Catalytic 1,3-Difunctionalization via Oxidative C-C Bond Activation

Article abstract of DOI:10.1021/jacs.7b05160

Electronegative substituents arrayed in 1,3-relationships along saturated carbon frameworks can exert strong influence over molecular conformation due to dipole minimization effects. Simple and general methods for incorporation of such functional group relationships could thus provide a valuable tool for modulating molecular shape. Here, we describe a general strategy for the 1,3-oxidation of cyclopropanes using aryl iodine(I-III) catalysis, with emphasis on 1,3-difluorination reactions. These reactions make use of practical, commercially available reagents and can engage a variety of substituted cyclopropane substrates. Analysis of crystal and solution structures of several of the products reveal the consistent effect of 1,3-difluorides in dictating molecular conformation. The generality of the 1,3-oxidation strategy is demonstrated through the catalytic oxidative ring-opening of cyclopropanes for the synthesis of 1,3-fluoroacetoxylated products, 1,3-diols, 1,3-amino alcohols, and 1,3-diamines.

Full text of DOI:10.1021/jacs.7b05160

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Communication
Catalytic 1,3-Difunctionalization via Oxidative C–C Bond Activation
Steven M. Banik, Katrina Mennie, and Eric N. Jacobsen
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Journal of the American Chemical Society
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Catalytic 1,3-Difunctionalization via Oxidative C–C Bond Activation
Steven M. Banik,† Katrina M. Mennie,† Eric N. Jacobsen*
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Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138 USA
Supporting Information Placeholder
clobutane intermediates.4 Strategies for non-DA cyclopro-
ABSTRACT: Electronegative substituents arrayed in 1,3-
pane functionalization have invoked both radical5 and elec-
relationships along saturated carbon frameworks can exert
trophilic addition,6 and a catalytic method that achieves 1,3-
strong influence over molecular conformation due to dipole
aminofluorination of arylcyclopropanes through the inter-
mediacy of radical cations has been reported recently.7 Anal-
yses of electrophilic additions to cyclopropanes have re-
vealed subtle nuances regarding the mechanism of ring-
opening,4a,8 but the development of general and practical
synthetic methods that capitalize on these reactivity mani-
folds has not yet been achieved.
minimization effects. Simple and general methods for incor-
poration of such functional group relationships could thus
provide a valuable tool for modulating molecular shape.
Here, we describe a general strategy for the 1,3-oxidation of
cyclopropanes using aryl iodide(I-III) catalysis, with empha-
sis on 1,3-difluorination reactions. These reactions make use
of practical, commercially available reagents and can engage
a variety of substituted cyclopropane substrates. Analysis of
crystal and solution structures of several of the products re-
veal the consistent effect of 1,3-difluorides in dictating mo-
lecular conformation. The generality of the 1,3-oxidation
strategy is demonstrated through the catalytic oxidative ring
opening of cyclopropanes for the synthesis of 1,3-
fluoroacetoxylated products, 1,3-diols, 1,3-amino alcohols,
and 1,3-diamines.
a.
b.
Allylic Strain (A1,3
)
Previous Work:
Me
Me
HX
[O]
X
Me
H
Me
Me
H
R1
ArI (catalyst)
Me
R1
R2
R2
G
3.4 kcal/mol
X
1,2-Oxidation of alkenes
g+g (syn-Pentane)
Me
Me
Me Me
This Work:
G
3.0 to 3.7 kcal/mol
HF/HX
[O]
ArI (catalyst)
R
F/X
1,3-Dipolar Repulsion
R
H
H
H
H
H
H
F/X
H
F
F
F
F
H
1,3-Difluorination and
1,3-Oxidation of cyclopropanes
G
3.3 kcal/mol
The strategic disposition of substituents in 1,3-
relationships is a well-established tool for influencing the
conformation of organic molecules. Control elements such
as syn-pentane and A1,3 interactions,1 which rely on minimi-
zation of steric repulsion between 1,3-substituents, are most
familiar and are broadly exploited in molecular design. Di-
pole minimization, although considerably less well devel-
oped as a design strategy, can provide biasing effects of simi-
lar magnitude in structures possessing electronegative func-
tional groups disposed in a 1,3-manner. For example, acy-
clic, saturated 1,3-difluoro compounds have been shown to
display a strong bias to adopting dipole-minimized confor-
mations (Figure 1a).2
c.
F
pyr 9HF (11.1 equiv.)
mCPBA (1.1 equiv.)
ArI (20 mol%)
F
CH2Cl2, 24 h, rt
EtO2C
I
EtO2C
1a
2a
I
I
I
I
I
ArI =
Cl
CO2Me
69%
NO2
52%
OMe
56%
Me
55%
78%
77%
Figure 1. 1,3-Difluorination of cyclopropanes. a. Conformational
properties of 1,3-difluorides. b. Aryl iodide-catalyzed oxidation of
alkenes and cyclopropanes. c. Catalyst optimization studies.
We and others have developed oxidative 1,2-
difunctionalization reactions of alkenes based on aryl io-
dine(I-III) catalysis,9 and we hypothesized that the alkene-
like π-donating properties of unactivated cyclopropanes
could give rise to promotion of 1,3-oxidation reactions by
similar mechanisms (Figure 1b). Indeed, Szabó and
coworkers demonstrated very recently that 1,1-disubstituted
cyclopropanes undergo 1,3-difluorination in the presence of
stoichiometric iodine (III) reagents together with stoichio-
In an effort to devise efficient and general routes from
simple precursors to products bearing 1,3-oxidation patterns,
we undertook an investigation of methods for the direct acti-
vation of substituted cyclopropanes. The majority of ap-
proaches to cyclopropane ring-opening have relied on vicinal
donor-acceptor (DA) substitution on the strained ring,3 or
oxidative addition by a transition metal to form metallacy-
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metric AgBF4.10 We describe here the discovery of a catalytic
and general method for the ring-opening 1,3-oxidation of
substituted cyclopropanes with simple aryl iodide catalysts.
Non-conjugated monosubstituted cyclopropanes also un-
1
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3
4
5
6
7
8
derwent oxidation under the catalytic conditions (Fig. 2b).
Increased catalyst loadings (20 mol%) were required for
non-conjugated cyclopropane substrates due to competitive
hydrofluorination, a known reaction of HF-pyridine and
aliphatic cyclopropanes.12 Substrates containing ether (4a,
4b) and amine (4c, 4d) functionality underwent difluorina-
tion in good yields. 1,1-Disubstituted cyclopropanes were
converted to the corresponding 1,3-difluorinated products
more cleanly in higher yields relative to the monosubstituted
analogs (4a, 4c vs. 4b, 4d). The compatibility of basic nitro-
gen functionality with the acidic, oxidizing conditions was
demonstrated by the isolation of triazole 4e and quinoline 4f
in good yields. Subjection of -cyclopropyl acrylamide 3h to
the reaction conditions resulted ring-opening 1,3-
difluorination to afford 4h, with no detectable difluorination
of the alkene.
We initiated experimental efforts toward the ring-opening
difluorination of substituted cyclopropanes using mCPBA as
an oxidant, and HF-pyridine as a nucleophilic fluoride
source, and commercially available aryl iodides as catalysts.
With this reagent protocol, the carboethoxy-substituted aryl-
cyclopropane 1a was converted to the corresponding 1,3-
difluorination product in the presence of a variety of electron
rich and electron deficient aryl iodides (Figure 1c). In con-
trast, cyclopropylbenzene and more electron-rich analogs
decomposed to uncharacterized products. Iodobenzene
afforded the highest yields in the difluorination of 1a, and
this simplest of potential aryl iodide catalysts was selected for
further investigation of the reaction scope.11
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In contrast to the established effectiveness of chiral aryl
iodide catalysts in enantioselective fluorofunctionalizations
of alkenes,9g,9j,13 only very low levels of enantiocontrol were
observed in the corresponding 1,3-difluorination of cyclo-
propanes such as 1a with a variety of catalysts (see Support-
ing Information). While the identification of effective chiral
catalysts for enantioselective ring-opening difluorination
reactions will demand further effort, we found that stereo-
chemically complex 1,3-difluorination products could be
accessed effectively with achiral aryl iodide catalysts from
readily accessible chiral cyclopropanes. For example,
tetrasubstituted substrates 5a–e underwent difluorination
stereospecifically in the presence of iodobenzene (>20:1 d.r.,
diastereomeric ratio, Fig. 3a). Cyclopropane 5f underwent
difluorination to afford a mixture of diastereomers; this sub-
strate required the use of high concentrations of pyr9HF
(5.6 equiv.) to reach complete conversion. The loss of dia-
stereospecificity is ascribable to the highly acidic medium, as
similarly diminished diastereoselectivities were obtained in
reactions of 5a and 5b using >2.2 equivalents of pyr9HF.
To gain insight into the stereospecificity of both C–F
bond-forming steps, cyclopropanes 5g and 7a-b were sub-
jected to the catalytic fluorination conditions (Fig. 3b).
Whereas 5g underwent ring-opening to provide 6g as a 1.3:1
mixture of diastereomers, the less highly substituted sub-
strates 7a-b underwent stereospecific difluorination to afford
diastereomerically pure products. The relative configuration
of the two fluoride-bearing stereocenters in 8b was deter-
mined to be syn via X-ray diffraction analysis of a crystalline
derivative. The divergent stereochemical behavior observed
between 5g and 7a-b can be rationalized according to the
mechanism outlined in Fig. 3c. The first C–F bond for-
mation is proposed to occur via regioselective invertive ring-
opening at the most electrophilic benzylic position to afford
fluoroiodinated species 5II. In the case of the fully substituted
intermediate (R = Et), ionization of the C-IIII bond would be
facile and yield tertiary carbocation 5III, which can be trapped
Figure 2. Evaluation of substrate scope for 1,3-difluorination. a.
Substrate scope evaluation for aryl cyclopropanes. b. Substrate
scope evaluation for aliphatic and vinyl cyclopropanes. Isolated
yields are indicated below each product (2 and 4); experimental
details are provided in the Supporting Information.
In general, aryl cyclopropanes bearing electron-
withdrawing substituents were useful substrates in the cata-
lytic reaction, undergoing regioselective difluorination in
moderate-to-good yields (Fig. 2a). Substrates bearing amine
substituents (1j) and N-heterocycles (1k) also underwent
successful difluorination, by virtue of basic groups undergo-
ing in situ protection via protonation by HF. The reaction
was chemoselective for the most electron rich cyclopropane
in 1l, providing 2l as the only detectable 1,3-difluorinated
product.
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by fluoride non-stereospecifically in an SN1 process. In the
case of the secondary intermediate (R = H), concerted, in-
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8
vertive fluoride substitution appears be favored, leading to
the observed syn product stereospecifically. The relative
stereochemistry observed in 8 is consistent with edge activa-
tion of cyclopropanes by IIII in a manner analogous to the
activation of alkenes by IIII activation of alkenes. The stereo-
specificity observed in the difluorination reactions described
above represents an important practical feature of this elec-
trophilic catalytic system.
6c
4a
4h
6d
Figure 4. X-ray crystal structures of 1,3-difluorides
The catalytic ring-opening difluorination protocol could
be applied successfully to 1,1-difluorocyclopropane sub-
strates, affording products corresponding formally to alkene
1,2-fluorotrifluoromethylation (Fig. 5). Several substituted
1,1-difluoroarylcyclopropanes were transformed to fluorotri-
fluoromethylated products 10a–f in good-to-excellent yields.
1,1-Difluorocyclopropanes have been calculated to possess
very high ring strain energies (ca. 40 kcal/mol),14 and this
might offset the expected deactivating inductive effect of
fluorine substitution on the cyclopropane ring and enable
the 1,3-difluorination reaction. However, large excesses of
pyr9HF (5.6-11.1 equiv.) were required to achieve com-
plete substrate conversion. Only modest diastereoselectivity
(3:1) was observed in the ring-opening of the substituted
cyclopropane 5g consistent with similar results obtained with
5f under strongly acidic conditions (see above).
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Figure 5. 1,3-Difluorination of 1,1-difluorocyclopropanes.
The protocol for catalytic 1,3-oxidation reactions of cyclo-
propanes could be adapted in a straightforward manner to
allow introduction of electronegative groups other than fluo-
rine. Introduction of excess acetic acid to the 1,3-
difluorination conditions led to formation of fluoroacetoxy-
lation products (11a–c) in good yields and with complete
regioselectivity (Fig. 6a). Net 1,3-dihydroxylation of cyclo-
propanes was achieved using trifluoroacetic acid as both an
acidic promoter and nucleophile (Fig. 6b). The initially
formed 1,3-trifluoroacetoxy products were subjected to hy-
drolysis under mild conditions to provide 1,3-diols (12a–c)
from cyclopropanes in moderate-to-excellent yields. When
the same reactions of cyclopropanes and trifluoroacetic acid
were conducted in acetonitrile, 1,3-amino alcohols could be
obtained with complete regioselectivity and in good yields
(Fig. 6c, 13a–c). The formation of 1,3-amino alcohol prod-
ucts in this reaction suggests Ritter-type substitution reac-
tions are available to the highly electrophilic species generat-
ed under IIII catalysis. Catalytic 1,3-cyclopropane oxidation
could also be applied to the synthesis of 1,3-diamine prod-
ucts (Fig. 6d). These reactions require BF3OEt2 as a stoi-
chiometric activator with a sulfonamide nitrogen source and
proceed in moderate yield (14a–c). Taken together, these
Figure 3. Stereospecificity in the generation of 1,3-difluorination
products. a, 1,3-Difluorination of chiral highly substituted cyclo-
propanes. b. Evaluation of the stereospecificity of both C–F bond
forming steps. c. Mechanistic proposals for the divergent stereo-
chemical outcomes observed between substrates 5 and 6. Isolated
yields are indicated for all products (6, 8); experimental details are
provided in the Supporting Information.
X-ray crystal structures were obtained for compounds 4a,
4h, 6c and 6d. In all cases, the molecules adopt solid-state
conformations wherein the 1,3-difluoro substituents are ori-
ented in the gauche-gauche relationships that minimize dipo-
lar interactions (Fig. 4). Both 6e and 6f were found to adopt
similar 1,3-dipolar minimized conformations in solution, as
determined by vicinal H-F NMR coupling constants (3JH-F).
These findings add to the growing body of crystallographic
and solution state data demonstrating that fluorides disposed
in a 1,3-relationship impose strong conformational biases to
saturated, acyclic carbon frameworks.
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1,3-difunctionalization reactions demonstrate the rich varie-
ty of 1,3-oxidation patterns that should be accessible from
unactivated cyclopropanes using ArI catalysis.
ASSOCIATED CONTENT
1
2
3
4
5
6
7
8
Supporting Information.
The Supporting Information is available free of charge on the ACS
Publications website at DOI:
Experimental procedures; characterization data (PDF)
Crystallographic data for 4a (CIF)
Crystallographic data for 4h (CIF)
pyr 9HF (11.1 equiv.)
mCPBA (1.1 equiv.)
a.
AcOH (30.0 equiv.)
PhI (10–20 mol%)
F
R
OAc
CH2Cl2, 24 h, rt
R
(
)-
11
1
Crystallographic data for 6c (CIF)
Crystallographic data for 6d (CIF)
F
F
CN
F
O2N
OAc
9
OAc
OAc
AUTHOR INFORMATION
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EtO2C
11a
61%
11b
62%
11c
60%
Corresponding Author
b.
1. mCPBA (1.1 equiv.)
PhI (20 mol%)
1:1 CF3COOH/CH2Cl2
24–36 h, rt
*jacobsen@chemistry.harvard.edu
OH
Author Contributions
R
1
R
OH
2. 4M NaOH, THF
8 h, rt
† S.M.B. and K.M.M. contributed equally.
or
3
(
)-
12
Cl
OH
Cl
OH
O2N
Notes
OH
OH
OH
The authors declare no competing financial interest.
OH
NC
12a
87%
12b
12c
55%
ACKNOWLEDGMENT
59%
This work was supported by the NIH (GM043214), and by an
NSF pre-doctoral fellowship to S.M.B. We thank Dr. Shao-Liang
Zheng (Harvard University) for determination of all of the X-ray
crystal structures.
1. mCPBA (1.1 equiv.)
PhI (20 mol%)
1:1 CF3COOH/MeCN
24 h, rt
c.
NHAc
R
1
R
OAc
2. Ac2O, pyr
12 h, rt
or
(
)-
13
3
REFERENCES
NHAc
NHAc
NHAc
OAc
F3C
OAc
OAc
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Me
EtO2C
13a
82%
13b
81%
13c
61%
O
R
d.
TsNHMe (2.5 equiv.)
BF3•OEt2 (2.0 equiv.)
mCPBA (1.1 equiv.)
PhI (20 mol%)
N(Ts)Me
N(Ts)Me
R
CH2Cl2, 24 h, 0 ºC–rt
N(Ts)Me
1
(
)-
14
N(Ts)Me
N(Ts)Me
F3C
NTsMe
Br
N(Ts)Me
N(Ts)Me
14a
44%
14b
46%
14c
48%
EtO2C
Figure 6. General 1,3-catalytic oxidative difunctionalization of cy-
clopropanes. a. Synthesis of fluoroacetoxylated products using
acetic acid as a cosolvent. b. Synthesis of 1,3-diols using trifluoroa-
cetic acid as a cosolvent followed by hydrolysis. c. Synthesis of 1,3-
amino alcohols using trifluoroacetic acid and acetonitrile as cosol-
vents.
d.
Synthesis
of
1,3-diamines
using
p-
tolylmethanesulfonamide and BF3OEt2. Isolated yields are indi-
cated below each product (11, 12, 13, 14); for experimental details,
see the Supporting Information.
The discovery of a direct, catalytic method for the con-
struction of 1,3-difluorinated compounds introduces a new
tool for the modulation of molecular conformation. General-
ization of this cyclopropane C-C bond activation strategy
holds promise for accessing a variety of 1,3-oxidation pat-
terns, as demonstrated here in the synthesis of 1,3-
fluoroacetoxy, 1,3-diol, 1,3-amino alcohol, and 1,3-diamine
products. Further efforts to exploit catalytic, electrophilic
activation for cyclopropane functionalization are currently
underway.
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̌
̌
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3
4
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6
7
8
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(11) A relatively high concentration of HF-pyridine is needed for the
1,3-difluorination reaction to occur in the presence of PhIF2. No in-
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