(2-Fluoroallyl)boration of Ketones with (2-Fluoroallyl)boronates

Article abstract of DOI:10.1021/acs.joc.9b03445

Efficient routes toward activation of gem-chlorofluorocyclopropane-derived (2-fluoroallyl)boronates for allylboration of various ketones including functionalized and low-reactive ones were developed. Increasing the boron electrophilicity by the transforma

Full text of DOI:10.1021/acs.joc.9b03445

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Article
(2-Fluoroallyl)boration of ketones with (2-fluoroallyl)boronates
Maxim A Novikov, Angelina Bobrova, Igor Mezentsev, Michael G. Medvedev, and Yury V. Tomilov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03445 • Publication Date (Web): 20 Apr 2020
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(
2-Fluoroallyl)boration of ketones with (2-fluoroallyl)boronates
1
1,2
1,2
1
Maxim A. Novikov *, Angelina Yu. Bobrova , Igor A. Mezentsev , Michael G. Medvedev and
Yury V. Tomilov1
1
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
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1
19991 Moscow, Russian Federation
2
Higher Chemical College of the Russian Academy of Sciences, D. I. Mendeleev University of
Chemical Technology of Russia, 9 Miusskaya pl., 125047 Moscow, Russian Federation
Fax: +7499 135 63 90; e-mail: manovikov@ioc.ac.ru
Abstract
Efficient routes toward activation of gem-chlorofluorocyclopropane-derived (2-
fluoroallyl)boronates for allylboration of various ketones including functionalized and low-reactive
ones were developed. Increasing of the boron electrophilicity by transformation of boronate moiety
n
into borinic ester with BuLi/TFAA, makes (2-fluoroallyl)boration of acetyl arenes/hetarenes and
aliphatic ketones possible with high diastereoselectivity. For low-reactive or sterically hindered
ketones (e.g. benzophenone, adamantanone), “CuF”-based catalysts were developed —
Cl
(NHC)CuF·HF and (NHC)CuOTf in the presence of an excess of KHF (NHC = IPr, SIPr, IPr ).
2
R4
R4
R5
O
R5
O
R2
R3
OH
F
R4 OH
R5
F
R4
(IPr)CuOTf
KHF2
R3 nBuLi/TFAA
R1
B(pin)
R5
R1 R2
–82°C to r.t.
F
1
R = Ph; r.t.
Ph
4
5–90%
53–91%
d.r. up to 3/1
O
(IPr)CuF·HF
R = Ph; r.t.
d.r. up to >95/5
1
Ph
R
diaryl ketones,
sterically hindered ketones,
,3-ketoesters
aliphatic ketones or
acetyl aryl/hetaryl ketones
F
OH
R
1
Ph
up to 99%
Ph
Keywords
-fluoroallyl boronates, allylboration, organofluorine compounds, fluorinated cyclopropanes, copper
catalysis
2
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Introduction
Allylboration of carbonyl compounds is a powerful tool in modern organic synthesis that allows
facile preparation of various homoallylic alcohols with high level of diastereo- and
1
enantioselectivities. The latter are good intermediates in total synthesis of natural compounds and
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drugs, as demonstrated by many recent publications. The most important advantages of allyl
boronates compared to other allyl-metal reagents include synthetic availability by many different
methods, high stability and functional group tolerance, low toxicity and reactivity easily tunable by
catalysts, inductors or other additives.
Allylboration approach is also very promising when applied to organofluorine synthesis, as it
can provide an easy access to functionalized fluoroalkenes that have found many applications as
3
biologically active compounds of different types. Important feature of fluoroalkene moiety is its
similarity by electronic and steric parameters to amide bond. As the result, substitution of amide
fragment in di- or oligopeptide or in any other biologically valuable molecule by monofluorinated
double bond can give bioisosteres with increased hydrolytic stability, higher lipophilicity and better
permeability through membranes.4
Nevertheless, active researches on the preparation of fluorinated allylboronates were started
only during the last decade; and only 3,3-difluoro-, 3-fluoro- and 1-fluoro substituted ones were
5
synthesized (Scheme 1, A). The first examples of 3,3-difluoroallylboronates were prepared by
Ramachandran group by reactions of 2,2-difluorovinyllithium reagents with -halomethylboronates6a-
e
6f
or by hydroboration of ,-difluoroallene. In past few years together with the continuously growing
interest to metal-catalyzed activation of inert C–F bond, efficient protocols for allylic substitution of
7a-e
fluorine in ,,-trifluoro- and ,-difluoroalkenes with B pin catalyzed by copper alkoxides or
2
2
7
f
FeCl were disclosed. 1-Fluoro substituted allylboronates were prepared by electrophilic fluorination
2
of -boronyl containing allylsilanes with SelectFluor.8
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Scheme 1. Examples of fluorinated allyl boronates
Scheme 2. Allylboration of ketones with allyl boronates (substituents are omitted for clarity)
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1
1
1
1
1
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1
1
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A. Fluorinated allyl boronates. Previous works:
A. Transmetalation approaches
M = Cu (ref. 10a)
M-X
X
X
OR
O-B(OR)2
1)
OR
B(pin)
R2C=O
Zn (refs. 10b,c)
In (refs. 10d,e)
Ga (ref. 11)
iPr
0
1
2
3
4
5
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0
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R
R
F
+
F
B
M
I
B
OR
Li
OR
refs. 6a-e
ref. 6f
F
F
OM
H
N
NMe2
F
F
B(Ipc)2
R
R
B(pin)
2)
·
+
HB(Ipc)2
B
O
O
F
ref. 12
F
G
High reactivity of allyl-metal species
Low d.r. and regioselectivity
Sensitive to substituents on allylboronate
t
G = SiPh or Bu;
3
3) F F
G
F
B(pin)
R
+
B (pin)
2 2
R
G
B. Borinic ester approach (ref. 13)
I
1
) nBuLi
O-B( Bu)(OR)
n
[
Cu ]/L refs. 7a-e
R C=O
O
2
R
R
FeCl2 ref. 7f
B(pin)
B
O–TFA
2) TFAA
nBu
B(pin)
F
4)
SelectFluor
ref. 8
Me Si
B(pin)
3
Broad substrate scope
High d.r. and ee transfer
Borinic esters can be configurationally unstable ar r.t.
Alk
Alk
C. Chiral Binol organocatalyst (ref. 14)
X
B. Our recent work:
Cl
HO *
R
HO *
O
O-B(OR)2
HO
HO
F
HO
R C=O
2
H
O
R
R
=
B (pin)2
2
B(OR)2
CuCl
B
HO
Cl
B(pin)
[Pd]
O
RO = HO, AlkO, O(CH) O
F
F
2
X
ref. 9
High ee
X = F, Cl, Br;
Pinacol esters are not applicable
C. The aim of the current study:
D. Neighboring group-assisted (refs. 15,16)
O
O-B(OR)2
O
F
F
OR
OH
O
O
R
R
R
B
B
O-B(OH)2
Bpin
+
R
R
OH
NH
OH
R
R
R'
O
R
R
B(OR)2
R
R'
H2N OH
N
O
1
2
for R = H
3
R
Comparison of
transmetalation and
borinic ester approaches
Allylboronic acids are highly air and
moisture sensitive and difficult to prepare
Tedious removal of directing group
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Recently, we have disclosed a facile preparation of 2-fluoroallyl boronates by Pd-catalyzed
borylation of 2-fluoroallyl chlorides derived from CuCl-catalyzed ring-opening isomerization of gem-
9
chlorofluorocyclopropanes. However, in this work 2-fluoroallyl boronates were used only for
allylboration of aldehydes, while ketones were found to be unreactive (Scheme 1, B, C).
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Allylboration of ketones in both diastereo- and enantioselective versions is nowadays a very
important and challenging task; and in the past decade significant progress was made. Transmetalation
approach is very powerful and is based on catalytic replacement of Bpin-group by metal (Cu,10a
Zn,10b,c, In10d,e, Ga ) or more reactive boron group (Scheme 2, A). However, despite high reactivity
of allyl-metal intermediates, these reactions usually led to low diastereoselectivity, or even low
regioselectivity in cases of substituted allylboronates. An efficient approach reported recently by
11
12
n
Aggarwal’s group involves conversion of pinacolboronate moiety into borinic ester with BuLi and
1
3
TFAA (Scheme 2, B). This approach can be used for a wide range of allylboronates and ketones and
gives high d.r. and e.r. values. Notably, it was the method of choice for activation of 3,3-difluoro- and
3
-fluoroallyl boronates to allylboration of ketones.7b,c
A popular method for enantioselective allylboration of ketones is to use 3,3´-disubstituted
BINOL derivatives as a chiral organocatalyst (Scheme 2, C).14,2c However, as this method involves
transesterification with BINOL, the most stable and widely available allyl pinacol boronates are not
applicable; and much less stable boronic esters of monoatomic alcohols or 1,3-propanediol are
required. Also, the presence of chelating groups on substrates can accelerate allylboration
significantly; and this was used in additions of allylboronic acids to hydroxy-substituted ketones and
ketimines (Scheme 2, D).15,16
Results and Discussion
Therefore, the aim of the current study was to find an appropriate route for the activation of our
2
-fluoroallyl boronates to the allylboration of ketones. Using benzophenone as a model low-reactive
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ketone, we have started with well-known “CuF”-based catalytic system derived from CuCl and
TBAT.10a,17 But neither itself, or in the presence of various additional ligands, it did not gave any trace
of the target product (Table 1, Entry 1). Further screening of “CuF” sources revealed that (IPr)CuOTf
in the presence of KHF is able to catalyze the target reaction affording 3a in moderate isolated yield
2
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(Entry 2). Increasing of copper electrophilicity by replacement of IPr with more electron-deficient
Cl
IPr , increases the catalyst activity, but makes the reaction less regioselective (Entry 4 vs. Entry 3).
Table 1. Screening of the reaction conditions for the allylboration of benzophenone with 1a. a
OH
F
O
Ph
Ph
OH
F
Ph
Ph
Ph
Bpin
+
+
Ph
Ph
Ph
THF
F
Ph
1a
2a
3a
4a
3a (%)b
4a (%)b
Entry
Catalytic system (10% on 1a)
t (h)
T (°C)
Z/E
1
2
3
4
5
6
7
8
9
CuCl/TBAT/Ligand (1:1:1)c
24
5
20
20
20
20
0
no reaction
(IPr)CuOTf/KHF (1:30)
68 d
59
–
–
–
2
(IPr)CuOTf/KHF (1:30)
5
–
2
Cl
(IPr )CuOTf/KHF (1:30)
5
88
10
53
0/100
94/6
2
(EtO) Zn/EtOH (1:12)
18
24
24
5
23
2
InI e
40
no reaction
no reaction
99 d
nBuLi/TFAA f
(IPr)CuF·HF g
(IPr)CuF·HF g
–82 to r.t.
20
20
20
–
–
–
3/97
3/97
2/98
1
64
Cl
g
1
0
(IPr )CuF·HF
1
85
a
b
19
0.25 mmol of 1a and 0.20 mmol of 2a were used. Yields were determined by F NMR after aqueous work-up
c
n
+
–
using 2-fluorocinnamyl acetate as an internal standard. TBAT = Bu N [Ph SiF ] , Ligand = PPh , dppe, dppp,
4
3
2
3
d
dppb, SPhos, (R)-BINAP, tmeda, Bipy or Phen. Isolated yields when 1.0 mmol of 1a and 0.8 mmol of 2a
e
f
n
g
were used. Generated in situ from In and InI . 1.1 equiv. of BuLi and 1.2 equiv. of TFAA were used. In
3
the presence of MS 4Å.
Abbreviations:
Cl
Cl
iPr
N
N
Ar
Ar
N
N
Ar =
Ar
Ar
iPr
IPrCl
IPr
1
0b
Other metals were also tested (see Scheme 2). Zinc ethylate (EtO) Zn is able to catalyze the
2
addition of boronate 1a to benzophenone. However, the reaction is not regioselective and gives a
mixture of isomeric alcohols 3a and 4a (Entry 5). Indium(I)-catalyzed conditions,10d as well as the
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method developed by Aggarwal’s group for enhancement of allyl boronate reactivity via conversion
1
3
of boronate moiety into borinic ester were found to be inefficient, and benzophenone remained
completely unreacted in these cases (Entries 6 and 7).
Remarkable regioselectivity change was observed when pre-synthesized hydrofluoride complex
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(
IPr)CuF·HF was used as the catalyst.18,19 (E)-Isomeric alcohol E-4a was obtained in almost
Cl
quantitative yield (Entry 8). Chlorinated complex (IPr )CuF·HF again was several times more active
than (IPr)CuF·HF (Entry 10 vs. Entry 9). (E)-configuration of the formed C=C double bond is clearly
identified from typical cis 3JH–F coupling constant between fluorine and alkene proton of E-4a (3JH-F
is 23.5 Hz for the major isomer assigned as E-4a; 3JH-F is 39.6 Hz for the minor isomer assigned as Z-
4
a).
We suggest that the key factor determining the regioselectivity of the copper catalyzed processes
in the case of 1a and benzophenone is the reversible addition of allyl copper intermediates to
benzophenone (Scheme 3). In other words, “(NHC)CuF” reacts with allyl boronate 1a forming allyl
1
9
metal intermediates I and II existing in a fast equilibrium to each other. However, conjugation of
C=C double bond with Ph ring in I probably makes this equilibrium shifted to I which readily reacts
with ketone forming copper alcoholate III. The additional KHF at this point likely serves as a mild
2
+
20
source of “H ”, which converts III to alcohol 3a regenerating “(IPr)CuF”. In the absence of any
+
21–23
“
H ” source, III due to steric hindrance is able for reversible de-allylation.
As the result, the
equilibrium is shifted to IV which is formed irreversibly. The irreversible formation of IV can be
assumed from the formation of thermodynamically less stable (E)-isomer (in other words, IV is also
a product of kinetic control and should not participate in any equilibrium).
Much more unambiguously such equilibrium shifting from branched alcohols 3 to linear 4 can
be seen on the allylboration of acetophenone 2b (Table 2). Aqueous work-up of the reaction mixture
after 3 hours gives mixtures of alcohols 3b and 4b (Entry 1 and 5). Increasing of the reactions time
(Entry 2 and 6) and/or temperature (Entry 4 and 8) results in disappearance of 3b and predominant or
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exclusive formation of E-4b. These data clearly indicate that isomerization of IIIb or 3b-Bpin into E-
4b-Bpin takes place as presented on Scheme 3. Notably, this isomerization proceeds faster in the case
Cl
more electrophilic (IPr )CuF·HF (Entry 5 vs. 1 and Entry 7 vs. 3).
Scheme 3. A proposed mechanism of the copper catalyzed allylboration of benzophenone.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
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5
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2
3
4
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2
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Ph
Bpin
OH
F
Route A, protonation
Ph
Ph
F
1a
KHF2
Ph
Cu(IPr)
fast
3a
O
F
Ph
Ph
B(pin)
1
a
Ph
Cu(IPr)
O
F
Ph
Ph
F
Ph
+
no "H " source
I
III
slow
Ph
Route B, transmetalation
3a-Bpin
B(pin)
Cu(IPr)
Cu(IPr)
1
a
O
F
O
F
Ph
Ph
Ph
Ph
+
no "H " source Ph
F
slow
Ph
Ph
II
IV
E-4a-Bpin
Table 2. Regioselectivity of allylboration of acetophenone 2b with 1a. a
F
Me OH
Ph
O
OH
F
(NHC)CuF·HF
Me
Ph
Ph
Bpin
+
+
Ph
Me
THF
MS 4A
F
Ph
Ph
1a
2b
3b
E-4b
Entry
Ligand
NHC
IPr
T
t
(h)
3
unreacted
Yields (%) b
(°C)
20
20
60
60
20
20
60
60
1a (%)
3b (%)c
4b (%)d
1
2
3
4
5
6
7
8
7
0
48
6
31
IPr
24
0.5
3
94
IPr
0
30
0
66
IPr
0
90
IPrCl
IPrCl
IPrCl
IPrCl
3
16
1
34
7
66
24
0.5
1
88
3
12
0
88
86 (74) e
1
a
b
19
0.25 mmol of 1a and 0.20 mmol of 2b were used. Yields were determined by F NMR after aqueous
c
work-up using 2-fluorocinnamyl acetate as an internal standard. d.r. 2/1 with slight deviations in all
d
e
the cases. E/Z > 95/5 in all the cases. Isolated yield when 1.0 mmol of 1a and 0.80 mmol of 2b were
used.
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5
5
6
Understanding the reasons for remarkably high (E)-selectivities is undergoing now. Preliminary
suggestion consists in addition of allyl copper intermediates to carbonyl group via six-membered
cyclic transitions state as illustrated below. High (E)-stereoselectivity is therefore determined by 1,2-
2
4
strain between Ph and IPr that disfavors TS (Scheme 4). Open-chain TS previously assumed by
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Z.T. Ball’s group19a also can be operated. However, examples of preferred “cis” over “trans”
selectivity in an allyl-metal addition via open-chain TS are extremely rare.25
Scheme 4. Suggested explanation of high (E)-selectivity
Ar
Ar
N
N
R'
R'
N
Ar
N
F
Cu
F
E-4a,b
R
vs.
Cu
Z-4a,b
O
R
O
Ar
H
H
H
Ph
H
Ph
H
H
TS
TS
2
1
favored
disfavored
R,R' = Ph, Me;
We also studied diastereoselectivity for the formation of compounds 3b that can be achieved in
the allylboration reaction of acetophenone 2b with 1a. Copper- and zinc-catalyzed conditions gave
low selectivity (Table 3). In the cases of (NHC)CuOTf complexes, still modest control of the
diastereomers ratio by NHC ligand was possible from 2:1 in the case of IPr (Table 3, Entry 1) to 3:1
ratio with SIPr and trans-diaminocyclohexane based ligand L (Entries 2 and 3).
1
n
However, in the presence of BuLi/TFAA conversion of 1a to borinic ester allowed to obtain
3
b almost as a single diastereomer (Table 3, Entry 5). The configuration was determined to be (R*,S*)
by X-Ray crystallography after benzoylation with para-nitrobenzoic acid anhydride in the presence
2
6
of MgBr according to Vedejs’s protocol (Figure 1).
2
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Table 3. Diastereoselectivity of the allylboration of acetophenone with 1a.a,b
F
HO Me F
Ph
O
Me OH
Ph
Bpin
+
+
Ph
Ph
Me
THF
F
Ph
(R*,S*)-3b
Ph
(S*,S*)-3b
1a
2b
Entry Catalytic system (10 mol. %)
t (h)
Yield of 3b (%)c
d.r.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
91 d
1
2
3
4
5
(IPr)CuOTf/KHF (1:30)
5
5
69/31
75/25
77/23
72/28
> 95/5
2
(SIPr)CuOTf/KHF (1:30)
89
25
2
(L )CuOTf/KHF (1:30)
5
1
2
Et Zn/EtOH (1:12)
18
18
22
84 d
2
nBuLi/TFAA e,f
a
b
0
.25 mmol of 1a and 0.20 mmol of 2b were used. Reactions were conducted at r.t. unless
otherwise specified. Yields were determined by 19F NMR after aqueous work-up using 2-
fluorocinnamyl acetate as an internal standard. Isolated yields when 1.0 mmol of 1a and 0.8
mmol of 2a were used. e 1.1 equiv. of BuLi and 1.2 equiv. of TFAA were used. Reaction
c
d
n
f
temperature from –82°C to r.t.
Abbreviations see in Table 1.
Ar
Cl
N
Ar =
N
±)-L1
(
Ar
Figure 1. Single crystal X-ray structure of para-nitrobenzoyl ester (R*,S*)-5. Atoms are represented as
thermal ellipsoids (р=50%) (CCDC 1988716)
NO2
O
Me O
F
Ph
Ph
R*,S*)-5
(
Both aromatic and aliphatic ketones, as well as ,-unsaturated ones can be successfully
allylated by 1a using borinic ester approach (Scheme 5). Yields are from moderate to high with
diastereoselectivities from good to excellent in most of the cases. The reaction conditions are tolerant
to ethoxycarbonyl and carbamate groups (examples 3h and 3i). Electron-deficient aryl ketones or
acetylpyridines react smoothly affording corresponding homoallylic alcohols (for example 3j and 3k)
in good yields. Unfortunately, only moderate diastereoselectivities were obtained for allylations of 1-
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
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5
5
5
5
5
5
5
5
6
acetylnaphthalene and 6-methyl-5-hepten-2-one (alcohols 3d and 3f, respectively), whereas allylation
of benzalacetone led to low diastereoselectivity of corresponding alcohol 3e.
Scheme 5. Substrate scope of borinic ester approach
R2
R3
5
) nBuLi/TFAA
R OH
F
1
R3
R1
R4
Bpin
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
5
2
) R R C=O
R1 R2
F
F
Me OH
F
Me OH
Ph
F
F
Me OH
Me OH
Ph
Ph
Ph
Ph
3d, 80%
Ph
3b, 84%
3c, 89%
3e, 83%
d.r. >95/5
d.r. >95/5
d.r. 86/14
d.r. 70/30
OH
F
OH
F
F
Me
F
Me OH
Me OH
EtO C
Me
2
N
EtO C
Ph
Ph
3g, 83%
Ph
3h, 81%
d.r. >95/5
2
Ph
3f, 74%
d.r. 88/12
3i, 56%
F
F
F
Me OH
Me OH
Me OH
F
Me OH
O
Ph
N
Ph
j, 67%
Ph
3k, 82%
Ph
HN
N
Me
3l, 0% a
(NMR: 81%, d.r. >95/5)
3m, 0% a
(NMR: n.d.)
3
b
c
d.r. >95/5
d.r. >95/5
F
Me OH
F
Me OH
F
Me OH
Me
Me Me
Me
3
n, 69%
3o, 70%
d.r. >95/5, Z/E 73/27
3p
, 88%
d.r. >95/5
F
F
Me OH
Me OH
Me Me
Me Me
O
HN
Me
3r, 0% a
(NMR: 87%)
3q, 71% d
(NMR: 92%)
b
b
a
b
Determined by 19F NMR after aqueous work-up using 2-
Decomposes during work-up.
fluorocinnamyl acetate as an internal standard; c Complex product mixture after aqueous work-up,
1
19
d
presumably, a mixture of diene compounds on the basis of H and F NMR; Volatile compound,
which is partially lost during a drying in vacuo.
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Alkyl substituted 2-fluoroallyl boronates also can be successfully activated by borinic ester
approach affording corresponding alcohols 3n,3o,3p in moderate to high yields (Scheme 5). However,
1
,3-dimethyl boronate (see alcohol 3o) gave low Z/E-selectivity of the formed C=C double bond.
Electron-rich aryl ketones undergo allylation (furan and indole derivatives, examples 3l and
m), but the formed alcohols are likely to be prone to facile dehydration followed by polymerization.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Therefore, non 3l or 3m could be isolated in pure form. Nevertheless, furan derivative 3l was
1
19
characterized by H and F NMR after aqueous work-up in a solution in benzene/THF mixture.
However, indole derivative 3m seams to dehydrate much more easily and it was not identified in a
product mixture after aqueous work-up. When phenyl group in 3l or 3m was replaced by two methyl
groups, corresponding alcohols 3q and 3r are much more stable (Scheme 5). Thus, furan derivative
3
q can be even isolated in pure form by column chromatography, but still decompose readily upon
storage. Indole derivative 3r again dehydrate easier, and only NMR yield could be determined.
Borinic ester method was found to be sensitive to the reactivity of ketones (Scheme 6). Along
with already shown in Table 1 benzophenone 2a, also 2-adamanthanone 2n, (+)-camphor 2o, acetyl
benzoin 2q are completely unreactive, as well as 1,3-dicarbonyl compound — ethyl benzoylacetate
2r. The catalytic system (IPr)CuOTf/KHF , which proved itself to be good for the allylation of
2
benzophenone (see Table 1), allowed us to expect that it can be also applicable for the allylation of
ketones 2n–2r. Indeed, ketones 2q and 2r reacted smoothly affording moderate yields of the target
alcohols 3t and 3u (Scheme 6). However, in both cases low diastereoselectivity was observed. Even
2
-adamanthanone reacted under action of this system, giving compound 3s in 53% yield, but much
slower than other ketones. However, (+)-camphor remained unreacted even under “CuF”-catalyzed
conditions.
1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
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3
4
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4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
Scheme 6. Allylboration of low-reactive ketones under “CuF”-
catalyzed conditions
2
Ph
Bpin
F
R OH
O
F
R1
R1
R2
A or B
Ph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
F
O
Ph
Ph
A: n.r.
B: 68%
Ph
Ph
O
Ph
a
2a
3
F
OH
A: n.r.
Ph
B: 73%
2n
3s
Me Me
Me
O
Ph
Ph
A: n.r.
B: n.r.
—
2o
O
F
Ph OH
Ph Ph
Ph
OAc
AcO
A: n.r.
B: 69%
d.r. 32/29/28/11
a
2q
3
t
O
O
Ph OH F
A: n.r.
B: 87%
d.r. 58/42
EtO C
2
OEt
Ph
3u
2r
n
Conditions: A 1) 1a, BuLi, TFAA, –82°C; 2) 2, –82°C to r.t.;
B: 1a, 2, (IPr)CuOTf (10 mol.%), KHF , r.t.; n.r. = no reaction.
2
a
Contained 9 w/w % of 2q.
Conclusions
In summary, we have developed efficient routes for activation of gem-chlorofluorocyclopropane
derived 2-fluoroallyl boronates toward allylboration of various ketones including functionalized and
low-reactive ones. 2-Fluoroallyl boration of acetyl arenes/hetarenes and aliphatic ketones can be
carried out by increasing of the boron electrophilicity by transformation of boronate moiety into
n
borinic ester with BuLi/TFAA. However, it should be noted that despite this route is reported in
literature as highly effective and stereoselective, we have found considerable range of examples,
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where it either gave low diastereoselectivity, or did not work at all due to not enough reactivity of
intermediate 2-fluoroallyl borinic esters.
Therefore, for low-reactive or sterically hindered ketones such as benzophenone and 2-
adamantanone and 1,3-ketoesters, we have developed a new “CuF”-based catalyst — (NHC)CuOTf
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in the presence of an excess of KHF (NHC = IPr, SIPr). Remarkable regioselectivity change was
2
Cl
observed, when (NHC)CuF·HF (NHC = IPr, IPr ) were used as a catalyst, leading to (E)-isomeric
linear alcohols. Preliminary studies indicated that the regioselectivity is controlled by reversible
addition of 2-fluorocinnamyl copper intermediates to aryl ketones. Despite high reactivity, these
“CuF”-routes has one serious limitation that is low diastereoselectivity. Further detailed investigations
of ligand effect on regio- and stereoselectivities is currently underway in our laboratory and the results
of these studies will be reported separately.
Experimental Section
Ketones and all other reagents were purchased from Acros, Aldrich or ABCR and used without
further purification unless otherwise specified. Acetyl benzoin 2q was prepared by acetylation of
2
7
18
Cl
benzoin with Ac O/pyridine. (IPr)CuF·HF was prepared as previously published ; (IPr )CuF·HF
2
was prepared by the same procedure. THF was distilled over LiAlH , stored over 4A Linde type
4
molecular sieves. All reactions were carried out under argon atmosphere using standard Schlenk
technique. Silica gel 60 (40–63 m, Merck) was used for column chromatography. TLC analysis was
made on standard Merck plates with F -inducator using UV or KMnO solution for visualization.
2
54
4
GC analysis was performed on Chromatec Crystal 2000M gas chromatographer (capillary column
Macherey-Nagel OPTIMA-1, 30 m x 0.25 mm, 100% dimethylpolysiloxane (0.25 m), carrier gas –
1
19
13
He, detector – FID). H, F and C NMR were recorded on Varian Inova 400 (400.1, 376.4 and 100.6
MHz, respectively) or Bruker AVANCE II 300 (300.1, 282.3 and 75.4 MHz, respectively) in CDCl3
containing TMS ( = 0 ppm) and C F ( = –162.2 ppm) as internal standards. MS data were registered
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2
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2
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5
5
5
5
5
5
5
5
6
on Finnigan MAT INCOS-50 (EI, 70 eV) using direct probe injections. HRMS were recorded on
Bruker micrOTOF equipment using electro-spray ionization (ESI). Melting points were determined
on Stuart SMP10 and reported uncorrected. Elemental analyses were made in Laboratory of
microanalysis IOC RAS on Perkin-Elmer Series II 2400 CHN Analyzer.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
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1
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8
9
0
Synthesis of (2-fluoroallyl)boronates 1a–d. General procedure A
Modified procedure from ref. 9 was used. A 10-mL Schlenk tube was charged with [(2-
MeAll)PdCl] (1.5–5 mol.% of [Pd]) and filled with argon on a Schlenk line, and dry degassed DCE
2
(2 mL) was added. Then tmeda (1.5–5 mol. %) was added and the yellow solution was stirred at room
temperature for 5 min. A 25-mL Schlenk tube was charged with 2-fluoroallyl chloride (5.0 mmol) and
B pin (5.5–6.0 mmol) and tube was filled with argon. Dry degassed DCE (8.0 mL) was added
2
2
followed by the solution of [(2-MeAll)PdCl] /tmeda in DCE. The reaction mixture was stirred for 2–
2
24 h at 60°C on an oil bath and concentrated on a rotary evaporator. Residual black oil (ca. 2 g) was
subjected to a column chromatography (silica gel 40–63 m, 10/1 g/g) and eluated with n-hexane/Et O
2
1
0/1 affording target boronate as a colorless oil.
Boronates 1a–d decompose readily upon storage in pure form but are stable as dry degassed
solutions. Therefore, obtained oil was dissolved in dry degassed THF (concentrations of 1a–d were
made 0.50 M) and stored over Linde type molecular sieves 4A.
(Z)-2-(2-Fluoro-3-phenylallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a)
F
O
B
Ph
O
Obtained by the General procedure A from 10 mmol of 2-fluoro-3-phenylallyl chloride (Z/E =
9
0/10) using 1.5 mol.% of [Pd]/tmeda after heating at 60°C for 2 h as a colorless oil (2.317 g, 88%
1
19
yield, Z/E = 96/4, R = 0.22 in hexane/Et O 10/1). This oil was dissolved in 15.4 mL of THF. H, F,
f
2
13C NMR data are in agreement with previously published.9
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2
-(2-Fluorocyclohept-2-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1b)
O
B
O
F
Obtained by the General procedure A from 5.0 mmol of 2-fluorocyclohept-2-enyl chloride (used
as a mixture with exo-7-chloro-endo-7-fluorobicyclo[4.1.0]heptane, see ref. 9) using 5 mol.% of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[
Pd]/tmeda after heating at 60°C for 13 h as a colorless oil (941.3 mg, 78% yield, R = 0.33 in
f
hexane/Et O 10/1). For column chromatography 30/1 g/g of silica were used. The oil was dissolved
2
1
9
9
in 6.6 mL of THF. F NMR data are in agreement with previously published.
1
H NMR (400.0 MHz, CDCl ) : 5.34 (dt, J = 22.2, J = 6.2 Hz, 1H), 2.25–2.12 (m, 1H), 2.05–
3
HF
1
9
1
.93 (m, 2H), 1.93–1.82 (m, 1H), 1.81–1.56 (m, 4H), 1.56–1.41 (m, 1H), 1.28 (s, 12H). F NMR
1
3
1
(376.4 MHz, CDCl ) : –89.0 (br. t, J = 20.5 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 164.6 (d, J
3
3
=
246.9 Hz), 105.2 (d, J = 23.5 Hz), 83.8, 29.3, 28.3 (very broad), 27.5, 26.6 (d, J = 7.6 Hz), 24.8,
4.8, 23.1 (d, J = 12.1 Hz).
Z)-2-(3-Fluoropent-3-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1c)
2
(
F
O
B
Me
O
Me
Obtained by the General procedure A from 5.0 mmol of 3-fluoropent-3-en-2-yl chloride (Z/E =
8
5/15) using 5 mol.% of [Pd]/tmeda and additional NaOAc (1.23 g, 15 mmol) after heating at 60°C
for 24 h as a colorless oil (894 mg, 84% yield, Z/E > 20/1, R = 0.60 in pentane/Et O 10/1). For column
f
2
chromatography pentane/Et O 10/1 as an eluent was used. The oil was dissolved in 7.5 mL of THF.
2
19F NMR data are in agreement with previously published.9
1
H NMR (400.0 MHz, CDCl ) : 4.51 (dqd, J = 38.3, J = 6.8, 0.9 Hz, 1H), 2.00 (m, 1H), 1.60–
3
HF
1
9
1
.55 (m, 3H), 1.26 (s, 12H), 1.14 (d, J = 7.4 Hz, 3H). F NMR (376.4 MHz, CDCl ) : –107.0 (br.
3
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dd, J = 38.2, 18.5 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 162.4 (d, J = 251.9 Hz), 97.6 (d, J =
3
17.4 Hz), 83.7, 24.7, 22.2 (very broad), 13.1 (d, J = 4.3 Hz), 9.0 (d, J = 6.8 Hz).
2
-(2-Fluoro-3-methylbut-2-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1d)
0
1
2
3
4
5
6
7
8
9
0
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F
O
B
Me
O
Me
Obtained by the General procedure A from 22.8 mmol of 2-fluoro-3-methylbut-2-enyl chloride
with total 10 mol. % of [Pd]/tmeda as a colorless oil (3.800 g, 77% yield, R = 0.42 in pentane/Et O
f
2
1
0/1). First, 5 mol.% of [Pd]/tmeda were added, and the reaction was heated for 10 h at 60°C. Then
additional 5 mol.% of [Pd]/tmeda were added, and the reaction was heated for 10 h more. For column
chromatography pentane/Et O 10/1 as an eluent was used. The oil was dissolved in 20.0 mL of THF.
2
19F NMR data are in agreement with previously published.9
1
H NMR (400.2 MHz, CDCl ) : 1.91 (d, J = 23.8 Hz, 2H), 1.64–1.61 (m, 3H), 1.55 (d, J =
3
HF
HF
1
9
2.4 Hz, 3H), 1.26 (s, 12H). F NMR (376.5 MHz, CDCl ) : –102.7 (dd sept, J = 23.8, 20.8, 3.0 Hz).
3
13
1
C{ H} NMR (100.6 MHz, CDCl ) : 151.2 (d, J = 239.2 Hz), 106.0 (d, J = 18.2 Hz), 83.7, 24.8,
3
1
8.1 (d, J = 5.9 Hz), 15.7 (d, J = 9.1 Hz), 13.3 (very broad).
General procedure B (for (IPr)CuOTf/KHF -catalyzed allylboration)
2
A screw-neck vial was quickly charged with (IPr)CuCl (48.8 mg, 0.10 mmol) and AgOTf (38.5
mg, 0.15 mmol) and sealed with a screw cup with septum. The vial was evacuated and backfilled with
argon 3 times through a needle on a Schlenk line. THF (5.0 mL) was added and the suspension was
stirred for 1 h.
A Schlenk tube (NOT-dried under high vacuum) was charged with KHF (58.6 mg, 0.75 mmol)
2
and a ketone (0.80 mmol) (low-boiling ketones were added after filling the Schlenk tube with argon).
The tube was evacuated and backfilled with argon 3 times on a Schlenk line. The suspension of
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IPr)CuOTf/AgCl in THF was added and the mixture was stirred for 2–3 min, then the solution of 2-
fluoroallyl boronate 1a in THF (2.0 mL, C = 0.50 M) was added and the reaction mixture was stirred
at room temperature for 5–24 h. [Approximately in 1 hour for benzophenone and acetophenone the
reaction mixture becomes very viscous; therefore, large stirring bar and powerful magnetic stirrer are
necessary. Moreover, it was noted, that a stirring bar should not only to stir the reaction mixture, but
also to crash crystals of KHF that are on the bottom. Crashing of KHF prior to addition in a mortal
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2
on air wasn’t done due to its’ hygroscopicity].
After the reaction complete (monitored by GC), it was diluted with satd. NH Cl. The resulted
4
mixture was vigorously stirred for 10 min and diluted with EtOAc. Organic phase was separated, dried
over MgSO and concentrated on a rotary evaporator. The residue was purified by two subsequent
4
column chromatography: the first — using 10/1 g/g of silica to remove most of the IPr-containing
impurities; the second — using 50/1 g/g of silica for final purification.
3
-Fluoro-1,1,2-triphenylbut-3-enol (3a)
OH
F
Ph
Ph
Ph
Obtained by the General procedure B as a colorless solid (172.6 mg, 68%, mp 117–118°C).
Reaction time — 5 hours. Eluent — benzene/EtOAc 100/1 (R = 0.54).
f
1
H NMR (400.0 MHz, CDCl ) : 7.69–7.64 (m, 2H), 7.38–7.32 (m, 2H), 7.27–7.18 (m, 3H),
3
7
.17–7.02 (m, 8H), 4.69 (dd, J = 19.7, J = 3.2 Hz, 1H), 4.66 (d, J = 22.2 Hz, 1H), 4.55 (dd, J =
HF HF HF
1
9
52.9, J = 3.2 Hz, 1H), 2.93 (br. d, JHF = 6.0 Hz, 1H). F NMR (376.4 MHz, CDCl ) : –94.7 (dddd,
3
13
1
J = 52.9, 22.2, 19.7, 6.0 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 165.5 (d, J = 259.0 Hz), 145.9,
3
1
45.0 (d, J = 1.2 Hz), 136.7 (d, J = 2.0 Hz), 130.0 (d, J = 0.8 Hz), 128.3, 128.0, 127.8, 127.3, 127.1,
126.6, 126.0, 125.7, 95.5 (d, J = 19.5 Hz), 79.5 (d, J = 2.8 Hz), 57.1 (d, J = 22.8 Hz). MS (EI) m/z 183
+
+·
(100, [Ph C(OH)] ), 136 (8, [PhCH=CFCH ] ), 115 (12), 105 (61), 77 (33), 51 (7). Anal.: calcd. for:
2
3
C H FO: C, 82.99%; H, 6.02%. Found: C, 82.87%; H, 5.90%.
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(
2R*,3S*),(2S*,3S*)-4-Fluoro-2,3-diphenylpent-4-en-2-ol (3b)
F
Me OH
Ph
Ph
Obtained by the General procedure B as a colorless oil (186.9 mg, 91%, (2R*,3S*)/(2S*,3S*) =
0
1
2
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9
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4
9/31). Reaction time — 5 h. Eluent — benzene/EtOAc 50/1 (R = 0.34).
f
(major isomer):
1
H NMR (400.0 MHz, CDCl ) : 7.48–7.20 (m, 10H), 4.52 (dd, J = 19.1, J = 2.9 Hz, 1H),
3
HF
.36 (dd, J = 51.7, J = 2.9 Hz, 1H), 3.85 (d, J = 25.4 Hz, 1H), 2.26 (br. d, J = 3.4 Hz, 1H), 1.43
HF
HF
HF
1
9
13
1
(
s, 3H). F NMR (376.4 MHz, CDCl ) : –95.6 (ddd, J = 51.7, 25.3, 19.1 Hz). C{ H} NMR (100.6
3
MHz, CDCl ) : 165.1 (d, J = 260.4 Hz), 146.6, 137.1, 130.0 (d, J = 2.0 Hz), 128.4, 128.1, 127.6,
3
126.8, 125.0, 94.3 (d, J = 19.9 Hz), 76.1, 59.8 (d, J = 22.4 Hz), 29.7 (d, J = 2.3 Hz). MS (EI) m/z 136
(
46), 121 (100), 115 (21), 105 (7), 77 (14). Anal.: calcd. for C H FO: C, 79.66%; H, 6.69%. Found:
17 17
C, 79.33%; H, 6.88%.
(minor isomer, selected peaks):
1
H NMR (400.0 MHz, CDCl ) : (aromatic signals are overlapped with major isomer), 4.69
3
(
ddd, JHF = 18.6, J = 2.9, 1.0 Hz, 1H), 4.46 (dd, JHF = 50.7, J = 2.9 Hz, 1H), 3.77 (br. d, JHF = 29.8
1
9
Hz, 1H), 2.21 (br. d, J = 3.2 Hz, 1H), 1.75 (s, 3H). F NMR (376.4 MHz, CDCl ) : –96.5 (ddd, J
HF
3
1
3
1
=
50.7, 29.8, 18.6 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 165.5 (d, J = 261.8 Hz), 145.8, 137.1
3
(
d, J = 2.2 Hz), 129.6 (d, J = 2.7 Hz), 128.0, 127.8, 127.2, 126.8, 125.3, 94.4 (d, J = 20.4 Hz), 75.9
d, J = 0.8 Hz), 60.5 (d, J = 22.1 Hz), 28.7 (d, J = 1.7 Hz).
(
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2
-(2-Fluoro-1-phenylallyl)adamantan-2-ol (3s)
F
OH
Ph
Obtained by the General procedure B as colorless solids (166.9 mg, 73%, mp 82–83°C).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
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0
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9
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3
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3
4
5
6
7
8
9
0
Reaction time — 48 h. Eluent — hexane/benzene/EtOAc 50/100/1 (R = 0.26).
f
1
H NMR (400.0 MHz, CDCl ) : 7.50–7.45 (m, 2H), 7.35–7.24 (m, 3H), 4.71 (ddd, J = 18.8,
3
HF
J = 2.8, 1.2 Hz, 1H), 4.52 (dd, J = 51.4, J = 2.8 Hz, 1H), 4.18 (d, J = 29.8 Hz, 1H), 2.34–2.26 (m,
HF
HF
1H), 2.16–2.07 (m, 2H), 2.03–1.93 (m, 2H), 1.93–1.88 (m, 1H), 1.88–1.75 (m, 3H), 1.75–1.63 (m,
1
9
13
1
3
H), 1.63–1.55 (m, 1H), 1.48–1.37 (m, 2H). F NMR (376.4 MHz, CDCl ) : –96.2 (m). C{ H}
3
NMR (100.6 MHz, CDCl ) : 166.1 (d, J = 263.4 Hz), 137.6, 129.8, 128.4, 127.2, 93.9 (d, J = 20.6
3
Hz), 76.2, 52.2 (d, J = 21.8 Hz), 38.3, 36.3, 34.6, 34.3, 34.2, 33.2, 32.7, 27.1, 27.0. MS (EI) m/z 151
(
100), 136 (52), 133 (35), 115 (68), 109 (15), 107 (11), 105 (5), 95 (8), 93 (8), 91 (18), 81 (12), 79
(22), 77 (15), 67 (10), 55 (12). Anal.: calcd. for C H FO: C, 79.68%; H, 8.10%. Found: C, 79.73%;
1
9
23
H, 8.24%.
4-Fluoro-2-hydroxy-1,2,3-triphenylpent-4-en-1-yl acetate (3t)
F
Ph OH
AcO
Ph Ph
Obtained by the General procedure B as a colorless oil contained based on NMR 91% (w/w) of
t and 9% of starting ketone 2q (236.6 mg, 69%, d.r. = 32/29/28/11). Reaction time — 24 h. Peak
3
1
13
1
13
1
13
assignments in H, C NMR were made using { H, C}-edited HSQC and { H, C}-HMBC 2D NMR
experiments.
(isomer 1):
1
H NMR (400.0 MHz, CDCl ) : 7.55–6.84 (m, 15H, arom., overlapped with other isomers),
3
6
.11 (s, 1H, CHOAc), 4.90 (ddd, JHF = 18.3, J = 3.0, 1.2 Hz, 1H, =CH (cis to F)), 4.68 (dd, J
=
HF
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0.4, J = 3.0 Hz, 1H, =CH (trans to F), 4.56 – 4.44 (m, 1H, CHPh), 2.53 (d, J = 4.1 Hz, 1H, OH),
2 HF
1
9
2.19 (s, 3H, OAc). F NMR (282.4 MHz, CDCl ) : –94.4 (dddd, J = 50.2, 27.4, 18.3, 4.2 Hz).
3
1
3
1
C{ H} NMR (75.5 MHz, CDCl ) : 169.1 (s, C=O in OAc), 165.4 (d, J = 262.5 Hz, –CF=), 139.9
3
(d, J = 1.3 Hz, C-arom.), 136.5 (s, C-arom.), 136.2 (s, C-arom.), 130.2–126.1 (aromatic CH-signals,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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overlapped with other isomers), 95.0 (d, J = 20.4 Hz, =CH ), 79.9 (s, CHOAc), 79.3 (s, >C(Ph)OH),
2
5
4.7 (d, J = 22.7 Hz, CHPh), 21.3 (s, CH in OAc).
3
(isomer 2):
1
H NMR (400.0 MHz, CDCl ) : (aromatic signals are overlapped with other isomers), 6.19 (s,
3
1
H, CHOAc), 4.56–4.47 (m, 1H, CH (cis to F)), 4.47–4.31 (m, 1H, =CH (trans to F)), 4.25 (d, J
2 2 HF
1
9
=
21.6 Hz, 1H, CHPh), 2.98 (d, JHF = 1.4 Hz, 1H, OH), 1.66 (s, 3H, OAc). F NMR (282.4 MHz,
1
3
1
CDCl ) : –94.8 (ddd, J = 51.5, 21.9, 18.5 Hz). C{ H} NMR (75.5 MHz, CDCl ) : 169.5 (s, C=O
3
3
in OAc), 164.9 (d, J = 260.2 Hz, –CF=), 140.6 (s, C-arom.), 137.3 (s, C-arom.), 136.6 (s, C-arom.),
aromatic CH-signals are overlapped with other isomers), 94.5 (d, J = 20.0 Hz, =CH ), 79.8 (d, J =
(
2
1
.4 Hz, >C(Ph)OH), 79.8 (s, CHOAc), 57.8 (d, J = 23.8 Hz, CHPh), 20.8 (s, CH in OAc).
3
(isomer 3):
1
H NMR (400.0 MHz, CDCl ) : (aromatic signals are overlapped with other isomers), 6.28 (s,
3
1
1
3
H, CHOAc), 4.68 (dd, J = 18.8, J = 3.0 Hz, 1H, =CH (cis to F)), 4.61 (dd, J = 50.5, J = 3.3 Hz,
HF 2 HF
H, =CH (trans to F)), 4.10 (d, J = 30.2 Hz, 1H, CHPh), 3.55 (d, JHF = 6.0 Hz, 1H, OH), 2.13 (s,
2
HF
1
9
13
1
H, OAc). F NMR (282.4 MHz, CDCl ) : –95.6 (dddd, J = 49.4, 29.9, 18.7, 5.9 Hz). C{ H} NMR
3
(75.5 MHz, CDCl ) : 169.9 (s, C=O in OAc), 166.4 (d, J = 262.3 Hz, –CF=), 139.8 (d, J = 0.9 Hz,
3
C-arom.), 137.6 (d, J = 1.7 Hz, C-arom.), 136.7 (s, C-arom.), (aromatic CH-signals are overlapped
with other isomers), 93.1 (d, J = 20.1 Hz, =CH ), 80.9 (d, J = 1.5 Hz, >C(Ph)OH), 80.2 (s, CHOAc),
2
5
7.8 (d, J = 21.7 Hz, CHPh), 21.3 (s, CH in OAc).
3
(isomer 4):
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H NMR (400.0 MHz, CDCl ) : (aromatic signals are overlapped with other isomers), 6.70–
3
6.66 (m, 2H, arom.), 5.36 (s, 1H, CHOAc), 4.54–4.44 (m, 2H, =CH (cis to F) and CHPh), 4.36 (dd,
2
19
J = 52.0, J = 3.1 Hz, 1H, =CH (trans to F)), 2.43 (d, J = 4.3 Hz, 1H, OH), 2.13 (s, 3H, OAc). F
HF
2
HF
1
3
1
NMR (282.4 MHz, CDCl ) : –95.5 (overlapped with isomers 1 and 2). C{ H} NMR (75.5 MHz,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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5
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2
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7
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2
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6
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1
2
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4
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CDCl ) : 168.6 (s, C=O in OAc), 165.0 (d, J = 259.4 Hz, –CF=), 140.7 (s, C-arom.), 136.2 (s, C-
3
arom.), 135.8 (s, C-arom.), (aromatic CH-signals are overlapped with other isomers), 94.8 (d, J = 20.0
Hz, =CH ), 79.1 (d, J = 1.3 Hz, >C(Ph)OH), 78.5 (d, J = 1.7 Hz, CHOAc), 54.8 (d, J = 23.3 Hz,
2
CHPh), 21.3 (s, CH in OAc).
3
(for all isomers): MS (EI) m/z 255 (6), 241 (11), 195 (30), 167 (27), 152 (5), 133 (7), 115 (15),
+
+
1
05 (100), 84 (22), 77 (26). HRMS (ESI) m/z: [M+NH ] , Calcd. for C H FO NH 408.1969;
4 25 23 3 4
+
+
+
Found 408.1959. [M+Na] , Calcd. for C H FO Na 413.1523; Found 413.1512. [M+K] , Calcd. for
2
5
23
3
+
C H FO K 429.1263; Found 429.1253.
2
5
23
3
Ethyl 5-fluoro-3-hydroxy-3,4-diphenylhex-5-enoate (3u)
F
Ph OH
EtO C
2
Ph
Obtained by the General procedure B as a colorless solid (266.1 mg, 87%, d.r. 58/42, mp 106–
1
10°C). Reaction time — 24 h. Eluent — benzene/EtOAc 100/1 (R = 0.28).
f
1
H NMR (400.0 MHz, CDCl ) : 7.45–7.11 (m, 10H), 4.73 (d, J = 1.1 Hz, 1H), 4.68 (d, J = 1.3
3
Hz, 1H), 4.69–4.62 (m, 1H), 4.52 (dd, JHF = 50.4, J = 2.9 Hz, 1H), 4.52 (dd, JHF = 18.7, J = 2.8 Hz,
1
H), 4.41 (dd, JHF = 50.8, J = 2.8 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 3.86 (qd, J = 7.2, 2.8 Hz, 2H),
.73 (d, JHF = 23.9 Hz, 1H), 3.68 (d, JHF = 28.0 Hz, 1H), 3.27 (d, J = 16.0 Hz, 1H), 3.09 (d, J = 16.0
3
Hz, 1H), 2.90 (d, J = 15.7 Hz, 1H), 2.67 (d, J = 15.7 Hz, 1H), 1.03 (t, J = 7.1, 7.1 Hz, 3H), 0.96 (t, J
19
=
7.1, 7.1 Hz, 3H). F NMR (376.4 MHz, CDCl ) : –94.0 (ddd, J = 45.0, 25.5, 15.8 Hz), –94.3 (ddd,
3
1
3
1
J = 51.1, 23.3, 19.2 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 173.0, 172.7, 164.9 (d, J = 262.1 Hz),
3
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64.2 (d, J = 261.1 Hz), 144.3, 143.9 (d, J = 0.7 Hz), 136.7 (d, J = 1.0 Hz), 136.6 (d, J = 1.7 Hz),
130.4 (d, J = 1.8 Hz), 130.1 (d, J = 2.4 Hz), 128.3, 128.0, 127.8, 127.8, 127.7, 127.2, 127.1, 127.1,
25.8, 125.7, 94.6 (d, J = 20.0 Hz), 94.2 (d, J = 19.8 Hz), 76.8 (d, J = 1.4 Hz), 76.7, 60.9, 60.8, 60.2
d, J = 23.1 Hz), 59.9 (d, J = 23.9 Hz), 44.0 (d, J = 2.6 Hz), 43.2 (d, J = 2.6 Hz), 13.9, 13.8. MS (EI)
m/z 193 (29), 147 (7), 133 (7), 115 (19), 105 (100), 91 (5), 77 (24). Anal.: calcd. for C H FO : C,
1
(
0
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20 21
3
7
3.15%; H, 6.45%. Found: C, 73.13%; H, 6.57%.
General procedure C (for (NHC)CuF·HF catalyzed allylboration)
A Schlenk tube was charged with powdered Linde type molecular sieves 4A (100 mg on 1.0
mmol of 1a) and heated under high vacuum with heatgun for 15 min. After filling with argon,
NHC)CuF·HF (0.10 mmol) and a ketone (0.80 mmol) were added, followed by the solution of 2-
fluoroallyl boronate 1a in THF (2.0 mL, C = 0.50 M). The reaction mixture was stirred for 5 h at r.t.
for benzophenone) or for 1 h at 60°C on an oil bath (for acetophenone), then diluted with satd. NH Cl.
(
(
4
The resulted mixture was vigorously stirred for 10 min and diluted with EtOAc. Organic phase was
separated, dried over MgSO and concentrated on a rotary evaporator. The residue was purified by
4
two subsequent column chromatography: the first — using 10/1 g/g of silica to remove most of the
IPr-containing impurities. The second — using 50/1 g/g of silica for final purification.
(E)-3-Fluoro-1,1,4-triphenylbut-3-enol (E-4a)
OH
F
Ph
Ph
Ph
Obtained by the General procedure C as colorless oil (254.1 mg, 99%, E/Z = 97/3). Reaction
time — 5 h at r.t. Eluent — benzene/EtOAc 100/1 (R = 0.41).
f
1
(E-isomer): H NMR (400.0 MHz, CDCl ) : 7.39–7.17 (m, 13H), 7.13–7.06 (m, 2H), 6.29 (d,
3
19
J = 23.5 Hz, 1H), 3.48 (d, J = 21.0 Hz, 2H), 3.00 (br. s, 1H). F NMR (376.4 MHz, CDCl ) : –
HF
HF
3
1
3
1
9
8.1 (dt, J = 23.5, 21.0 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 159.1 (d, J = 250.8 Hz), 145.8,
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33.4 (d, J = 13.9 Hz), 128.7 (d, J = 2.6 Hz), 128.6, 128.2, 127.2, 127.2, 126.0, 112.4 (d, J = 27.7 Hz),
+
+
78.0 (d, J = 2.3 Hz), 41.2 (d, J = 21.9 Hz). MS (EI) m/z 300 (1, [M–H O] ), 183 (100, [Ph C(OH)] ),
2
2
1
8
36 (7), 115 (9), 105 (70), 77 (34). Anal.: calcd. for C H FO: C, 82.99%; H, 6.02%. Found: C,
22 19
2.82%; H, 5.93%.
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1
(Z-isomer, selected signals): H NMR (400.0 MHz, CDCl ) : (aromatic signals are overlapped
3
19
with E-isomer), 5.44 (d, JHF = 39.6 Hz, 1H), 3.34 (d, JHF = 21.1 Hz, 2H). F NMR (376.4 MHz,
CDCl ) : –96.2 (dt, J = 39.6, 21.1 Hz)
3
(E)-4-Fluoro-2,5-diphenylpent-4-en-2-ol (E-4b)
F
Me OH
Ph
Ph
Cl
Obtained by the General procedure C using (IPr )CuF·HF as the catalyst as a colorless oil
(152.2 mg, 74%, E/Z > 95/5). Reaction time – 1 h at 60°C. Eluent – benzene/EtOAc 50/1 (R = 0.26).
f
1
H NMR (400.0 MHz, CDCl ) : 7.42–7.33 (m, 2H), 7.34–7.24 (m, 4H), 7.28–7.17 (m, 2H),
3
7
.16–7.08 (m, 2H), 6.32 (d, J = 23.2 Hz, 1H), 3.02 (dd, J = 25.8, J = 14.9 Hz, 1H), 2.93 (dd, J
HF HF HF
1
9
=
21.9, J = 14.9 Hz, 1H), 2.35 (d, JHF = 4.8 Hz, 1H), 1.62 (s, 3H). F NMR (376.4 MHz, CDCl ) :
3
13
1
–
95.7 (dddd, J = 26.7, 22.4, 22.4, 4.8 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 159.2 (d, J = 250.8
3
Hz), 147.0, 133.5 (d, J = 13.8 Hz), 128.6 (d, J = 2.7 Hz), 128.5, 128.3, 127.1, 127.0, 124.6, 112.0 (d,
J = 27.9 Hz), 74.4 (d, J = 3.2 Hz), 42.9 (d, J = 23.6 Hz), 30.1 (d, J = 2.2 Hz). MS (EI) m/z 136 (56),
1
33 (24), 121 (100), 115 (25), 105 (5), 77 (27). Anal.: calcd. for C H FO: C, 79.66%; H, 6.69%.
17 17
Found: C, 79.59%; H, 6.50%.
General procedure D (for borinic ester approach, see ref. 13b)
A Schlenk flask was heated under high vacuum with heatgun for 15 min. After filling with
argon, it was charged with the solution of 2-fluoroallyl boronate in THF (2.0 mL, C = 0.50 M) and
n
THF (8.0 mL) and cooled to –82°C on a bath with melting EtOAc. A solution of BuLi in n-hexane
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(
0.44 mL, 1.1 mmol, C = 2.5 M) was added dropwise, and the resulted solution was stirred for 15 min.
Next, TFAA (0.168 mL, 1.2 mmol) was added dropwise, and the solution was stirred for 30 min.
Then, ketone (0.80 mmol) was added, and the cooling bath was removed. The reaction mixture was
allowed to warm slowly to r.t. (approximately over 30–45 min) and stirred for 4–48 h. After the
0
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reaction complete (monitored by GC), satd. NH Cl was added. The resulted mixture was vigorously
4
stirred for 10 min and diluted with EtOAc. Organic phase was separated, dried over MgSO and
4
concentrated on a rotary evaporator. The residue was purified by two subsequent column
chromatography: the first – using 10/1 g/g of silica to remove most of the pinacol-containing
impurities. The second – using 50/1 g/g of silica for final purification.
(2R*,3S*)-4-Fluoro-2,3-diphenylpent-4-en-2-ol (3b)
F
Me OH
Ph
Ph
Obtained by the General procedure D as a light brown solid (172.9 mg, 84%, d.r. > 95/5, mp
1
19
5
8–59°C). Reaction time – 18 h (overnight). Eluent – benzene/EtOAc 50/1 (R = 0.36). (For H, F,
f
13C NMR, MS data and elemental analysis, see above).
(2R*,3S*)-4-Fluoro-2-(naphthalen-2-yl)-3-phenylpent-4-en-2-ol (3c)
F
Me OH
Ph
Obtained by the General procedure D as a colorless solid (217.6 mg, 89%, d.r. > 95/5, mp 100–
101°C). Reaction time – 18 h (overnight). Eluent – benzene/EtOAc 100/1 (R = 0.31).
f
1
H NMR (400.0 MHz, CDCl ) : 7.97–7.94 (m, 1H), 7.86–7.79 (m, 3H), 7.53 (dd, J = 8.6, 1.9
3
Hz, 1H), 7.50–7.40 (m, 4H), 7.37–7.28 (m, 3H), 4.48 (dd, JHF = 19.1, J = 3.0 Hz, 1H), 4.36 (dd, JHF
1
9
=
51.6, J = 2.9 Hz, 1H), 3.99 (d, JHF = 25.4 Hz, 1H), 2.39 (br. d, JHF = 3.6 Hz, 1H), 1.50 (s, 3H). F
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NMR (376.4 MHz, CDCl ) : –95.5 (dddd, J = 51.6, 25.2, 19.0, 3.2 Hz). C{ H} NMR (100.6 MHz,
3
CDCl ) : 165.1 (d, J = 260.4 Hz), 144.1, 137.1, 133.2, 132.4, 130.0 (d, J = 2.0 Hz), 128.4, 128.3,
3
1
27.7, 127.7, 127.6, 126.1, 125.9, 123.8, 123.6, 94.4 (d, J = 19.9 Hz), 76.3, 59.6 (d, J = 22.5 Hz), 29.8
(
d, J = 2.3 Hz). MS (EI) m/z 171 (100), 155 (14), 136 (19), 127 (16), 115 (26). Anal.: calcd. for
1
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C H FO: C, 82.33%; H, 6.25%. Found: C, 82.18%; H, 6.23%.
2
1
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(
2R*,3S*)-4-Fluoro-2-(naphthalen-1-yl)-3-phenylpent-4-en-2-ol (3d)
F
Me OH
Ph
Obtained by the General procedure D as a colorless oil (244.1 mg, 80%, d.r. = 86/14). Reaction
time — 18 h (overnight). Eluent — benzene/EtOAc 100/1 (R = 0.39).
f
(major isomer):
1
H NMR (400.0 MHz, CDCl ) : 8.77 (d, J = 8.7 Hz, 1H), 7.96–7.74, 7.60–7.28, 7.25–7.10 (m,
3
11H, overlapped with signals of minor isomer), 4.70 (d, JHF = 28.5 Hz, 1H), 4.64 (d, JHF = 19.2 Hz,
19
1
H), 4.40 (d, JHF = 51.3 Hz, 1H), 2.56 (d, JHF = 3.2 Hz, 1H), 1.76 (s, 3H). F NMR (376.4 MHz,
1
3
1
CDCl ) : –96.2 (ddd, J = 49.1, 28.5, 19.0 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 165.3 (d, J =
3
3
2
62.6 Hz), 141.2, 137.5 (d, J = 1.9 Hz), 135.0, 130.0 (d, J = 2.0 Hz), 129.7, 129.6 (d, J = 2.7 Hz),
29.0, 128.1, 127.3, 126.3, 125.8, 125.1, 125.0, 124.7, 94.8 (d, J = 20.5 Hz), 77.9, 57.9 (d, J = 21.6
1
Hz), 28.0 (d, J = 3.0 Hz). MS (EI) m/z 171 (100), 155 (10), 136 (15), 127 (15), 115 (23). Anal.: calcd.
for C H FO: C, 82.33%; H, 6.25%. Found: C, 82.01%; H, 6.02%.
2
1
19
(minor isomer, selected peaks):
1
H NMR (400.0 MHz, CDCl ) : (aromatic signal are overlapped with major isomer), 4.48 (dd,
3
JHF = 15.7, J = 3.0 Hz, 1H), 4.36 (dd, JHF = 51.6, J = 3.0 Hz, 1H), 3.99 (d, JHF = 25.4 Hz, 1H), 2.38
1
9
(
d, JHF = 3.6 Hz, 1H), 1.49 (s, 3H). F NMR (376.4 MHz, CDCl ) : –95.9 (dddd, J = 51.1, 24.6,
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9.2, 3.4 Hz). C{ H} NMR (100.6 MHz, CDCl ) : 165.0 (d, J = 260.5 Hz), 144.0, 137.1 (d, J = 1.4
3
Hz), 133.2, 132.3, 130.6, 128.5, 128.3, 127.7, 127.7, 127.5, 126.1, 125.9, 123.8, 123.6, 94.5 (d, J =
9.8 Hz), 76.3, 59.5 (d, J = 22.4 Hz), 29.8 (d, J = 2.3 Hz).
1
(
3S*,4S*,1E)-5-Fluoro-3-methyl-1,4-diphenylhexa-1,5-dien-3-ol (3e)
0
1
2
3
4
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F
Me OH
Ph
Ph
Obtained by the General procedure D as a colorless oil (187.9 mg, 83%, d.r. = 70/30). Reaction
time — 18 hours (overnight). Eluent — benzene/EtOAc 100/1 (R = 0.26).
f
(
major diastereomer):
1
H NMR (400.0 MHz, CDCl ) : 7.46–7.17 (m, 10H, overlapped with minor isomer), 6.58 (d,
3
J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 1.4 Hz, 1H), 4.70 (ddd, JHF = 18.4, J = 2.9, 0.9 Hz, 1H), 4.53
1
9
(
dd, J = 50.5, J = 2.9 Hz, 1H), 3.61 (d, J = 27.5 Hz, 1H), 1.95 (br. s, 1H), 1.40 (s, 3H). F NMR
HF HF
1
3
1
(376.4 MHz, CDCl ) : –96.2 (ddd, J = 50.5, 27.5, 18.4 Hz). C{ H} NMR (100.6 MHz, CDCl ) :
3
3
1
65.4 (d, J = 261.6 Hz), 137.0 (d, J = 12.5 Hz), 135.1 (d, J = 2.0 Hz), 129.9 (d, J = 2.3 Hz), (lines for
aromatic CH for both isomers that could not be resolved: 128.6, 128.6, 128.4, 128.4, 128.4, 128.1,
127.7, 127.6, 127.5, 126.6), 94.1 (d, J = 20.4 Hz), 74.6, 60.1 (d, J = 22.3 Hz), 27.8 (d, J = 1.8 Hz).
+
+
MS (EI) m/z 264 (1, [M–H O] ), 147 (100, [PhCH=CH-C(OH)CH ] ), 136 (6), 128 (22), 115 (20),
2
3
1
03 (7), 91 (6), 77 (9). Anal.: calcd. for C H FO: C, 80.82%; 6.78H, %. Found: C, 80.48%; H,
19 19
7.00%.
(
minor diastereomer, selected signals):
1
H NMR (400.0 MHz, CDCl ) : (aromatic signals are overlapped with major isomer), 6.53 (d,
3
J = 16.0 Hz, 1H), 6.33 (dd, J = 16.0, 0.9 Hz, 1H), 4.75 (ddd, JHF = 18.6, J = 2.9, 1.0 Hz, 1H), 4.56
19
(
dd, J = 50.5, J = 2.9 Hz, 1H), 3.64 (d, J = 27.8 Hz, 1H), 2.08 (br. s, 1H), 1.44 (s, 3H). F NMR
HF
HF
1
3
1
(
376.4 MHz, CDCl ) : –95.2 (ddd, J = 50.4, 27.8, 18.5 Hz). C{ H} NMR (100.6 MHz, CDCl ) :
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65.2 (d, J = 262.3 Hz), 137.1 (d, J = 13.8 Hz), 134.4, 129.7 (d, J = 2.5 Hz), (other signals of aromatic
CH are overlapped with the major isomer), 94.3 (d, J = 20.2 Hz), 74.3, 60.2 (d, J = 22.3 Hz), 27.3.
(3S*,4S*)-2-Fluoro-4,8-dimethyl-3-phenylnona-1,7-dien-4-ol (3f)
Me
F
Me OH
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
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8
9
0
Me
Ph
Obtained by the General procedure D as a colorless oil (155.7 mg, 74%, d.r. = 88/12). Reaction
time — 18 hours (overnight). Eluent — benzene/EtOAc 100/1 (R = 0.29).
f
(major diastereomer):
1
H NMR (400.0 MHz, CDCl ) : 7.45–7.38 (m, 2H), 7.36–7.26 (m, 3H), 5.13–5.06 (m, 1H),
3
4.71 (ddd, JHF = 18.6, J = 2.8, 1.1 Hz, 1H), 4.53 (dd, JHF = 50.9, J = 2.8 Hz, 1H), 3.47 (d, J = 29.7
HF
Hz, 1H), 2.16–2.03 (m, 2H), 1.80 (d, J = 3.0 Hz, 1H), 1.68 (s, 3H), 1.69–1.57 (m, 2H), 1.61 (s, 3H),
1
9
13
1
1
.16 (s, 3H). F NMR (282.4 MHz, CDCl ) : –96.3 (ddd, J = 50.9, 29.3, 18.5 Hz). C{ H} NMR
3
(75.5 MHz, CDCl ) : 166.0 (d, J = 262.4 Hz), 137.9, 131.9, 129.7 (d, J = 2.4 Hz), 128.4, 127.3,
3
1
24.2, 93.9 (d, J = 20.7 Hz), 74.1, 58.8 (d, J = 22.0 Hz), 40.9, 25.8, 25.1 (d, J = 2.0 Hz), 22.8, 17.7.
MS (EI) m/z 136 (85), 127 (30), 115 (25), 109 (100), 69 (92). Anal.: calcd. for C H FO: C, 77.82%;
1
7
23
H, 8.84%. Found: C, 77.89%; H, 8.84%.
(minor diastereomer, selected signals):
1
H NMR (400.0 MHz, CDCl ) : (aromatic signals are overlapped with major isomer), 5.08–
3
5.01 (m, 1H), 4.73–4.65 (m, 1H)), 4.51 (dd, JHF = 50.5, J = 2.8 Hz, 1H), 3.50 (d, J = 30.9 Hz, 1H),
19
2
.16–2.03 (m, 2H), 1.63 (s, 3H), 1.58 (s, 3H), 1.57–1.46 (m, 2H), 1.31 (s, 3H). F NMR (376.4 MHz,
CDCl ) : –96.3 (overlapped with major isomer).
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-(2-Fluoro-1-phenylallyl)cyclohexanol (3g)
OH
F
Ph
Obtained by the General procedure D as a colorless oil (155.7 mg, 83%). Reaction time — 18 h
0
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(
overnight). Eluent — benzene/EtOAc 50/1 (R = 0.29).
f
1
H NMR (400.0 MHz, CDCl ) : 7.45–7.37 (m, 2H), 7.37–7.24 (m, 3H), 4.69 (ddd, J = 18.6,
3
HF
J = 2.8, 1.2 Hz, 1H), 4.51 (dd, J = 50.9, J = 2.8 Hz, 1H), 3.42 (d, J = 30.6 Hz, 1H), 1.82–1.73 (m,
HF
HF
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H), 1.70–1.13 (m, 10H). F NMR (282.4 MHz, CDCl ) : –96.0 (ddd, J = 49.9, 30.4, 18.6 Hz).
3
13
1
C{ H} NMR (100.6 MHz, CDCl ) : 165.9 (d, J = 262.6 Hz), 137.5, 129.7 (d, J = 2.5 Hz), 128.3,
3
1
27.3, 93.8 (d, J = 20.5 Hz), 72.7, 59.1 (br. d, J = 21.8 Hz), 36.5, 35.9, 25.6, 22.1, 21.9. MS (EI) m/z
136 (100), 115 (26), 99 (64), 81 (53), 55 (16). Anal.: calcd. for C H FO: C, 76.89%; H, 8.17%.
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5
19
Found: C, 76.25%; H, 8.25%.
Ethyl (2R*,3S*)-4-fluoro-2-hydroxy-2-methyl-3-phenylpent-4-enoate (3h)
F
Me OH
EtO C
2
Ph
Obtained by the General procedure D as a yellowish oil solidified in few days at r.t. (162.3 mg,
8
5
1%, d.r. > 95/5, mp 45–46°C). Reaction time — 18 hours (overnight). Eluent — benzene/EtOAc
0/1 (R = 0.19).
f
1
H NMR (400.0 MHz, CDCl ) : 7.51–7.46 (m, 2H), 7.39–7.28 (m, 3H), 4.69 (dd, J = 19.2, J
3
HF
=
3.1 Hz, 1H), 4.41 (dd, J = 51.5, J = 3.2 Hz, 1H), 4.37–4.24 (m, 2H), 3.89 (d, J = 13.8 Hz, 1H),
HF HF
1
9
3
.49 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.19 (s, 3H). F NMR (282.4 MHz, CDCl ) : –94.9 (ddd, J =
3
1
3
1
51.3, 19.2, 14.0 Hz). C{ H} NMR (75.5 MHz, CDCl ) : 176.5, 165.32 (d, J = 260.0 Hz), 135.7 (d,
3
J = 2.8 Hz), 130.5, 128.4, 127.8, 93.6 (d, J = 19.6 Hz), 75.6, 62.5, 55.7 (d, J = 24.8 Hz), 25.6, 14.2.
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Page 29 of 45
The Journal of Organic Chemistry
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MS (EI) m/z 234 (2, [M–H O] ), 193 (3), 179 (2), 136 (100), 117 (21), 115 (22), 109 (3), 89 (11).
2
Anal.: calcd. for C H FO : C, 66.65%; H, 6.79%. Found: C, 66.76%; H, 6.68%.
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Ethyl 4-(2-fluoro-1-phenylallyl)-4-hydroxypiperidine-1-carboxylate (3i)
OH
F
1
1
1
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1
1
1
1
1
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N
EtO C
Ph
2
Obtained by the General procedure D as a yellow oil (138.5 mg, 56%). Reaction time — 18 h
(
overnight). Eluent – CH Cl /EtOAc/NEt , gradient from 15/1/0.1 to 10/1/0.1 (R = 0.25 in 10/1/0.1).
2
2
3
f
1
H NMR (400.0 MHz, CDCl ) : 7.42–7.26 (m, 5H), 4.74 (ddd, J = 18.7, J = 3.0, 1.1 Hz, 1H),
3
HF
4.53 (dd, J = 50.9, J = 3.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.07–3.79 (m, 2H), 3.36 (d, J = 30.2
HF
HF
Hz, 1H), 3.24–2.98 (m, 2H), 1.84–1.63 (m, 3H), 1.61–1.47 (m), 1.45–1.35 (m), 1.24 (t, J = 7.1 Hz,
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1
3
H). F NMR (282.4 MHz, CDCl ) : –96.4 (br s). C{ H} NMR (75.5 MHz, CDCl ) : 165.1 (d, J
3
3
= 262.3 Hz), 155.5, 136.5, 129.6 (d, J = 2.6 Hz), 128.6, 127.7, 94.5 (d, J = 20.2 Hz), 71.1, 61.3, 59.7
(
d, J = 21.8 Hz), 39.7, 39.6, 36.0, 35.5, 14.8. MS (EI) m/z 262 (1), 172 (45), 142 (8), 136 (100), 126
+
(
39), 115 (59), 109 (8), 102 (29), 90 (5), 83 (8), 71 (7), 56 (15). HRMS (ESI), m/z: [M+H] , Calcd.
+
+
+
for C H FNO 308.1656; Found 308.1660. [M+Na] , Calcd. for C H FNO Na 330.1476; Found
17 23
3
17 22
3
+
+
330.1476. [M+K] , Calcd. for C H FNO K 346.1215; Found 346.1214.
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(2R*,3S*)-4-Fluoro-3-phenyl-2-(pyridin-4-yl)pent-4-en-2-ol (3j)
F
Me OH
N
Ph
Obtained by the General procedure D as a yellowish solid (137.6 mg, 67%, d.r. > 95/5, mp 134–
1
4
35°C). Reaction time — 18 h (overnight). Eluent — CH Cl /EtOAc/NEt , gradient from 10/1/0.1 to
2
2
3
/6/0.1 (R = 0.21 in 4/6/0.1).
f
1
H NMR (300.1 MHz, DMSO-d ) : 8.54–8.48 (m, 2H), 7.60–7.50 (m, 4H), 7.39–7.25 (m, 3H),
6
5
.48 (br. s, 1H), 4.50 (dd, JHF = 52.9, J = 2.6 Hz, 1H), 4.41 (dd, J = 19.5, J = 2.6 Hz, 1H), 3.98 (d,
HF
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