Synthesis of Alkylidene(gem-Difluorocyclopropanes) from Propargyl Glycolates by a One-Pot Difluorocyclopropenation/Ireland-Claisen Rearrangement Sequence

Article abstract of DOI:10.1021/acs.joc.7b00197

A one-pot difluorocyclopropenation/Ireland-Claisen rearrangement sequence applied to readily available propargyl glycolates was developed as a route toward functionalized alkylidene(gem-difluorocyclopropanes). This strategy conveniently avoids the isolation of the unstable 3,3-difluorocyclopropenylcarbinyl glycolates arising from the difluorocyclopropenation. The Ireland-Claisen rearrangement proceeds with high diastereoselectivity and chirality transfer to afford alkylidene(gem-difluorocyclopropanes) incorporating a quaternary stereocenter and a protected glycolic acid moiety, which are useful building blocks for the preparation of functionalized gem-difluorocyclopropanes.

Full text of DOI:10.1021/acs.joc.7b00197

Subscriber access provided by University of Newcastle, Australia
Note
Synthesis of Alkylidene(gem-Difluorocyclopropanes) from
Propargyl Glycolates by a One-Pot Difluorocyclopropenation/
Ireland-Claisen Rearrangement Sequence
Guillaume Ernouf, Jean-Louis Brayer, Benoît Folleas, Jean-
Pierre Demoute, Christophe Meyer, and Janine Cossy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00197 • Publication Date (Web): 09 Mar 2017
Downloaded from http://pubs.acs.org on March 9, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of Alkylidene(gem-Difluorocyclopropanes) from Propargyl Glycolates by a
One-Pot Difluorocyclopropenation/Ireland-Claisen Rearrangement Sequence
Guillaume Ernouf,† JeanꢀLouis Brayer,‡ Benoît Folléas,‡ JeanꢀPierre Demoute,‡ Christophe
Meyer,*† and Janine Cossy*†
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI),
ESPCI Paris, CNRS (UMR8231), PSL Research University,
10 rue Vauquelin 75231 Paris Cedex 05, France
‡Diverchim, 6 rue du Noyer, ZAC du Moulin, 95734 Roissy CDG, France
*Eꢀmail: christophe.meyer@espci.fr, janine.cossy@espci.fr
F
F
R'
F
F
CF2
R
O
[3,3]
R
R'
R'
R
O
OMe
OPMB
O
OPMB
OPMB
O
O
One-pot difluorocyclopropenation/Ireland-Claisen rearrangement
40-76% overall yield (12 examples)
High diastereoselectivity (dr > 96:4), chirality transfer
Access to gem-difluorocyclopropanes
ABSTRACT: A oneꢀpot difluorocyclopropenation/IrelandꢀClaisen rearrangement sequence
applied to readily available propargyl glycolates was developed as a route toward
functionalized alkylidene(gemꢀdifluorocyclopropanes). This strategy conveniently avoids the
isolation of the unstable 3,3ꢀdifluorocyclopropenylcarbinyl glycolates arising from the
difluorocyclopropenation. The IrelandꢀClaisen rearrangement proceeds with high
diastereoselectivity and chirality transfer to afford alkylidene(gemꢀdifluorocyclopropanes)
incorporating a quaternary stereocenter and a protected glycolic acid moiety, which are useful
building blocks for the preparation of functionalized gemꢀdifluorocyclopropanes.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 42
1
2
3
4
5
6
7
8
9
In the development of drug candidates, medicinal chemists have often relied on the beneficial
effects of the incorporation of a cyclopropyl ring1 or fluorine atoms2 in a molecule for
conformational control as well as improvement of the potency, metabolic stability, membrane
permeability and pharmacokinetic properties. Accordingly, the development of efficient and
stereoselective methods for the preparation of functionalized monofluoroꢀ or
difluorocyclopropanes, which combine both of these latter relevant structural features, has
elicited significant interest.3–5 Among the different classes of difluorocyclopropanes, the
synthesis and reactivity of alkylidene(gemꢀdifluorocyclopropanes) A which could serve as
valuable precursors of a wide variety of gemꢀdifluorocyclopropanes, has not been thoroughly
investigated.3,5 The threeꢀmembered ring in compounds A can be constructed by
regioselective cyclopropanation of the more electronꢀrich bond of allenes with
difluorocarbene, generated from various precursors (Scheme 1, route a).6 However, further
reaction of alkylidene(gemꢀdifluorocyclopropanes) A with difluorocarbene can occur and this
strategy has seldom been applied to functionalized allenes besides examples of
difluorocyclopropanation of one βꢀallenic ester6e and γ,γꢀdialkylated allenyl sulfones.6f
Alternatively, the exocyclic alkene in alkylidene(gemꢀdifluorocyclopropanes) A can be
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
created by an elimination step applied to selenoxydes
B
derived from
gemꢀdifluorocyclopropanemethanols (Scheme 1, route b),7,8 vicinal dihalides C (Scheme 1,
route c)8,9 or esters derived from (gemꢀdifluoroꢀαꢀtrimethylsilylcyclopropyl)carbinols D
(Scheme 1, route d).10 3,3ꢀDifluorocyclopropenes have occasionally been considered as
precursors of alkylidene(gemꢀdifluorocyclopropanes) A. One example of isomerization of an
(arylmethyl)difluorocyclopropene E, in the presence of a base (DBU), was disclosed but
conjugation of the olefin with the aromatic ring provides the driving force of this
transformation (Scheme 1, route e).11 In contrast to the nonꢀfluorinated series, it is worth
noting that methylene(gemꢀdifluorocyclopropanes) are isomerized to the thermodynamically
2
ACS Paragon Plus Environment

Page 3 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
favored 1ꢀmethyl(3,3ꢀdifluorocyclopropenes) under basic conditions.10 Whereas the strong
electronꢀwithdrawing effect of fluorine provides a partial aromatic cyclopropenium character
to gemꢀdifluorocyclopropenes,3,12 this property also paradoxically accounts for their chemical
instability and ease of hydrolysis into cyclopropenones.3,13 Two examples of SN2’
nucleophilic displacements of cyclopropenylcarbinyl esters and mesylates F (with
KꢀSelectride® and Me2CuLi•LiCN, respectively) were also reported in the context of the
synthesis of pyrethrinoids analogs (Scheme 1, route f).14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Synthetic approaches toward alkylidene(gem-difluorocyclopropanes) A
CF2
F
F
F
F
R'
O
H
•
R'
"
"
Se
R
Nu
+
R
(a)
F
(f)
(b)
R"O
B
F
NO2
F
F
F
(R" = Ac, Ms)
R'
R
F
(e)
(c)
F
F
A
X
(d)
F
Y
Ar
R
E
C
Me3Si
R'
(X = Y = Cl, Br)
R
R"O
D
(R" = Ac, Bz)
Thus, the development of alternative routes toward alkylidene(gemꢀdifluorocyclopropanes) A
remains a challenging goal and in particular processes that would allow a stereoselective
access to functionalized and highly substituted compounds. Recently, we reported that
cyclopropenylcarbinyl glycolates G undergo an efficient and highly diastereoselective
IrelandꢀClaisen rearrangement leading to functionalized alkylidenecyclopropanes H
incorporating a glycolic acid moiety.15,16 Herein, we disclose our results on the expansion of
the scope of the IrelandꢀClaisen rearrangement of cyclopropenylcarbinol derivatives to
3,3ꢀdifluorocyclopropenylcarbinyl glycolates I with the aim of synthesizing functionalized
alkylidene(gemꢀdifluorocyclopropanes) J (Scheme 2). One critical issue was whether the
unstable 3,3ꢀdifluorocyclopropenes I13 could withstand the conditions of the IrelandꢀClaisen
rearrangement and how the fluorine atoms would affect the reactivity.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 42
1
2
3
Scheme 2. Ireland-Claisen Rearrangement of Cyclopropenylcarbinyl Glycolates
4
5
6
7
Previous work15
R''
R''
3
1) KHMDS/TMSCl
THF, −78 °C to rt
R''
R''
3
O
R
R'
2
1
R'
OPMB
R
2
OMe
1
2) HCl or NH4Cl, H2O
3) TMSCH=N2
MeOH/toluene, rt
8
9
O
OPMB
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
G
H
(dr > 96:4)
54-96%
R = Alkyl, Aryl, HetAryl; R' = H, Me
R'',R'' = H,H; Me,Me; (CH2)2NTs(CH2)2
This work
F
F
3
F
F
3
Ireland-Claisen
Rearrangement
O
R
O
R'
2
1
R'
R
2
1
OMe
OPMB
OPMB
O
I
J
Our initial studies were conducted with propargyl glycolate 3a, readily prepared by
condensation of alcohol 1a with carboxylic acid 2 in the presence of EDCI and DMAP
(20 mol %) (CH2Cl2, rt, 82% yield). The difluorocyclopropenation of the triple bond in 3a
was initially attempted using RuppertꢀPrakash’s reagent (TMSCF3, 2 equiv) in the presence of
NaI (2.2 equiv) in THF (sealed tube, 80 °C, 2 h)17 but the 3,3ꢀdifluorocyclopropene 4a was
isolated in modest yield (43%) because unidentified sideꢀproducts were formed. Much more
satisfactory results were obtained by slow addition (via syringe pump within 2 h) of an excess
of Dolbier’s reagent (trimethylsilyl fluorosulfonyldifluoroacetate, TFDA)18 to a concentrated
solution (c = 2 M) of propargyl glycolate 3a in diglyme at 120 °C. The desired 3,3ꢀ
difluorocyclopropene 4a was isolated in 86% yield after purification by flash column
chromatography on silica gel. However, as already mentioned for other
3,3ꢀdifluorocyclopropenes,13 compound 4a turned out to be unstable and underwent rapid
decomposition into a complex mixture of products, despite the presence of a phenyl
substituent
on
the
double
bond.
To
overcome
the
instability
of
3,3ꢀdifluorocyclopropenylcarbinyl glycolates, we reasoned that isolation of compound 4a may
not be required19 because gaseous (CO2, SO2) or volatile (TMSF) byꢀproducts are generated
4
ACS Paragon Plus Environment

Page 5 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
during the difluorocyclopropenation with TFDA and the ethereal solvent (diglyme) should be
compatible with the conditions of the IrelandꢀClaisen rearrangement. Thus, once the
difluorocyclopropenation of alkyne 3a was complete, the reaction mixture was diluted with
THF and the residual gaseous/volatile byꢀproducts were removed by sparging with argon.
Enolization of the 3,3ꢀdifluorocyclopropenylcarbinyl glycolate 4a was then triggered by
successive addition of TMSCl (4 equiv) and KHMDS (4 equiv) at –78 °C, to generate the
corresponding silylketene acetal 5a of (Z) configuration.15,20 Upon warming to rt, 5a
underwent a [3,3]ꢀsigmatropic rearrangement leading to trimethylsilyl ester 6a. After
hydrolysis under slightly acidic conditions, the resulting crude carboxylic acid 7a was treated
with trimethylsilyldiazomethane21 to afford methyl ester 8a, as a single detectable
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
diastereomer by H NMR spectroscopy (dr > 96:4). After purification by flash column
chromatography on silica gel, alkylidene(gemꢀdifluoroꢀcyclopropane) 8a was isolated in a
satisfying 73% overall yield (three steps from glycolate 3a). The synthesis of 8a could be
easily achieved at the gram scale (1.1 g) with no adverse effect on the overall yield (72%).
Cleavage of the PMB ether in compound 8a with DDQ afforded the secondary alcohol 9a
(75%) which was subjected to an intramolecular iodoetherification22 that led to oxabicyclic
compound 10a as a single detectable diastereomer (dr > 96:4) in quantitative yield. The cis
relationship between the protons adjacent to the oxygen atom and the phenyl group at the ring
junction in 10a, which was assigned by NMR spectroscopy (NOESY), confirmed the relative
configuration of two adjacent stereocenters as well as the (Z) configuration of the exocyclic
alkene in alkylidene(gemꢀdifluorocyclopropane) 8a. As observed with other
cyclopropenylcarbinyl glycolates,15 the IrelandꢀClaisen rearrangement of 4a proceeds through
a chairlike transition state T1 in which the 2ꢀphenylethyl group preferentially occupies an
equatorial position (Scheme 3).15,20
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 42
1
2
Scheme 3. One-pot difluorocyclopropenation of propargyl glycolate 3a and Ireland-
Claisen rearrangement of 3,3-difluorocyclopropenylmethyl glycolate 4a
3
4
5
6
7
8
9
OH
Ph
PMBO
2
Ph
Ph
O
EDCI, DMAP (20 mol %)
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
OPMB
CH2Cl2, rt
82%
OH
1a
O
3a
FSO2CF2CO2TMS (3 equiv)
(slow addition, 2 h)
EtN
•
N(CH2)3NMe2.HCl
(EDCI)
Diglyme, 120 °C
NaF (10 mol %)
3
3
F
F
F
F
TMSCl (4 equiv)
Ph
Ph
2
1
2
1
Ph
KHMDS (4 equiv)
Ph
OPMB
O
O
THF, −78 °C, 1 h
OPMB
OTMS
5a
O
4a (86%)
(unstable)
Ph
F
3
F
F
F
H
O
[3,3]
O
Ph
Ph
2
1
OR
OPMB
−78 °C to rt
then rt, 3 h
H
O
Ph
TMSO
PMB
6a, R = TMS
T1
NH4Cl, H2O
7a, R = H
8a, R = Me
TMSCHN2, MeOH/toluene (1:1), rt
(dr > 96:4)
73% (3 steps from 3a)
DDQ, CH2Cl2/H2O (16:1), rt 75%
3
F
I
F
F
F
O
NIS
Ph
H
Ph
2
OMe
1
Ph
CO2Me
O
MeCN/H2O (2:1)
50 °C, 1 h
99%
H
H
NOE
OH
10a (dr > 96:4)
9a
The use of propargyl alcohols as precursors of 3,3ꢀdifluorocyclopropenylcarbinyl glycolates
was an appealing feature of the method because these latter alcohols are readily accessible
and possibly in an enantioenriched form.23 To determine the substrate scope of the oneꢀpot
difluorocyclopropenation/IrelandꢀClaisen rearrangement sequence, the reactivity of diversely
substituted propargyl glycolates 3bꢀ3n was investigated (Scheme 4). The behaviour of
glycolates 3b-3g possessing an aromatic group at the acetylenic position was first explored.
The oneꢀpot difluorocyclopropenation/IrelandꢀClaisen rearrangement sequence was
successfully implemented for 3b, incorporating a pꢀmethoxyphenyl substituent, as shown by
the isolation of ethylidene(gemꢀdifluoroꢀcyclopropane) 8b (76%, three steps from 3b).
Importantly, when enantioenriched (S)ꢀ3b (ee = 96%) was used as substrate, the
corresponding optically active ethylideneꢀ(gemꢀdifluorocyclopropane) 8b was obtained (72%,
6
ACS Paragon Plus Environment

Page 7 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ee = 95%), thereby indicating that chirality transfer occurred in the IrelandꢀClaisen
rearrangement of enantioenriched glycolate 4b.24 The sequence also operated well in the case
of 3c possessing a pꢀbromophenyl substituent and produced alkylidene(gemꢀdifluoroꢀ
cyclopropane) 8c (75%, three steps from 3c). However, one limitation was identified with
glycolate 3d substituted by pꢀnitrophenyl group. Although the difluorocyclopropenation of 3d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
proceeded
efficiently,
the
IrelandꢀClaisen
rearrangement
of
the
resulting
3,3ꢀdifluorocyclopropenylcarbinyl glycolate 4d could not be achieved and led to a complex
mixture of products. This result was explained by considering that the pꢀnitrophenyl group
would significantly increase the acidity of the proton on the carbon adjacent to the
difluorocyclopropene (at the α position of the oxygen atom). Competitive abstraction of this
proton by the base would generate a carbanion adjacent to the difluorocyclopropene ring that
may be responsible for the observed degradation of 4d. Although ethylidene(gemꢀdifluoroꢀ
cyclopropane) 8e was obtained in good yield (65%) from glycolate 3e possessing an electronꢀ
withdrawing acetyl group at the para position of the aromatic ring, the methyl ketone was
presumably converted into a silyl enol ether under the conditions of the IrelandꢀClaisen
rearrangement. The presence of an aromatic group substituted at the ortho position did not
hamper the efficiency of the sigmatropic rearrangement as shown with the successful
formation of ethylidene(gemꢀdifluorocyclopropanes) 8f (67%) and 8g (63%), possessing a
2ꢀchlorophenyl and a 1ꢀnaphthyl substituent at the quaternary stereocenter, respectively.
Interestingly, the presence of atropodiastereomers was observed in the NMR spectra of
compounds 8f and 8g, because of restricted rotation around the aryl–C2 bond. Propargyl
glycolates possessing a moderately electronꢀrich heteroaromatic group at the acetylenic
position were compatible with the difluorocyclopropenation/IrelandꢀClaisen rearrangement
sequence. Hence, the preparation of the alkylidene(gemꢀdifluorocyclopropanes) 8h and 8i,
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 42
1
2
3
possessing a NꢀBocꢀindolꢀ3ꢀyl and a 3ꢀthienyl group, respectively, was achieved in good
4
5
6
overall yield (70%) (Scheme 4).
7
8
9
Further exploration of the substrate scope was carried out with propargyl glycolates bearing
an alkyl chain at the acetylenic position.25 For such substrates, the substituent at the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
propargylic position could not be
a
phenyl group. Indeed, whereas the
difluorocyclopropenation of glycolate 3j could be achieved, the resulting
difluorocyclopropene 4j decomposed under the conditions of the IrelandꢀClaisen
rearrangement. This behaviour is in striking contrast with the reactivity of the related
3,3ꢀdimethylcyclopropenylcarbinyl glycolates G in the IrelandꢀClaisen rearrangement which
accommodate an aromatic ring at the adjacent position (Scheme 2).15 The strong electronꢀ
withdrawing effect of the fluorine atoms on the cyclopropene probably enhances the acidity of
the proton on the adjacent (benzylic) carbon. As previously observed with cyclopropene 4d,
competitive abstraction of this latter proton by the base would account for the failure to
achieve the IrelandꢀClaisen rearrangement of 4j. Accordingly, the reactivity of glycolates 3kꢀ
3n, substituted at the propargylic position by aliphatic substituents (a 2ꢀphenylethyl or a
benzyloxymethyl group), was examined. The corresponding alkylidene(gemꢀdifluoroꢀ
cyclopropanes) 8k (61%), 8l (48%), 8m (43%) and 8n (40%) were isolated in good to
moderate overall yields. Interestingly, protected hydroxymethyl and 2ꢀhydroxyethyl
substituents could be introduced on the quaternary stereocenter (C2) in
gemꢀdifluorocyclopropanes 8l and 8n. The lower yields generally observed for
alkylidene(gemꢀdifluorocyclopropanes) 8kꢀ8n, compared to those attained with 8b, 8c, 8e-8i
possessing an aromatic group, is due to the lower stability of the alkylꢀsubstituted
gemꢀdifluorocyclopropenes (Scheme 4).13
8
ACS Paragon Plus Environment

Page 9 of 42
The Journal of Organic Chemistry
1
2
Scheme 4. Scope of propargyl glycolates
3
4
5
6
7
8
3
F
F
R
TFDA (3 equiv)
(Slow addition over 2 h)
NaF (10 mol %)
3
F
F
1) TMSCl (4 equiv), KHMDS (4 equiv)
THF, −78 °C to rt
O
R'
R'
R
R
2
1
R'
1
2
OMe
OPMB
O
O
OPMB
Diglyme, 120 °C
2) NH4Cl, H2O
OPMB
9
O
then rt, dilution with THF
and argon sparging
3) TMSCHN2, toluene/MeOH (1:1), rt
O
3b-3n
8b-8n
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4b-4n
Z
S
Boc
N
Cl
F
F
F
F
F
F
F
F
F
F
O
O
O
O
O
Me
Me
Ph
Me
Me
OMe
OPMB
OMe
OMe
OPMB
8i (70%)a
OMe
OPMB
OMe
OPMB
OPMB
8h (70%)a
8b, Z = OMe (76%)a (ee = 95%)b
8f (67%)a
8g (63%)a
(75%)a
(0%)c
8c, Z = Br
8d, Z = NO2
8e, Z = COCH3 (65%)a
OTBDPS
OTBDPS
F
F
F
F
F
F
F
F
F
F
O
O
O
O
O
Me
Me
Me
Ph
Ph
Ph
OMe
OPMB
8j (0%)c
OMe
OPMB
8k (61%)a
BnO
OMe BnO
OMe
OPMB
8n (40%)a
OMe
OPMB
OPMB
8m (43%)a
8l (48%)a
a
Isolated yield of analytically pure material (three steps from the corresponding propargyl glycolates).
b Obtained from optically active (S)ꢀ3b (ee = 96%). The corresponding gemꢀdifluorocyclopropenes were
c
formed but decomposed under the conditions of the IrelandꢀClaisen rearrangement.
To illustrate that alkylidene(gemꢀdifluorocyclopropanes) J enable access to other classes of
substituted gemꢀdifluorocyclopropanes, a few transformations of these latter compounds were
carried out. To our knowledge, no examples of hydrogenation of alkylidene(gemꢀdifluoroꢀ
cyclopropanes) have been disclosed to date, so the feasilibity of this transformation which
would create an additional stereocenter was worth studying. Because the presence of a
quaternary stereocenter at C2 in the alkylidenecyclopropanes J would not allow for a
satisfactory discrimination of the diastereofaces of the exocyclic alkene,16b a substrateꢀ
directed hydrogenation was investigated.15 Thus, the αꢀhydroxy ester 9a, obtained from 8a by
cleavage of the PMB ether, underwent a highly diastereoselective hydrogenation in the
presence of Crabtree’s catalyst [Ir]ꢀI (6 mol %)26 which afforded gemꢀdifluorocyclopropane
11 in 91% yield with high diastereoselectivity (dr > 96:4). It is worth noting that no ringꢀ
opening occurred under these conditions. In the case of compound 8l, cleavage of the silyl
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 42
1
2
3
4
5
ether afforded the primary alcohol 12 (55%) which underwent a highly diastereoselective
directed hydrogenation leading to gemꢀdifluorocyclopropane 13 (92%) (Scheme 5).27
6
7
8
9
Scheme 5. Diastereoselective hydrogenation of alkylidene-(gem-difluorocyclopropanes)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H2 (1 bar)
F
F
F
F
F
F
O
O
Ph
Ph
[Ir]-I (6 mol %)
Ph
Ph
Ph
Ph
OMe
H
OMe
CH2Cl2, rt
91%
OH
OH
9a
11 (dr > 96:4)
OTBDPS
O
OH
n-Bu4NF (5 equiv)
F
F
O
AcOH (5 equiv)
OMe
OMe
THF, rt
55%
OPMB
OPMB
12
8l
H2 (1 bar), [Ir]-I (6 mol %)
92%
OH
F
CH2Cl2, rt
PCy3
N
F
PF6
O
Ir
H
Ph
OMe
OPMB
13 (dr > 96:4)
[Ir]-I
The glycolic acid moiety can be converted into a valuable aldehyde functional group. Thus,
reduction of the methyl ester 11 with LiAlH4, followed by oxidative cleavage of the resulting
1,2ꢀdiol with NaIO4 adsorbed on silica gel,28 delivered aldehyde 14 (72%, two steps from 11)
possessing an adjacent quaternary stereocenter on the difluorinated cyclopropane (Scheme
6).29
Scheme 6. Synthesis of aldehyde 14
F
F
F
F
O
1) LiAlH4, THF, 0 °C
Ph
Ph
O
Ph
Ph
H
H
OMe
H
2) NaIO4.SiO2
CH2Cl2, rt
72%
OH
11
14
In conclusion, we have developed a oneꢀpot sequence involving the difluorocyclopropenation
of propargyl glycolates followed by the IrelandꢀClaisen rearrangement of the resulting
3,3ꢀdifluorocyclopropenyl glycolates as a route toward of alkylidene(gemꢀdifluoroꢀ
cyclopropanes) incorporating a quaternary stereocenter and a glycolic acid moiety. The
substrates are readily available from propargylic alcohols and the IrelandꢀClaisen
10
ACS Paragon Plus Environment

Page 11 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
rearrangement of 3,3ꢀdifluorocyclopropenylcarbinyl glycolates proceeds with high
diastereoselectivity and chirality transfer. This sequence provides an interesting entry to a
variety of gemꢀdifluorocyclopropanes that would not be readily obtained by other routes.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General information. All reactions were carried out under anhydrous conditions, using
flameꢀdried glassware and under an argon atmosphere. THF was distilled from
Na/benzophenone. CH2Cl2, Et3N, iPr2NEt and diglyme were distilled from CaH2. Other
reagents were obtained from commercial suppliers and used as received. Flash
chromatography was performed on silica gel (230ꢀ400 mesh). Optical rotations were
measured using a polarimeter with a 1 dm path length at 589 nm. IR spectra were recorded
with attenuated total reflectance (ATR) sampling technique. H NMR, 13C NMR and
1
19F NMR spectra were recorded at 400 MHz, 100 MHz and 282 MHz, respectively. The
chemical shifts (δ) are reported in parts per million (ppm) and were referenced to the residual
isotopomer solvent signals (CHCl3:
δ = 7.26 ppm, C6D5H: δ = 7.16 ppm, CD3S(=O)CHD2:
1
δ
= 2.50 ppm) for H NMR spectra, the solvent signal (CDCl3:
δ
= 77.16 ppm, C6D6:
δ
δ
=
=
128.06 ppm, DMSOꢀd6:
δ
= 39.52 ppm) for 13C NMR spectra or to external CFCl3 (
0 ppm) for 19F spectra. Coupling constants are given in Hertz (Hz) and multiplicities are
indicated using the conventional abbreviations (s = singlet, d = doublet, t = triplet, q = quartet,
13
m = multiplet or overlap of nonꢀequivalent resonances, br = board, app = apparent). All C
spectra were broadband 1Hꢀdecoupled and the carbon environment (C, CH, CH2 or CH3) was
deduced from DEPT experiments. High resolution mass spectra (HRMS) were performed
with an orbitrap mass analyzer by electrospray ionization. Enantiomeric purities of optically
active compounds were determined by supercritical fluid chromatography (SFC) analysis,
after calibration with the racemic sample, using a mixture of supercritical CO2 (scCO2) and
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 42
1
2
3
4
5
6
7
8
9
MeOH as eluent and a chiral stationary phase. The known propargylic alcohols 1a,30 1j,31
1k,32 1m33 and 1n34 were prepared by reaction of the corresponding lithium alkynylide to the
appropriate aldehyde. Alcohol 1i was prepared in the same manner but was directly converted
into glycolate 3i. The known propargylic alcohols 1b,35 1c,36 1d,37 1e,38 1g,39 were prepared
by Sonogashira crossꢀcoupling reactions between the corresponding (hetero)aromatic iodide
and propargyl alcohol possessing a terminal alkyne. Enantioenriched (S)ꢀ1b was prepared in a
similar manner as racemic 1b, by Sonogashira crossꢀcoupling between commercially
available (S)ꢀ3ꢀbutynꢀ2ꢀol and 4ꢀiodoanisole.35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)ꢀ4ꢀ(4ꢀMethoxyphenyl)butꢀ3ꢀynꢀ2ꢀol ((S)ꢀ1b). To a degassed mixture (argon sparging,
10 min) of Pd(PPh3)2Cl2 (25.6 mg, 0.036 mmol, 2 mol %), CuI (17.4 mg, 0.091 mmol,
5 mol %) and 4ꢀiodoanisole (426 mg, 1.82 mmol) in THF (7 mL) at 0 °C, were added
successively (S)ꢀ3ꢀbutynꢀ2ꢀol (214 ꢀL, 2.73 mmol, 1.5 equiv) and Et3N (760 ꢀL, 13.7 mmol,
3 equiv). After 16 h stirring at rt, the reaction mixture was filtered through Celite (EtOAc).
The filtrate was successively washed with a saturated aqueous solution of NH4Cl, brine, dried
over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by
flash chromatography (petroleum ether/EtOAc = 80:20) to afford 279 mg (87%) of (S)ꢀ1b as a
yellow oil; IR: ν 3357, 2228, 1607, 1509, 1290, 1248, 1174, 1104, 1029, 832 cm–1; 1H NMR
(400 MHz, CDCl3)
δ
7.36 (app d, J = 8.9 Hz, 2H), 6.82 (app d, J = 8.9 Hz, 2H), 4.74 (m, 1H),
13
3.80 (s, 3H), 2.11 (d, J = 5.2 Hz, 1H, OH), 1.54 (d, J = 6.6 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 159.7 (C), 133.2 (2CH), 114.8 (C), 114.0 (2CH), 89.7 (C), 84.0 (C), 59.0 (CH), 55.4
(CH3), 24.6 (CH3). Spectral data matched those previously reported for this compound.35
26
[α]D20 –21.4 (c 0.252, CHCl3) {[α]D litt –29.6 (c 1.44, CHCl3)}.40 The enantiomeric excess of
(S)-1b was determined by supercritical fluid chromatography using a chiral stationary phase
(ADꢀH column, 100 bar, 3 mL/min, scCO2/MeOH = 96:4): minor (R)ꢀenantiomer: tR =
10.9 min; major (S)ꢀenantiomer: tR = 11.9 min. ee = 96%.
12
ACS Paragon Plus Environment

Page 13 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4ꢀ(2ꢀChlorophenyl)butꢀ3ꢀynꢀ2ꢀol (1f). Prepared by Sonogashira crossꢀcoupling between
1ꢀchloroꢀ2ꢀiodobenzene and 3ꢀbutynꢀ2ꢀol. After purification by flash chromatography
(petroleum ether/EtOAc = 80:20), 1f was isolated as an orange oil (958 mg, 97%); IR: ν 3320,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1473, 1105, 1061, 1031, 935, 855, 751 cm–1; 1H NMR (400 MHz, CDCl3)
δ 7.43 (dd, J = 7.6,
1.8 Hz, 1H), 7.35 (dd, J = 7.8, 1.6 Hz, 1H), 7.20 (app td, J = 7.7, 1.9 Hz, 1H), 7.15 (app td,
J = 7.5, 1.5 Hz, 1H), 4.81 (q, J = 6.6 Hz, 1H), 2.94 (s, 1H, OH), 1.57 (d, J = 6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
δ 135.9 (C), 133.4 (CH), 129.4 (CH), 129.2 (CH), 126.4 (CH),
122.6 (C), 96.4 (C), 80.7 (C), 58.8 (CH), 24.3 (CH3); HRMS (ESI) m/z calcd for C10H9ClONa
[M (35Cl) + Na]+ and [M (37Cl) + Na]+: 203.0234 and 205.0205, found: 203.0237 and
205.0206.
4ꢀ(Naphthalenꢀ1ꢀyl)butꢀ3ꢀynꢀ2ꢀol (1g). Prepared by Sonogashira crossꢀcoupling between
1ꢀiodonaphthalene and 3ꢀbutynꢀ2ꢀol. After purification by flash chromatography (petroleum
ether/EtOAc = 80:20), 1g was isolated as a yellow oil (1.06 g, 99%); IR: ν 3316, 3058, 2221,
1587, 1507, 1395, 1327, 1118, 1079, 799, 772 cm–1; 1H NMR (400 MHz, CDCl3)
δ 8.33 (br d,
J = 8.2 Hz, 1H), 7.86–7.81 (m, 2H), 7.67 (dd, J = 7.1, 1.1 Hz, 1H), 7.61–7.49 (m, 2H), 7.41
13
(m, 1H), 4.93 (m, 1H), 2.43 (br s, 1H, OH), 1.68 (d, J = 6.6 Hz, 3H); C NMR (100 MHz,
CDCl3)
δ 133.3 (C), 133.2 (C), 130.6 (CH), 129.0 (CH), 128.4 (CH), 126.9 (CH), 126.5 (CH),
126.1 (CH), 125.2 (CH), 120.3 (C), 96.1 (C), 82.2 (C), 59.2 (CH), 24.7 (CH3); HRMS (ESI)
m/z calcd for C14H12ONa [M + Na]+: 219.0780, found: 219.0782.
tertꢀButyl 3ꢀ(3ꢀhydroxybutꢀ1ꢀynꢀ1ꢀyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate (1h). Prepared by Sonogashira
crossꢀcoupling between tertꢀbutyl 3ꢀiodoꢀ1Hꢀindoleꢀ1ꢀcarboxylate41 and 3ꢀbutynꢀ2ꢀol. After
purification by flash chromatography (petroleum ether/EtOAc = 80:20), 1h was isolated as an
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 42
1
2
3
4
orange solid (1.26 g, 97%); Mp 104–106 °C; IR: ν 3376, 2230, 1738, 1452, 1369, 1232, 1155,
1
1088, 747 cm–1; H NMR (400 MHz, CDCl3)
δ 8.12 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.64
5
6
7
8
(app br d, J = 7.8 Hz, 1H), 7.38–7.24 (m, 2H), 4.83 (m, 1H), 2.16 (d, J = 5.3 Hz, 1H, OH),
9
13
1.66 (s, 9H), 1.60 (d, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl3)
δ 149.2 (C), 134.7 (C),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
130.5 (C), 129.1 (CH), 125.3 (CH), 123.3 (CH), 120.1 (CH), 115.3 (CH), 102.8 (C), 94.7 (C),
84.5 (C), 76.1 (C), 59.1 (CH), 28.2 (3CH3), 24.7 (CH3); HRMS (ESI) m/z calcd for
C17H19NO3Na [M + Na]+: 308.1257, found: 308.1259.
6ꢀ[(tertꢀButyldiphenylsilyl)oxy]ꢀ1ꢀphenylhexꢀ4ꢀynꢀ3ꢀol (1l). To a solution of tertꢀbutylꢀ
diphenyl(2ꢀpropynyloxy)silane42 (1.20 g, 4.06 mmol, 1.5 equiv) in THF (14 mL) at –78 °C,
was added dropwise a solution of nꢀBuLi (1.52 mL, 2.5 M in hexanes, 3.79 mmol, 1.4 equiv).
After 0.5 h stirring at –78 °C, 3ꢀphenylpropanal (400 ꢀL, 2.71 mmol) was added dropwise.
The reaction mixture was allowed to warm to rt, stirred for 0.5 h and then poured into a
saturated aqueous solution of NH4Cl. The resulting mixture was extracted with Et2O and the
combined organic layers were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash chromatography
(petroleum ether/Et2O = 90:10 to 70:30) to afford 1.10 g (94%) of 1l as a colorless oil; IR:
1
ν 3370, 1428, 1372, 1260, 1129, 1111, 1070, 1029, 998; 823, 739, 698, 613 cm–1; H NMR
(400 MHz, CDCl3)
δ 7.74–7.70 (m, 4H), 7.46–7.35 (m, 6H), 7.31–7.25 (m, 2H), 7.22–7.14
(m, 3H), 4.39 (d, J = 1.6 Hz, 2H), 4.28 (m, 1H), 2.72 (t, J = 7.8 Hz, 2H), 1.97–1.86 (m, 2H),
13
1.61 (d, J = 5.2 Hz, 1H, OH), 1.06 (s, 9H); C NMR (100 MHz, CDCl3)
δ 141.4 (C), 135.7
(4CH), 133.2 (2C), 129.9 (2CH), 128.5 (2CH), 128.4 (2CH), 127.7 (4CH), 126.0 (CH), 86.0
(C), 83.7 (C), 61.7 (CH), 52.7 (CH2), 39.0 (CH2), 31.3 (CH2), 26.7 (3 CH3), 19.2 (C); HRMS
(ESI) m/z calcd for C28H32O2SiNa [M + Na]+: 451.2064, found: 451.2054.
14
ACS Paragon Plus Environment

Page 15 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Representative procedure for the preparation of propargyl glycolates: To a solution of
propargyl alcohol 1a (1.06 g, 4.48 mmol, 1.0 equiv) and (4ꢀmethoxybenzyloxy)acetic acid 243
(1.32 g, 6.72 mmol, 1.5 equiv) in CH2Cl2 (20 mL) at 0 °C, were added EDCI (1.29 g,
6.72 mmol, 1.5 equiv) and DMAP (109 mg, 0.896 mmol, 20 mol %). After stirring overnight
at rt, the reaction mixture was hydrolyzed with a saturated aqueous solution of NH4Cl and
diluted with EtOAc. The layers were separated and the aqueous phase was extracted with
EtOAc. The combined organic extracts were successively washed with a saturated aqueous
solution of NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum
ether/EtOAc = 80:20) to afford 1.33 g (72%) of glycolate 3a as a colorless oil.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,5ꢀDiphenylpentꢀ1ꢀynꢀ3ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (3a). IR: ν 2231, 1757,
1612, 1513, 1248, 1118, 1033, 821, 757, 692 cm–1; 1H NMR (400 MHz, CDCl3)
δ 7.49–7.44
(m, 2H), 7.36–7.28 (m, 7H), 7.24–7.20 (m, 3H), 6.89 (app d, J = 8.7 Hz, 2H), 5.72 (t, J =
6.5 Hz, 1H), 4.60 (s, 2H), 4.14 (dABsyst, J = 16.5 Hz, 1H), 4.07 (dABsyst, J = 16.5 Hz, 1H), 3.80
(s, 3H), 2.85 (t, J = 7.9 Hz, 2H), 2.27–2.18 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 169.6
(C), 159.6 (C), 140.7 (C), 132.0 (2CH), 130.0 (2CH), 129.2 (C), 128.9 (CH), 128.7 (2CH),
128.5 (2CH), 128.4 (2CH), 126.3 (CH), 122.2 (C), 114.0 (2CH), 86.3 (C), 85.8 (C), 73.1
(CH2), 66.9 (CH2), 64.7 (CH), 55.4 (CH3), 36.5 (CH2), 31.5 (CH2); HRMS (ESI) m/z calcd for
C27H26O4Na [M + Na]+: 437.1723, found: 437.1722.
4ꢀ(4ꢀMethoxyphenyl)butꢀ3ꢀynꢀ2ꢀyl
2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate
(3b).
After
purification by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20), 3b was
isolated as a yellow oil (788 mg, 98%); IR: ν 2229, 1754, 1607, 1510, 1291, 1246, 1174,
1
1106, 1083, 1025, 946, 831, 796, 732 cm–1; H NMR (400 MHz, CDCl3)
δ 7.37 (app d, J =
8.9 Hz, 2H), 7.31 (app d, J = 8.8 Hz, 2H), 6.88 (app d, J = 8.7 Hz, 2H), 6.82 (app d, J =
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 42
1
2
3
4
5
8.9 Hz, 2H), 5.78 (q, J = 6.7 Hz, 1H), 4.58 (s, 2H), 4.13 (dABsyst, J = 16.5 Hz, 1H), 4.08
(dABsyst, J = 16.5 Hz, 1H), 3.793 (s, 3H), 3.792 (s, 3H), 1.60 (d, J = 6.7 Hz, 3H); 13C NMR
6
7
8
(100 MHz, CDCl3)
δ 169.6 (C), 160.0 (C), 159.6 (C), 133.5 (2CH), 130.0 (2CH), 129.2 (C),
9
114.3 (C), 114.01 (2CH), 114.00 (2CH), 85.7 (C), 85.1 (C), 73.1 (CH2), 67.0 (CH2), 61.7
(CH), 55.4 (2CH3), 21.8 (CH3); HRMS (ESI) m/z calcd for C21H22O5Na [M + Na]+: 377.1359,
found: 377.1361.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)ꢀ4ꢀ(4ꢀMethoxyphenyl)butꢀ3ꢀynꢀ2ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate ((S)ꢀ3b). After
purification by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20), (S)ꢀ3b was
isolated as a yellow oil (389 mg, 92%); [α]D20 –56.5 (c 0.154, CHCl3) (ee = 96%).
4ꢀ(4ꢀBromophenyl)butꢀ3ꢀynꢀ2ꢀyl
2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate
(3c).
After
purification by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20), 3c was
isolated as a white solid (443 mg, 82%); Mp 72–74 °C; IR: ν 1756, 1613, 1586, 1513, 1248,
1
1188, 1109, 1070, 1030, 1011, 823 cm–1; H NMR (400 MHz, CDCl3)
δ 7.44 (app d, J =
8.7 Hz, 2H), 7.33–7.27 (m, 4H), 6.88 (app d, J = 8.7 Hz, 2H), 5.75 (q, J = 6.7 Hz, 1H), 4.59
(s, 2H), 4.13 (dABsyst, J = 16.5 Hz, 1H), 4.08 (dABsyst, J = 16.5 Hz, 1H), 3.80 (s, 3H), 1.60 (d,
J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.6 (C), 159.7 (C), 133.4 (2CH), 131.7
(2CH), 130.0 (2CH), 129.1 (C), 123.2 (C), 121.2 (C), 114.0 (2CH), 88.2 (C), 84.1 (C), 73.2
(CH2), 66.9 (CH2), 61.4 (CH), 55.4 (CH3), 21.5 (CH3); HRMS (ESI) m/z calcd for
C20H19BrO4Na [M (79Br)+ Na]+ and [M (81Br)+ Na]+: 425.0359 and 427.0338, found:
425.0360 and 427.0337.
4ꢀ(4ꢀNitrophenyl)butꢀ3ꢀynꢀ2ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (3d). After purification
by flash chromatography (petroleum ether/EtOAc = 95:5 to 90:10), 3d was isolated as a
yellow oil (770 mg, 99%); IR: ν 1756, 1612, 1595, 1514, 1342, 1247, 1186, 1107, 1084,
16
ACS Paragon Plus Environment

Page 17 of 42
The Journal of Organic Chemistry
1
2
3
4
1
1028, 855, 750, 688 cm–1; H NMR (400 MHz, CDCl3)
δ 8.13 (app d, J = 9.0 Hz, 2H), 7.54
5
6
(app d, J = 9.0 Hz, 2H), 7.28 (app d, J = 8.8 Hz, 2H), 6.85 (app d, J = 8.8 Hz, 2H), 5.76 (q,
7
8
J = 6.7 Hz, 1H), 4.57 (s, 2H), 4.13 (dABsyst, J = 16.5 Hz, 1H), 4.09 (dABsyst, J = 16.5 Hz, 1H),
9
13
3.76 (s, 3H), 1.61 (d, J = 6.7 Hz, 3H); C NMR (100 MHz, CDCl3)
δ 169.3 (C), 159.5 (C),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
147.3 (C), 132.6 (2CH), 129.8 (2CH), 128.95 (C), 128.88 (C), 123.5 (2CH), 113.8 (2CH),
92.1 (C), 83.0 (C), 73.0 (CH2), 66.7 (CH2), 60.9 (CH), 55.2 (CH3), 21.1 (CH3); HRMS (ESI):
calcd for C20H19NO6Na [M + Na]+: 392.1105, found: 392.1103.
4ꢀ(4ꢀAcetylphenyl)butꢀ3ꢀynꢀ2ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (3e). After purification
by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20), 3e was isolated as a
yellow solid (788 mg, 98%); Mp 76–78 °C; IR: ν 1756, 1683, 1602, 1514, 1249, 1182, 1108,
1086, 1029, 955, 833 cm–1; 1H NMR (400 MHz, CDCl3)
δ 7.90 (app d, J = 8.6 Hz, 2H), 7.51
(app d, J = 8.6 Hz, 2H), 7.31 (app d, J = 8.7 Hz, 2H), 6.88 (app d, J = 8.7 Hz, 2H), 5.78 (q,
J = 6.7 Hz, 1H), 4.59 (s, 2H), 4.14 (dABsyst, J = 16.5 Hz, 1H), 4.09 (dABsyst, J = 16.5 Hz, 1H),
3.80 (s, 3H), 2.60 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 197.4 (C),
169.5 (C), 159.6 (C), 136.7 (C), 132.1 (2CH), 130.0 (2CH), 129.1 (C), 128.3 (2CH), 127.0
(C), 114.0 (2CH), 90.2 (C), 84.3 (C), 73.1 (CH2), 66.9 (CH2), 61.3 (CH), 55.4 (CH3), 26.7
(CH3), 21.4 (CH3); HRMS (ESI) m/z calcd for C22H22O5Na [M + Na]+: 389.1359, found:
389.1361.
4ꢀ(2ꢀChlorophenyl)butꢀ3ꢀynꢀ2ꢀyl
2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate
(3f).
After
purification by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20), 3f was
isolated as an orange oil (572 mg, 96%); IR: ν 1756, 1612, 1513, 1247, 1187, 1107, 1087,
1060, 1026, 948, 820, 755 cm–1; 1H NMR (400 MHz, CDCl3)
δ 7.46 (dd, J = 7.4, 2.0 Hz, 1H),
7.38 (dd, J = 7.9, 1.5 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.25 (app td, J = 7.5, 1.8 Hz, 1H),
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 42
1
2
3
4
5
7.19 (app td, J = 7.6, 1.4 Hz, 1H), 6.88 (app d, J = 8.8 Hz, 2H), 5.82 (q, J = 6.7 Hz, 1H), 4.59
(s, 2H), 4.14 (dABsyst, J = 16.5 Hz, 1H,), 4.09 (dABsyst, J = 16.5 Hz, 1H), 3.79 (s, 3H), 1.64 (d,
6
7
8
J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.5 (C), 159.6 (C), 136.2 (C), 133.6 (CH),
9
130.0 (2CH), 129.8 (CH), 129.3 (CH), 129.1 (C), 126.5 (CH), 122.1 (C), 114.0 (2CH), 92.2
(C), 81.8 (C), 73.1 (CH2), 66.9 (CH2), 61.4 (CH), 55.3 (CH3), 21.5 (CH3); HRMS (ESI) m/z
calcd for C20H19ClO4Na [M(35Cl) + Na]+ and [M(37Cl) + Na]+: 381.0864 and 383.0835, found:
381.0864 and 383.0834.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4ꢀ(Naphthalenꢀ1ꢀyl)butꢀ3ꢀynꢀ2ꢀyl
2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate
(3g).
After
purification by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20), 3g was
isolated a yellow oil (558 mg, 97%); IR: ν 2225, 1755, 1612, 1586, 1513, 1247, 1191, 1175,
1
1117, 1073, 1046, 1034, 801, 774 cm–1; H NMR (400 MHz, CDCl3)
δ 8.29 (app d, J =
8.3 Hz, 1H), 7.84 (app d, J = 7.5 Hz, 2H), 7.69 (dd, J = 7.2, 1.1 Hz, 1H), 7.57 (app ddd, J =
8.3, 6.9, 1.4 Hz, 1H), 7.52 (app ddd, J = 8.1, 6.9, 1.4 Hz, 1H), 7.42 (dd, J = 8.3, 7.2 Hz, 1H),
7.32 (app d, J = 8.7 Hz, 2H), 6.88 (app d, J = 8.7 Hz, 2H), 5.94 (q, J = 6.7 Hz, 1H), 4.62 (s,
2H), 4.18 (dABsyst, J = 16.5 Hz, 1H), 4.13 (dABsyst, J = 16.5 Hz, 1H), 3.79 (s, 3H), 1.73 (d, J =
6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.7 (C), 159.6 (C), 133.4 (C), 133.2 (C), 131.0
(CH), 130.0 (2CH), 129.4 (CH), 129.2 (C), 128.4 (CH), 127.1 (CH), 126.6 (CH), 126.1 (CH),
125.2 (CH), 119.8 (C), 114.0 (2CH), 91.9 (C), 83.3 (C), 73.1 (CH2), 67.0 (CH2), 61.7 (CH),
55.4 (CH3), 21.8 (CH3); HRMS (ESI) m/z calcd for C24H22O4Na [M + Na]+: 397.1410, found:
397.1411.
tertꢀButyl
3ꢀ[3ꢀ({2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetyl}oxy)butꢀ1ꢀynꢀ1ꢀyl]ꢀ1Hꢀindoleꢀ
1ꢀcarboxylate (3h). After purification by flash chromatography (petroleum ether/EtOAc =
90:10 to 80:20), 3h was isolated as an orange oil (567 mg, 93%); IR: ν 2237, 1739, 1613,
18
ACS Paragon Plus Environment

Page 19 of 42
The Journal of Organic Chemistry
1
2
3
1
1514, 1453, 1371, 1251, 1233, 1155, 1077, 1034, 821, 760, 749 cm–1; H NMR (400 MHz,
4
5
6
CDCl3) 8.16 (br d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.67 (br d, J = 7.7 Hz, 1H), 7.41–7.27 (m,
δ
7
8
4H), 6.89 (d, J = 8.7 Hz, 2H), 5.87 (q, J = 6.7 Hz, 1H), 4.62 (s, 2H), 4.17 (dABsyst, J = 16.5 Hz,
9
13
1H), 4.13 (dABsyst, J = 16.5 Hz, 1H), 3.80 (s, 3H), 1.68 (s, 9H), 1.68 (d, J = 6.7 Hz, 3H); C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (100 MHz, CDCl3)
δ 169.6 (C), 159.6 (C), 149.0 (C), 134.7 (C), 130.4 (C), 130.0
(2CH), 129.7 (CH), 129.2 (C), 125.3 (CH), 123.4 (CH), 120.1 (CH), 115.3 (CH), 114.0
(2CH), 102.3 (C), 90.6 (C), 84.5 (C), 77.3 (C), 73.1 (CH2), 66.9 (CH2), 61.7 (CH), 55.3
(CH3), 28.2 (3CH3), 21.7 (CH3); HRMS (ESI) m/z calcd for C27H29NO6Na [M + Na]+:
486.1887, found: 486.1887.
5ꢀPhenylꢀ1ꢀ(thiophenꢀ3ꢀyl)pentꢀ1ꢀynꢀ3ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (3i). To a
solution of 3ꢀethynylthiophene (209 mg, 1.86 mmol, 1.5 equiv) in THF (4 mL) at –78 °C, was
added dropwise nꢀBuLi (0.69 mL, 2.5 M solution in hexanes, 1.73 mmol, 1.4 equiv). After
0.5 h stirring at –78 °C, 3ꢀphenylpropanal (183 µL, 1.24 mmol, 1 equiv) was added dropwise.
The reaction mixture was warmed to rt, stirred for a further 0.5 h and then poured into a
saturated aqueous solution of NH4Cl. After dilution with ether, the layers were separated and
the aqueous phase was extracted with ether. The combined extracts were washed with brine,
dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude
propargyl alcohol 1i was dissolved in CH2Cl2 (7 mL) and to the resulting solution were
successively added carboxylic acid 2 (364 mg, 1.86 mmol), EDCI (356 mg, 1.86 mmol) and
DMAP (30.3 mg, 0.248 mmol). After stirring overnight at rt, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl and diluted with EtOAc. The layers
were separated and the aqueous phase was extracted with EtOAc. The combined organic
extracts were successively washed with a saturated aqueous solution of NaHCO3 and brine,
then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 42
1
2
3
purified by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20) to afford 432 mg
4
5
6
(83%) of glycolate 3i as a yellow oil; IR: ν 2234, 1756, 1612, 1513, 1248, 1179, 1117, 1033,
7
8
820, 785, 700, 627 cm–1; 1H NMR (400 MHz, CDCl3)
δ 7.48 (dd, J = 3.0, 1.2 Hz, 1H), 7.33–
9
7.27 (m, 4H), 7.26 (dd, J = 5.0, 3.0 Hz, 1H), 7.23–7.18 (m, 3H), 7.12 (dd, J = 5.0, 1.2 Hz,
1H), 6.88 (app d, J = 8.7 Hz, 2H), 5.68 (t, J = 6.6 Hz, 1H), 4.59 (s, 2H), 4.12 (dABsyst, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16.5 Hz, 1H), 4.06 (dABsyst, J = 16.5 Hz, 1H), 3.80 (s, 3H), 2.83 (t, J = 7.9 Hz, 2H), 2.27–2.14
13
(m, 2H); C NMR (100 MHz, CDCl3)
δ 169.7 (C), 159.7 (C), 140.7 (C), 130.1 (CH), 130.0
(2CH), 129.9 (CH), 129.2 (C), 128.7 (2CH), 128.5 (2CH), 126.3 (CH), 125.5 (CH), 121.2 (C),
114.0 (2CH), 85.5 (C), 81.5 (C), 73.1 (CH2), 66.9 (CH2), 64.7 (CH), 55.4 (CH3), 36.4 (CH2),
31.5 (CH2); HRMS (ESI) m/z calcd for C25H24O4SNa [M + Na]+: 443.1287, found: 443.1289.
1ꢀPhenylbutꢀ2ꢀynꢀ1ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (3j). After purification by flash
chromatography (petroleum ether/EtOAc = 95:5 to 90:10), 3j was isolated as a colorless oil
1
(292 mg, 90%); IR: ν 1755, 1613, 1514, 1249, 1185, 1120, 1034, 821, 759, 699 cm–1; H
NMR (400 MHz, CDCl3) δ 7.54–7.49 (m, 2H), 7.40–7.31 (m, 3H), 7.26 (app d, J = 8.7 Hz,
2H), 6.86 (app d, J = 8.7 Hz, 2H), 6.52 (q, J = 2.2 Hz, 1H), 4.55 (s, 2H), 4.12 (dABsyst, J =
16.6 Hz, 1H), 4.05 (dABsyst, J = 16.6 Hz, 1H), 3.79 (s, 3H), 1.90 (d, J = 2.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.5 (C), 159.6 (C), 137.2 (C), 130.0 (2CH), 129.2 (C), 129.0 (CH),
128.7 (2CH), 127.8 (2CH), 113.9 (2CH), 84.5 (C), 75.6 (C), 73.0 (CH2), 66.9 (CH2), 66.6
(CH), 55.4 (CH3), 3.9 (CH3); HRMS (ESI) m/z calcd for C20H20O4Na [M + Na]+: 347.1254,
found: 347.1255.
1ꢀPhenylhexꢀ4ꢀynꢀ3ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (3k).After purification by flash
chromatography (petroleum ether/EtOAc = 95:5 to 90:10), 3k was isolated as a colorless oil
(484 mg, 98%); IR: ν 2247, 1757, 1613, 1514, 1249, 1192, 1192, 1121, 1034, 821, 752,
20
ACS Paragon Plus Environment

Page 21 of 42
The Journal of Organic Chemistry
1
2
3
4
701 cm–1; 1H NMR (400 MHz, CDCl3)
δ
7.33–7.26 (m, 4H), 7.22–7.16 (m, 3H), 6.89 (app d,
5
6
J = 8.7 Hz, 2H), 5.44 (tq, J = 6.5, 2.1 Hz, 1H), 4.57 (s, 2H), 4.09 (dABsyst, J = 16.5 Hz, 1H),
7
8
4.03 (dABsyst, J = 16.5 Hz, 1H), 3.81 (s, 3H), 2.76 (t, J = 7.9 Hz, 2H), 2.15–2.03 (m, 2H), 1.87
9
13
(d, J = 2.1 Hz, 3H); C NMR (100 MHz, CDCl3)
δ 169.7 (C), 159.6 (C), 140.9 (C), 130.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2CH), 129.3 (C), 128.6 (2CH), 128.5 (2CH), 126.2 (CH), 114.0 (2CH), 82.9 (C), 76.2 (C),
73.1 (CH2), 66.9 (CH2), 64.8 (CH2), 55.4 (CH3), 36.6 (CH2), 31.4 (CH2), 3.8 (CH3); HRMS
(ESI) m/z calcd for C22H24O4Na [M + Na]+: 375.1567, found: 375.1567.
6ꢀ[(tertꢀButyldiphenylsilyl)oxy]ꢀ1ꢀphenylhexꢀ4ꢀynꢀ3ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate
(3l). After purification by flash chromatography (petroleum ether/EtOAc = 90:10 to 80:20), 3l
was isolated as a colorless oil (412 mg, 93%); IR: ν 1759, 1613, 1514, 1249, 1176, 1111,
1086, 1035, 823, 741, 701 cm–1; 1H NMR (400 MHz, CDCl3)
δ 7.74–7.69 (m, 4H), 7.45–7.35
(m, 6H), 7.33–7.26 (m, 4H), 7.23–7.14 (m, 3H), 6.89 (d, J = 8.6 Hz, 2H), 5.46 (m, 1H), 4.57
(s, 2H), 4.38 (app br s, 2H), 4.07 (dABsyst, J = 16.5 Hz, 1H), 4.02 (dABsyst, J = 16.5 Hz, 1H),
13
3.80 (s, 3H), 2.72 (t, J = 7.9 Hz, 2H), 2.12–1.97 (m, 2H), 1.07 (s, 9H); C NMR (100 MHz,
CDCl3)
δ 169.5 (C), 159.6 (C), 140.7 (C), 135.7 (4CH), 133.13 (C), 133.11 (C), 129.97
(2CH), 129.95 (2CH), 129.2 (C), 128.5 (2CH), 128.5 (2CH), 127.9 (4CH), 126.3 (CH), 114.0
(2CH), 84.9 (C), 81.9 (C), 73.1 (CH2), 66.8 (CH2), 64.2 (CH), 55.4 (CH3), 52.8 (CH2), 36.2
(CH2), 31.3 (CH2), 26.8 (3CH3), 19.3 (C); HRMS (ESI) m/z calcd for C38H42O5SiNa
[M + Na]+: 629.2694, found: 629.2689.
1ꢀ(Benzyloxy)pentꢀ3ꢀynꢀ2ꢀyl 2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (3m). After purification
by flash chromatography (petroleum ether/EtOAc = 95:5 to 90:10), 3m was isolated as a
colorless oil (479 mg, 99%); IR: ν 2246, 1758, 1613, 1513, 1247, 1189, 1109, 1031, 820,
1
739, 699 cm–1; H NMR (400 MHz, CDCl3)
δ
7.36–7.25 (m, 7H), 6.87 (app d, J = 8.3 Hz,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 42
1
2
3
4
5
2H), 5.68 (m, 1H), 4.60 (dABsyst, J = 12.1 Hz, 1H), 4.56 (s, 2H), 4.55 (dABsyst, J = 12.1 Hz, 1H),
4.13 (dABsyst, J = 16.6 Hz, 1H), 4.08 (dABsyst, J = 16.6 Hz, 1H), 3.79 (s, 3H), 3.71–3.63 (m,
6
7
8
2H), 1.83 (d, J = 2.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.7 (C), 159.6 (C), 137.7 (C),
9
130.0 (2CH), 129.3 (C), 128.6 (2CH), 127.9 (CH), 127.8 (2CH), 114.0 (2CH), 83.6 (C), 73.7
(C), 73.3 (CH2), 73.0 (CH2), 71.4 (CH2), 66.8 (CH2), 63.8 (CH), 55.4 (CH3), 3.8 (CH3);
HRMS (ESI) m/z calcd for C22H24O5Na [M + Na]+: 391.1516, found: 391.1512.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1ꢀ(Benzyloxy)ꢀ6ꢀ[(tertꢀbutyldiphenylsilyl)oxy]hexꢀ3ꢀynꢀ2ꢀyl
2ꢀ[(4ꢀmethoxyphenyl)methoxy]
acetate (3n). After purification by flash chromatography (petroleum ether/EtOAc = 95:5 to
90:10), 3n was isolated as a pale yellow oil (540 mg, 97%); IR: ν 1758, 1612, 1513, 1248,
1
1175, 1108, 1084, 1033, 822, 739, 700 cm–1; H NMR (400 MHz, CDCl3)
δ 7.68–7.63 (m,
4H), 7.44–7.34 (m, 6H), 7.32–7.23 (m, 7H), 6.85 (app d, J = 8.7 Hz, 2H), 5.71 (m, 1H), 4.57
(dABsyst, J = 12.1 Hz, 1H), 4.54 (s, 2H), 4.51 (dABsyst, J = 12.1 Hz, 1H), 4.08 (s, 2H), 3.79 (s,
3H), 3.74 (t, J = 7.0 Hz, 2H), 3.66 (dd, J = 11.0, 7.3 Hz, 1H), 3.62 (dd, J = 11.0, 4.2 Hz, 1H),
13
2.47 (td, J = 7.0, 2.0 Hz, 2H), 1.03 (s, 9H); C NMR (100 MHz, CDCl3)
δ 169.7 (C), 159.6
(C), 137.7 (C), 135.7 (4CH), 133.6 (2C), 130.0 (2CH), 129.8 (2CH), 129.3 (C), 128.6 (2CH),
127.9 (CH), 127.84 (4CH), 127.82 (2CH), 114.0 (2CH), 85.0 (C), 75.6 (C), 73.2 (CH2), 73.0
(CH2), 71.5 (CH2), 66.8 (CH2), 63.6 (CH), 62.1 (CH2), 55.4 (CH3), 26.9 (3CH3), 23.0 (CH2),
19.3 (C); HRMS (ESI) m/z calcd for C39H44O6SiNa [M + Na]+: 659.2799, found: 659.2802.
Difluorocyclopropenation of 3a: An ovenꢀdried (resealable) vial was successively charged
with NaF (1.7 mg, 0.040 mmol, 10 mol %), alkyne 3a (166 mg, 0.400 mmol, 1 equiv) and
diglyme (200 ꢀL). The vial was closed with a Teflon coated rubber cap, flushed with argon
and immersed in a preꢀheated oil bath at 120 °C. To the resulting mixture (under argon
atmosphere) was slowly added TFDA (300 ꢀL, 1.20 mmol, 3.0 equiv) via syringe pump over
22
ACS Paragon Plus Environment

Page 23 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2 h. Once the addition was complete, the reaction mixture was stirred for further 15 min at
120 °C, cooled to rt and then directly subjected to purification by flash chromatography on
silica gel (petroleum ether/Et2O = 80:20) to afford 160 mg (86%) of 4a as a colorless oil. This
compound could be characterized but rapidly turned brown and underwent decomposition
upon storage even in a freezer at –23 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1ꢀ(3,3ꢀDifluoroꢀ2ꢀphenylcyclopropꢀ1ꢀenꢀ1ꢀyl)ꢀ3ꢀphenylpropyl
2ꢀ[(4ꢀmethoxyphenyl)ꢀ
methoxy]acetate (4a). IR: ν 1801, 1760, 1613, 1513, 1286, 1248, 1175, 1117, 1017, 823,
1
766, 692 cm–1; H NMR (400 MHz, C6D6)
δ 7.67–7.62 (m, 2H), 7.30 (d, J = 8.7 Hz, 2H),
7.28–7.05 (m, 8H), 6.86 (d, J = 8.7 Hz, 2H), 5.98 (m, 1H), 4.54 (dABsyst, J = 11.4 Hz, 1H),
4.47 (dABsyst, J = 11.4 Hz, 1H), 3.99 (s, 2H), 3.39 (s, 3H), 2.78–2.64 (m, 2H), 2.21–2.05 (m,
13
2H); C NMR (100 MHz, C6D6)
δ 169.4 (C), 160.0 (C), 140.6 (C), 131.4 (CH), 130.9 (CH),
129.9 (2CH), 129.7 (C), 129.3 (2CH), 128.9 (2CH), 128.7 (2CH), 126.6 (2CH), 125.2 (C, t,
1
2JCꢀF = 11.6 Hz), 123.5 (C), 114.2 (2CH), 102.7 (C, t, JCꢀF = 272.4 Hz), 73.1 (CH2), 68.4
(CH), 66.9 (CH2), 54.8 (CH3), 34.7 (CH2), 31.3 (CH2) (The signal corresponding to one
quaternary cyclopropene carbon was not visible presumably because of overlap with the
19
1
solvent signal); F NMR (282 MHz, C6D6)
δ –106.1 (dABsyst, JFꢀF = 126.8 Hz, 1F), –107.4
(dABsyst, 1JFꢀF = 126.8 Hz, 1F); HRMS (ESI) m/z calcd for calcd for C28H26F2O4Na [M + Na]+:
487.1691, found: 487.1688.
Representative procedure for the difluorocyclopropenation/Ireland-Claisen rearrangement:
An ovenꢀdried (resealable) vial was successively charged with NaF (13.5 mg, 0.322 mmol,
10 mol %), alkyne 3a (1.33 g, 3.22 mmol, 1.0 equiv) and diglyme (1.9 mL). The vial was
closed with a Teflon coated rubber cap, flushed with argon and immersed in a preꢀheated oil
bath at 120 °C. To the resulting mixture (under argon atmosphere) was slowly added TFDA
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 42
1
2
3
4
5
6
7
8
9
(1.90 mL, 9.65 mmol, 3.0 equiv) via syringe pump over 2 h. Once the addition was complete,
the reaction mixture was stirred for further 15 min at 120 °C, cooled to rt and then diluted
with THF (56 mL). The resulting solution was sparged with argon for 15 min and then cooled
to –78 °C. TMSCl (1.64 mL, 12.9 mmol, 4 equiv) and KHMDS (25.7 mL, 0.5 M solution in
toluene, 12.9 mmol, 4 equiv) were successively added dropwise. After 1 h at –78 °C, the
reaction mixture was warmed to rt, stirred for further 3 h and then poured into a saturated
aqueous solution of NH4Cl (100 mL). The layers were separated and the aqueous phase was
extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was dissolved in a MeOH/toluene mixture
(1:1, 20 mL) and trimethylsilyldiazomethane (3.2 mL, 2 M solution in Et2O, 6.4 mmol,
2 equiv) was slowly added to the resulting solution. The reaction mixture was concentrated
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
under reduced pressure and subsequent analysis of the residue by H NMR spectroscopy
indicated the formation of 8a as a single detectable diastereomer (dr > 96:4). The crude
material was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 90:10
to 80:20) to afford 1.10 g (72%) of 8a as a pale yellow oil. On smaller scale, 8a was obtained
in similar yield (134 mg, 73%).
Methyl (2S*)ꢀ2ꢀ[(1R*,3Z)ꢀ2,2ꢀdifluoroꢀ1ꢀphenylꢀ3ꢀ(3ꢀphenylpropylidene)cyclopropyl]ꢀ2ꢀ[(4ꢀ
methoxyphenyl)methoxy]acetate (8a). IR: ν 1757, 1735, 1613, 1514, 1389, 1249, 1145, 1127,
1032, 1008, 823, 750, 721, 699 cm–1; 1H NMR (400 MHz, CDCl3)
δ 7.37–7.23 (m, 9H), 7.23–
7.15 (m, 3H), 6.90 (m, 2H), 6.64 (m, 1H), 4.72 (dABsyst, J = 11.4 Hz, 1H), 4.59 (dABsyst, J =
11.4 Hz, 1H), 4.05 (d, J = 2.2 Hz, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 2.92–2.82 (m, 2H), 2.69–
13
2.60 (m, 2H); C NMR (100 MHz, CDCl3)
δ
170.4 (C, d, 4JC–F = 1.9 Hz), 159.5 (C), 141.0
3
(C), 132.7 (CH), 131.4 (C, d, JCꢀF = 3.6 Hz), 130.5 (2CH), 129.8 (2CH), 129.5 (C), 128.58
2
(2CH), 128.56 (2CH), 128.3 (CH), 128.2 (2CH), 126.3 (CH), 122.9 (C, t, JCꢀF = 6.4 Hz),
24
ACS Paragon Plus Environment

Page 25 of 42
The Journal of Organic Chemistry
1
2
3
1
3
113.9 (2CH), 107.6 (C, t, JC–F = 295.3 Hz), 78.4 (CH, d, JC–F = 3.9 Hz), 72.4 (CH2), 55.4
4
5
6
(CH3), 52.1 (CH3), 41.7 (C, t, 2JC–F = 12.5 Hz), 34.4 (CH2), 34.1 (CH2); 19F NMR (282 MHz,
7
8
1
1
CDCl3)
δ –128.90 (dABsyst, JF–F = 168.2 Hz, 1F), –130.65 (dABsyst, JF–F = 168.2 Hz, 1F);
9
HRMS (ESI) m/z calcd for C29H28F2O4Na [M + Na]+: 501.1848, found: 501.1842.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl (2S*)ꢀ2ꢀ[(1R*,3Z)ꢀ3ꢀethylideneꢀ2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)cyclopropyl]ꢀ2ꢀ[(4ꢀ
methoxyphenyl)methoxy]acetate (8b). After purification by flash chromatography (petroleum
ether/EtOAc = 95:5 to 90:10), 8b was isolated as a pale yellow oil (165 mg, 76%); IR:
1
ν 1755, 1611, 1511, 1246, 1176, 1139, 1112, 1031, 1006, 818 cm–1; H NMR (400 MHz,
CDCl3)
2H), 6.73 (app d, J = 8.9 Hz, 2H), 6.46 (m 1H), 4.65 (dABsyst, J = 11.4 Hz, 1H), 4.51 (dABsyst
J = 11.4 Hz, 1H), 3.99 (d, J = 2.3 Hz, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.56 (s, 3H), 1.93 (d, J =
δ 7.25 (app d, J = 8.7 Hz, 2H), 7.18 (app d, J = 8.9 Hz, 2H), 6.81 (app d, J = 8.8 Hz,
,
13
4
6.9 Hz, 3H); C NMR (100 MHz, CDCl3)
δ
170.5 (C, d, JC–F = 1.9 Hz), 159.6 (C), 159.5
5
2
(C), 131.6 (2CH, JCꢀF = 1.7 Hz), 129.8 (2CH), 129.5 (C), 128.2 (CH), 123.6 (C, t, JCꢀF
=
=
3
1
5.7 Hz), 123.4 (C, d, JCꢀF = 3.7 Hz), 113.8 (2CH), 113.7 (2CH), 107.8 (C, t, JCꢀF
294.9 Hz), 78.4 (CH, d, 3JCꢀF = 3.1 Hz), 72.3 (CH2), 55.4 (CH3), 55.3 (CH3), 52.1 (CH3), 41.5
2
1
(C, t, JCꢀF = 12.5 Hz), 18.4 (CH3); 19F NMR (282 MHz, CDCl3)
1JFꢀF = 168.0 Hz, 1F); HRMS (ESI) m/z calcd for
C23H24F2O5Na [M + Na]+: 441.1484, found: 441.1481.
δ –131.2 (dABsyst, JFꢀF =
168.0 Hz, 1F), –133.2 (dABsyst
,
Methyl
(2S)ꢀ2ꢀ[(1R,3Z)ꢀ3ꢀethylideneꢀ2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)cyclopropyl]ꢀ2ꢀ[(4ꢀ
methoxyphenyl)methoxy]acetate ((+)ꢀ8b). After purification by flash chromatography
(petroleum ether/EtOAc = 95:5 to 90:10), (+)ꢀ8b was isolated as pale yellow oil (163 mg,
20
72%); [α]D +61.8 (c 0.68, CHCl3). The enantiomeric excess of (+)ꢀ8b (ee = 95%) was
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 42
1
2
3
4
5
determined by supercritical fluid chromatography analysis of compound (+)ꢀ9b obtained after
cleavage of the PMB ether (vide infra).
6
7
8
9
Methyl
(2S*)ꢀ2ꢀ[(1R*,3Z)ꢀ1ꢀ(4ꢀbromophenyl)ꢀ3ꢀethylideneꢀ2,2ꢀdifluorocyclopropyl]ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (8c). After purification by flash chromatography
(petroleum ether/EtOAc = 95:5 to 90:10), 8c was isolated as a pale yellow oil (222 mg, 75%);
1
IR: ν 1756, 1736, 1613, 1514, 1247, 1147, 1112, 1010, 824, 808, 730 cm–1; H NMR (400
MHz, CDCl3)
δ 7.40 (app d, J = 8.6 Hz, 2H), 7.31 (app d, J = 8.7 Hz, 2H), 7.22 (app d, J =
8.6 Hz, 2H), 6.88 (app d, J = 8.7 Hz, 2H), 6.56 (m, 1H), 4.72 (dABsyst, J = 11.2 Hz, 1H), 4.57
(dABsyst, J = 11.2 Hz, 1H), 4.07 (d, J = 2.2 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 2.01 (app br d,
4
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ
170.2 (C, d, JC–F = 1.9 Hz), 159.5 (C),
3
132.22 (CH), 132.21 (CH), 131.3 (2CH), 130.6 (C, d, JC–F = 3.7 Hz), 129.8 (2CH), 129.21
2
1
(C), 129.15 (CH), 122.8 (C, t, JCꢀF = 6.0 Hz), 122.7 (C), 113.8 (2CH), 107.3 (C, t, JC–F
=
3
293.4 Hz), 78.1 (CH, d, JCꢀF = 3.7 Hz), 72.5 (CH2), 55.3 (CH3), 52.2 (CH3), 41.5 (C, t,
2JC–F = 12.6 Hz), 18.4 (CH3); HRMS (ESI) m/z calcd for C22H21BrF2O4Na [M(79Br) + Na]+
and [M(81Br) + Na]+: 489.0483 and 491.0463, found: 489.0438 and 491.0458.
Methyl
(2S*)ꢀ2ꢀ[(1R*,3Z)ꢀ1ꢀ(4ꢀacetylphenyl)ꢀ3ꢀethylideneꢀ2,2ꢀdifluorocyclopropyl]ꢀ
2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (8e). After purification by flash chromatography
(petroleum ether/Et2O = 90:10), 8e was isolated as a pale yellow oil (156 mg, 65%); IR:
1
ν 1758, 1687, 1609, 1516, 1267, 1251, 1149, 1120, 1035, 827 cm–1; H NMR (400 MHz,
CDCl3)
δ 7.87 (app br d, J = 8.6 Hz, 2H), 7.45 (app d, J = 8.6 Hz, 2H), 7.32 (app d, J =
8.8 Hz, 2H), 6.90 (app d, J = 8.8 Hz, 2H), 6.61 (m, 1H), 4.74 (dABsyst, J = 11.2 Hz, 1H), 4.59
(dABsyst, J = 11.2 Hz, 1H), 4.11 (d, J = 2.3 Hz, 1H), 3.81 (s, 3H), 3.63 (s, 3H), 2.56 (s, 3H),
13
4
2.04 (app d, J = 6.9 Hz, 3H); C NMR (100 MHz, CDCl3)
δ 197.9 (C), 170.2 (C, d, JCꢀF =
26
ACS Paragon Plus Environment

Page 27 of 42
The Journal of Organic Chemistry
1
2
3
3
1.9 Hz), 159.6 (C), 136.9 (C, d, JCꢀF = 3.7 Hz), 136.8 (C), 130.8 (2CH), 129.8 (2CH), 129.5
4
5
6
2
1
(CH), 129.2 (C), 128.1 (2CH), 122.6 (C, t, JCꢀF = 6.1 Hz), 113.9 (2CH), 107.3 (C, t, JCꢀF
=
=
=
295.4 Hz), 78.2 (CH, d, 2JCꢀF = 3.3 Hz), 72.6 (CH2), 55.4 (CH3), 52.2 (CH3), 41.9 (C, t, 2JCꢀF
7
8
9
19
1
12.7 Hz), 26.7 (CH3), 18.4 (CH3); F NMR (282 MHz, CDCl3)
δ –130.66 (dABsyst, JF–F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
168.8 Hz), –133.04 (dABsyst, JFꢀF = 168.8 Hz); HRMS (ESI) m/z calcd for C24H24F2O5Na
[M + Na]+: 453.1484, found: 453.1487.
Methyl
(2S*)ꢀ2ꢀ[(1S*,3Z)ꢀ1ꢀ(2ꢀchlorophenyl)ꢀ3ꢀethylideneꢀ2,2ꢀdifluorocyclopropyl]ꢀ2ꢀ[(4ꢀ
methoxyphenyl)methoxy]acetate (8f). After purification by flash chromatography (petroleum
ether/Et2O = 90:10), 8f was isolated as a pale yellow oil (222 mg, 67%); IR: ν 1755, 1613,
1514, 1205, 1175, 1246, 1147, 1108, 1038, 1004, 824, 757, 739 cm–1; H NMR (400 MHz,
1
DMSOꢀd6, 375K)
δ 7.41–7.25 (m, 4H), 7.20 (app d, J = 8.6 Hz, 2H), 6.88 (app d, J = 8.7 Hz,
2H), 6.75 (app qt, J = 6.9, 1.7 Hz, 1H), 4.52 (dABsyst, J = 11.6 Hz, 1H), 4.45 (dABsyst, J =
11.6 Hz, 1H), 4.17 (s, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.00 (dt, J = 6.9, 2.1 Hz, 3H); 13C NMR
4
(100 MHz, DMSOꢀd6, 375K)
δ
168.5 (C, d, JCꢀF = 1.9 Hz), 158.7 (C), 134.5 (C), 130.4 (C),
129.10 (CH), 129.07 (2CH), 128.8 (C), 128.6 (2CH), 125.8 (CH), 120.3 (C), 113.3 (2CH),
1
99.0 (C, t, JCꢀF = 314.8 Hz), 77.2 (CH), 71.1 (CH2), 54.7 (CH3), 51.1 (CH3), 40.7 (C), 17.2
(CH3) (One quaternary aromatic carbon signal is not detected presumably because of
overlap); 19F NMR (282 MHz, CDCl3, 295 K) The presence of a 72:28 mixture of rotamers
1
1
was observed,
173.5 Hz, 0.28
165.2 Hz, 0.72
δ
–135.61 (dABsyst, JFꢀF = 165.2 Hz, 0.72
x
1F), –132.38 (dABsyst, JFꢀF
=
=
1
1
x
1F), –128.89 (dABsyst, JFꢀF = 173.5 Hz, 0.28
x
1F), –127.76 (dABsyst, JFꢀF
x
1F); HRMS (ESI) m/z calcd for C22H21ClF2O4Na [M(35Cl) + Na]+ and
[M(37Cl) + Na]+: 445.0989 and 447.0959, found: 445.0989 and 447.0962.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 42
1
2
3
Methyl (2S*)ꢀ2ꢀ[(1R*,3Z)ꢀ3ꢀethylideneꢀ2,2ꢀdifluoroꢀ1ꢀ(naphthalenꢀ1ꢀyl)cyclopropyl]ꢀ2ꢀ[(4ꢀ
4
5
6
methoxyphenyl)methoxy]acetate (8g). After purification by flash chromatography (petroleum
7
8
ether/Et2O = 90:10), 8g was isolated as a yellow oil (137 mg, 63%); IR: ν 1756, 1733, 1613,
9
1
1514, 1248, 1144, 1032, 822, 800, 778 cm–1; H NMR (400 MHz, DMSOꢀd6, 375K)
δ 8.23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, app br s, 1H), 7.89–7.82 (m, 2H), 7.50–7.40 (m, 4H), 7.18 (app d, J = 8.1 Hz, 2H), 6.87
(app d, J = 8.5 Hz, 2H), 6.82 (qt, J = 6.9, 2.0 Hz, 1H), 4.53 (dABsyst, J = 11.5 Hz, 1H), 4.45
(dABsyst, J = 11.5 Hz, 1H), 4.34 (s, 1H), 3.77 (s, 3H), 3.63 (br s, 3H), 2.02 (dt, J = 6.9, 2.0 Hz,
3H); 13C NMR (100 MHz, CDCl3, 296K) Signals with an asterisk can be assigned to a minor
4
4
rotamer when distinction is possible
δ 170.9* (C, d, JCꢀF = 2.0 Hz), 170.4 (C, d, JCꢀF = 1.6
Hz), 159.5* (C), 159.4 (C), 134.1* (C), 134.0 (C), 133.6 (C), 132.7* (C), 132.1 (CH),
130.15* (CH), 130.1 (C, d, 4JCꢀF = 3.9 Hz), 129.9* (CH), 129.7 (2CH), 129.35 (CH), 129.20*
(CH), 129.16* (C), 129.14 (C), 129.0* (CH), 128.4* (CH), 128.37 (CH), 127.9 (CH), 127.4
(CH), 125.9 (CH), 125.76* (CH), 125.72 (CH), 125.34* (CH), 125.3* (CH), 124.8 (CH),
2
1
123.9* (CH), 123.5 (C, t, JCꢀF = 6.0 Hz), 113.8* (CH), 113.7 (2CH), 108.0 (C, t, JCꢀF
=
2
295.5 Hz), 79.9 (CH, d, JCꢀF = 4.2 Hz), 77.8* (C), 72.7 (CH2), 72.2* (CH2), 55.4 (CH3),
2
52.2* (CH3), 52.0 (CH3), 40.7 (C, t, JCꢀF = 13.1 Hz), 18.6* (CH3), 18.5 (CH3); HRMS (ESI)
m/z calcd for C26H24F2O4Na [M + Na]+: 461.1535, found: 461.1532.
tertꢀButyl
3ꢀ((1R*,3Z)ꢀ3ꢀethylideneꢀ2,2ꢀdifluoroꢀ1ꢀ{(1S*)ꢀ2ꢀmethoxyꢀ1ꢀ[(4ꢀmethoxyꢀ
phenyl)methoxy]ꢀ2ꢀoxoethyl}cyclopropyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate (8h). After purification by
flash chromatography (petroleum ether/Et2O = 80:20), 8h was isolated as a pale yellow oil
(152 mg, 70%); IR: ν 1736, 1613, 1515, 1451, 1372, 1247, 1155, 1108, 822, 763, 748 cm–1;
1H NMR (400 MHz, CDCl3)
δ 8.06 (br d, J = 7.0 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.55 (s,
1H), 7.31 (d, J = 8.7 Hz, 2H), 7.24 (m, 1H), 7.15 (m, 1H), 6.87 (app d, J = 8.7 Hz, 2H), 6.62
(m, 1H), 4.72 (dABsyst, J = 11.3 Hz, 1H), 4.58 (dABsyst, J = 11.3 Hz, 1H), 4.11 (d, J = 2.2 Hz,
28
ACS Paragon Plus Environment

Page 29 of 42
The Journal of Organic Chemistry
1
2
3
13
1H), 3.79 (s, 3H), 3.61 (s, 3H), 2.02 (d, J = 6.9 Hz, 3H), 1.64 (s, 9H); C NMR (100 MHz,
4
5
6
CDCl3)
δ
170.8 (C), 159.5 (C), 149.6 (C), 135.3 (C), 130.3 (C), 129.9 (2CH), 129.3 (C), 129.1
7
8
9
2
(CH), 127.4 (CH), 124.3 (CH), 122.7 (C, t, JCꢀF = 5.8 Hz), 122.5 (CH), 120.6 (CH), 115.3
(CH), 113.8 (2CH), 111.3 (C), 107.5 (C, t, 1JCꢀF = 295.0 Hz), 83.9 (C), 77.9 (CH), 72.4 (CH2),
55.4 (CH3), 52.3 (CH3), 36.0 (C, t, 2JCꢀF = 12.6 Hz), 28.3 (3CH3), 18.4 (CH3); 19F NMR (282
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3)
(ESI) m/z calcd for C29H31F2NO6Na [M + Na]+: 550.2012, found: 550.2008.
δ
–129.50 (dABsyst, 1JFꢀF = 167.1 Hz), –134.04 (dABsyst, 1JFꢀF = 167.1 Hz); HRMS
Methyl
(2S*)ꢀ2ꢀ[(1S*,3Z)ꢀ2,2ꢀdifluoroꢀ3ꢀ(3ꢀphenylpropylidene)ꢀ1ꢀ(thiophenꢀ3ꢀyl)ꢀ
cyclopropyl]ꢀ2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (8i). After purification by flash
chromatography (petroleum ether/Et2O = 80:20), 8i was isolated as a yellow oil (129 mg,
70%); IR: ν 1756, 1613, 1514, 1249, 1145, 1125, 1033, 1011, 827, 750, 699 cm–1; 1H NMR
(400 MHz, CDCl3)
δ 7.36 (app d, J = 8.7 Hz, 2H), 7.33–7.28 (m, 2H), 7.25–7.18 (m, 5H),
7.07 (dd, J = 4.2, 2.1 Hz, 1H), 6.92 (app d, J = 8.7 Hz, 2H), 6.61 (m, 1H), 4.76 (dABsyst, J =
11.2 Hz, 1H), 4.62 (dABsyst, J = 11.2 Hz, 1H), 4.03 (s, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 2.90 (t,
J = 7.8 Hz, 2H), 2.72–2.63 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 170.5 (C), 159.5 (C),
140.9 (C), 132.8 (CH), 131.8 (C), 129.8 (2CH), 129.4 (C), 129.0 (CH), 128.57 (2CH), 128.56
2
(2CH), 126.3 (CH), 125.6 (CH), 125.1 (CH), 123.0 (C, t, JCꢀF = 6.3 Hz, C6), 113.9 (2CH),
1
107.1 (C, t, JCꢀF = 296.2 Hz), 78.1 (CH), 72.4 (CH2), 55.4 (CH3), 52.2 (CH3), 38.3 (C, t,
2JCꢀF = 12.9 Hz), 34.2 (CH2), 34.1 (CH2); HRMS (ESI) m/z calcd for C27H26F2O4SNa
[M + Na]+: 507.1412, found: 507.1405.
Methyl
(2S*)ꢀ2ꢀ[(1R*,3Z)ꢀ2,2ꢀdifluoroꢀ1ꢀmethylꢀ3ꢀ(3ꢀphenylpropylidene)cyclopropyl]ꢀ
2ꢀ[(4ꢀmethoxyphenyl)methoxy]acetate (8k). After purification by flash chromatography
(petroleum ether/Et2O = 80:20), 8k was isolated as a slightly yellow oil (216 mg, 61%); IR:
ν 1752, 1734, 1614, 1515, 1250, 1106, 1033, 822, 751, 729, 700 cm–1; 1H NMR (400 MHz,
29
ACS Paragon Plus Environment