Photoredox Catalyzed Intramolecular Fluoroalkylarylation of Unactivated Alkenes

Article abstract of DOI:10.1021/acs.joc.6b03012

The first example of photoredox catalyzed difluoromethylation of unactivated alkenes coupled with C-C bond formation to an aryl ring is reported. The reactions are conducted under mild conditions and afford tetralin derivatives bearing difluoromethyl as well as other fluoroalkyl groups in good to high yields. In addition, the study indicates that 6-exo radical cyclization of an alkyl radical to a phenyl ring is faster than the respective 5-exo radical cyclization. A computational study provides insights to the experimental results.

Full text of DOI:10.1021/acs.joc.6b03012

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Article
Photo-redox catalyzed intramolecular
fluoroalkylarylation of unactivated alkenes
Zuxiao Zhang, Henry Martinez, and William R. Dolbier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03012 • Publication Date (Web): 10 Feb 2017
Downloaded from http://pubs.acs.org on February 10, 2017
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Photo-redox catalyzed intramolecular fluoroalkylarylation of unactivated alkenes
Zuxiao Zhang, Henry Martinez and William R. Dolbier, Jr.*
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Department of Chemistry, University of Florida, Gainesville, FL 32611ꢀ7200
*Email: wrd@chem.ufl.edu
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ABSTRACT: The first example of photoꢀredox catalyzed difluoromethylation of unactivated alkenes coupled with
CꢀC bond formation to an aryl ring is reported. The reactions are conducted under mild conditions and afford tetralin
derivatives bearing difluoromethyl as well as other fluoroalkyl groups in good to high yields. In addition, the study
indicates that 6ꢀexo radical cyclization of an alkyl radical to a phenyl ring is faster than the respective 5ꢀexo radical
cyclization. A computational study provides insights to the experimental results.
INTRODUCTION
Fluorine substituents and fluoroalkyl groups have been widely recognized as playing a strategic role in
pharmaceutical research and drug development due to their demonstrated ability to enhance properties related to
biological activity, such as improved lipophilicity, metabolic stability, and bioavailability.1 Therefore substantial
effort has been devoted to the development of synthetic methods for introduction of the fluorine substituent and
fluoroalkyl groups into various organic building block molecules. Foremost among them has been the development
of methods for incorporation of the trifluoromethyl group, work extending over the last few decades.2 In contrast,
methods for introduction of partially fluorinated alkyl groups has been much more limited.3 In particular, the
difluoromethyl group, which can offer a more lipophilic Hꢀbond donor than either an OH or NH, is of great current
interest,4 and recently much elegant work related to difluoromethylation of aromatics or heteroaromatics has been
reported.5 Also, alkene difluoromethylation reactions that simultaneously incorporate H, halogen and N or O
functionalities have been shown to constitute an efficient strategy for construction of Csp3ꢀCF2H.6 A worthy
extension of such chemistry is the making of a CꢀC bond as part of the chain process. Recent chemistry of that type
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includes our 2014 report of the photoꢀredox catalyzed difluoromethylation of Nꢀarylacrylamides, which was
accompanied by a tandem 5ꢀexoꢀtrig cyclization onto the aryl ring to construct oxindoles7 In the same year Tan’s
group developed a silver catalyzed difluoromethylation that produced the same result.7,8 In 2015, Hu and coworkers
reported a novel fluoroalkylative aryl migration of conjugated Nꢀarylsulfonylated amides,9 and earlier this year our
group reported a photoꢀredox catalyzed intramolecular difluoromethylation of Nꢀbenzylacrylamides that led to a
dearomatizing spirocyclization reaction.10 All of these previous arylative difluoromethylation reactions used α,βꢀ
unsaturated amide derivatives as substrates. In this paper we will present a further extension of this methodology
that allows the formation of carbocycle rings.
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Figure 1. Representative drugs and bioactive molecules.
Carbocycles such as tetralin are found in many natural products and bioactive compounds (Figure 1), and it
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is reasonable to consider that their fluoroalkylated analogues might exhibit altered potency
However, the
approaches for their preparation are extremely limited. So far only one example involving a copper catalyzed carbo
trifluoromethylation of alkenes to introduce CF3 has been reported by the Sodeoka group.12 Introducing other
fluoroalkyl groups such as CF2H, CF2CH3 or CF2COOEt using this kind of chemistry has until now been unreported,
and it was considered that a synthesis of fluoroalkylated tetralin derivatives using a photoꢀredox catalyzed
intramolecular fluoroalkylarylation initiated by the addition of fluoroalkyl radicals to arylalkenes would be
worthwhile. Our previous experience indicated that the treatment of an alkene not conjugated to an electron
withdrawing group under photoꢀredox difluoromethylative conditions leads primarily to the chloro or bromo
products by radical or cation pathways.
RESULTS AND DISCUSSION - EXPERIMENTAL WORK
Inspired by Sodeoka’s work,12 we envisioned that cyclization could be induced to compete satisfactorily
with simple addition by taking advantage of the ThorpeꢀIngold effect. Indeed, we report here the effective use of
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bisꢀcarboalkoxy groups to facilitate
fluoroalkyltetralin derivatives.
a photoꢀredox catalyzed sixꢀmemberedꢀring cyclization to form
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Exploration of reaction conditions for difluoromethylation. In our initial experiments designed to
determine the feasibility of the proposed process, compound 1a was chosen as the model substrate. It was
encouraging to find that, using facꢀIr(ppy)3 as catalyst in DCM at room temperature and difluoromethanesulfonyl
chloride as the source of difluoromethyl radicals, 28% of the desired cyclization product was formed, along with 61%
of remaining starting material (Table 1, entry 1). Surprisingly, only trace amounts of the undesired chlorination
product were found. Other solvents were then screened, with CH3CN turning out to be the best solvent, affording 46%
of product with 33% starting material recovered (entry 4). In order to increase the conversion, the amount of catalyst
was increased to 2 mol %, with the result that the yield increased to 64% (entry 5).
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Table 1. Screening of reaction conditions. a
entry
1
Catalyst
solvent
DCM
base
yield b /%
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facꢀIr(ppy)3 1 mol%
facꢀIr(ppy)3 1 mol%
facꢀIr(ppy)3 1 mol%
facꢀIr(ppy)3 1 mol%
facꢀIr(ppy)3 2 mol%
facꢀIr(ppy)3 2 mol%
facꢀIr(ppy)3 2 mol%
facꢀIr(ppy)3 3 mol%
facꢀIr(ppy)3 2 mol%
facꢀIr(ppy)3 2 mol%
facꢀIr(ppy)3 2 mol%
facꢀIr(ppy)3 2 mol%
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
Na2HPO4
Na2CO3
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
2
DCE
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3
dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
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a Reactions were run using 0.1 mmol of 1a, 0.2 mmol of HCF2SO2Cl, 0.2 mmol of base, and 0.001 mmol of catalyst
b
in 1 mL of solvent under visible light. All yields were based on 1a using N,Nꢀdimethyltrifluoroacetamide as the
internal standard. c reaction run 36 hours. d reaction carried out at 50 ℃. e reaction carried out at 75 ℃. f using blue
led
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A change of base to Na2HPO4, led to a slight increase in yield (entry 6). Further increases in amounts of catalyst
did not prove beneficial (entry 8). When the reaction was run for a longer time (36 hours) a higher yield was
obtained (entry 9), and higher temperatures were also beneficial (entries 9ꢀ11). Finally, switching the light source to
a blue LED provided the best results, with 80% being obtained after only 18 hours at room temperature (entry 12).
Scope of the reaction for difluoromethylation. Having established optimal reaction conditions, the scope
of the reaction with respect to substrates was examined (Scheme 1). First, the electronic effect of substituents on the
phenyl ring was tested, with modest effect being observed for either electronꢀdonating or electronꢀwithdrawing
substituents, affording the six membered ring products in good yield (2aꢀ2i). Two meta substituents on the phenyl
ring, such as methyl, fluoro and methoxy groups, also led to cyclization products 2jꢀ2l in good yield. In contrast,
when a naphthalene ring was used, only product 2m was isolated in a moderate yield. For these 6ꢀexo cyclizations,
substituents at the βꢀposition of the alkene such as methyl and carbomethoxy did not have a significant effect on the
desired reaction, with products 3a and 3b being observed in 77% and 61% yields, respectively.
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Scheme 1. Difluoromethylation coupled with construction of carbocycles. a,b,c
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When no ester groups were present in the substrate, only 8% yield of product 4 could be observed by 19F
NMR, with the major product being that derived from chlorine addition. (Product 4 was not isolated or fully
characterized.) Moving the gemꢀdiester groups one carbon farther from the alkene reaction site led to a diminished,
but still moderate yield of product 5. Comparing the relative yields of products 2a (under conditions of Table 1,
entry 9, 78%) and 6a (48%) indicated that the 6ꢀexo cyclization process was more competitive than the analogous 5ꢀ
exo cyclization process. The high yield of 6b indicated that an ester group at the radical site enhances the
competitiveness of the 5ꢀexo cyclization with respect to chlorine atom transfer.
Incorporation of other fluoroalkyl groups. To develop a more general strategy for introduction of
various fluoroalkyl groups into the tetralin system, other fluoroalkylsulfonyl chlorides were examined as possible
fluoroalkyl radical sources (Scheme 2). Thus, it was found that the CH3CF2 group could be introduced into the
carbocyclic product 7 smoothly in moderate yield, while perfluoroalkyl groups such as CF3 and C4F9 could also be
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transferred to form desired products 8 & 9 in 70% and 90% yield, respectively. Considering the broad existence of
the difluoroester and difluoroamide functionality in drugs and bioactive compounds, and because the respective
bromo compounds have been shown to be good radical sources
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Scheme 2. Construction of 6ꢀmembered ring carbocycles bearing other fluoroalkyl groups. a,b
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under photoꢀredox catalysis,13 a bromodifluoroacetic ester and respective amides were examined as radical sources
under the usual conditions (Scheme 2). Due to the relative stability of the bromo compounds under the reaction
conditions, only 1.2 equivalents of bromo compounds were needed to give good yields of desired products 10ꢀ12.
Mechanistic considerations. A reasonable mechanism for these reactions, is proposed in Scheme 3. In
earlier publications related to photoredox chemistry of CF2HSO2Cl, it was demonstrated that both photocatalyst and
light were required for the reaction to occur, and that thermal free radical initiators were ineffective to initiate
formation of the observed products.6e First the sulfonyl chloride is reduced by the excited Ir catalyst, inducing
formation of the difluoromethyl radical. Then the CF2H radical attacks the double bond to form intermediate radical
A, which quickly undergoes cyclization to form the intermediate radical B. Intermediate B then is oxidized by the
high valence Ir catalyst to form intermediate carbocation C, thus regenerating the catalyst. Finally, the carbocation
is deprotonated to form the product. Consistent with our earlier reports on the use of CF2HSO2Cl as a source of the
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difluoromethyl radical, a cyclic catalytic process involving efficient reductive and oxidative steps is required for
such an effective photoredox process as is observed in this study.
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Scheme 3. Proposed mechanism.
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RESULTS AND DISCUSSION - COMPUTATIONAL
As was proposed by Sodeoka12, and regarding the relative ease of formation of product 2a versus 6a in our
study, 6ꢀexoꢀcyclization to the ortho position of the aryl ring must be faster than the analogous 5ꢀexo cyclization.
There are few experimental or computational studies of radical cyclization rates that involve cyclization to a
benzene ring. In order to have a better understanding of the relative reactivities of the radicals generated in this work,
ground and transition states including acetonitrile as a solvent (SMD model), were calculated at the M06ꢀ2X/6ꢀ
311+G(2df,p) // M06ꢀL/6ꢀ31G(d) level of theory.14ꢀ17 Details related to the computational methodology may be
found in the Experimental Section.
Methodology validation. In order to validate the computational method, four radical cyclization systems
were evaluated (13-16, Figure 2): the 5ꢀexo cyclizations of the 5ꢀhexenyl and 3ꢀphenylpropyl radicals (13 and 15),
and the 6ꢀexo cyclizations of the 6ꢀheptenyl and 4ꢀphenylbutyl radicals (14 and 16). While 13 and 14 are well
studied systems both experimentally and computationally,18ꢀ25 there are to our knowledge no experimental data for
cyclizations of 15 and 16, with only a few related computational papers having appeared recently.26ꢀ29
Figure 2. Radicals examined in the computational study.
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Table 2 shows that although the calculated transition state free energies for cyclization of radicals 13 and
14 are slightly different from those reported in the literature,18ꢀ25 they all follow the same expected trends; that is a
lower transition state free energy for the 5ꢀexo cyclization of 13 than for the 6ꢀexo cyclization of 14. Both have
chairꢀlike transition states and the free energy of the reaction (product) is significantly exergonic in both cases.
Table 2. Relative 298 K free energies (kcal/mol) in CH3CN for transition states (TS) and products (PD) for
structures 13-16. Computational method validation.
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15
16
9.2
10.5
ꢀ18.5
18.8
ꢀ1.3
11
TS
PD
ꢀ14.6
ꢀ8.7
The calculated CꢀC bond distances for the new bonds at the transition states for 13 and 14 are 2.243 and 2.295 Å,
respectively. In both cyclizations the radical approaches the double bond at a nearly tetrahedral angle. These results
are similar to those previously reported. 18ꢀ25
The calculations for cyclization of radicals 15 and 16 confirmed that the transition state free energy for the
5ꢀexo cyclization of the 3ꢀphenylpropyl radical (15) is much higher than that for the 6ꢀexo cyclization of the 4ꢀ
phenylbutyl radical (16) (Table 2). In order for radical 15 to follow the BurgiꢀDunitz trajectory23 and approach the
double bond at as close to a tetrahedral angle as possible, the CH2 at the ipso carbon has to be out of the benzene
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plane by 9.9°, which increases strain and thus the transition state energy. The additional carbon in radical 16 allows
for a less strained cyclization transition state, with the CH2 at the ipso carbon only being 5.40° out of the benzene
plane. These factors are also reflected in the free energy of the product radicals. The reaction free energy for
cyclization of 16 is significantly more exergonic than that for 15 (Table 2). The calculated distances for the new CꢀC
bonds for the cyclization transition states are 2.126 and 2.171 Å for 15 and 16, respectively. These results are similar
to those previously reported.26ꢀ29
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Computational results for new systems. Thus the results for the systems used for validation of the
computational method follow the expected energy and structure trends and this allowed us to use this same level of
theory to examine more specifically the experimental systems that were studied in this work. One of the questions
that we wanted to answer is how the gemꢀdiester groups and their location affect the rates of cyclization. The
transition state structures (and products) for the 5ꢀexo cyclization of 17-19 and 20-23 (Figure 2) were therefore
calculated.
The unsubstituted system (17) has a significantly higher free energy at the transition state compared to the
gemꢀdiester substituted systems (18 and 19, Table 3). This has been previously described in the literature as a kinetic
effect.21 Since the substituents increase the number of gauche interactions in the open chain system, both ꢁH and –
TꢁS decrease for the transition state and product. This can also be observed in the less endergonic cyclization
reactions of 18 and 19 compared to 17 (Table 3). The transition state energy is lower for 19 than 18 due to higher
steric interactions in the latter; however, structure 19 could also benefit from the ThorpeꢀIngold effect which may
lower the energy of the transition state.19 The calculated distances for the new CꢀC bonds at the transition state are
similar for all structures (17-19), 2.101 Å.
Table 3. Relative 298 K free energies (kcal/mol) in CH3CN for transition states (TS) and products (PD) for
structures 17ꢀ23 ꢀ gemꢀdiester substituent effect.
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18
19
20-a 21
22
23
18.9
4.5
16.8
2.2
16.4
ꢀ0.2
12.6
ꢀ0.5
13
12.4
10.2
ꢀ6
TS
PD
ꢀ1.6 ꢀ3.1
The 6ꢀexo cyclizations of radicals 20-a - 23, follow a similar trend to those of the 17-19 radicals (Table 3).
With the exception of 21, the free energy at the transition state is lower when the gemꢀdiester is present. In structure
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21 there seems to be an unfavorable interaction between the CF2H group and the syn ester group, which could
increase the energy at the transition state. Nevertheless, in all cases the exergonicities of the cyclizations of the gemꢀ
diester substituted systems are greater than that for the cyclization of 20-a. The farther away the substituents are
from the radical, the lower the free energy of the transition state and product. The calculated distances for the new
CꢀC bonds in the transition states range between 2.11ꢀ2.16 Å. The shorter the distance, the higher the free energy at
the transition state. These results help us to understand why product 2a (Scheme 1) was formed in 80% yield,
whereas 3 was only formed in 8% yield. Not only is the free energy lower at the transition state for the cyclization of
radical 1a, but the reaction is also significantly more exergonic, which drives the reaction equilibrium more in favor
of the product in a radical system such as 1a.
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It is important to highlight that none of the experimental systems in this work yielded an ipsoꢀ5ꢀexo
cyclization product such as that which was observed in one of our previous studies.10 This is the case even with the
MeOꢀ substituent in the paraꢀposition (1c, Scheme 1). We previously hypothesized that the methoxy group might
favor the ipsoꢀ5ꢀexo cyclization due to stabilization of the cyclic radical intermediates. In order to provide insight
into these contrasting results, we included calculations of the transition states (and product) structures for the 6ꢀexo
and ipsoꢀ5ꢀexo cyclizations of 20, 24 and 25 within the current computational study.
For 20 and 24, the transition state free energies are significantly lower for the 6ꢀexo cyclizations (a) than
for the alternative ipsoꢀ5ꢀexo cyclizations (b) (Table 4). However, for the amide system (25) used in our earlier
spirocyclization report,10 the ipsoꢀ5ꢀexo cyclization (25-b) has a significantly lower transition state energy and the
cyclization process is significantly exergonic. A careful look at both the transition state and product structures of 25-
a and 25-b indicates that the amide system is more planar in 25-b than in 25-a (Figure 3, Experimental Section).
Table 4. Relative 298 K free energies (kcal/mol) in CH3CN for transition states (TS) and products (PD) for
structures 17, 21 and 22: 6ꢀexo vs ipsoꢀ5ꢀexo cyclization.
20-a
12.6
ꢀ0.5
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16
24-a
11.7
0.5
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16.6
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0.1
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8.7
TS
PD
0.2
ꢀ8.2
That is, there is greater conjugation within the NꢀCO function (shorter distance) in 25-b than in 25-a. This seems to
be due to the intrinsically favored planar structure of a 5ꢀmembered ring, compared to a 6ꢀmembered ring.
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These results lead us to conclude that the ipsoꢀ5ꢀexo cyclization of radical 25 is most likely kinetically
favored because of its amide function and not because of its pꢀmethoxy substituent, which then explains why we
observed only the 6ꢀexo cyclization products in the present work.
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The computational calculations show that the presence of the gemꢀdiester groups favors the cyclization
both kinetically (lower transition state free energy) and thermodynamically (more exergonic reactions), relative to
the unsubstituted systems. The farther the gemꢀdiester groups are from the reactive CH radical site of the
intermediate (i.e., A), the more favorable is its cyclization. Finally, the ipsoꢀ5ꢀexo cyclizations are preferred only
for the rigid systems, such radical 25 with its amide group, which facilitate the intrinsically planar structure of the 5ꢀ
membered ring that is being formed.
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CONCLUSIONS
In conclusion, photoꢀredox catalyzed radical difluoromethylations and fluoroalkylations of unactivated
alkenes coupled with cyclization of the resultant radical with an aryl ring to form fluoroalkyl tetralins is reported. In
order for the cyclization reactions to be efficient, gemꢀdiester substituents are crucial, likely as a result of the
resultant ThorpeꢀIngold effect, which allows cyclization to compete favorably with the chlorination side reaction.
This work comprises the first example of introduction of difluoromethyl groups into the tetralin skeleton system.
Furthermore, the study provides a unified strategy for introduction of other valuable perfluoroalkyl and partially
fluorinated alkyl groups into the tetralin system under mild conditions in moderate to good yield. A computational
study provided mechanistic insights, including that 6ꢀexo cyclizations to a phenyl ring are faster than 5ꢀexo
cyclizations. Further investigations of this reaction system, including kinetic studies are under way in our laboratory.
EXPERIMENTAL SECTION
All reactions were carried out under N2 atmosphere. All anhydrous solvents were purchased from Aldrich and stored
over 4A molecular sieves. Reagents were purchased at commercial quality and were used without further
1
purification. All NMR spectra were run using CDCl3 as solvent, unless otherwise specified. H NMR spectra were
recorded at 500 MHz unless otherwise specified, and chemical shifts are reported in ppm relative to TMS. 19F NMR
spectra were recorded at 282 MHz, and chemical shifts are reported in ppm relative to CFCl3 as the external
standard. 13C NMR spectra were recorded at 126 MHz unless otherwise specified, with proton decoupling, and
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chemical shifts are reported in ppm relative to CDCl3 (ꢀ77.0 ppm) as the reference. The visible light was generated
from a fluorescent light bulb (daylight GE Energy Smart™, 26 W, 1600 lumens). Blue led was bought from FEIT
Electric (16 W, 120 VAC, 60 Hz, 130 mA). All the sulfonyl chlorides and difluoroacetic esters and amides were
prepared by literature procedures.7,12
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Synthesis of substrates. All starting materials were prepared according to previously reported procedures, which
are exemplified by the equations in Scheme 4.13b
Scheme 4. Synthesis of starting matierials
fac-Ir(ppy)3 catalyzed intramolecular fluoroalkylarylation of unactived alkenes. To an ovenꢀdried 17 × 60 mm
(8 mL) borosilicate vial equipped with a magnetic stirrer, were added diethyl 2-allyl-2-benzylmalonate (1a) (58.0 mg,
0.2 mmol), facꢀIr(ppy)3 (2.4 mg, 0.004 mmol, 0.002 eq) and Na2HPO4 (57 mg, 0.4 mmol, 2.0 equiv). To this mixture
were added 2 mL CH3CN and CF2HSO2Cl (60 mg, 0.4 mmol, 2 equiv) under a blanket of nitrogen. The vial was
sealed, and stirred under blue led at room temperature for 18 hr. The temperature would gradually increasing to 55
℃ heated by the light. After this time, the CH3CN was removed in vacuo, and the residue purified by column
chromatography on silica gel eluting with hexanes/ethyl acetate (15:1) to (5:1). This gave product 2a as colorless oil
(54 mg, 80% yield).
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Diethyl 4-(2,2-difluoroethyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2a). H NMR δ 7.16 (d, J =
14.7 Hz, 4H), 5.98 (tdd, J = 56.7, 6.0, 3.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.10 (tq, J = 7.1, 3.3, 2.5 Hz, 2H), 3.34
(dd, J = 15.8, 2.3 Hz, 1H), 3.26 – 3.16 (m, 2H), 2.73 (dd, J = 13.2, 5.7 Hz, 1H), 2.57 – 2.37 (m, 1H), 2.17 – 2.01 (m,
1H), 1.97 (dd, J = 13.6, 10.1 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.67 , 170.49 ,
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136.87 , 134.09 , 129.27 , 126.84 , 126.70 , 126.60 , 119.37 – 112.50 (m), 61.81 , 61.49 , 53.73 , 40.60 (t, J = 20.6
Hz), 35.19 , 34.53 , 30.71 (t, J = 5.7 Hz), 14.06 , 13.94 . 19F NMR δ ꢀ110.54 – ꢀ120.33 (m). HRMS (ESI/TOF) m/z:
[M + H]+ Calcd for C18H23F2O4 341.1559; Found 341.1562.
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Diethyl 4-(2,2-difluoroethyl)-6-methyl-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2b).
Prepared
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according to general method and isolated in 82% yield after chromatography as a colorless oil (58.0 mg ). H NMR
δ 7.03 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 10.3 Hz, 2H), 5.98 (tdd, J = 56.6, 5.9, 3.5 Hz, 1H), 4.21 (qd, J = 7.1, 1.4 Hz,
2H), 4.11 (qd, J = 7.1, 5.5 Hz, 2H), 3.30 (dd, J = 16.2, 2.1 Hz, 1H), 3.20 (d, J = 7.2 Hz, 1H), 3.14 (d, J = 16.0 Hz,
1H), 2.71 (ddd, J = 13.8, 7.0, 2.1 Hz, 1H), 2.46 (qt, J = 15.7, 5.2 Hz, 1H), 2.30 (s, 3H), 2.14 – 1.99 (m, 1H), 1.95 (dd,
J = 13.6, 10.1 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR δ 171.8, 170.6, 136.6, 136.4,
131.0, 129.2, 127.6, 127.4, 116.6 (t, J = 239.4 Hz), 61.8, 61.5, 53.8, 40.8 (t, J = 20.6 Hz), 34.9, 34.6, 31.1, 30.4 (m),
21.3, 14.2, 14.0 . 19F NMR δ ꢀ114.70 – ꢀ115.26 (m). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C19H25F2O4
355.1715; Found 355.1708.
Diethyl 4-(2,2-difluoroethyl)-6-methoxy-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2c). Prepared
according to general method and isolated in 74% yield after chromatography as a colorless oil (55 mg ). 1H NMR δ
7.05 (d, J = 8.3 Hz, 1H), 6.75 – 6.69 (m, 1H), 6.69 (d, J = 2.6 Hz, 1H), 5.98 (tdd, J = 56.5, 5.9, 3.6 Hz, 1H), 4.20 (qd,
J = 7.1, 1.7 Hz, 2H), 4.10 (qd, J = 7.1, 3.4 Hz, 2H), 3.77 (s, 3H), 3.30 – 3.23 (m, 1H), 3.20 (t, J = 5.2 Hz, 1H), 3.14
– 3.08 (m, 1H), 2.70 (ddd, J = 13.6, 6.7, 2.0 Hz, 1H), 2.52 – 2.32 (m, 1H), 2.14 – 1.97 (m, 1H), 1.93 (dd, J = 13.6,
10.0 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.8, 170.6, 158.5, 138.1, 130.2, 126.2,
116.5 (t, J = 239.4 Hz), 112.5, 112.2, 61.8, 61.5, 55.4, 53.9, 40.8 (t, J = 20.7 Hz), 34.6, 34.5, 31.4, 30.5 (m), 14.1,
14.0. 19F NMR δ ꢀ114.93 (AB, ddd, J = 56.7, 27.5, 15.9 Hz, 1F), ꢀ115.00 (AB, ddd, J = 56.6, 32.4, 15.9 Hz, 1F).
HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C19H25F2O5 371.1665; Found 371.1674.
Diethyl 4-(2,2-difluoroethyl)-6-phenyl-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2d).
Prepared
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according to general method and isolated in 80% yield after chromatography as a colorless oil (67 mg ). H NMR δ
7.58 – 7.53 (m, 2H), 7.44 (dd, J = 8.5, 6.8 Hz, 2H), 7.41 – 7.37 (m, 2H), 7.37 – 7.31 (m, 1H), 7.23 (d, J = 8.3 Hz,
1H), 6.03 (tdd, J = 56.5, 5.9, 3.5 Hz, 1H), 4.25 (qd, J = 7.1, 1.5 Hz, 2H), 4.15 (qd, J = 7.1, 5.0 Hz, 2H), 3.43 – 3.37
(m, 1H), 3.35 – 3.28 (m, 1H), 3.24 (d, J = 16.0 Hz, 1H), 2.78 (ddd, J = 13.9, 6.6, 2.1 Hz, 1H), 2.63 – 2.44 (m, 1H),
2.21 – 2.07 (m, 1H), 2.03 (dd, J = 13.6, 10.1 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR δ
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171.7, 170.6, 141.0, 140.0, 137.3, 133.2, 129.8, 128.9, 127.4, 127.1, 125.6, 116.5 (t, J = 239.4 Hz), 61.9, 61.6, 53.8,
40.8 (t, J = 20.7 Hz), 35.0, 34.6, 31.2, 30.6 (m), 14.1, 14.0. 19F NMR δ ꢀ114.87 (AB, ddd, J = 56.7, 21.4, 16.0 Hz,
1F), ꢀ114.93 (AB, ddd, J = 54.0, 24.3, 16.2 Hz, 1F). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C24H26F2O4
417.1872; Found 417.1865.
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Diethyl 4-(2,2-difluoroethyl)-6-fluoro-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2e).
Prepared
according to general method and isolated in 85% yield after chromatography as a colorless oil (61 mg ). 1H NMR δ
7.13 – 7.06 (m, 1H), 6.87 (ddd, J = 13.5, 7.3, 4.2 Hz, 2H), 5.98 (tdd, J = 56.4, 5.7, 3.4 Hz, 1H), 4.21 (qd, J = 7.1, 1.3
Hz, 2H), 4.11 (qd, J = 7.1, 2.2 Hz, 2H), 3.30 (dd, J = 15.7, 2.0 Hz, 1H), 3.20 (dq, J = 10.2, 5.1 Hz, 1H), 3.12 (d, J =
15.9 Hz, 1H), 2.72 (ddd, J = 13.7, 6.8, 2.0 Hz, 1H), 2.48 – 2.30 (m, 1H), 2.15 – 1.98 (m, 1H), 1.93 (dd, J = 13.6,
10.2 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.5, 170.4, 161.8 (d, J = 244.5 Hz),
139.1 (d, J = 6.8 Hz), 130.7 (d, J = 8.1 Hz), 129.8 (d, J = 3.0 Hz), 116.3 (t, J = 240.0 Hz), 113.9(d, J = 21.4 Hz),
113.4 (d, J = 21.7 Hz), 62.0, 61.7, 53.8, 40.5 (t, J = 20.8 Hz), 34.6, 34.3, 30.9 (t, J = 5.3 Hz), 14.1, 14.0. 19F NMR δ
ꢀ115.02 (AB, ddd, J = 56.5, 19.6, 16.1 Hz, 1F), ꢀ115.09 (AB, ddd, J = 54.0, 21.6, 16.1 Hz, 1F), ꢀ115.62 – ꢀ115.87 (m,
1F). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C18H22F3O4 359.1465; Found 359.1433.
Diethyl 6-chloro-4-(2,2-difluoroethyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2f).
Prepared
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according to general method and isolated in 86% yield after chromatography as a colorless oil (64 mg ). H NMR δ
7.16 (d, J = 2.1 Hz, 1H), 7.14 – 7.10 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 5.98 (tdd, J = 56.3, 5.9, 3.5 Hz, 1H), 4.21 (qd,
J = 7.1, 1.2 Hz, 2H), 4.15 – 4.06 (m, 2H), 3.33 – 3.25 (m, 1H), 3.19 (dq, J = 10.2, 5.4, 4.9 Hz, 1H), 3.12 (d, J = 16.1
Hz, 1H), 2.77 – 2.66 (m, 1H), 2.51 – 2.32 (m, 1H), 2.04 (dddd, J = 24.4, 18.7, 12.2, 3.6 Hz, 1H), 1.93 (dd, J = 13.7,
10.2 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR δ 171.4, 170.3, 138.9, 132.7, 132.6, 130.6,
126.9, 126.9, 116.2 (t, J = 239.7 Hz), 62.0, 61.7, 53.6, 40.5 (t, J = 20.8 Hz), 34.7, 34.3, 31.1, 30.3 (m), 14.1, 14.0.
19F NMR δ ꢀ114.76 – ꢀ115.57 (m). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C18H22ClF2O4 375.1169; Found
375.1155.
Diethyl 6-bromo-4-(2,2-difluoroethyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2g).
Prepared
according to general method and isolated in 86% yield after chromatography as a colorless oil (72 mg ). 1H NMR δ
7.33 (s, 1H), 7.28 (dt, J = 8.6, 1.5 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.99 (tdd, J = 56.4, 5.7, 3.3 Hz, 1H), 4.27 – 4.19
(m, 2H), 4.13 (qd, J = 7.2, 5.4 Hz, 2H), 3.30 (dd, J = 15.9, 2.0 Hz, 1H), 3.26 – 3.16 (m, 1H), 3.12 (d, J = 16.1 Hz,
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1H), 2.73 (dd, J = 13.6, 6.1 Hz, 1H), 2.44 (qt, J = 15.7, 4.8 Hz, 1H), 2.06 (ddt, J = 14.3, 10.2, 4.6 Hz, 1H), 1.95 (dd,
J = 13.7, 10.2 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.4, 170.3, 139.3, 133.2,
130.9, 129.8, 129.8, 120.6, 118.5, 113.64 (m), 62.0, 61.7, 53.5, 40.4 (t, J = 20.8 Hz), 34.7, 34.2, 30.7 (t, J = 5.7 Hz),
14.1, 14.0. 19F NMR δ ꢀ114.87 – ꢀ115.34 (m). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C18H22BrF2O4 419.0664;
Found 419.0683.
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Diethyl 4-(2,2-difluoroethyl)-6-(trifluoromethyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2h).
Prepared according to general method and isolated in 87% yield after chromatography as a colorless oil (75 mg ).
1H NMR δ 7.43 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.00 (tdd, J = 56.3, 5.7, 3.4 Hz, 1H), 4.25
– 4.18 (m, 2H), 4.16 – 4.08 (m, 2H), 3.39 (d, J = 16.3 Hz, 1H), 3.30 – 3.15 (m, 2H), 2.83 – 2.71 (m, 1H), 2.55 – 2.39
(m, 1H), 2.15 – 2.02 (m, 1H), 1.99 (dd, J = 13.7, 10.2 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).
13C NMR δ 171.3, 170.3, 138.4, 137.9, 129.8, 129.3 (q, J = 32.3 Hz), 124.2 (q, J = 271.9 Hz), 123.7 (q, J = 3.9 Hz),
123.5 (q, J = 3.8 Hz), 116.2 (t, J = 239.8 Hz), 62.1, 61.8, 53.5, 40.4 (t, J = 20.8 Hz), 35.2, 34.3, 31.8, 29.80 (m), 14.1,
14.0. 19F NMR δ ꢀ62.50 (s, 3F), ꢀ114.97 – ꢀ115.52 (m, 2F). HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for
C19H21F5O4Na 431.1252; Found 431.1254.
Diethyl 6-cyano-4-(2,2-difluoroethyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2i).
Prepared
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according to general method and isolated in 58% yield after chromatography as a colorless oil (42 mg ). H NMR δ
7.50 (s, 1H), 7.48 – 7.41 (m, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.01 (tdd, J = 56.1, 5.6, 3.4 Hz, 1H), 4.23 (q, J = 7.1 Hz,
2H), 4.18 – 4.10 (m, 2H), 3.40 (d, J = 16.9 Hz, 1H), 3.22 (d, J = 16.5 Hz, 2H), 2.76 (dd, J = 13.6, 5.7 Hz, 1H), 2.46
(tdd, J = 16.2, 11.2, 5.1 Hz, 1H), 2.09 (ddt, J = 18.2, 8.4, 4.0 Hz, 1H), 1.99 (dd, J = 13.7, 10.3 Hz, 1H), 1.31 – 1.24
(m, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.1, 170.1, 140.1, 138.6, 130.7, 130.2, 130.1, 118.8, 116.0 (td, J =
240.5, 239.9, 3.0 Hz), 110.9, 62.2, 61.9, 53.3, 40.1 (t, J = 21.1 Hz), 35.3, 34.1, 30.5, 14.1, 14.0. 19F NMR δ ꢀ115.01
– ꢀ115.48 (m). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C19H22F2NO4 366.1511; Found 366.1522.
Diethyl 4-(2,2-difluoroethyl)-5,7-dimethyl-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2j). Prepared
according to general method and isolated in 73% yield after chromatography as a colorless oil (54 mg ), 1H NMR δ
6.85 (d, J = 1.9 Hz, 1H), 6.80 (d, J = 1.9 Hz, 1H), 5.91 (tdd, J = 56.5, 5.7, 3.5 Hz, 1H), 4.30 – 4.16 (m, 2H), 4.04 (q,
J = 7.1 Hz, 2H), 3.45 (ddt, J = 11.2, 8.1, 4.2 Hz, 1H), 3.19 (s, 2H), 2.61 (dd, J = 14.3, 7.5 Hz, 1H), 2.28 – 2.26 (m,
1H), 2.25 (d, J = 3.8 Hz, 6H), 2.10 – 1.82 (m, 2H), 1.28 (td, J = 7.1, 0.9 Hz, 3H), 1.07 (td, J = 7.1, 0.9 Hz, 3H). 13
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NMR δ 172.5, 171.1, 136.1, 135.12, 134.0, 133.7, 130.4, 127.8, 116.8 (t, J = 239.4 Hz), 61.9, 61.5, 54.0, 39.9 (t, J =
20.2 Hz), 35.3, 34.1, 28.8 (dd, J = 7.0, 4.1 Hz), 20.9, 19.1, 14.1, 14.0. 19F NMR δ ꢀ115.17 (AB, dddd, J = 296.1,
56.4, 16.3, 13.6 Hz), ꢀ116.88 (AB, dddd, J = 284.8, 57.1, 22.6, 16.0 Hz). HRMS (ESI/TOF) m/z: [M + H]+ Calcd
for C20H27F2O4 369.1872; Found 369.1889.
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Diethyl 4-(2,2-difluoroethyl)-5,7-dimethoxy-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2k) Prepared
according to general method and isolated in 85% yield after chromatography as a colorless oil (68 mg ), 1H NMR δ
6.29 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.87 (tt, J = 57.0, 5.1 Hz, 1H), 4.21 (dddd, J = 17.9, 10.8, 7.1, 3.7
Hz, 2H), 4.07 (dt, J = 7.5, 6.5 Hz, 2H), 3.77 (s, 6H), 3.40 (qd, J = 7.5, 3.4 Hz, 1H), 3.24 – 3.04 (m, 2H), 2.68 (ddd, J
= 13.9, 7.9, 2.0 Hz, 1H), 2.41 – 2.25 (m, 1H), 2.08 (dd, J = 14.0, 7.0 Hz, 1H), 1.99 – 1.74 (m, 1H), 1.27 (t, J = 7.1
Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H). 13C NMR δ 172.0, 170.6, 159.2, 158.1, 136.2, 118.2, 117.6 (t, J = 239.0 Hz), 104.8,
97.2, 61.9, 61.4, 55.4 (d, J = 7.8 Hz), 53.8, 39.9 (t, J = 19.9 Hz), 36.0, 34.7, 26.7 (t, J = 5.9 Hz), 14.1, 14.0. 19F
NMR δ ꢀ113.92 (AB, dddd, J = 282.0, 57.1, 21.2, 14.5 Hz), ꢀ115.34 (AB, dddd, J = 282.0, 56.8, 20.2, 13.7 Hz).
HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for C20H26F2O6Na 423.1590; Found 423.1591.
Diethyl 4-(2,2-difluoroethyl)-5,7-difluoro-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (2l) Prepared
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according to general method and isolated in 63% yield after chromatography as a colorless oil (47 mg ), H NMR δ
6.81 – 6.50 (m, 2H), 5.91 (tt, J = 56.5, 4.8 Hz, 1H), 4.29 – 4.16 (m, 2H), 4.11 – 4.05 (m, 2H), 3.48 (d, J = 8.8 Hz,
1H), 3.26 – 3.14 (m, 2H), 2.74 (dd, J = 14.6, 8.1 Hz, 1H), 2.44 – 2.23 (m, 1H), 2.10 – 2.02 (m, 1H), 2.04 – 1.91 (m,
1H), 1.28 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.2, 169.9, 162.1 (dd, J = 53.6, 12.9 Hz), 160.1
(dd, J = 53.8, 13.4 Hz), 138.1 (dd, J = 9.3, 5.9 Hz), 120.4 (m), 116.4 (t, J = 239.8 Hz), 111.6 (dd, J = 21.0, 3.4 Hz),
102.5 (dd, J = 26.7, 25.3 Hz), 62.0, 61.6, 53.5, 40.6, 38.7 (m), 35.3, 34.0, 26.37 (d, J = 5.6 Hz), 14.0, 13.9. 19F NMR
δ ꢀ110.91 (t, J = 9.3 Hz, 1F), ꢀ112.77 (q, J = 8.4 Hz), ꢀ114.70 – ꢀ115.39 (m). HRMS (ESI/TOF) m/z: [M + H]+
Calcd for C18H21F4O4 377.1370; Found 377.1376.
Diethyl 1-(2,2-difluoroethyl)-1,4-dihydrophenanthrene-3,3(2H)-dicarboxylate (2m) Prepared according to
1
general method and isolated in 49% yield after chromatography as a colorless oil (38 mg ), H NMR δ 8.08 – 8.02
(m, 1H), 7.85 – 7.78 (m, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.56 – 7.53 (m, 1H), 7.50 – 7.45 (m, 1H), 7.30 (d, J = 8.6 Hz,
1H), 6.15 – 5.82 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.14 – 3.95 (m, 3H), 3.92 (d, J = 16.5 Hz, 1H), 3.51 – 3.29 (m,
2H), 2.83 (dd, J = 13.8, 6.8 Hz, 1H), 2.61 – 2.29 (m, 1H), 2.07 (dd, J = 13.6, 9.7 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H),
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1.05 (t, J = 7.1 Hz, 3H). 13C NMR δ 172.0, 170.5, 133.8, 132.3, 132.1, 129.3, 128.5, 127.3, 126.6, 125.7, 125.2,
123.2, 116.6 (t, J = 241.5 Hz), 62.1, 61.6, 53.7, 42.4, 39.99 (m), 34.1, 31.5, 31.2, 14.2, 14.0. 19F NMR δ ꢀ114.82
(AB, ddd, J = 56.7, 48.1, 15.8 Hz), δ ꢀ114.82 (AB, ddd, J = 56.7, 15.8, 11.1 Hz). HRMS (ESI/TOF) m/z: [M + H]+
Calcd for C22H25F2O4 391.1715; Found 371.1698.
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Diethyl 4-(2,2-difluoroethyl)-4-methyl-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (3a).
Prepared
1
according to general method and isolated in 77% yield after chromatography as a colorless oil (50 mg ), H NMR δ
7.31 – 7.21 (m, 2H), 7.21 – 7.17 (m, 2H), 5.76 (tdd, J = 56.1, 5.8, 3.5 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.36 (d, J
= 16.1 Hz, 1H), 3.18 (d, J = 16.0 Hz, 1H), 2.59 (d, J = 14.6 Hz, 1H), 2.38 (d, J = 14.6 Hz, 1H), 2.24 (qd, J = 15.2,
5.9 Hz, 1H), 2.12 (tdd, J = 18.6, 15.0, 3.5 Hz, 1H), 1.37 (s, 3H). 13C NMR δ 172.1, 171.8, 140.8, 133.2, 129.3, 127.2,
126.8, 126.0, 116.6 (t, J = 239.0 Hz), 53.0, 52.7, 52.5, 47.0 (t, J = 19.8 Hz), 39.8, 35.3, 34.9 (t, J = 5.1 Hz), 30.5. 19
F
NMR δ ꢀ111.06 (ddd, J = 56.2, 18.5, 15.3 Hz). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C19H25F2O4 327.1402;
Found 327.1409.
Trimethyl 1-(2,2-difluoroethyl)-1,4-dihydronaphthalene-1,3,3(2H)-tricarboxylate (3b). Prepared according
1
to general method and isolated in 61% yield after chromatography as a colorless oil (45 mg ), H NMR δ 7.33 – 7.22
(m, 3H), 7.22 – 7.17 (m, 1H), 5.89 (tdd, J = 56.1, 5.5, 3.7 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.67 (s, 3H), 3.35 (d, J
= 15.9 Hz, 1H), 3.16 (d, J = 15.8 Hz, 1H), 3.13 (d, J = 15.1 Hz, 1H), 2.84 (qd, J = 14.6, 14.0, 5.4 Hz, 1H), 2.61 (d, J
= 14.8 Hz, 1H), 2.42 (dtd, J = 20.8, 14.4, 3.7 Hz, 1H). 13C NMR δ 174.4 , 171.8, 171.2, 134.5, 134.4, 129.4, 127.9,
127.3, 127.2, 35.0, 34.6 (m), 116.0 (t, J = 239.5 Hz), 53.1, 53.0 , 52.8, 46.5– 46.2 (m), 43.4 (t, J = 21.9 Hz), 41.3,
35.3, 34.9. 19F NMR δ ꢀ112.01 – ꢀ112.50 (m). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C18H21F2O6 371.1301;
Found 371.1305.
Diethyl 4-(2,2-difluoroethyl)-3,4-dihydronaphthalene-1,1(2H)-dicarboxylate (5). Prepared according to
1
general method and isolated in 64% yield after chromatography as a colorless oil (44 mg), H NMR δ 7.43 (dd, J =
7.9, 1.5 Hz, 1H), 7.28 (dd, J = 7.5, 1.5 Hz, 1H), 7.23 – 7.15 (m, 2H), 5.93 (tt, J = 56.5, 4.6 Hz, 1H), 4.35 – 4.09 (m,
4H), 3.15 (dd, J = 9.6, 4.9 Hz, 1H), 2.45 (qd, J = 5.5, 4.7, 3.3 Hz, 2H), 2.33 – 1.94 (m, 3H), 1.87 – 1.71 (m, 1H),
1.28 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.7, 171.3, 139.2, 132.3, 130.8, 128.8, 128.3, 126.4,
116.7 (t, J = 239.3 Hz), 62.0, 62.0, 58.9, 40.9 (t, J = 20.4 Hz), 32.4 (t, J = 5.3 Hz), 27.4 , 24.8, 14.2, 14.1. 19F NMR
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δ ꢀ115.48 (dddd, J = 56.5, 31.6, 18.5, 16.3 Hz). HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for C18H22F2O4Na
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363.1384; Found 363.1385.
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Diethyl 3-(2,2-difluoroethyl)-2,3-dihydro-1H-indene-1,1-dicarboxylate (6a). Prepared according to general
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method and isolated in 25% yield after chromatography as a colorless oil (16.3 mg ), H NMR δ 7.59 (dd, J = 7.5,
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1.6 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.22 – 7.18 (m, 1H), 6.00 (tt, J = 56.4, 4.6 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.23
– 4.14 (m, 2H), 3.52 (dt, J = 11.8, 5.9 Hz, 1H), 3.05 (dd, J = 13.6, 7.9 Hz, 1H), 2.56 – 2.34 (m, 2H), 2.13 – 1.93 (m,
1H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR δ 170.7, 170.4, 145.8, 139.0, 129.1, 127.6, 127.1,
123.6, 119.9, 112.7 (m), 65.0, 61.98, 61.95, 40.6, 39.6 (t, J = 21.0 Hz), 37.3, 14.2, 14.1. 19F NMR δ ꢀ115.15 (dtd, J
= 56.4, 17.4, 9.2 Hz). HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for C17H20F2O4Na 349.1222; Found 349.1215.
1,1-Diethyl 3-methyl 3-(2,2-difluoroethyl)-2,3-dihydro-1H-indene-1,1,3-tricarboxylate (6b). Prepared
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according to general method and isolated in 98% yield after chromatography as a colorless oil (75 mg ), H NMR δ
7.59 – 7.53 (m, 1H), 7.36 (d, J = 2.7 Hz, 3H), 5.97 (tt, J = 56.1, 4.8 Hz, 1H), 4.29 – 4.18 (m, 4H), 3.64 (s, 3H), 3.41
(d, J = 14.4 Hz, 1H), 3.07 (d, J = 14.5 Hz, 1H), 2.88 (dddd, J = 19.5, 14.6, 13.0, 4.6 Hz, 1H), 2.27 (dddd, J = 19.4,
14.6, 12.7, 4.9 Hz, 1H), 1.29 (td, J = 7.1, 3.5 Hz, 6H). 13C NMR δ 173.5, 170.1, 170.0, 143.7, 138.9, 129.5, 129.0,
127.0, 124.3, 115.9 (t, J = 239.9 Hz), 65.0, 62.4, 62.0, 53.9 (t, J = 5.2 Hz), 52.8, 42.6 (t, J = 21.5 Hz), 41.1, 14.1. 19
F
NMR δ ꢀ113.16 (AB, dddd, J = 290.5, 56.0, 18.4, 13.8 Hz), δ ꢀ114.50 (AB, dddd, J = 290.5, 56.2, 19.5, 13.5 Hz).
HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for C19H22F2O6Na 407.1277; Found 407.1278.
Diethyl 4-(2,2-difluoropropyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (7). Prepared according to
1
general method and isolated in 64% yield after chromatography as a colorless oil (45 mg ), H NMR δ 7.21 – 7.08
(m, 4H), 4.21 (qd, J = 7.0, 1.4 Hz, 2H), 4.15 – 4.06 (m, 2H), 3.33 (dd, J = 15.9, 2.2 Hz, 1H), 3.28 (d, J = 9.2 Hz, 1H),
3.22 – 3.17 (m, 1H), 2.90 – 2.79 (m, 1H), 2.51 (dtd, J = 22.0, 15.2, 3.0 Hz, 1H), 2.07 (ddt, J = 20.1, 14.6, 9.8 Hz,
1H), 1.93 (dd, J = 13.8, 10.3 Hz, 1H), 1.70 (t, J = 18.4 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H).
13C NMR δ 171.9, 170.7, 138.0, 134.2, 129.2, 127.1, 126.9, 126.4, 126.3, 122.1 (m), 61.8, 61.5, 54.0, 45.2 (t, J =
24.5 Hz), 35.8, 35.4, 31.1 (t, J = 3.7 Hz), 24.1 (t, J = 27.8 Hz), 14.2, 14.0. 19F NMR δ ꢀ87.02 (AB, ddqd, J =229.5,
21.4, 18.6, 10.2 Hz, 1F), ꢀ89.63 (AB, dpd, J = 229.5, 18.5, 15.1 Hz, 1F). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for
C19H25F2O4 355.1715; Found 355.1714.
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Diethyl 4-(2,2,2-trifluoroethyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (8). Prepared according to
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general method and isolated in 70% yield after chromatography as a colorless oil (50 mg ), H NMR δ 7.23 – 7.10
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(m, 4H), 4.22 (qd, J = 7.1, 0.9 Hz, 2H), 4.15 – 4.07 (m, 2H), 3.34 (dd, J = 16.0, 2.1 Hz, 1H), 3.24 – 3.15 (m, 1H),
2.84 (dd, J = 13.7, 6.6 Hz, 1H), 2.77 (ddd, J = 15.1, 11.7, 3.3 Hz, 1H), 2.28 (dt, J = 15.3, 10.4 Hz, 1H), 1.97 (dd, J =
13.8, 10.1 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H). 13C NMR δ 171.7, 170.5, 136.3, 134.2, 129.4,
127.1, 127.0 (q, J = 278.4 Hz), 126.89, 126.88, 61.9, 61.6, 53.8, 41.0 (q, J = 27.5 Hz), 35.3, 35.0, 30.7 (d, J = 2.8
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Hz), 14.2, 14.0. 19F NMR δ ꢀ63.53 (t, J = 11.2 Hz). Its H NMR, 13C and 19F NMR were consistent with data
reported in the literature.30
Diethyl
4-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate
(9).
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Prepared according to general method and isolated in 90% yield after chromatography as a colorless oil (91 mg ), H
NMR δ 7.32 – 7.11 (m, 4H), 4.24 (m, 2H), 4.19 – 4.05 (m, 2H), 3.51 (dd, J = 10.3, 7.3 Hz, 1H), 3.37 (dd, J = 16.4,
2.0 Hz, 1H), 3.27 – 3.20 (m, 1H), 2.91 (ddt, J = 13.9, 6.7, 2.1 Hz, 1H), 2.75 (ddd, J = 34.5, 15.9, 7.5 Hz, 1H), 2.30
(ddt, J = 31.6, 16.2, 8.9 Hz, 1H), 2.07 – 1.99 (m, 1H), 1.30 (t, J = 7.1 Hz, 4H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR δ
171.6, 170.4, 136.6, 134.3, 129.5, 127.2, 127.1, 126.9, 121.5, 106.1 (m), 62.0, 61.6, 53.9, 38.2 (t, J = 20.9 Hz), 35.8
(d, J = 3.1 Hz), 35.3, 29.6 (d, J = 3.1 Hz), 14.1, 14.0. 19F NMR δ ꢀ81.04 (tt, J = 9.7, 3.3 Hz), ꢀ109.84 – ꢀ115.91 (m),
ꢀ124.37 (ddd, J = 10.3, 5.1, 2.8 Hz), ꢀ125.64 – ꢀ126.12 (m). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C21H22F9O4
509.1369; Found 509.1379.
Diethyl
4-(3-ethoxy-2,2-difluoro-3-oxopropyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate
(10).
Prepared according to general method and isolated in 84% yield after chromatography as a colorless oil (69.2 mg ),
1H NMR (300 MHz) δ 7.20 – 7.16 (m, 2H), 7.14 – 7.10 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H),
4.09 (qd, J = 7.1, 1.9 Hz, 2H), 3.39 – 3.27 (m, 2H), 3.18 (dd, J = 15.9, 1.2 Hz, 1H), 2.90 – 2.62 (m, 2H), 2.28 (dddd,
J = 20.1, 15.2, 12.2, 9.4 Hz, 1H), 2.07 – 1.89 (m, 1H), 1.36 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.12 (t, J =
7.1 Hz, 3H). 13C NMR δ 171.8, 170.5, 164.7 ꢀ 163.8 (m), 137.0, 134.3, 129.3, 127.2, 127.0, 126.7, 63.2, 61.9, 61.5,
53.9, 41.9 (t, J = 22.4 Hz), 35.5, 35.4, 31.7, 14.2, 14.1, 14.0. 19F NMR δ ꢀ102.22 (AB, ddd, J = 260.9, 21.6, 12.2 Hz),
ꢀ105.17 (AB, ddd, J = 260.9, 20.1, 16.4 Hz). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C21H27F2O6 413.1770;
Found 413.1773.
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Diethyl 4-(2,2-difluoro-3-oxo-3-(phenylamino)propyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (11).
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Prepared according to general method and isolated in 82% yield after chromatography as a colorless oil (75 mg ), H
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NMR δ 8.22 (s, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.9 Hz, 2H), 7.27 (d, J = 8.2 Hz, 1H), 7.20 (q, J = 8.7, 7.9
Hz, 2H), 7.15 (d, J = 5.9 Hz, 2H), 4.22 (qd, J = 7.0, 2.0 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 3.41 – 3.30 (m, 2H), 3.23
(d, J = 16.0 Hz, 1H), 2.94 (dddd, J = 28.5, 15.2, 7.0, 4.3 Hz, 2H), 2.46 – 2.30 (m, 1H), 2.08 – 1.94 (m, 1H), 1.27 (t, J
= 7.2 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H). 13C NMR δ 171.7, 170.6, 162.1 (t, J = 28.5 Hz), 137.1, 136.1, 134.1, 129.3,
129.2, 127.2, 127.0, 126.6, 125.7, 120.5, 118.5 (t, J = 254.9 Hz), 61.8, 61.5, 53.9, 40.9 (t, J = 22.2 Hz), 35.7 , 35.3,
30.4 (t, J = 3.1 Hz), 14.1, 13.9. 19F NMR δ ꢀ101.37 (AB, dddd, J = 256.6, 21.9, 12.0, 2.7 Hz, 1F), ꢀ105.04 (AB, dddd,
J = 256.6, 20.7, 18.0, 3.2 Hz, 1F). HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C25H28F2NO5 460.1930; Found
460.1952.
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Diethyl 4-(2,2-difluoro-3-morpholino-3-oxopropyl)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (12).
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Prepared according to general method and isolated in 88% yield after chromatography as a colorless oil (80 mg ), H
NMR δ 7.29 (d, J = 7.7 Hz, 1H), 7.17 (td, J = 7.3, 2.2 Hz, 1H), 7.14 – 7.08 (m, 2H), 4.20 (tdd, J = 8.7, 6.5, 1.4 Hz,
2H), 4.09 (dddd, J = 14.1, 12.0, 7.1, 3.6 Hz, 2H), 3.78 (t, J = 4.6 Hz, 2H), 3.76 – 3.69 (m, 4H), 3.67 (dd, J = 10.5,
5.0 Hz, 2H), 3.38 (q, J = 8.8 Hz, 1H), 3.35 – 3.30 (m, 1H), 3.19 (d, J = 15.9 Hz, 1H), 2.99 – 2.81 (m, 2H), 2.32 (ddt,
J = 25.2, 15.7, 10.4 Hz, 1H), 1.98 (dd, J = 13.7, 10.1 Hz, 1H), 1.26 (td, J = 7.1, 1.1 Hz, 3H), 1.11 (td, J = 7.2, 1.2 Hz,
3H). 13C NMR δ 171.8, 170.6, 162.1 (t, J = 29.3 Hz), 137.8, 134.1, 129.1, 127.4, 126.9, 126.5, 119.8 (t, J = 255.5
Hz), 66.9, 66.8, 61.8, 61.4, 54.0 , 46.7 (t, J = 6.4 Hz), 43.6, 42.0 (t, J = 21.7 Hz), 36.1, 35.4, 30.3, 14.1, 14.0. 19F
NMR δ ꢀ95.51 (AB, ddd, J = 282.0, 26.4, 11.5 Hz, 1F), ꢀ99.74 (AB, ddd, J = 282.0, 24.4, 15.6 Hz, 1F). HRMS
(ESI/TOF) m/z: [M + H]+ Calcd for C23H30F2NO6 454.2036; Found 454.2050.
Computational details and results (Table 5 and Figure 3). Molecular optimizations were done at the
M06ꢀ2X/6ꢀ311+G(2df,p) // M06ꢀL/6ꢀ31G(d) level of theory.14,16,30 Frequency calculations were used to characterize
the optimized structures as either minima or transition state, and also to compute thermal contributions to enthalpy
and free energy.31,32 The influence of acetonitrile as a solvent was evaluated using the SMD continuum solvation
model.17
Composite free energies in acetonitrile were computed by summing gasꢀphase M06ꢀL thermal
contributions with SMD/M06ꢀ2X singleꢀpoint energies. Since the Gibbs free energies in the gas phase are calculated
at 0.0446 M (1 atm), and in acetonitrile are reported in a standard state of 1 M, the correction was made by adding ꢀ
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1.9 kcal/mol (RT Ln ([Sln]/[Gas])) to the free energy of each molecule. All density functional calculations were
accomplished with Gaussian 09 revision D.01.33 The discussion presented in the next section is all based on the free
energies obtained for both transition states and products including the solvent effect, and which are contained in
Table 5.
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Table 5. Relative 298 K free energies (kcal/mol) in the gas phase and in CH3CN for transition states (TS) and
products (PD) of all structures calculated.
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TS1
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PD
TS1
8.8
PD
TS1
18.2
20.9
PD
ꢀ2.0
0.7
TS1
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PD
ꢀ14.6
ꢀ13.3
ꢀ21.0
ꢀ17.4
ꢀ10.6
ꢀ7.0
ꢀH(gas)
ꢀG(gas)
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12.3
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8.5
9.2
ꢀ14.0
ꢀ14.6
8.9
ꢀ20.3
ꢀ18.5
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18.8
ꢀ2.1
ꢀ1.3
9.6
ꢀ10.4
ꢀ8.7
ꢀH(slv)
ꢀG(slv)
10.5
11.0
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18
19
TS1
17.1
20.1
PD
2.0
5.5
TS1
19.2
18.8
PD
4.8
4.6
TS1
16.7
17.9
PD
0.5
1.0
ꢀH(gas)
ꢀG(gas)
17.8
18.9
2.9
4.5
19.0
16.8
4.4
2.2
17.1
16.4
1.2
ꢀH(slv)
ꢀG(slv)
ꢀ0.2
20a
21
22
23
TS1
10.4
14.6
PD
ꢀ4.1
0.5
TS1
12.5
15.0
PD
ꢀ3.1
0.1
TS1
13.2
15.7
PD
TS1
8.7
PD
ꢀ4.0
ꢀ0.3
ꢀ7.7
ꢀ4.0
ꢀH(gas)
ꢀG(gas)
12.0
10.4
12.6
ꢀ3.2
ꢀ0.5
12.3
13.0
ꢀ3.0
ꢀ1.6
11.9
12.4
ꢀ4.9
ꢀ3.1
8.7
ꢀ7.9
ꢀ6.0
ꢀH(slv)
ꢀG(slv)
10.2
20a
24a
25a
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TS1
10.4
14.6
PD
ꢀ4.1
0.5
TS1
10.2
13.7
PD
ꢀ2.8
1.8
TS1
15.7
17.0
PD
1.1
2.4
ꢀH(gas)
ꢀG(gas)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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10.4
12.6
ꢀ3.2
ꢀ0.5
10.1
11.7
ꢀ2.2
0.5
15.5
14.8
0.7
0.1
ꢀH(slv)
ꢀG(slv)
20b
TS1
13.5
17.4
24b
TS1
12.9
17.2
25b
TS1
11.8
11.9
PD
ꢀ3.1
0.6
PD
PD
ꢀ4.0
ꢀ0.6
ꢀ6.6
ꢀ6.0
ꢀH(gas)
ꢀG(gas)
14.0
16.0
ꢀ1.6
0.2
14.2
16.6
ꢀ2.4
ꢀ0.9
10.5
8.7
ꢀ6.9
ꢀ8.2
ꢀH(slv)
ꢀG(slv)
Figure 3. Transition state structures for the ipsoꢀ5ꢀexo (left) and 6ꢀexo cyclization of 22 (amide system). Hydrogen
atoms are omitted for clarity.
Supporting Information: NMR spectra of all new compounds and table of atom coordinates
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