts were dried over MgSO4, filtered, and concentrated un-
der vacuum.
HRMS (mixture of oxime isomers, EI): m/z [M]+ calcd for
C10H19NO: 169.1467; found: 169.1467.
Major Oxime Isomer
Rf = 0.53 (hexanes–EtOAc, 90:10).
1H NMR (500 MHz, CDCl3): d = 3.76 (s, 3 H), 2.13 (dd, J = 8.0, 7.5
Hz, 2 H), 1.53–1.44 (multiple peaks, 3 H), 1.36–1.25 (multiple
peaks, 4 H), 0.94–0.87 (multiple peaks, 5 H), 0.70 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 161.99, 61.07, 32.05, 27.35,
2-Cyclopropyl-4-methylpyridine (6)
25.96, 22.39, 13.98, 13.96, 5.02.
Substrate 6 was obtained as a clear oil after purification by chroma-
tography on silica gel using hexanes–EtOAc (90:10); yield: 310 mg
(40%); Rf = 0.22 (hexanes–EtOAc, 90:10).
IR (film): 3089 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 5.2 Hz, 1 H), 6.94 (m,
1 H), 6.84 (m, 1 H), 2.29 (s, 3 H), 1.98 (dddd, J = 8.0, 8.0, 5.2, 5.2
Hz, 1 H), 0.98–0.96 (multiple peaks, 3 H), 0.95 (m, 1 H).
Minor Oxime Isomer
Rf = 0.28 (hexanes–EtOAc, 90:10).
1H NMR (500 MHz, CDCl3): d = 3.85 (s, 3 H), 2.19 (dddd, J = 11.0,
11.0, 5.5, 5.5 Hz, 1 H), 1.76 (dd, J = 8.0, 8.0 Hz, 2 H), 1.48 (m, 2
H), 1.36–1.25 (multiple peaks, 4 H), 0.82 (m, 2 H), 0.71–0.66 (mul-
tiple peaks, 5 H).
13C NMR (100 MHz, CDCl3): d = 161.12, 61.26, 31.71, 28.98,
27.30, 22.42, 14.03, 8.64, 5.06.
13C NMR (100 MHz, CDCl3): d = 162.56, 148.97, 146.75, 122.03,
121.46, 20.90, 16.94, 9.49.
HRMS (ESI): m/z [M + H]+ calcd for C9H12N: 134.0964; found:
134.0964.
1-(1-Methylcyclopropyl)ethanone O-Methyl Oxime (4)
Methyl 1-methylcyclopropyl ketone (1.0 g, 10.2 mmol) reacted to
form 4 as a single detectable oxime isomer as a clear oil (0.88 g,
68%). Purification by column chromatography was not necessary.
IR (film): 3084, 1613 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.82 (s, 3 H), 1.72 (s, 3 H), 1.24
(s, 3 H), 0.85 (m, 2 H), 0.51 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 160.06, 61.13, 21.78, 20.13,
12.51, 11.29.
HRMS (EI): m/z [M]+ calcd for C7H13NO: 127.0997; found:
127.0999.
2-Cyclopropyl-6-methylpyridine (7)
2-Bromo-6-methylpyridine (344 mg, 2.0 mmol) reacted to afford
substrate 7 as a clear oil after purification by chromatography on
silica gel using PE–Et2O (90:10); yield: 168 mg (63%); Rf = 0.41
(hexanes–EtOAc, 90:10).
IR (film): 3064 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40 (t, J = 7.6 Hz, 1 H), 6.88 (d,
J = 7.6 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 1 H), 2.47 (s, 3 H), 2.02 (m, 1
H), 0.96 (m, 2 H), 0.94 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 162.18, 157.66, 136.06, 119.79,
117.09, 24.57, 17.25, 9.45.
HRMS (ESI): m/z [M + H]+ calcd for C9H12N: 132.0964; found:
132.0965.
1-Cyclopropyl-5-phenylpentan-2-one O-Methyl Oxime (5)
Reaction with 1-cyclopropyl-5-phenylpentan-2-one (1.27 g, 6.3
mmol) afforded 5 as 1:1 mixture of oxime isomers as a clear oil after
purification by chromatography on silica gel using hexanes–EtOAc
(95:5); yield: 1.41 g (97%).
IR (film, mixture of oxime isomers): 3079 cm–1.
HRMS (mixture of oxime isomers, EI): m/z [M]+ calcd for
2-Cyclopropyl-3-methylpyridine (8)
2-Bromo-3-methylpyridine (5.0 g, 29.1 mmol) reacted to afford
substrate 8 as a clear oil after purification by chromatography on sil-
ica gel using PE–Et2O (90:10); yield: 3.1 g (80%); Rf = 0.28 (hex-
anes–EtOAc, 90:10).
C15H21NO: 231.1631; found: 231.1625.
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SPECIAL TOPIC
Cyclopropane Oxidative Functionalization
2585
IR (film): 3087 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.70 (d, J = 9.2 Hz, 1 H), 4.28 (m,
1 H), 4.11–4.05 (multiple peaks, 2 H), 2.03 (s, 3 H), 1.31 (s, 3 H),
1.18 (dd, J = 3.2, 9.6 Hz, 1 H), 1.12 (dd, J = 3.2, 9.6 Hz, 1 H), 0.95
(s, 9 H), 0.56 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 174.79, 171.42, 63.54, 55.85,
33.94, 26.69, 20.91, 19.59, 19.10, 15.82, 15.74.
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 4.8 Hz, 1 H), 7.36 (m,
1 H), 6.93 (dd, J = 7.6, 4.8 Hz, 1 H), 2.41 (s, 3 H), 2.08 (dddd,
J = 9.6, 9.6, 5.2, 5.2 Hz, 1 H), 1.06 (m, 2 H), 0.95 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 160.45, 146.56, 136.75, 130.98,
120.07, 18.83, 13.54, 8.76.
HRMS (EI): m/z [M – H]+ calcd for C9H10N: 132.0813; found:
132.0816.
HRMS (ESI): m/z [M + Na]+ calcd for C13H23NO + Na: 264.1570;
found: 264.1565.
4-tert-Butyl-2-cyclopropyl-4,5-dihydrooxazol-3-ium Acetate
Salt (2b)
Substrate 2 (100 mg, 0.60 mmol, 1.0 equiv) yielded 2b as a white
solid; yield: 80 mg (59%); mp 53.8–54.9 °C; Rf = 0.31 (hexanes–
EtOAc, 50:50).
2-Cyclopropyl-3-methoypyridine (10)
2-Bromo-3-methoxypyridine (1.0 g, 5.3 mmol) afforded substrate
10 as a clear oil after purification by chromatography on silica gel
using PE–Et2O (90:10); yield: 590 mg (74%); Rf = 0.36 (hexanes–
EtOAc, 85:15).
IR (thin film with CH2Cl2): 3301, 3010, 1739, 1645 cm–1.
IR (film): 3063, 1430 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.64 (d, J = 9.6 Hz, 1 H), 4.22 (dd,
J = 11.6, 8.8 Hz, 1 H), 4.13–4.05 (multiple peaks, 2 H), 2.02 (s, 3
H), 1.62 (dddd, J = 8.0, 8.0, 4.4, 4.4 Hz, 1 H), 0.95 (s, 9 H), 0.93 (m,
2 H), 0.71 (dd, J = 8.0, 2.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 173.54, 171.38, 63.68, 55.80,
33.85, 26.67, 20.89, 14.79, 7.01, 6.97.
1H NMR (400 MHz, CDCl3): d = 8.03 (dd, J = 4.8, 1.2 Hz, 1 H),
7.05 (dd, J = 8.4, 1.2 Hz, 1 H), 6.93 (dd, J = 8.4, 4.8 Hz, 1 H), 3.86
(s, 3 H), 2.47 (dddd, J = 10.0, 10.0, 4.8, 4.8 Hz, 1 H), 1.05 (m, 2 H),
0.95 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 153.68, 152.55, 140.57, 120.28,
116.05, 55.37, 10.24, 9.01.
HRMS (ESI): m/z [M + Na]+ calcd for C12H21NO3 + Na: 250.1414;
found: 250.1412.
HRMS (EI): m/z [M – H]+ calcd for C9H10NO; 148.0762; found:
148.0766.
Iodination of 2-Cyclopropyl-Substituted Pyridines; Represen-
tative Procedure (for Iodination of 8)
Substrate 9
2-Cyclopropyl-3-ethylpyridine (9)
The pyridine substrate (0.45 mmol, 1.0 equiv), Pd(OAc)2 (10
mol%), PhI(OAc)2 (1.0 equiv), and I2 (1.0 equiv) were weighed into
a scintillation vial containing a stir bar. CH2Cl2 was added to make
a 0.2 M solution (in substrate), and the vial was sealed with a
Teflon-lined cap. The reaction was stirred at r.t. for 96 h. The reac-
tion mixture was washed with sat. aq Na2S2O3 (3 × 3 mL). The or-
ganic layer was collected, the solvent was removed under vacuum,
NO2Ph (0.25 equiv, 1H NMR resonance at 8.2 ppm) was added as
A solution of 8 (1.0 g, 7.5 mmol, 1.0 equiv) in THF (1.5 mL) was
added to a solution of LDA (1.5 equiv) in THF (23 mL) at –40 °C
under N2. The reaction mixture was stirred for 30 min and then
cooled to –78 °C. MeI (5.3 g, 37.5 mmol, 5.0 equiv) was added, and
the resulting solution was stirred for 2 h at –78 °C. The reaction was
quenched with H2O (15 mL) at –78 °C and then slowly warmed to
r.t. The product was obtained using the same workup procedure as
that for the synthesis of substrates 6, 7, and 10. Compound 9 was ob-
tained as a clear oil after purification by chromatography on silica
gel using PE–Et2O (97.5:2.5); yield: 1.1 g (98%); Rf = 0.23 (hex-
anes–EtOAc, 95:5).
1
an internal standard, and the crude mixture was analyzed by H
NMR spectroscopy.
2-(cis-2-Iodocyclopropyl)-3-methylpyridine (8a)
IR (film): 3051, 1586, 1572 cm–1.
1H NMR spectroscopic analysis of the crude reaction mixture after
96 h at r.t. showed that substrate 8 reacted to form 8a in 19% yield.
To isolate 8a, substrate 8 (60 mg, 0.45 mmol) was stirred for 96 h
under the reaction conditions. Product 8a was purified by chroma-
tography on silica gel using CH2Cl2–EtOAc (90:10) and was isolat-
ed as a white solid; yield: 19 mg (16%); Rf = 0.42 (CH2Cl2–EtOAc,
90:10).
1H NMR (400 MHz, CDCl3): d = 8.29 (d, J = 4.8 Hz, 1 H), 7.37 (d,
J = 7.6 Hz, 1 H), 6.97 (dd, J = 7.6, 4.8 Hz, 1 H), 2.79 (q, J = 7.6 Hz,
2 H), 2.13 (dddd, J = 9.6, 9.6, 4.8, 4.8 Hz, 1 H), 1.27 (t, J = 7.6 Hz,
3 H), 1.08 (m, 2 H), 0.95 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 159.90, 146.53, 136.76, 135.17,
120.22, 25.49, 14.55, 13.09, 9.03.
IR (thin film with CH2Cl2): 3051 cm–1.
HRMS (EI): m/z [M – H]+ calcd for C10H12N: 146.0970; found:
146.0971.
1H NMR (400 MHz, CDCl3): d = 8.40 (m, 1 H), 7.48 (m, 1 H), 7.12
(dd, J = 7.6, 4.8 Hz, 1 H), 3.02 (td, J = 7.6, 5.6 Hz, 1 H), 2.38 (s, 3
H), 2.25 (td, J = 8.0, 7.6 Hz, 1 H), 1.98 (td, J = 6.4, 5.6 Hz, 1 H),
1.65 (ddd, J = 8.8, 7.6, 6.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 156.67, 146.11, 137.31, 133.27,
121.94, 21.07, 18.70, 13.54, –7.97.
Oxazolium Acetate Salts 1b, 2b
The appropriate substrate (0.1 mmol, 1.0 equiv) was weighed into a
scintillation vial containing a stir bar. AcOH (0.12 M) was added,
and the vial was sealed with a Teflon-lined cap. The resulting solu-
tion was stirred at 100 °C for 12 h. The reaction mixture was con-
centrated under vacuum, and the product was recovered as a white
solid.
HRMS (ESI): m/z [M + H]+ calcd for C9H11IN: 259.9936; found:
259.9936.
2-(cis-2-Iodocyclopropyl)-3-ethylpyridine (9a)
4-tert-Butyl-2-(1-methylcyclopropyl)-4,5-dihydrooxazol-3-ium
Acetate Salt (1b)
Substrate 1 (100 mg, 0.55 mmol, 1.0 equiv) yielded 1b as a white
solid; yield: 82 mg (62%); mp 92.8–93.7 °C; Rf = 0.48 (hexanes–
EtOAc, 50:50).
1H NMR spectroscopic analysis of the crude reaction mixture after
96 h at r.t. showed that substrate 9 reacted to form 9a in 21% yield.
To isolate 9a, substrate 9 (50 mg, 0.34 mmol) was stirred for 60 h
under the reaction conditions. Product 9a was purified by chroma-
tography on silica gel using hexanes–EtOAc (85:15) and was isolat-
ed as a yellow oil; yield: 15 mg (16%); Rf = 0.32 (hexanes–EtOAc,
85:15).
IR (thin film with CH2Cl2): 3310, 3002, 1739, 1632 cm–1.
Synthesis 2011, No. 16, 2579–2589 © Thieme Stuttgart · New York

2586
A. Kubota, M. S. Sanford
SPECIAL TOPIC
IR (film): 3049 cm–1.
(Z)-1c
Yield: 5 mg (8%); Rf = 0.25 (hexanes–EtOAc, 85:15).
IR (film): 1744 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.85 (t, J = 6.0 Hz, 1 H), 5.03 (dd,
J = 15.2, 6.0 Hz, 1 H), 4.96 (dd, J = 15.2, 6.0 Hz, 1 H), 4.20 (dd,
J = 10.0, 8.4 Hz, 1 H), 4.08 (dd, J = 8.4, 8.0 Hz, 1 H), 3.93 (dd,
J = 10.0, 8.0 Hz, 1 H), 2.07 (s, 3 H), 1.98 (br s, 3 H), 0.90 (s, 9 H).
1H NMR (400 MHz, CDCl3): d = 8.41 (dd, J = 4.8,1.2 Hz, 1 H), 7.52
(dd, J = 7.6, 1.6 Hz, 1 H), 7.15 (dd, J = 7.6, 5.2 Hz, 1 H), 3.02 (td,
J = 7.6, 5.6 Hz, 1 H), 2.76 (q, J = 3.6 Hz, 2 H), 2.08 (td, J = 7.6, 7.6
Hz, 1 H), 1.98 (td, J = 6.4, 6.4 Hz, 1 H), 1.64 (td, J = 8.0, 6.4 Hz, 1
H), 1.31 (t, J = 3.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 155.94, 145.93, 138.75, 135.32,
122.05, 24.76, 20.29, 13.70, 13.52, –7.04.
13C NMR (100 MHz, CDCl3): d = 170.87, 163.17, 132.60, 126.33,
75.88, 68.27, 62.91, 33.81, 25.82, 21.08, 20.99.
HRMS (EI): m/z [M + H]+ calcd for C10H13IN: 274.0087; found:
274.0085.
HRMS (ESI): m/z [M + H]+ calcd for C13H22NO3; 240.1594; found:
240.1586.
2-(cis-2-Iodocyclopropyl)-3-methoxypyridine (10a)
1H NMR spectroscopic analysis of the crude reaction mixture after
96 h at r.t. showed that substrate 10 reacted to form 10a in 19%
yield. To isolate 10a, substrate 10 (50 mg, 0.34 mmol) was stirred
for 45 h under the reaction conditions. Product 10a was purified by
chromatography on silica gel using hexanes–EtOAc (85:15) and
was isolated as a yellow oil; yield: 14 mg (15%); Rf = 0.21 (hex-
anes–EtOAc, 85:15).
(2E)-4-(Methoxyimino)non-2-en-1-yl Acetate (3a)
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 3 reacted with benzoquinone to
afford 3a in 82% yield. To isolate 3a, substrate 3 (50 mg, 0.30
mmol) was heated for 12 h under the reaction conditions. Product
3a was purified by chromatography on silica gel using hexanes–
EtOAc (95:5) and was isolated as a 3.0:1.0 mixture of oxime iso-
mers as a clear oil; yield: 44 mg (66%).
IR (film): 3058, 1435 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.16 (dd, J = 4.0, 2.0 Hz, 1 H),
7.19–7.13 (multiple peaks, 2 H), 3.89 (s, 3 H), 3.01 (td, J = 8.0, 5.6
Hz, 1 H), 2.48 (td, J = 8.0, 7.2 Hz, 1 H), 1.90 (td, J = 7.2, 5.6 Hz, 1
H), 1.59 (td, J = 8.0, 6.4 Hz, 1 H).
IR (film, mixture of isomers): 1741 cm–1.
HRMS (mixture of isomers, ESI): m/z [M + Na]+ calcd for
C12H21NO3 + Na: 250.1419; found: 250.1417.
13C NMR (100 MHz, CDCl3): d = 154.97, 148.38, 139.98, 122.34,
116.68, 55.45, 17.93, 13.29, –6.87.
Major Oxime Isomer
Rf = 0.40 (hexanes–EtOAc, 85:15).
HRMS (EI): m/z [M + H]+ calcd for C9H11INO: 275.9880; found:
275.9881.
1H NMR (400 MHz, CDCl3): d = 6.26 (dt, J = 16.0, 1.6 Hz, 1 H),
6.06 (dt, J = 16.0, 6.0 Hz, 1 H), 4.68 (dd, J = 6.0, 1.6 Hz, 2 H), 3.89
(s, 3 H), 2.42 (m, 2 H), 2.09 (s, 3 H), 1.46 (m, 2 H), 1.35–1.29 (mul-
tiple peaks, 4 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.66, 158.51, 129.93, 127.48,
64.29, 61.81, 31.96, 26.22, 24.64, 22.38, 20.89, 13.94.
Acetoxylation with PhI(OAc)2 or Benzoquinone; Representa-
tive Procedure (for Acetoxylation of 3)
Substrate (0.34 mmol, 1.0 equiv), Pd(OAc)2 (10 mol%), and
PhI(OAc)2 (2.0 equiv) or benzoquinone (2.0 equiv) were weighed
into a scintillation vial containing a stir bar. Solvent was added to
make a 0.12 M solution (in substrate), and the vial was sealed with
a Teflon-lined cap. The reaction was stirred at 100 °C for 12 h. The
reaction mixture was filtered through Celite, and the Celite was
washed with Et2O (5 mL). The solvent was removed under vacuum,
NO2Ph (0.25–0.5 equiv, 1H NMR resonance at 8.2 ppm) was added
as an internal standard, and the crude mixture was analyzed by 1H
NMR spectroscopy.
Minor Oxime Isomer
Rf = 0.47 (hexanes–EtOAc, 85:15).
1H NMR (400 MHz, CDCl3): d = 6.87 (dt, J = 16.4, 1.6 Hz, 1 H),
6.15 (dt, J = 16.4, 5.6 Hz, 1 H), 4.69 (dd, J = 5.6, 1.6 Hz, 2 H), 3.87
(s, 3 H), 2.34 (m, 2 H), 2.10 (s, 3 H), 1.54 (m, 2 H), 1.34–1.29 (mul-
tiple peaks, 4 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.61, 154.67, 131.08, 121.41,
64.30, 61.60, 31.63, 30.95, 27.42, 22.38, 20.88, 13.99.
3-(4-tert-Butyl-4,5-dihydrooxazol-2-yl)but-2-en-1-yl Acetate
(1c)
4-(Methoxyimino)-3-methylpent-2-en-1-yl Acetate (4a)
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 4 reacted with benzoquinone to
afford 4a in 24% yield. To isolate 4a, substrate 4 (60 mg, 0.47
mmol) was heated for 12 h under the reaction conditions. Product
4a was purified by chromatography on silica gel using hexanes–
EtOAc (90:10) and was isolated as a 7.0:1.0 mixture of oxime iso-
mers as a clear oil; yield: 29 mg (33%).
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 1 (50 mg, 0.28 mmol) reacted
with PhI(OAc)2 in DCE to form 1c in 29% yield as a 2.6:1 mixture
of E/Z-isomers. The products were purified by chromatography on
silica gel using CH2Cl2–EtOAc (90:10) and were isolated as clear
oils.
(E)-1c
Yield: 12 mg (18%); Rf = 0.16 (hexanes–EtOAc, 85:15).
IR (film): 1741 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.41 (t, J = 6.4 Hz, 1 H), 4.74 (d,
J = 6.4 Hz, 2 H), 4.20 (dd, J = 9.6, 8.8 Hz, 1 H), 4.10 (dd, J = 8.8,
8.0 Hz, 1 H), 3.93 (dd, J = 9.6, 8.0 Hz, 1 H), 2.08 (s, 3 H), 1.99 (br
s, 3 H), 0.89 (s, 9 H).
Major Oxime Isomer
Rf = 0.42 (hexanes–EtOAc, 85:15).
IR (film, major oxime isomer): 1589, 1739 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.90 (t, J = 6.8 Hz, 1 H), 4.76 (d,
J = 6.8 Hz, 2 H), 3.92 (s, 3 H), 2.08 (s, 3 H), 1.96 (s, 3 H), 1.91 (s,
3 H).
13C NMR (125 MHz, CDCl3): d = 170.79, 164.03, 129.95, 128.09,
13C NMR (100 MHz, CDCl3): d = 170.93, 155.64, 137.14, 124.61,
76.13, 68.47, 60.96, 33.93, 25.79, 20.86, 13.70.
61.83, 61.37, 20.94, 12.86, 10.55.
HRMS (ESI): m/z [M + H]+ calcd for C13H22NO3: 240.1594; found:
240.1586.
HRMS (for E-isomer, ESI): m/z [M + Na]+ calcd for C9H15NO3 +
Na: 208.0950; found: 208.0947.
Synthesis 2011, No. 16, 2579–2589 © Thieme Stuttgart · New York

SPECIAL TOPIC
Cyclopropane Oxidative Functionalization
2587
Minor Oxime Isomer
Rf = 0.35 (hexanes–EtOAc, 85:15).
1H NMR (400 MHz, CDCl3): d = 5.56 (t, J = 6.4 Hz, 1 H), 4.70 (d,
J = 6.4 Hz, 2 H), 3.89 (s, 3 H), 2.05 (s, 3 H), 1.92 (s, 3 H), 1.90 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 170.52, 170.43, 155.77, 141.64,
135.75, 128.35, 128.30, 126.21, 125.88, 65.22, 62.99, 61.45, 35.66,
28.66, 27.51, 20.85, 20.79.
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NO5 + Na: 370.1630;
found: 370.1621.
13C NMR (100 MHz, CDCl3): d = 170.83, 155.43, 136.22, 124.92,
62.23, 61.74, 21.37, 20.98, 13.44.
Minor Oxime Isomer
Rf = 0.42 (hexanes–EtOAc, 70:30).
3-Hydroxy-4-(methoxyimino)-3-methylpentane-1,2-diyl Diace-
tate (4b)
1H NMR (400 MHz, CDCl3): d = 7.26 (m, 2 H), 7.18–7.16 (multiple
peaks, 3 H), 5.94 (s, 1 H), 4.64 (s, 2 H), 4.50 (s, 2 H), 3.84 (s, 3 H),
2.62 (t, J = 7.6 Hz, 2 H), 2.29 (t, J = 7.6 Hz, 2 H), 2.10 (s, 3 H), 2.03
(s, 3 H), 1.81 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 170.46, 170.39, 154.08, 141.69,
135.36, 128.42, 128.33, 125.88, 122.73, 64.51, 62.01, 61.63, 35.35,
33.97, 28.39, 20.84, 20.68.
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 4 reacted with PhI(OAc)2 to af-
ford 4a in 19% and 4b in 24% yield. To isolate 4b, substrate 4 (100
mg, 0.79 mmol) was heated for 12 h under the reaction conditions.
Product 4b was purified by chromatography on silica gel using hex-
anes–EtOAc (80:20) and was isolated as a 1.7:1.0 mixture of
diastereomers as a yellow oil; yield: 83 mg (40%).
(Z)-2-[2-(Methoxyimino)-5-phenylpentyl]prop-1-ene-1,3-diyl
Diacetate (5b)
Major Oxime Isomer
Rf = 0.47 (hexanes–EtOAc, 70:30).
IR (film): 1761, 1740 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27 (m, 2 H), 7.20–7.16 (multiple
peaks, 3 H), 7.08 (s, 1 H), 4.65 (s, 2 H), 3.81 (s, 3 H), 3.06 (s, 2 H),
2.63 (t, J = 7.6 Hz, 2 H), 2.19 (t, J = 7.6 Hz, 2 H), 2.16 (s, 3 H), 2.04
(s, 3 H), 1.84 (quint, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 170.80, 167.30, 156.51, 141.82,
135.25, 128.44, 128.34, 125.85, 115.03, 61.30, 59.80, 35.41, 33.10,
29.69, 28.14, 20.77, 20.65.
Major Diastereomer
Rf = 0.17 (hexanes–EtOAc, 80:20).
IR (film): 3481, 1744 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.21 (dd, J = 8.0, 2.8 Hz, 1 H),
4.51 (dd, J = 12.0, 2.8 Hz, 1 H), 4.16 (dd, J = 12.0, 8.0 Hz, 1 H),
4.03 (s, 1 H), 3.87 (s, 3 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 1.82 (s, 3 H),
1.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.75, 170.03, 156.93, 74.64,
74.18, 62.41, 62.08, 23.10, 20.78, 20.74, 10.93.
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NO6 + Na: 284.1105;
found: 284.1100.
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NO5 + Na: 370.1630;
found: 370.1640.
Minor Diastereomer
Rf = 0.12 (hexanes–EtOAc, 80:20).
IR (film): 3475, 1744 cm–1.
Minor Oxime Isomer
Rf = 0.41 (hexanes–EtOAc, 70:30).
1H NMR (400 MHz, CDCl3): d = 5.27 (dd, J = 8.4, 3.6 Hz, 1 H),
4.49 (dd, J = 12.0, 3.6 Hz, 1 H), 4.02 (s, 1 H), 4.01 (dd, J = 12.0,
8.4 Hz, 1 H), 3.86 (s, 3 H), 2.14 (s, 3 H), 1.98 (s, 3 H), 1.90 (s, 3 H),
1.29 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.27 (m, 2 H), 7.20–7.16 (multiple
peaks, 3 H), 7.11 (s, 1 H), 4.70 (s, 2 H), 3.81 (s, 3 H), 2.89 (s, 2 H),
2.61 (t, J = 7.6 Hz, 2 H), 2.29 (t, J = 7.6 Hz, 2 H), 2.17 (s, 3 H), 2.03
(s, 3 H), 1.77 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 170.71, 170.65, 156.90, 74.89,
13C NMR (100 MHz, CDCl3): d = 170.80, 167.36, 157.57, 135.26,
128.45, 128.33, 126.23, 125.89, 115.78, 61.33, 59.27, 36.38, 35.83,
34.88, 27.27, 20.82, 20.67.
73.80, 62.71, 62.18, 23.32, 20.88, 20.69, 11.13.
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NO6 + Na: 284.1105;
found: 284.1099.
(3E)-5-(Methoxyimino)-8-phenyloct-3-ene-1,2-diyl Diacetate
(5c)
Acetoxylation of Substrate 5
1H NMR analysis of the crude reaction mixture showed a single
oxime isomer of 5c. However, this compound underwent isomeriza-
tion to a mixture of oxime isomers during chromatographic purifi-
cation on silica gel.
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 5 (200 mg, 0.87 mmol) reacted
with PhI(OAc)2 to form 5a (26% yield as a 2.3:1.0 mixture of oxime
isomers), 5b (16% yield as a 3.0:1.0 mixture of oxime isomers), and
5c (8% yield as a single detectable oxime isomer). The products
were purified by chromatography on silica gel using hexanes–
EtOAc (gradient 90:10 to 80:20). The mixture of isomers 5a–c was
isolated as a yellow oil (145 mg, 48% total yield). Each isomer was
separated and isolated using HPLC (hexanes–EtOAc, 93:7, 22 mL/
min, Waters SunFire Prep Silica 5 mm).
Major Oxime Isomer
Rf = 0.43 (hexanes–EtOAc, 70:30).
IR (film): 1744 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.29 (m, 2 H), 7.21–7.17 (multiple
peaks, 3 H), 6.27 (dd, J = 16.4, 1.6 Hz, 1 H), 5.75 (dd, J = 16.4, 6.0
Hz, 1 H), 5.57 (m, 1 H), 4.24 (dd, J = 12.0, 4.0 Hz, 1 H), 4.08 (dd,
J = 12.0, 6.8 Hz, 1 H), 3.90 (s, 3 H), 2.64 (t, J = 7.6 Hz, 2 H), 2.45
(t, J = 7.6 Hz, 2 H), 2.10 (s, 3 H), 2.05 (s, 3 H), 1.77 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 170.59, 169.89, 157.81, 141.67,
129.94, 128.40, 128.34, 127.56, 125.94, 71.15, 64.58, 61.92, 35.75,
27.87, 24.10, 21.02, 20.74.
2-[2-(Methoxyimino)-5-phenylpentylidene]propane-1,3-diyl
Diacetate (5a)
Major Oxime Isomer
Rf = 0.47 (hexanes–EtOAc, 70:30).
IR (film): 1742 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.28 (m, 2 H), 7.20–7.16 (multiple
peaks, 3 H), 6.00 (s, 1 H), 4.96 (s, 2 H), 4.67 (s, 2 H), 3.90 (s, 3 H),
2.62 (t, J = 7.6 Hz, 2 H), 2.42 (t, J = 7.6 Hz, 2 H), 2.08 (s, 3 H), 2.06
(s, 3 H), 1.78 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NO5 + Na: 370.1625;
found: 370.1622.
Synthesis 2011, No. 16, 2579–2589 © Thieme Stuttgart · New York

2588
A. Kubota, M. S. Sanford
SPECIAL TOPIC
Minor Oxime Isomer
Rf = 0.45 (hexanes–EtOAc, 70:30).
13C NMR (100 MHz, CDCl3): d = 170.65, 170.04, 169.61, 152.55,
147.18, 138.26, 136.62, 123.56, 72.34, 69.64, 62.03, 24.27, 20.92,
20.76, 20.68, 14.68.
HRMS (EI): m/z [M + H]+ calcd for C16H22NO6: 324.1442; found:
324.1443.
1H NMR (400 MHz, CDCl3): d = 7.29 (m, 2 H), 7.21–7.17 (multiple
peaks, 3 H), 6.89 (dd, J = 16.4, 1.6 Hz, 1 H), 5.90 (dd, J = 16.4, 6.0
Hz, 1 H), 5.57 (m, 1 H), 4.27 (dd, J = 12.0, 4.0 Hz, 1 H), 4.10 (dd,
J = 11.6, 6.8 Hz, 1 H), 3.88 (s, 3 H), 2.64 (t, J = 7.6 Hz, 2 H), 2.36
(t, J = 7.6 Hz, 2 H), 2.11 (s, 3 H), 2.05 (s, 3 H), 1.77 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 170.57, 169.88, 153.68, 141.82,
130.95, 128.48, 128.35, 125.89, 121.72, 71.33, 64.49, 61.72, 35.42,
30.20, 29.06, 21.01, 20.72.
Minor Diastereomer
1H NMR (400 MHz, CDCl3): d = 8.49 (m, 1 H), 7.54 (m, 1 H), 7.22
(m, 1 H), 6.37 (d, J = 7.6 Hz, 1 H), 5.85 (ddd, J = 7.6, 4.8, 3.2 Hz,
1 H), 4.36 (dd, J = 12.4, 3.2 Hz, 1 H), 3.79 (dd, J = 12.4, 4.8 Hz, 1
H), 2.86 (m, 2 H), 2.08 (s, 3 H), 2.06 (s, 3 H), 2.06 (s, 3 H), 1.26 (t,
J = 7.2 Hz, 3 H).
1-(3-Methylpyridin-2-yl)propane-1,2,3-triyl Triacetate (8b)
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 8 reacted with PhI(OAc)2 to af-
ford 8b in 29% yield. To isolate 8b, substrate 8 (20 mg, 0.15 mmol)
was heated for 12 h under the reaction conditions. Product 8b was
purified by chromatography on silica gel using hexanes–EtOAc
(50:50) and was isolated as a 2.6:1.0 mixture of diastereomers as a
yellow oil; yield: 17 mg (37%). Pure samples of each diastereomer
were obtained from individual column fractions.
13C NMR (100 MHz, CDCl3): d = 170.39, 170.16, 169.99, 151.99,
147.29, 138.22, 136.84, 123.87, 72.06, 70.13, 62.44, 23.99, 20.90,
20.84, 20.71, 14.59.
1-(3-Methoxypyridin-2-yl)propane-1,2,3-triyl Triacetate (10b)
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 10 reacted with PhI(OAc)2 to
afford 10b in 34% yield. To isolate 10b, substrate 10 (50 mg, 0.34
mmol) was heated for 12 h under the reaction conditions. Product
9b was purified by chromatography on silica gel using hexanes–
EtOAc (60:40) and was isolated as a 1.4:1.0 mixture of diastereo-
mers as a yellow oil; yield: 37 mg (34%). Pure samples of each dia-
stereomer were obtained from individual column fractions.
IR (film, mixture of diastereomers): 1739 cm–1.
Major Diastereomer
Rf = 0.30 (EtOAc–hexanes, 60:40).
1H NMR (400 MHz, CDCl3): d = 8.45 (m, 1 H), 7.46 (m, 1 H), 7.13
(m, 1 H), 6.15 (d, J = 6.4 Hz, 1 H), 5.52 (td, J = 6.4, 2.4 Hz, 1 H),
4.60 (dd, J = 12.0, 2.4 Hz, 1 H), 4.46 (dd, J = 12.0, 6.4 Hz, 1 H),
2.48 (s, 3 H), 2.13 (s, 3 H), 2.05 (s, 3 H), 1.93 (s, 3 H).
IR (film, mixture of diastereomers): 1734 cm–1.
HRMS (mixture of diastereomers, ESI): m/z [M + Na]+ calcd for
C15H19NO7 + Na: 348.1059; found: 348.1051.
13C NMR (100 MHz, CDCl3): d = 170.63, 170.03, 169.65, 153.25,
147.20, 138.25, 132.40, 123.29, 72.23, 70.24, 62.02, 20.84, 20.74,
20.68, 18.08.
HRMS (ESI): m/z [M + Na]+ calcd for C15H19NO6 + Na: 332.1110;
found: 332.1106.
Major Diastereomer
Rf = 0.16 (EtOAc–hexanes, 60:40).
1H NMR (400 MHz, CDCl3): d = 8.19 (m, 1 H), 7.22 (m, 1 H), 7.17
(m, 1 H), 6.40 (d, J = 5.6 Hz, 1 H), 5.74 (ddd, J = 6.4, 5.6, 4.0 Hz,
1 H), 4.29 (dd, J = 12.0, 4.0 Hz, 1 H), 4.09 (dd, J = 12.0, 6.4 Hz, 1
H), 3.88 (s, 3 H), 2.14 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.52, 170.05, 170.05, 153.29,
144.06, 141.03, 124.12, 117.83, 70.80, 68.72, 62.47, 55.63, 20.88,
20.72, 20.70.
Minor Diastereomer
Rf = 0.27 (EtOAc–hexanes, 60:40).
1H NMR (400 MHz, CDCl3): d = 8.48 (m, 1 H), 7.48 (m, 1 H), 7.16
(m, 1 H), 6.25 (d, J = 8.0 Hz, 1 H), 5.82 (ddd, J = 8.0, 4.8, 3.2 Hz,
1 H), 4.38 (dd, J = 12.0, 3.2 Hz, 1 H), 3.74 (dd, J = 12.0, 4.8 Hz, 1
H), 2.49 (s, 3 H), 2.08 (s, 3 H), 2.07 (s, 3 H), 2.05 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.35, 170.26, 169.98, 152.78,
147.44, 138.70, 132.57, 123.63, 71.85, 70.82, 62.43, 20.82, 20.73,
20.67, 18.11.
Minor Diastereomer
Rf = 0.22 (EtOAc–hexanes, 60:40).
1H NMR (400 MHz, CDCl3): d = 8.19 (m, 1 H), 7.22 (m, 1 H), 7.18
(m, 1 H), 6.37 (d, J = 4.8 Hz, 1 H), 5.62 (m, 1 H), 4.47 (dd, J = 12.0,
2.0 Hz, 1 H), 4.36 (dd, J = 12.0, 7.2 Hz, 1 H), 3.88 (s, 3 H), 2.15 (s,
3 H), 2.00 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.68, 169.95, 169.87, 153.48,
144.15, 140.99, 124.09, 117.83, 71.14, 69.46, 62.23, 55.65, 20.91,
20.84, 20.74.
1-(3-Ethylpyridin-2-yl)propane-1,2,3-triyl Triacetate (9b)
1H NMR spectroscopic analysis of the crude reaction mixture after
6 h at 100 °C showed that substrate 9 reacted with PhI(OAc)2 to af-
ford 9b in 21% yield. To isolate 9b, substrate 9 (50 mg, 0.34 mmol)
was heated for 12 h under the reaction conditions. Product 9b was
purified by chromatography on silica gel using hexanes–EtOAc
(50:50) and was isolated as a 3.2:1.0 mixture of diastereomers as a
yellow oil; yield: 23 mg (21%). Pure samples of each diastereomer
were obtained from individual column fractions.
3-(3-Methylpyridin-2-yl)allyl Acetate (8c)
Substrate 8 (200 mg, 1.5 mmol, 1.0 equiv), Pd(OAc)2 (33.7 mg,
0.15 mmol, 10 mol%), and PhI(OAc)2 (484 mg, 1.5 mmol, 1.0
equiv) were weighed into a scintillation vial containing a stir bar.
CH2Cl2 (7.5 mL) was added, and the vial was sealed with a Teflon-
lined cap. The reaction mixture was stirred at r.t. for 48 h. The sol-
vent was then removed under vacuum. The product 8c was obtained
as a yellow oil after purification by flash chromatography on silica
gel using PE–Et2O (80:20) [5 mg (E)-8c, 14 mg (Z)-8c, 7% total
yield].
Major Diastereomer
IR (film): 1741 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.47 (m, 1 H), 7.51 (m, 1 H), 7.18
(m, 1 H), 6.24 (d, J = 6.8 Hz, 1 H), 5.55 (ddd, J = 6.8, 6.0, 2.4 Hz,
1 H), 4.61 (dd, J = 12.4, 2.4 Hz, 1 H), 4.46 (dd, J = 12.4, 6.0 Hz, 1
H), 2.86 (m, 2 H), 2.12 (s, 3 H), 2.06 (s, 3 H), 1.91 (s, 3 H), 1.23 (t,
J = 7.2 Hz, 3 H).
(E)-8c
Rf = 0.35 (EtOAc–hexanes, 70:30).
IR (film, isomer 1): 1736 cm–1.
Synthesis 2011, No. 16, 2579–2589 © Thieme Stuttgart · New York

SPECIAL TOPIC
Cyclopropane Oxidative Functionalization
2589
1H NMR (400 MHz, CDCl3): d = 8.45 (d, J = 4.8 Hz, 1 H), 7.43 (d,
J = 7.6 Hz, 1 H), 7.05 (dd, J = 7.6, 4.8 Hz, 1 H), 6.68 (d, J = 11.6
Hz, 1 H), 5.97 (ddd, J = 11.6, 5.6, 5.6 Hz, 1 H), 5.22 (dd, J = 5.6,
1.6 Hz, 2 H), 2.33 (s, 3 H), 2.08 (s, 3 H).
(5) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154. (b) Shabashov, D.; Daugulis, O.
J. Am. Chem. Soc. 2010, 132, 3965.
(6) Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem. Int. Ed. 2005, 44,
2112.
13C NMR (100 MHz, CDCl3): d = 170.98, 154.00, 146.61, 137.57,
(7) Giri, R.; Maugel, N.; Li, J. J.; Wang, D. H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J. Q. J. Am. Chem. Soc. 2007, 129,
3510.
(8) Wang, D. H.; Wasa, M.; Giri, R.; Yu, J. Q. J. Am. Chem. Soc.
2008, 130, 7190.
131.58, 131.52, 126.98, 121.85, 63.48, 21.07, 18.95.
HRMS (EI): m/z [M + H]+ calcd for C11H14NO2: 192.1019; found:
192.1017.
(Z)-8c
(9) Wasa, M.; Engle, K. M.; Yu, J. Q. J. Am. Chem. Soc. 2010,
Rf = 0.17 (EtOAc–hexanes, 70:30).
IR (film, isomer 1): 1736 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.41 (m, 1 H), 7.43 (m, 1 H), 7.07
(dd, J = 7.6, 4.8 Hz, 1 H), 6.90–6.89 (multiple peaks, 2 H), 4.81 (dd,
J = 2.8, 1.2 Hz, 2 H), 2.36 (s, 3 H), 2.10 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.71, 152.47, 147.06, 138.19,
130.62, 129.04, 128.81, 122.51, 64.60, 20.95, 18.65.
HRMS (EI): m/z [M + H]+ calcd for C11H14NO2: 192.1019; found:
192.1019.
132, 3680.
(10) Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem.
Soc. 2011, 133, 6541.
(11) The Chemistry of the Cyclopropyl Group; Rappoport, Z.,
Ed.; Wiley: Chichester, 1987.
(12) For selected reviews on synthetic applications of
cyclopropanes, see: (a) Reissig, H. U.; Zimmer, R. Chem.
Rev. 2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L.
Tetrahedron 2005, 61, 321. (c) Carson, C. A.; Kerr, M. A.
Chem. Soc. Rev. 2009, 38, 3051.
(13) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (b) Kalyani, D.; Sanford, M. S. Org. Lett.
2005, 7, 4149. (c) Desai, L. V.; Malik, H. A.; Sanford, M. S.
Org. Lett. 2006, 8, 1141. (d) Desai, L. V.; Stowers, K. J.;
Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285.
(e) Stowers, K. J.; Sanford, M. S. Org. Lett. 2009, 11, 4584.
(f) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532.
(14) (a) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A: Chem.
1996, 108, 35. (b) Gou, F. R.; Wang, X. C.; Huo, P. F.; Bi,
H. P.; Guan, Z. H.; Liang, Y. M. Org. Lett. 2009, 11, 5726.
(c) Mutule, I.; Suna, E.; Olofsson, K.; Pelcman, B. J. Org.
Chem. 2009, 74, 7195.
(15) He, Z.; Yudin, A. K. Org. Lett. 2006, 8, 5829.
(16) (a) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008,
130, 2962. (b) Wang, W.; Wang, F.; Shi, M.
Organometallics 2010, 29, 928.
(17) Wallace, D. J.; Chen, C. Y. Tetrahedron Lett. 2002, 43,
6987.
Acknowledgment
This work was supported by the NIH (R01-GM073836). We also
thank Dr. Lopa Desai for preliminary studies of palladium-cataly-
zed oxidative functionalization of cyclopropanes.
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